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World Health Organization Classification of Tumours

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World Health Organization Classification of Tumours


International Agency for Research on Cancer (IARC)

Pathology and Genetics of

Skin Tumours

Edited by

Philip E. LeBoit
Günter Burg
David Weedon
Alain Sarasin

Lyon, 2006
World Health Organization Classification of Tumours

Series Editors Paul Kleihues, M.D.

Leslie H. Sobin, M.D.

Pathology and Genetics of Skin Tumours

Editors Philip E. LeBoit, M.D.
Günter Burg, M.D.
David Weedon, M.D.
Alain Sarasin, Ph.D.

Coordinating Editors Wojciech Biernat, M.D.

Hiroko Ohgaki, Ph.D.

Editorial assistants Asiedua Asante

Agnès Meneghel

Layout Marlen Grassinger

Stephan Rappo
Sibylle Söring

Illustrations Nobert Wey

Thomas Odin

Printed by Team Rush

69603 Villeurbanne, France

Publisher IARCPress
International Agency for
Research on Cancer (IARC)
69008 Lyon, France
This volume was produced in collaboration with the

International Academy of Pathology (IAP)

European Organization for Research and Treatment of Cancer (EORTC)

and the

Department of Pathology, University Hospital, Zurich, Switzerland

The WHO Classification of Skin Tumours

presented in this book reflects the views of a Working Group that convened for an
Editorial and Consensus Conference in Lyon, France,
September 22-25, 2003.

Members of the Working Group are indicated

in the List of Contributors on page 295.
Published by IARC Press, International Agency for Research on Cancer,
150 cours Albert Thomas, F-69008 Lyon, France

© International Agency for Research on Cancer, 2005

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Format for bibliographic citations:

LeBoit P.E., Burg G., Weedon D, Sarasain A. (Eds.): World Health Organization
Classification of Tumours. Pathology and Genetics of Skin Tumours. IARC Press:
Lyon 2006

IARC Library Cataloguing in Publication Data

Pathology and genetics of skin tumours/ edited by Philip E. LeBoit... [et. al.].

(World Health Organization classification of tumours ; 10)

1. Skin Neoplasms – genetics

2. Skin Neoplasms – pathology

I. LeBoit, P.E.
II. Series

ISBN 92 832 2414 0 (NLM Classification: WR 500)


1 Keratinocytic tumours 9 Persistent melanoma and local

WHO and TNM classification 10 metastasis of melanoma 90
Introduction 11 Congenital melanocytic naevus 93
Basal cell carcinoma 13 Superficial type 93
Superficial basal cell carcinoma 15 Proliferative nodules in congenital
Nodular basal cell carcinoma 16 melanocytic naevi 93
Micronodular basal cell carcinoma 16 Blue naevi 95
Infiltrating basal cell carcinoma 17 Common blue naevus 95
Fibroepithelial basal cell carcinoma 17 Mongolian spot 96
Basal cell carcinoma with adnexal differentiation 18 Naevus of Ito and naevus of Ota 96
Basosquamous carcinoma 18 Cellular blue naevus 96
Keratotic basal cell carcinoma 19 Deep penetrating naevus 98
Other variants 19 Combined naevus 100
Squamous cell carcinoma 20 Melanotic macules 103
Acantholytic squamous cell carcinoma 21 Simple lentigo – lentiginous melanocytic naevus 104
Spindle-cell squamous cell carcinoma 22 Dysplastic naevus 105
Verrucous squamous cell carcinoma 22 Site specific and Meyerson naevi 110
Pseudovascular squamous cell carcinoma 23 Acral naevus 110
Adenosquamous carcinoma 24 Genital naevus 110
Bowen disease 26 Meyerson naevus 111
Bowenoid papulosis 28 Persistent (recurrent) melanocytic naevus 113
Actinic keratosis 30 Spitz naevus 114
Arsenical keratosis 32 Pigmented spindle cell naevus (Reed) 117
PUVA keratosis 33 Halo naevus 118
Verrucas 34
Verruca vulgaris 36 3 Appendageal tumours 121
Verruca plantaris 37 WHO and TNM classification 122
Verruca plana 38 Introduction 123
Acanthomas 39 Malignant tumours with apocrine and
Epidermolytic acanthoma 39 eccrine differentiaton 125
Warty dyskeratoma 39 Tubular carcinoma 125
Acantholytic acanthoma 40 Microcystic adnexal carcinoma 125
Lentigo simplex 40 Malignant mixed tumour 127
Seborrhoeic keratosis 41 Porocarcinoma 128
Melanoacanthoma 43 Spiradenocarcinoma 130
Clear cell acanthoma 43 Hidradenocarcinoma 131
Large cell acanthoma 44 Mucinous carcinoma 131
Keratoacanthoma 44 Digital papillary carcinoma 133
Lichen planus-like keratosis 47 Adenoid cystic carcinoma 134
Apocrine carcinoma 135
2 Melanocytic tumours 49 Paget disease and extramammary
WHO classification 50 Paget disease 136
TNM classification 51 Benign tumours with apocrine and
Malignant melanoma: Introduction 52 eccrine differentiation 139
Superficial spreading melanoma 66 Hidrocystoma 139
Nodular melanoma 68 Syringoma 140
Lentigo maligna 70 Poroma 141
Acral-lentiginous melanoma 73 Syringofibroadenoma 142
Desmoplastic melanoma and desmoplastic Hidradenoma 143
neurotropic melanoma 76 Spiradenoma 143
Melanoma arising from blue naevus 79 Cylindroma 145
Melanoma arising in giant congenital naevi 83 Tubular and tubular papillary adenoma 145
Childhood melanoma 84 Syringocystadenoma papilliferum 146
Naevoid melanoma 86 Hidradenoma papilliferum 147
Mixed tumour (chondroid syringoma) 147 B-cell lymphoma 199
Malignant tumours with follicular differentiation 149 Intravascular large B-cell lymphoma 200
Pilomatrical carcinoma 149 Lymphomatoid granulomatosis 202
Proliferating tricholemmal tumour 150 Cutaneous involvement in primary extracutaneous
Benign tumours with follicular differentiation 152 B-cell lymphoma 204
Trichoblastoma 152 Mantle cell lymphoma 204
Pilomatricoma 153 Burkitt lymphoma 205
Tricholemmoma 155 Chronic lymphocytic leukaemia / small
Trichofolliculoma 156 lymphocytic lymphoma 205
Pilar sheath acanthoma 157 Hodgkin lymphoma 207
Tumour of the follicular infundibulum 158 Blastic NK-cell lymphoma 208
Fibrofolliculoma / trichodiscoma 158 Precursor T-lymphoblastic leukaemia / lymphoma
Tumours with sebaceous differentiation 160 and precursor B-lymphoblastic
Sebaceous carcinoma 160 leukaemia / lymphoma 210
Sebaceous adenoma 161 Cutaneous involvement by myeloid leukaemia 211
Sebaceoma 162 Lymphoid infiltrates of the skin mimicking
Cystic sebaceous tumour 163 lymphoma 212
Parapsoriasis 215
4 Haematolymphoid tumours 165 Small plaque parapsoriasis 215
WHO / EORTC classification 166 Parapsoriasis – Large patch type,
TNM classification 167 with or without poikiloderma 215
Introduction 168 Langerhans cell histiocytosis 217
Mycosis fungoides (MF) 169 Indeterminate cell histiocytosis 220
Pagetoid reticulosis 173 Sinus histiocytosis with massive lymphadenopathy
Syringotropic MF 173 (Rosai-Dorfman) 221
Folliculotropic MF 173 Juvenile xanthogranuloma 222
Granulomatous MF 174 Reticulohistiocytosis 224
Sézary syndrome 175 Mastocytosis 226
Granulomatous slack skin 178
CD30+ T-cell lymphoproliferative disorders 179 5 Soft tissue tumours 229
Lymphomatoid papulosis (LyP) 179 WHO and TNM classification 230
Primary cutaneous anaplastic large-cell Introduction 231
lymphoma 180 Vascular tumours 233
Subcutaneous panniculitis-like T-cell lymphoma 182 Haemangioma of infancy 233
Primary cutaneous peripheral T-cell lymphoma, Cherry haemangioma 233
unspecified 184 Sinusoidal haemangioma 234
Cutaneous γδ T-cell lymphoma 184 Hobnail haemangioma 234
Primary cutaneous aggressive epidermotropic Glomeruloid haemangioma 235
CD8+ cytotoxic T-cell lymphoma 185 Microvenular haemangioma 236
Primary cutaneous small-medium CD4+ T-cell Angiolymphoid hyperplasia with eosinophilia 237
lymphoma 186 Spindle cell haemangioma 239
Primary cutaneous PTL, unspecified 186 Tufted angioma 239
Cutaneous adult T-cell leukaemia / lymphoma 189 Bacillary angiomatosis 240
Extranodal NK/T-cell lymphoma, nasal-type 191 Reactive angioendotheliomatosis 241
Hydroa vacciniforme-like cutaneous T-cell Verrucous haemangioma 242
lymphoma 192 Pyogenic granuloma 243
Cutaneous involvement in primary extracutaneous Cavernous haemangioma 243
T-cell lymphoma 193 Angiokeratomas 244
Systemic anaplastic large cell lymphoma (ALCL) 193 Arteriovenous haemangioma 245
Angioimmunoblastic T-cell lymphoma (AITL) 193 Cutaneous angiosarcoma 246
Cutaneous marginal zone B-cell lymphoma 194 Lymphatic tumours 247
Cutaneous follicle centre lymphoma 196 Lymphangioma circumscriptum 247
Cutaneous diffuse large B-cell lymphoma 198 Progressive lymphangioma 248
Diffuse large B-cell lymphoma, leg-type 198 Lymphangiomatosis 249
Diffuse large B-cell lymphoma, other 198 Smooth and skeletal muscle tumours 250
T-cell / histiocyte-rich large B-cell lymphoma 199 Smooth muscle hamartoma 250
Plasmablastic lymphoma 199 Pilar leiomyoma 251
Secondary skin involvement by diffuse large Cutaneous leiomyosarcoma 251
Rhabdomyomatous mesenchymal hamartoma 252
Fibrous, fibrohistiocytic and histiocytic tumours 254
Keloid scar 254
Hypertrophic scar 254
Dermatomyofibroma 255
Infantile myofibromatosis 256
Sclerotic fibroma 256
Digital mucous cyst 257
Digital fibrokeratoma 257
Pleomorphic fibroma 258
Giant cell fibroblastoma 258
Dermatofibrosarcoma protuberans 259
Dermatofibroma (fibrous histiocytoma) 261

6 Neural tumours 263

WHO and TNM classification 264
Palisaded, encapsulated neuroma and traumatic
neuroma 265
Palisaded encapsulated neuroma 265
Traumatic neuroma 266
Primary malignant peripheral primitive
neuroectodermal tumour (PNET) /
Extraskeletal Ewing sarcoma (ES) 268
Nerve sheath myxoma / neurothekeoma 270
Merkel cell carcinoma 272
Granular cell tumour 274

7 Inherited tumour syndromes 277

Familial cutaneous melanoma 279
Xeroderma pigmentosum 282
Naevoid basal cell carcinoma (Gorlin) syndrome 285
Cowden syndrome 288
Carney complex 291

Contributors 295

Source of charts and photographs 300

References 301

Subject index 341


Keratinocytic Tumours

Keratinocytic tumours are derived from epidermal and adnexal

keratinocytes and comprise a large spectrum of lesions rang-
ing from benign proliferations (acanthomas) to malignant squa-
mous cell carcinomas which occasionally show aggressive
growth and even metastatic potential. Keratinocytic tumours
are very frequent and, despite their low mortality rate, pose a
significant public health problem, The main etiologic factor is
solar radiation which causes DNA alterations, including pyrim-
idine dimers which during DNA replication may lead to CC:TT
mutations in the TP53 tumour suppressor gene. Other genes
involved in the multistep formation of skin cancer include PTCH
and the RAS oncogene.
Verrucas, epidermal proliferations produced by infection with
human papilloma viruses (HPV), are also included in this sec-
WHO histological classification of keratinocytic skin tumours

Keratinocytic tumours Actinic keratosis

Basal cell carcinoma 8090/3 Arsenical keratosis
Superficial basal cell carcinoma 8091/3 PUVA keratosis
Nodular (solid) basal cell carcinoma 8097/3
Micronodular basal cell carcinoma 8090/3 Verrucas
Infiltrating basal cell carcinoma 8092/3 Verruca vulgaris
Fibroepithelial basal cell carcinoma 8093/3 Verruca plantaris
Basal cell carcinoma with adnexal differentiation 8098/3 Verruca plana
Basosquamous carcinoma 8094/3
Keratotic basal cell carcinoma 8090/3 Acanthomas
Epidermolytic acanthoma
Squamous cell carcinoma 8070/3 Warty dyskeratoma
Acantholytic squamous cell carcinoma 8075/3 Acantholytic acanthoma
Spindle-cell squamous cell carcinoma 8074/3 Lentigo simplex
Verrucous squamous cell carcinoma 8051/3 Seborrhoeic keratosis
Pseudovascular squamous cell carcinoma 8075/3 Melanoacanthoma
Adenosquamous carcinoma 8560/3 Clear cell acanthoma
Large cell acanthoma
Bowen disease 8081/2 Keratoacanthoma 8071/1
Bowenoid papulosis Lichen planus-like keratosis

Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, /2 for in situ carcinoma and /1 for borderline or uncertain behaviour.

TNM classification of skin carcinomas

TNM classification 1,2 M – Distant metastasis
MX Distant metastasis cannot be assessed
T – Primary tumour M0 No distant metastasis
TX Primary tumour cannot be assessed M1 Distant metastasis
T0 No evidence of primary tumour
Tis Carcinoma in situ
Stage grouping
T1 Tumour 2 cm or less in greatest dimension Stage 0 Tis N0 M0
T2 Tumour more than 2 cm but no more than 5 cm in greatest Stage I T1 N0 M0
dimension Stage II T2, T3 N0 M0
T3 Tumour more than 5 cm in greatest dimension Stage III T4 N0 M0
T4 Tumour invades deep extradermal structures, i.e., cartilage, Any T N1 M0
skeletal muscle, or bone Stage IV Any T Any N M1
Note: In the case of multiple simultaneous tumours, the tumour with the
highest T category is classified and the number of separate tumours is
indicated in parentheses, e.g., T2(5).

N – Regional lymph nodes

NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis

A help desk for specific questions about the TNM classification is available at www.uicc.org/index.php?id=508 .

10 Keratinocytic tumours
Keratinocytic tumours: Introduction D. Weedon
R. Marks
G. F. Kao
C.A. Harwood

The keratinocytic tumours are a clinically may be precursors of squamous cell car- genes and/or inactivation of tumour sup-
and histopathologically diverse group of cinoma. These include actinic keratosis pressor genes in the human skin ker-
lesions derived from the proliferation of and Bowen disease (intraepidermal car- atinocytes. NMSCs are caused by genet-
epidermal and adnexal keratinocytes. At cinoma/squamous cell carcinoma in- ic abnormalities, most often induced by
one end of the spectrum the prolifera- situ). UVB exposure. Actinic keratoses, which
tions are benign (acanthomas) and usu- Actinic keratoses are erythematous, lead to SCCs, have gene mutations in K-
ally of cosmetic importance only, while at scaling lesions occurring on heavily sun- ras {2235}. H-rasV12 and cyclin depend-
the other there are malignant tumours, light exposed areas that increase in ent kinase 4 (CDK4) produce human epi-
which uncommonly may be aggressive prevalence with increasing age in fair dermal neoplasia. Therefore, a combina-
with metastatic potential, as seen with skinned people. Histologically, they tion of these genetic abnormalities might
some squamous cell carcinomas. demonstrate confluent keratinocytic be crucial to the carcinogenesis at least
Included in the spectrum are the epider- atypia involving predominantly the ker- in a subset of SCCs {1336}.
mal dysplasias (actinic keratosis, arseni- atinocytes in the basal layer of the epi- High doses of ultraviolet light can also
cal keratosis and PUVA keratosis) and dermis {2475}. lead to skin cancers by inducing reactive
intraepidermal carcinomas (Bowen dis- It is difficult to determine the incidence of oxygen species (ROS) that play an
ease and bowenoid papulosis). actinic keratoses as they come and go important role in tissue injury. Increased
Ackerman and others have proposed over time {788}. Longitudinal studies production of ROS and/or decreased effi-
that solar keratoses should be regarded suggest that they are likely to be a pre- ciency of antioxidant defence system
as squamous cell carcinoma de novo cursor of squamous cell carcinoma, contribute to a number of degenerative
and not as pre-malignancies or pre-can- although the malignant transformation processes including cancer {1161}. UV
cers that evolve into squamous cell car- rate is small, certainly less than one in a induces pyrimidine dimers and loss of
cinoma {994,1443,1701}. hundred per year {1517}. Data suggest, heterozygosity (LOH). TP53 and PTCH,
also, that remission of these lesions will two tumour suppressor genes, have LOH
Epidemiology occur if sunlight exposure can be which lead to basal cell carcinoma
Keratinocytic tumours are an important reduced. Thus the majority of lesions do (BCC) {1265}. LOH in TP53 is related to
public health problem, despite their com- not progress to squamous cell carcino- elevated microsatellite instability at
paratively low mortality rate {2484}. The ma {1516,2349}. selected tetranucleotide repeats {587}.
lifetime risk for the development of skin Bowen disease demonstrates ker- LOH at 9q22 loci in PTCH genes causes
cancer in the USA is now 1 in 5 {1937}. It atinocyte atypia involving the full thick- non-melanoma skin cancer tumours
is much higher in subtropical Australia. ness of the epidermis. There is also {1265}. The type of mutations for TP53
There is an increasing incidence of squa- involvement of the hair follicle and rarely and PTCH are predominantly UV-signa-
mous cell carcinoma of the skin in some the sweat duct. Although Bowen disease ture transitions, C->T and CC->TT at
countries {2462}. Keratinocytic tumours has been classified as a full thickness in- dipyrimidine sites {1265}. SCCs have
account for approximately 90% or more situ squamous cell carcinoma, there are mutations of H-Ras gene and the INK4a
of all skin malignancies, of which approx- no longitudinal studies published on the locus whereas BCC has missense muta-
imately 70% are basal cell carcinomas. frequency of malignant transformation. tions leading to rasGTPase activating
The latter exceed squamous cell carci- Even if invasive squamous cell carcino- protein {168}. Further, mutations have
nomas in frequency by a factor of ma does occur within one of these been found in both TP53 tumour sup-
approximately 5:1 although in lower lati- lesions, it is believed that the in-situ pressor gene and ras in patients with
tudes the incidence of squamous cell phase may be very prolonged, lasting xeroderma pigmentosum (XP), a disease
carcinoma increases and this ratio many years {1203}. of DNA repair deficiencies {1717}.
becomes 3:1. If solar keratoses are Common exogenous carcinogenic
regarded as squamous cell carcinomas Etiology agents in addition to UV radiation include
(see above), then squamous cell carci- Findings regarding the genetic basis of 1) tobacco use {2457}, 2) human papillo-
noma becomes the more common non-melanoma skin cancer (NMSC) have ma viruses {1703}, 3) arsenic {2184}, 4)
tumour {300}. confirmed that UV radiation, especially industrial chemicals such as vinyl chlo-
UVB (290-320 nm in the solar spectrum), ride {1362}, polycyclic aromatic hydro-
Precursor lesions contributes to the formation of squamous carbons {1086}, 5) MNNG (N-methyl-N’-
There are no known precursor lesions to {1336} and basal cell carcinomas {602}. nitro-N-nitrosoguanidine), an alkylating
basal cell carcinoma. On the other hand, Squamous cell carcinomas (SCCs) of the agent {335}, and 6) exposure to gasoline
there are a number of intra-epidermal skin develop through a multistep process or gasoline vapours {1567}.
proliferative disorders (dysplasias) that that involves activation of proto-onco-

Introduction 11
Clinical features ciated keratinocytic lesions detected by of non-melanoma skin cancer develop-
Keratinocytic tumours vary in their clini- ligation mediated PCR assay. The lower ing in an individual diagnosed with SCC
cal appearance depending on the type level of TIG-3 mRNA expression in SCC is 35-60% and the risk of melanoma is
of lesion and stage of development. is visualized by immunohistochemistry or also increased {1507}. Five-year cure
by in situ mRNA hybridization. Upre- rates for BCC of up to 99% are obtain-
Histopathology gulation of S100 protein subtypes in spe- able with surgical techniques {1617,
The histopathologic changes noted in cific keratinocyte disorders is confirmed 1984}, and metastasis is extremely rare,
keratinocytic proliferative lesions involve by immunohistochemistry. occurring in approximately 0.05% of
disturbance of normal surface matura- cases {1440}. As with SCC, patients with
tion. The degree and extent of ker- Prognosis and predictive factors BCC are at high risk of further primary
atinocytic atypia vary in these lesions. Most patients with primary cutaneous BCCs; in patients with one lesion the 5-
The atypical keratinocytes show non-melanoma skin cancer (NMSC) have year risk is 27%, and in those with 10
enlarged nuclei with hyperchromasia, an excellent prognosis. The overall mor- lesions the risk is 90% {1208}, and the
dyskeratosis and mitoses in any layer of tality rates are generally low, on average risk of SCC and malignant melanoma is
the epidermis. In lesions of epidermal approximately 0.1% of the incidence also increased {1208,1430}.
dysplasias (AK, arsenical, and PUVA ker- rates, but significantly higher for SCCs
atoses), surface keratinocytic maturation than BCCs {2483}. Invasive SCC has the
is present, i.e. a granular cell layer is usu- potential to recur and metastasize with
ally noted. an overall 5-year rate of recurrence for
In intraepidermal carcinomas (Bowen primary tumours of 8%. With the excep-
disease, bowenoid papulosis), there is tion of lip tumours, sqamous cell carcino-
full-thickness involvement of the epider- mas arising in actinic keratoses have a
mis by the atypical keratinocytes. frequency of metastatic spread of 0.5-3%
{1459,1630}. For those with metastatic
Molecular markers disease the long-term prognosis is poor;
A number of potentially useful molecular 10-year survival rates are <20% for
markers or tests have been proposed. patients with regional lymph node
These include the demonstration of a dif- involvement and <10% for patients with
ferent pattern of basic fibroblast growth distant metastases {50}. More than 70%
factor expression in neoplastic ker- of SCC recurrences and metastases
atinocytes by in situ hybridization and the develop within 2 years of treatment of the
persistence of integrated HPV sequen- primary tumour {635}, and 95% within 5
ces in the host cell genome of HPV asso- years {1985}. The 3-year cumulative risk

12 Keratinocytic tumours
Basal cell carcinoma S. Kossard
E.H. Epstein, Jr.
R. Cerio
L.L. Yu
D. Weedon

Definition Australia. The rate of basal cell carcino- growth, or superficial erythematous
A group of malignant cutaneous tumours mas has increased in the older age patches that appear as a dermatitis or
characterised by the presence of lob- groups. Older men have a higher inci- tumours complicating vaccination scars,
ules, columns, bands or cords of basa- dence of basal cell carcinoma than rhinophyma or a venous ulcer. The clini-
loid cells (“germinative cells”). women, but women have been found to cal capacity to differentiate some basal
outnumber men in younger age groups. cell carcinomas from squamous cell car-
ICD-O code 8090/3 The latter may be due to increased sun cinoma or even melanoma may be
exposure in younger women in associa- impossible without skin biopsy. In coun-
Synonyms tion with tanning bed use as well as tries with a high incidence of basal cell
Basal cell epithelioma, trichoblastic car- smoking {293}. carcinomas it is not unusual to have indi-
cinoma. viduals with multiple basal cell carcino-
Clinical features mas, and regular review is required to
Epidemiology Basal cell carcinomas typically have a deal with new skin tumours. Incomplete
Basal cell carcinomas (BCC) develop pearly appearance with telangiectasia removal of basal cell carcinoma may
predominantly in sun-damaged skin in that may appear as a papule or nodule result in delayed recurrences that may
individuals who are fair skinned and that can be eroded or ulcerated. These not be recognized for years, particularly
prone to sunburn {330,888,889}. features may be more subtle in the if the tumour recurrence is deep or
Migration of such individuals particularly superficial forms that appear as erythe- masked by skin grafts.
as children, to countries with high UV matous patches resembling an area of
radiance is associated with increased dermatitis. Pale scar-like lesions may Genetics
rates of skin cancer. Although basal cell also be a presentation of basal cell car- Genetic analysis of sporadic basal cell
carcinomas typically occur in adults, the cinoma and these slowly grow over carcinoma {2024} has been propelled by
tumours also develop in children {1873}. years. Pigmented basal cell carcinomas the identification of mutations in PTCH1
Arsenic exposure {924} and ionizing may masquerade as melanomas but (chromosome 9q22.3) as the cause of
radiation may also induce basal cell car- usually can be distinguished by the pres- the basal cell nevus syndrome (BCNS), a
cinomas. ence of a pearly component. Derma- rare autosomal dominant disorder {110,
Nodular basal cell carcinomas occur at a toscopy is also helpful in analysing pig- 1146,2395}. These patients develop mul-
later age than superficial basal cell car- mented basal cell carcinoma and distin- tiple basal cell carcinomas which may
cinomas and are more frequently on the guishing these from melanocytic tumours appear in childhood (see Chapter 2).
head whereas the trunk is the most fre- {1587}. Erosive lesions on the lower limbs PTCH1 encodes a protein that functions
quent site for superficial tumours {1550, may be mistaken for slowly healing trau- as an inhibitor of the hedgehog signaling
2121}. matic wounds. Delays in clinical diagno- pathway, and BCCs, whether sporadic or
Basal cell carcinomas are very frequent sis may occur for basal cell carcinomas occurring in BCNS patients, all have
tumours particularly in light-skinned indi- that are localized within non-sun abnormalities of this signaling pathway
viduals living in countries at low latitudes. exposed sites {225} such as the perianal {110,1146,2272,2395}. In most sporadic
Incidences of 2000 per 100,000 popula- area {1312} or between the toes, young BCCs this is due to somatically-acquired
tion have been recorded in Queensland, age of onset, tumours with very slow mutations in PTCH1 {802}, and in many

Fig. 1.1 Basal cell carcinoma, nodular type. A and B The epidermis is raised with flattening of the rete ridges overlying solid and cystic groups of atypical basaloid
cells with peripheral palisading showing invasion of the deep dermis in a nodular pattern. C High power view of nodular basal cell carcinoma showing focal cys-
tic change, peripheral palisading and cleft between tumour nests and stroma.

Basal cell carcinoma 13


Fig. 1.2 A Basal cell carcinoma, superficial type. A solid group of atypical basaloid cells is present at the dermo-epidermal junction showing peripheral palisading
and cleft formation between tumour nest and dermis. The dermis shows fibrosis and a patchy lymphocytic infiltrate which frequently accompany basal cell carci-
noma of the superficial type. B Basal cell carcinoma, nodular type, pigmented. The appearances are those of typical nodular basal cell carcinoma with the addi-
tional feature of melanin pigmentation of the tumour nests. C Basal cell carcinoma, cystic type. There is extensive cystic change in an otherwise nodular basal
cell carcinoma. The cystic space contains connective tissue type mucin. In the purely cystic variant, tumour cells may be compressed to only 1 to 2 cell layers thick.
D Basal cell carcinoma, micronodular type. The tumour cell nests are tightly packed, with a diameter of 3 to 10 cells across with deep dermal invasion. In this exam-
ple, there is also tumour-associated amyloid in the stroma.

tumours the type of PTCH1 mutations are BCCs and either spontaneously or in mis {475}. Apoptosis is usually apparent.
those expected from UV-mutagenesis response to environmental mutagens The release of keratin into the stroma as
{108,1265}. Approximately 10% of spo- (i.e. UV or ionizing radiation) develop a result of apoptosis may lead to the for-
radic BCCs have mutations in BCCs and adnexal basaloid tumours. mation of amyloid deposits {2067}.
SMOOTHENED which encodes the pro- Mucinous cystic degeneration, focal vac-
tein whose function is inhibited by the Histopathology uolation with lipid or ductular differentia-
PATCHED1 protein {2553}. Thus it The multiple variants of basal cell carci- tion, and in rare cases, sebocytes or fol-
appears that the relevant dysfunction noma are connected by the common his- licular differentiation with squamous
driving BCCs is abnormal hedgehog sig- tological feature of lobules, columns, eddies, trichohyaline granules and blue-
naling, irrespective of which gene con- bands and cords of basaloid cells (“ger- grey corneocytes may be seen.
trolling that signaling is mutated. The minative cells”) associated with scant Melanocytes may proliferate within some
identification of hedgehog signaling cytoplasm and a characteristic outer pal- tumours and produce pigmentation by
abnormalities as crucial to BCC forma- isade of cells associated with a sur- melanin production that can be stored in
tion has stimulated the development of rounding loose fibromucinous stroma tumour cells or in surrounding
genetically-engineered mice with hedge- {2147,2282}. Artefactual retraction melanophages {1365}.
hog signaling abnormalities {109,708, spaces between the tumour and stroma Problematic lesions include tumours that
1716,2163}. Unlike previously studied are often present. The tumour-stromal merge with squamous cell carcinoma
mouse carcinogenesis models, which interaction is weakened by the charac- (basaloid squamous cell carcinoma) or
uniformly produce tumours of the squa- teristic lack of the hemidesmosomes that those that share adnexal differentiation
mous cell lineage, these mice develop anchor the normal epidermis to the der- demonstrating trichilemmal or seba-

14 Keratinocytic tumours
ceous areas. Some examples of mor- less than 1 in 10,000 tumours {1440, deeply infiltrating and recurrent {70}. The
phoeic or sclerotic basal cell carcinoma 1950,2443}. Morbidity is increased with risk of further primary BCCs is increased
may resemble desmoplastic trichoep- deeply invasive tumours which may by male gender, age over 60 years and
ithelioma or microcystic adnexal carcino- extend into the deep tissue to bone and truncal site {1208,1378}.
ma particularly when a small sample is follow fusion planes particularly on the Rarely, extensive perineural invasion is
obtained for analysis. The growth pattern face where they follow nerves through seen in infiltrative primary BCCs of the
of the basal cell carcinoma should be bony channels. Morbidity also increases face, presenting life-threatening compli-
included in the pathology report as well with neglected tumours that may meas- cations of CNS extension {317,946}.
as the presence of perineural involve- ure more than 10 cm in diameter and Distance to the closest resection margin
ment and excision margins particularly if have been described as giant basal cell is an important predictor of BCC recur-
less than 1 mm. Although the majority of carcinomas {1502,2009}. Multiple recur- rence {639}.
basal cell carcinomas can be classified rences with deep residual tumour on the
into the nodular, micronodular, superfi- head may be associated with particular
cial, sclerosing/morpheic or infiltrative morbidity as basal cell carcinomas can Superficial basal cell
subtypes, it is not unusual to have a ultimately penetrate the cranium. carcinoma
mixed pattern. Increased recurrences are associated
with infiltrative, morphoeic and micron- ICD-O code 8091/3
Immunoprofile odular basal cell carcinomas as surgical
Occasionally in curette specimens, dif- margins may be underestimated {639, Clinical features
ferentiation from small cell melanoma 1940}. The possibility of the BCNS This variant appears as erythematous
may require the use of a combination of should be considered in children who patches that are often multiple and may
light-weight keratin markers and S100 develop BCCs. Families can be vary from a few millimetres to over 10 cm
acidic protein to differentiate the screened for mutations of the PTCH1 in diameter. A fine pearly border or cen-
tumours. BerEP4, a keratin marker, has gene. Low bcl-2 protein expression has tral superficial erosions with a history of
been used to differentiate basal cell car- been found to correlate with clinically contact bleeding may be present. Areas
cinoma from squamous cell carcinomas aggressive basal cell carcinomas with of regression may appear as pale patch-
{2334}. CK20, a marker for Merkel cells, infiltrative, sclerosing/morphoeic pat- es or fibrosis. This variant makes up 10-
has been used to differentiate some terns as compared to superficial and 30% of basal cell carcinomas and occurs
forms of trichoblastoma, trichoepithe- nodular tumours {296,1883}. most frequently on the trunk.
lioma or fibroepitheliomas as these have BCC recurrences are more common in
scattered CK20 positive Merkel cells lesions on the nose and nasolabial fold, Histopathology
compared to basal cell carcinoma where but this may be in part due to the difficul- The histopathology consists of superfi-
they are rare or absent {13,2104}. ty in achieving adequate margins in cial lobules of basaloid cells which proj-
these sites {638,651}. Tumours recurring ect from the epidermis or from the sides
Prognosis and predictive factors after radiotherapy are usually aggressive of follicles or eccrine ducts into the der-
Basal cell carcinomas are locally inva- and infiltrative {2209}. Lesions which mis and are surrounded by loose myxoid
sive tumours and metastases occur in metastasize are usually large, ulcerated, stroma. The lobules are usually confined

Fig. 1.3 Nodular BCC. Cribriform nodular basal cell carcinoma. Fig. 1.4 Nodular BCC with monster giant cells.

Basal cell carcinoma 15

Fig. 1.5 A Infiltrative basal cell carcinoma. B 0172.Mixed nodular and infiltrative basal cell carcinoma.

to the papillary dermis. Some examples associated with telangiectasia but may Micronodular basal cell
of superficial basal cell carcinoma become ulcerated or cystic. Endophytic carcinoma
appear multifocal on vertical sections but nodules may present as flat indurated
may be connected by a stroma when lesions. Haemorrhagic lesions may ICD-O code 8090/3
reconstructed by three-dimensional resemble haemangiomas or melanoma
techniques using digital image analysis. when pigmented. Nodular basal cell car- Clinical features
There are, however, examples of multi- cinomas make up 60-80% of tumours Micronodular basal cell carcinoma pres-
focal superficial basal cell carcinoma and occur most frequently on the head. ents as elevated or flat infiltrative
where the lobules are separated by large tumours. The most common site is the
distances and represent discrete Histopathology back.
tumours that are truly multifocal and may Histopathology shows large lobules of
measure only a few millimetres in diame- basaloid cells (“germinative cells”) with Histopathology
ter. Mixed patterns with a nodular, peripheral palisading nuclei that project This variant has small nodules that per-
micronodular or infiltrative component into the reticular dermis or deeper. The meate the dermis {1010}. Individual nod-
may be seen in some tumours. lobules may have associated mucinous ules may appear to be separated by nor-
degeneration with cysts or have an ade- mal collagen. The tumour nodules may
noid (cribriform) pattern. Some nodules approximate the size of follicular bulbs
Nodular basal cell carcinoma may have an organoid appearance with and form subtle extensions into deep tis-
smaller basaloid lobules that are con- sue. In contrast to nodular basal cell car-
ICD-O code 8097/3 nected by loose fibromucinous stroma. cinoma the surgical margins of micron-
Clinical features The periphery of such nodules should be odular basal cell carcinoma may be
Nodular (solid) basal cell carcinomas scanned to ensure that an outlying underestimated. Perineural extension
often appear as elevated pearly nodules micronodular pattern has not developed. may be seen.

Fig. 1.6 Nodular cystic BCC A There are well circumscribed cystic nodules of atypical basaloid cells pushing into the deep dermis in a nodular pattern. B High
power view of nodulocystic basal cell carcinoma showing cribriform cystic spaces filled with stromal mucin.

16 Keratinocytic tumours
Fig. 1.7 Fibroepithelial basal cell carcinoma (fibroepithelioma of Pinkus). Fig. 1.8 BCC with adnexal differentiation; basaloid
follicular hamartoma.

Infiltrating basal cell highlighting subtle groups of tumour most often found on the back and are
carcinoma cells (that may consist of 1-2 ker- rarely multiple {1834}. Prior radiotherapy
atinocytes on cross section), in assess- may predispose to these tumours.
Definition ing clearance of the tumour and in con-
This variant of BCC is composed of thin firming perineural involvement. Histopathology
strands, cords and columns of basaloid The histopathology is characterised by
cells that infiltrate between the collagen Differential diagnosis an arborising network of cords of basa-
bundles of the dermis and may extend Due to the cord-like arrangement of this loid cells that extend downwards from
into deeper tissues. variant there is a morphological overlap the epidermis and create a fenestrating
with the tumour pattern seen in micro- pattern. There are strands of basaloid
ICD-O code 8092/3 cystic adnexal carcinoma (sclerosing cells that surround fibrovascular stroma.
sweat duct carcinoma), desmoplastic Ductules may be present in some of the
Clinical features squamous cell carcinoma and desmo- cords which may represent extension of
The infiltrative basal cell carcinoma pres- plastic trichoepithelioma. the tumour down pre-existing eccrine
ents as a pale, indurated poorly-defined ducts {2263}. The cords also are associ-
plaque. These tumours are usually found ated with small follicle-like bulbs which
on the upper trunk or face. Paraesthesia Fibroepithelial basal cell project into the surrounding connective
or loss of sensation may develop rarely carcinoma tissue.
as a manifestation of perineural exten-
sion, particularly in lesions on the face. Definition Histogenesis
This variant is important in that the mar- This variant of BCC is characterised by a Fibroepitheliomas, like BCCs, may be
gins at the time of surgery may be fre- unique clinicopathological presentation best classified as a form of appendageal
quently underestimated. and an indolent behaviour. tumour. These tumours have mutations of
the PTCH1 gene. In some fibroepithe-
Histopathology ICD-O code 8093/3 liomas transition to classical basal cell
Infiltrative patterns of basal cell carcino- carcinomas may be seen, and this con-
ma appear as strands, cords and Synonyms version may reflect a further mutation. A
columns of basaloid cells with scant Fibroepithelioma of Pinkus, Pinkus variant of fibroepithelioma with extra-
cytoplasm. Peripheral palisading and tumour mammary Paget’s cells has been
retraction spaces are usually not seen. described in the perianal area {2461}.
There is no fibrosis/sclerosis as seen in Clinical features
the sclerosing/morphoeic variant. The These tumours usually appear as an ele-
infiltrative pattern is particularly associat- vated flesh coloured or erythematous
ed with perineural invasion. Low molecu- nodule that may resemble a seborrhoeic
lar-weight keratin markers are useful in keratosis or acrochordon. The lesions are

Basal cell carcinoma 17

classified as benign adnexal tumour
such as a basaloid follicular hamartoma,
trichoepithelioma, trichoblastoma or

The cytokeratin profile of basal cell carci-
noma is essentially identical to that of tri-
choblastomas (immature trichoepithe-
lioma) and developing fetal hair follicles
linking all basal cell carcinomas to the
pilosebaceous pathway of differentiation
{2086}. It has been proposed that basal
cell carcinoma be renamed trichoblastic
A carcinoma {1623}.

Prognosis and predictive factors

These patterns of adnexal differentiation
do not appear to have any prognostic

Basosquamous carcinoma

B C Basosquamous carcinoma is a term
Fig. 1.9 Basal cell carcinoma, nodular type, with follicular differentiation. A The overall view shows a used to describe basal cell carcinomas
resemblance to typical nodular basal cell carcinoma, with the addition of a cellular fibrous stroma. B There that are associated with squamous differ-
is follicular bulbar differentiation in parts of the tumour, with formation of hair bulb accompanied by mes- entiation {285,2102}.
enchymal bodies. Focal dystrophic calcification. C 1603 High power view showing groups of atypical basa-
loid cells with peripheral palisading with trichohyaline granules and abrupt trichilemmal keratinization.
ICD-O code 8094/3

Histopathology Synonyms
Basal cell carcinoma with This variant is characterized by the pres- Metatypical carcinoma, basosquamous
adnexal differentiation ence of adnexal differentiation including cell carcinoma
basaloid buds, ductal, sebaceous and
Definition trichilemmal elements. Follicular differen- Clinical features
This variant is characterized histological- tiation may be prominent in more superfi- This variant has no distinguishing clinical
ly by adnexal differentiation in a BCC. cial BCCs. Eccrine or apocrine differenti- features.
ation has also been observed in some
ICD-O code 8098/3 basal cell carcinomas {997,2022}. It is Histopathology
important to distinguish such tumours The tumour cells have more abundant
from sweat gland carcinomas which cytoplasm with more marked keratiniza-
Clinical features have an increased risk for metastases. tion than typical basal cell carcinomas.
This variant has no distinguishing clinical Some forms of adnexal basal cell carci- The nuclei have vesicular chromatin with
features. nomas show overlap and may be better pleomorphism and palisading may be
focally lost. Some examples of this vari-
ant may merge with sebaceous carcino-
ma as lipid vacuoles or ducts may be
focally apparent. This tumour may also
have central fibrosis and a radiating
peripheral rim of infiltrative cells extend-
ing into the deep dermis or subcutis.

Prognosis and predictive factors

This variant has a more aggressive
behaviour and has been associated with
A B regional or widespread metastases
Fig. 1.10 Basal cell carcinoma, keratotic type. A Prominent keratin horn cysts in the center of the tumour {1525}.
nests. B Detail of trichilemmal keratinization.

18 Keratinocytic tumours
Keratotic basal cell carcinoma

This variant is characterized by the pres-
ence of prominent keratin formation (horn
cysts) in the centre of tumour islands.

ICD-O code 8090/3

Clinical features
This variant characteristically appears
pearly and may be studded with small
keratin cysts (milia).

These tumours share the overall archi-
tectural features of a nodular BCC.
Keratinization may be laminated and
infundibular in type or hyaline and
trichilemmal in type or consist of kera-
tinised shadow cells representing pilo-
matricomal differentiation {66}. Dys-
trophic calcification is frequently present.
Trichilemmal keratin may be associated
with accentuated apoptosis in surround-
ing tumour cells and the presence of
pale keratinocytes.

Differential diagnosis
This variant is distinguished from
basosquamous carcinoma by the pres- C D
ence of numerous, superficial small ker- Fig. 1.11 Basal cell carcinoma (BCC). A Adenoid BCC. B Morpheiform BCC. C BCC with rosettes. D BCC
atin cysts. Basosquamous carcinoma is with sebaceous differentiation.
usually larger and less well circum-
embedded in a dense fibrous stroma variants including the nodular, micron-
{1932}. Some authors use the term mor- odular, multifocal superficial and keratot-
Other variants phoeic for any BCC with a fibrous stro- ic types. Melanocytes are scattered
ma, while others restrict it to those BCC’s through the tumour nests, while
Other variants account for less than 10% with keloidal collagen bundles in the stro- melanophages are present in the stroma
of all basal cell carcinomas. Many of ma {1923}. Enhanced procollagen gene {1495}. This variant can be misdiag-
them do not have distinctive clinical fea- expression has been found in this variant nosed clinically as malignant melanoma.
tures. {1657}. Furthermore, smooth muscle α-
actin is often present in the stroma. This Miscellaneous
Cystic variant usually presents as an indurated, Other rare variants, subject to isolated
One or more cystic spaces, of variable pale plaque with a slightly shiny surface case reports, include the clear-cell {165},
size, are present near the centre of the and indistinct margins. "signet-ring"-cell {1269,2503}, granular-
tumour nests. There is sometimes in- cell {1659} and giant ("monster")-cell
creased mucin between the cells border- Infundibulocystic {680} types. Adamantanoid {1403}, neu-
ing the central space {2112}. Often confused with the keratotic type, roendocrine {817} and schwannoid
this variant is composed of small {2032} variants have also been
Adenoid infundibular-like structures with a central described.
There are thin strands of basaloid cells in keratinous plug and a peripheral compo-
a reticulate pattern. Stromal mucin is nent of basaloid cells {1218}. The nests
often present. The adenoid type may are arranged in an anastomosing pat-
occur in association with the nodular tern. Multiple lesions are sometimes
(solid) type. present {1178}.

Sclerosing / morpheiform Pigmented

Strands and nests of tumour cells are Pigmentation may occur in several of the

Basal cell carcinoma 19

Squamous cell carcinoma D. Weedon
M.B. Morgan
C. Gross
E. Nagore
L.L. Yu

Definition ing skin usually shows changes of actinic are immunocompromised (including
Squamous cell carcinoma is a malignant damage. those infected with the human immunod-
neoplasm of epidermal (and mucous eficiency virus {1704}, are usually more
membrane) keratinocytes in which the Histopathology aggressive. Tumours with deep invasion,
component cells show variable squa- Squamous cell carcinoma consists of poor differentiation, perineural invasion
mous differentation. nests, sheets and strands of squamous and acantholytic features are more likely
epithelial cells which arise from the epi- to recur or metastasize. Narrow surgical
ICD-O code 8070/3 dermis and extend into the dermis for a margins are another risk factor for recur-
variable distance. The cells have abun- rence {2389}.
Epidemiology dant eosinophilic cytoplasm and a large, The clinical setting in which the SCC aris-
Most cases arise on the sun-exposed often vesicular, nucleus. There are promi- es also influences the risk of metastasis.
skin of elderly people. They can occur on nent intercellular bridges. There is vari- Tumours arising in sun-damaged skin
all cutaneous surfaces and mucous able central keratinization and horn pearl have the lowest risk, in the order of 0.5%
membranes, and in younger patients, formation, depending on the differentia- or less, while for those arising in skin not
especially those with a fair complexion tion of the tumour. exposed to the sun, the risk is 2-3%. The
who tan poorly. Its incidence in an The degree of anaplasia in the tumour risk is further increased for tumours aris-
Australian study was 166 cases per nests is used to grade the tumours. A ing in Bowen disease {1203}, on the lip,
100,000 of the population, the highest in rather subjective assessment is usually vulvar, perineal and penile skin and in a
the world {828}. It is relatively uncommon made using the categories of ‘well,’ Marjolin ulcer, radiation scar or thermal
in Black people. ‘moderately’ and ‘poorly’ differentiated. burn. Tumour thickness is a prognostic
Most squamous cell carcinomas arise in variable, just as it is for melanoma. SCCs
Etiology solar keratoses and evidence of this less than 2 mm in thickness rarely metas-
Ultraviolet-B radiation is the most impor- lesion is usually present at the periphery tasize, while those between 2 and 5 mm
tant etiological factor. Less important fac- of the invasive tumour. thick are of intermediate risk (about 5%).
tors include radiation therapy, previous Squamous cell carcinomas occasionally Tumours greater than 5 mm in thickness
burns, arsenic, coal tar {1759}; industrial infiltrate along nerve sheaths, the adven- have a risk of metastasis of about 20%
carcinogens, immunosuppresion, HPV titia of blood vessels, lymphatics, fascial {1254}. Tumours greater than 2 cm in
infection, and inflammatory lesions and planes and embryological fusion plates diameter are more likely to recur and
ulcers of long standing (see Intro- {218}. The presence of perineural lym- metastasize than smaller lesions {1985}.
duction). Organ transplant recipients are phocytes is a clue to the likely presence
particularly prone to develop these of perineural invasion in deeper sections
tumours. Most of the fatal cases have {2289}.
been reported from Australia, suggesting There may be a mild to moderate chronic
that sunlight, which also has a profound inflammatory cell infiltrate at the periph-
effect on the cutaneous immune system ery of the tumours. This infiltrate some-
plays a role in the formation of these times includes eosinophils {1455}.
aggressive tumours {1974}. HPV infec- Rare histological variants of SCC include
tion is commonly found in these immuno- clear-cell {1344}, signet-ring {1557}, pig-
supressed patients {264}. mented {451}, basaloid {573}, inflamma-
tory, infiltrative {1395}, desmoplastic
Localization {1546} and rhabdoid {1534} types.
Most SCCs arise in areas of direct expo- The cells in SCC are positive for epithe-
sure to the sun, such as the forehead, lial membrane antigen and cytokeratin.
face, ears, scalp, neck and dorsum of The keratins are of higher molecular
the hands. The vermilion part of the lower weight than those found in basal cell car-
lip is another common site. cinoma {1672}.

Clinical features Prognosis and predictive factors

Squamous cell carcinomas present as The majority of squamous cell carcino- Fig. 1.12 Squamous cell carcinoma in an elderly
shallow ulcers, often with a keratinous mas are only locally aggressive and are male with delayed medical treatment. This is an
crust and elevated, indurated surrounds, cured by several different modalites unusually large neoplasm which spread to the
or as plaques or nodules. The surround- {1656}. SCC developing in patients who regional lymph nodes.

20 Keratinocytic tumours
Acantholytic squamous cell Clinical features neous epithelial markers that include
carcinoma ASCC presents similarly to conventional high molecular weight keratins such as
SCC, as a slowly growing scaly and AE-2/3. Involucrin, vimentin and EMA
Definition occasionally ulcerated papule/plaque on immunostains may also be positive
Acantholytic squamous cell carcinoma the sun-exposed skin. {1808,2011}. Low-molecular weight ker-
(ASCC) is a histologic variant of cuta- atins such as AE-1, CAM 5.2 are typical-
neous squamous cell carcinoma (SCC) Histopathology ly negative. Various intercellular peptides
that is histologically defined by loosening Invasive lesions typically show a thick- have been invoked in the pathogenesis
of the intercellular bridges resulting in ened, and/or ulcerated epithelium. of acantholysis including the intercellular
acantholysis. These tumours may pres- Scanning magnification reveals a flat- adhesion molecule syndecan, E-cad-
ent as intraepidermal (in-situ) or invasive tened thinned, normal or hyperplastic herin and the anhidrotic ectodermal dys-
SCC. epidermis with or without asymmetric plasia gene product {183,1635}. It has
and infiltrating dermal tumour islands. At also been recently shown that decreased
ICD-O code 8075/3 intermediate power, prominent TP53 and PCNA expression correlated
suprabasilar or intratumoural acantholy- with a decrement in desmosomes seen
Synonyms sis is seen. Zones of acantholysis are ultrastructurally {1889}.
Adenoid squamous cell carcinoma, capable of producing large intra-epider-
pseudoglandular squamous cell carcino- mal cavities. Acantholytic areas may Differential diagnosis
ma extend down adjacent follicular struc- The changes described above constitute
tures involving the follicular epithelium an important histologic means of sepa-
Epidemiology and rarely, circumscribe the follicle simu- rating this entity from acantholytic disor-
The acantholytic variant accounts for 2- lating a glandular arrangement. ders. The differential also includes true
4% of all cutaneous SCC {1149,1687, Acantholytic foci may also produce a adenosquamous cell carcinoma of the
1819,2549}. The age range is wide but it pseudovascular pattern mimicking skin that exhibits squamous and glandu-
usually affects aged individuals with a angiosarcoma (pseudovascular SCC) lar differentiation on ultrastructural exam-
male predominance. {139,1675,1688}. At high power typical ination and histochemical staining {2482}.
features of squamous malignancy are
Etiology identified including dyskeratosis, ker- Prognosis and predictive factors
As in conventional SCC, ultraviolet light atinocytic atypia, consisting of an The behaviour of ASCC like other SCCs
constitutes the most important etiologic increased nuclear-to-cytoplasmic ratio is depth-dependent and may be more
risk factor. and nuclear hyperchromasia, altered aggressive than conventional SCC {461,
maturation within the epithelium, and 1097,1149,1687,1819,1985}. In-situ le-
Localization increased typical and atypical mitotic fig- sions are capable of recurrence and in
The tumour involves predominantly the ures. up to 10% of cases, may show micro-
skin of the head and neck region, partic- invasion. The overall rate of metastases
ularly on and around the ears {1149, Immunoprofile with lesions greater than 2.0 cm of inva-
1687,1819,2549}. The lesional cells in ASCC stain for cuta- sion ranges from 5-19%.

Fig. 1.13 A Acantholytic SCC, Intermediate-power photomicrograph depicting acantholysis extending down adjacent follicle epithelium. B Squamous cell carcino-
ma (acantholytic)

Squamous cell carcinoma 21

Fig. 1.14 Squamous cell carcinoma (acantholytic) A, B Note the pseudoglandular pattern and the loss of cohesion between tumour cells.

Spindle-cell squamous cell cell carcinoma. Sometimes there is a his- CAM5.2 or MNF116. Some tumours may
carcinoma tory of rapid growth. coexpress cytokeratin and vimentin, sug-
gesting metaplastic change to a neo-
Definition Histopathology plasm with mesenchymal characteristics
This is an uncommon variant of squa- It may be composed entirely of spindle {1116}.
mous cell carcinoma that exhibits a cells, or have a variable component of
prominent spindle cell morphology. more conventional squamous cell carci- Prognosis and predictive factors
noma. The spindle cells have a large Spindle-cell squamous cell carcinoma is
ICD-O code 8074/3 vesicular nucleus and scanty a poorly differentiated variant of squa-
eosinophilic cytoplasm, often with indis- mous cell carcinoma that may be associ-
Etiology tinct cell borders. There is variable pleo- ated with an aggressive clinical course
Lesions usually arise in sun-damaged or morphism, usually with many mitoses. {2180}. These tumours account for slight-
irradiated skin. A case has been report- ly over one-third of cutaneous squamous
ed in association with lichen sclerosus of Differential diagnosis cell carcinomas which metastasize
the vulva {2057}. The incidence of this It may be difficult to separate from other {1985}. Metastases usually occur to the
variant may be higher in immuosup- cutaneous spindle cell neoplasms regional lymph nodes in the first
pressed patients. including spindle cell melanoma, atypi- instance.
cal fibroxanthoma and, less often,
Clinical features leiomyosarcoma. Some cases can only
Spindle-cell squamous cell carcinoma be confirmed ultrastructurally, as all ker- Verrucous squamous cell
presents as a plaque or nodule on the atin markers are negative {2180}. CK5/6 carcinoma
skin. It may be clinically indistinguishable is positive in two-thirds of all cases, a
from the more usual type of squamous higher figure than obtained with AE1/3, Definition
Verrucous squamous cell carcinoma is a
rare variant of well-differentiated squa-
mous cell carcinoma with low malignant

ICD-O code 8051/3

Oral florid papillomatosis, Ackerman’s
tumour {32,348}, epithelioma cunicula-
tum {41,2096,2108}, giant condyloma
acuminatum, Buschke-Löwenstein tu-
mour {359,1347,1947,2124,2570}, papil-
lomatosis cutis carcinoides {218,870,

Fig. 1.15 Verrucous squamous cell carcinoma Fig. 1.16 Verrucous squamous cell carcinoma Verrucous carcinoma comprises 2-12%

22 Keratinocytic tumours
of all oral carcinomas, and is found pre-
dominantly in men (age peak in 5th
decade, range 34-85) {348}. Verrucous
carcinoma of the extremities (epithelioma
cuniculatum) most often affects men in
the 6th decade {2108}. The incidence of
the genital type (Buschke-Löwenstein
tumour) varies between 5- and 24% of all
penile cancers; the tumour tends to
occur in men younger than 50 years
(range 18-86) {218}.

Leading theories of the pathogenesis
include chronic irritation, inflammation
and impaired immune response {2096,
2108}. Important factors for the develop-
ment of oral verrucous carcinomas are
poor oral hygiene with ill-fitting dentures
or decaying teeth, chewing of tobacco or
betel nuts, and use of snuff. In genital
lesions poor hygiene and phimosis play
a major role. Other theories include HPV A B
infection (mostly HPV 6, 11) {898} and Fig. 1.17 Verrucous squamous cell carcinoma A, B Note the well-differentiated proliferative process and
chemical carcinogens {2096,2108}. the bulbous nature of the squamous downgrowths.

Common sites include buccal and retro- epithelium shows an asymmetric exo- Prognosis and predictive factors
molar mucosa, gingiva, floor of mouth, and endophytic growth pattern with If the tumour is completely excised,
tongue and hard palate. They also arise pushing rather than destructive or infiltra- prognosis is excellent; after inadequate
on the soles, rarely the palms and distal tive margins. Usually, there is deep pen- excision, the recurrence rate is high and
fingers, and on amputation stumps. etration below the level of the surround- the survival decreases. In long-standing
Genital lesions occur primarily on the ing epidermis / mucosa. Tumour cells cases or after irradiation and / or
glans and prepuce of the penis {778, exhibit only minimal atypia and very low chemotherapy the biologic character of
2108,2570}. It is uncommon in the vagina mitotic activity. The presence of neu- the disease may change into a metasta-
and the perianal region {1347,1947, trophils is an important diagnostic clue; sizing squamous cell carcinoma {1216}.
2124}. Rare cases have been described they may form small intraepidermal
on the scalp, face, back and extremities, abscesses. Draining sinuses containing
sometimes associated with long-stand- inflammatory cells and keratin debris Pseudovascular squamous
ing ulcerations or scars, especially in the may also be present. No foci of the usual cell carcinoma
pretibial area (papillomatosis cutis carci- squamous cell carcinoma should be
noides) {218,870,2096,2108}. found {1833}. Definition
Pseudovascular SCC is an aggressive
Clinical features Differential diagnosis variant of SCC with marked acantholysis
These lesions show cauliflower-like The separation from benign reactive resulting in angiosarcoma-like areas
appearance with exophytic and endo- processes and SCC of the more usual {139,1688}.
phytic growth, and a papillomatous sur- type can be difficult. The presence of
face. They are pale in colour and some- blunted projections of squamous epithe- ICD-O code 8075/3
times have draining sinuses. Some are lium in the mid and/or deep dermis is
tender and painful, particularly on the suspicious for verrucous carcinoma. The Synonyms
sole of the foot. There is slow but relent- squamous downgrowths are bulbous. Pseudoangiosarcomatous SCC,
less growth over the course of a long Small collections of neutrophils may pseudoangiomatous SCC
time {2570}. extend into the tips. Clinicopathological
correlation and adequate sampling are Epidemiology
Histopathology often helpful. The tumour is exceedingly rare.
In all cases a well-differentiated prolifera-
tive epithelial process is visible, the Precursor lesions Clinical features
malignant nature of which may easily be Oral lesions may develop in areas of pre- It usually presents as a circumscribed
overlooked, particularly if the biopsy is vious leukoplakia, lichen planus, lupus white-grey ulcer or a nodular tan-red/pink
small and superficial. The squamous erythematosus or candidiasis {218}. tumour, most often located on sun-

Squamous cell carcinoma 23

exposed areas of middle-aged or elderly ing from pluripotential cells related to
patients. acrosyringia, characterized by the for-
mation of mucin secreting glands.
It is characterized by areas of anasto- ICD-code 8560/3
mosing cord-like arrays of polygonal or
flattened tumour cells, with internal Epidemiology
pseudolumina that contain detached Most reported cases occurred on the
tumour cells and amorphous basophilic head and neck of elderly patients, with
material {550,1675,2558}. Erythrocytes male predominance {120,140,572,
may also be seen in pseudovascular 1933,2482}. The penis can also be
spaces. Immunohistochemical examina- involved {120}.
tion is essential to differentiate it from
angiosarcoma. Pseudovascular SCC is Clinical features
positive for one or more monoclonal anti- It can present as an asymptomatic
bodies to cytokeratin and consistently smooth surfaced dermal nodule or a
negative for CD31 and factor VIII-related large ulcerated deeply invasive tumour
antigen. indistinguishable from squamous cell
carcinoma or basal cell carcinoma.
Differential diagnosis
In classical angiosarcoma vascular Histopathology
markers are positive, keratin staining is The tumour consists of invasive tongues,
Fig. 1.18 Adenosquamous carcinoma of the ear.
negative; in epithelioid angiosarcoma in sheets, columns and strands of atypical
There are deeply invasive tongues, columns and
addition to vascular markers epithelial dyskeratotic squamous cells, merging strands of atypical dyskeratotic squamous cells
markers are frequently expressed. with glandular structures with epithelial abutting the cartilage.
mucin secretion, which can be demon-
Prognosis and predictive factors strated by a PAS, mucicarmine or alcian
The prognosis is worse than it is for other blue stain at pH 2.5. The mucin is Differential diagnosis
variants of SCC, with a mortality up to hyaluronidase resistant and sialidase Adenosquamous carcinoma should be
50%. Large size may confer a worse sensitive. Intracytoplasmic neolumina distinguished from mucoepidermoid car-
prognosis {1675}. containing targetoid mucin secretions cinoma, which had been reported as
can also be seen. The tumour cells are adenosquamous carcinoma in early
positive for cytokeratin and epithelial reports. Adenosquamous carcinoma
Adenosquamous carcinoma membrane antigen, whereas those cells has well formed glands with mucin
forming glands stain with carcinoembry- secretion and no goblet cells. Muco-
Definition onic antigen. There may be connection epidermoid carcinoma consists of polyg-
Adenosquamous carcinoma is a rare between tumour cells and acrosyringia, onal squamous cells and goblet cells
variant of squamous cell carcinoma aris- as well as perineural invasion. without glands. Signet ring squamous

Fig. 1.19 Adenosquamous carcinoma. A Overt squamous differentiation in parts of the tumour. B Sheets of atypical dyskeratotic squamous cells from the squa-
mous area of the tumour.

24 Keratinocytic tumours
Fig. 1.20 Adenosquamous carcinoma. A Well formed glandular structures containing mucinous secretion in the glandular area of the tumour. B PAS stain.
Intracytoplasmic targetoid PAS positive and diastase sensitive globules in the glandular areas of the tumour. C CEA immunohistochemical stain. Positive luminal
staining in glandular structures.

cell carcinoma has foamy cytoplasmic

mucin globules with displacement of the
cell nucleus but no glands. Microcystic
adnexal carcinoma (syringomatous car-
cinoma, sclerosing sweat duct carcino-
ma) shows a more ductal appearance
with prominent tubular structures but no
mucin secretion. Metastatic adenosqua-
mous carcinoma from other primary sites
such as the lung, salivary gland, female
genital tract should also be excluded.

Prognosis and predictive factors

The tumours usually follow an aggressive
course with the capacity for metastasis
and local recurrence. Early superficially
located tumours tend to have a better

Squamous cell carcinoma 25

Bowen disease G.F. Kao
R. Cerio
R. Salom
S. Pala

Definition and the average age at first biopsy is 55 {2567,2572}. Human papillomavirus
Bowen disease (BD) is a form of squa- years. Both exposed and non-exposed (HPV) genomes have been demonstrat-
mous cell carcinoma in situ. It is a distinct skin sites are equally affected. The dis- ed by in situ hybridization in the nuclei of
clinicopathologic entity of the skin and ease uncommonly affects black skin, in keratinocytes in the stratum malpighii
mucocutaneous junction. which it is found more commonly on non- and stratum corneum of the BD lesions.
sun-exposed areas. HPV types 16 and 18 have been linked to
ICD-O code 8081/2 lesions of genital BD and non-condylo-
Etiology matous genital warts, i.e., bowenoid
Synonyms The exact underlying cause of BD papulosis {1098}. HPV is less commonly
Squamous cell carcinoma in situ remains unclear, although multiple fac- associated with nongenital BD. HPV
(SCCIS), intraepidermal carcinoma, tors are likely to be responsible for it. types 15 and 16 have been identified in
bowenoid dysplasia, bowenoid squa- Many lesions arise without an apparent some cases of BD of the distal extremi-
mous carcinoma in situ (BSCIS), vulvar cause. However, it is known that chronic ties. Evidence of other papillomavirus
intraepithelial neoplasia (VIN III). sun damage disrupts normal keratinocyt- types, including HPV31, 54, 58, 61, 62
The terms bowenoid dysplasia and ic maturation, causes mutation of the and 73, have also been identified in
BSCIS are customarily applied to cuta- tumour suppressor gene protein (TP53) some cases of BD. Aberrations in local
neous and mucocutaneous lesions of the {375,1075}, and results in the develop- and systemic immunity, trauma, chronic
male and female external genitalia. BD is ment of keratinocytic atypia as seen in irritation, mutagenic factors, and tobacco
no longer used in gynaecological pathol- lesions of BD. The predilection for exposure are other possible etiologies of
ogy. It has been replaced by the concept anatomic sites affected by BD on sun- BD.
of vulvar intraepithelial neoplasia (VIN). exposed glabrous skin and lesions being
The degree of epithelial atypia seen in reported more commonly in patients with Localization
BD corresponds to VIN, grade III (VIN III) a history of PUVA or UVB therapy {1410}, Based upon a large series of 1001 biop-
{362,1580}. attest to the critical role of causal rela- sy-proven BD in Australia, most lesions
tionship between UV damage and BD. occurred on a sun-exposed glabrous
Epidemiology Ingestion of inorganic arsenic may play a area {1315}. About one-third (33%) of the
Bowen disease occurs predominantly in role, as lesions of arsenical keratosis (As- lesions occured in the head and neck
fair-complexioned Caucasian men, but K) may display identical histopathologic areas, especially the face. Men had pre-
both sexes are affected. One in five features to BD. A large number of cases dominance of lesions on the scalp and
patients (20%) is a woman. The disease of As-K with associated invasive carcino- ears, whereas women had a predomi-
commonly affects patients in the 6-8th ma have been reported in a rural popula- nant involvement of the legs and cheeks.
decades of life. However, the average tion using well water containing a high BD rarely affects the nail bed and peri-
age at onset of the disease is 48 years, concentration of inorganic arsenic ungual area {2070}.

Clinical features
The classic appearance of cutaneous
BD is a single or multiple erythematous,
rounded to irregular, lenticular, scaly, ker-
atotic, fissured, crusty, nodular, eroded,
pigmented patches or plaques. The
plaques are devoid of hair, and usually
appear sharply demarcated from the sur-
rounding unaffected skin. Areas of nor-
mal-appearing skin may occur within the
boundaries of larger lesions of BD. The
plaques vary from 1-5 cm in overall
dimensions. In intertriginous areas, BD
may appear as moist patches without
scale. In anogenital locations, the lesions
A B appear polypoid or verrucoid, frequently
Fig. 1.21 A Bowen disease. Sharply circumscribed, bright red plaque of erythroplasia of Queyrat (EPQ). pigmented. Erythroplasia of Queyrat
B Bowen disease. Erythematous, scaly, fissuring plaques of BD on lower leg of a middle-aged woman. (EPQ) presents as an asymptomatic,

26 Keratinocytic tumours

Fig. 1.22 Bowen disease (BD). A Low-power photomicrograph of BD. Note hyperkeratosis, full-thickness of epidermal atypia, extensive pilar epithelial involvement,
and a lichenoid upper dermal mixed chronic inflammatory infiltrate. B Atypical keratinocytes encircle an acrosyringium. C Atypical squamous cells extend along
acrosyringia. D Prominent vacuolated atypical cells, focally mimicking koilocytotic change and pagetoid appearance seen in BD.

bright red, velvety to shiny, sharply cir- glans penis. Such lesions have a greater These changes are confined by an intact
cumscribed plaque. The mucocuta- potential for developing into invasive car- dermoepidermal basement membrane.
neous junction of the glans penis, coro- cinoma than does BD involving glabrous Lesions of BD from hair-bearing areas
nal sulcus, or undersurface of the fore- skin {875}. Although evidence for the invariably demonstrate involvement of
skin is involved, and lesions are usually association of BD and internal malignan- the pilar acrotrichium, infundibulum, and
found in older, uncircumcised men. cies is reported in earlier studies, more sebaceous gland. In some lesions,
There are two clinical variants of BD: recent population-based cohort studies prominent vacuolated atypical cells
those involving glabrous skin, and those do not confirm the link {484}. focally mimic koilocytotic viral cytopathic
of the anogenital area. On the glabrous change and exhibit a pagetoid appear-
skin, BD manifests as asymptomatic, Histopathology ance. The acrosyringium is occasionally
slowly enlarging, scaly patches or The typical low-power microscopic fea- involved. An inflammatory infiltrate of
plaques. The average duration of the tures of BD are hyperkeratosis, paraker- lymphocytes, macrophages, and plasma
lesion is 6.4 years. Plaques of BD atosis, hypo- or hypergranulosis, plaque- cells is seen in the upper dermis.
enlarge slowly, and expand centrifugally, like acanthosis with increased cellularity, Capillary ectasia is commonly noted.
sometimes for decades. Anogenital BD and a chronic inflammatory infiltrate in Prominent solar elastosis is also present
involves the mucocutaneous junction the upper corium. The epidermis exhibits in lesions on sun-exposed skin. An inva-
and adjacent mucosa. If untreated, 5-8% loss of normal polarity and progression of sive carcinoma arising in BD shows vari-
of patients may develop invasive carci- normal surface keratinocytic maturation. able histologic differentiation, with squa-
noma. The invasive carcinomas are larg- A “windblown” appearance of crowding mous, basosquamous, pilar, sebaceous
er (up to 15 cm), rapidly growing tumours of atypical keratinocytes, with hyperchro- {1120}, pilosebaceous, poorly-differenti-
that occur in pre-existing scaly plaques matism, pale-staining to vacuolated ated, and occasionally ductal features
{1203}. cells, occasional multinucleated cells, {1203,2016}. The atypical vacuolated
The clinical entity of erythroplasia of individual cell keratinization (dyskerato- keratinocytes are negative for cytoplas-
Queyrat (EPQ) is regarded as BD of the sis), and abnormal mitoses are noted. mic mucin; some, however, contain

Bowen disease 27
glycogen. Melanin pigment may be pres-
ent in the atypical cells, and in the pig-
mented genital lesions, melanophages
are numerous. The abnormal keratinizing
cells are intensely reactive with glucose-
6-phosphate dehydrogenase. Ultrastruc-
tural changes of BD include decrease in
tonofilament-desmosomal attachments,
aggregated tonofilaments and nuclear
substance, and absence of keratohya- A B
line granules {1204}.

Differential diagnosis
Bowenoid solar keratosis differs from BD
by its clinically smaller size, exclusive
location on sun-exposed skin, and pres-
ence of superficial keratinocytic matura-
tion. Bowenoid papulosis is distin-
guished from BD by its clinical appear-
ance of multiple papular to coalescing
lesions on the anogenital areas, and the C D
typical microscopic salt and pepper dis- Fig. 1.23 Bowen disease. A Full thickness squamous cell atypia. B There is full thickness squamous cell
tribution of atypical keratinocytes and atypia with apparent sparing of the basal keratinocytes and hyperpigmentation of the basal keratinocytes.
mitoses in the affected cutaneous and C Full thickness squamous cell atypia with scattered bizzare keratinocytes. D Full thickness squamous cell
mucocutaneous lesions, as well as fre- atypia with marked nuclear pleomorphism.
quent HPV positive koilocytotic cells
{1790}. The pagetoid variant of BD is
sometimes difficult to distinguish from Genetics Bowenoid papulosis
extramammary Paget disease. In the lat- The atypical keratinocytes of BD contain
ter, mucicarmine, Cam 5.2 and CEA pos- large numbers of aneuploid cells {241}. Definition
itive tumour cells are present in the epi- Increased expression and mutation of Bowenoid papulosis is a clinicopatholog-
dermis, individually or in small nests, TP53 observed in lesions of BD suggest ical entity characterised by the presence
forming glandular structures at the der- that loss of normal TP53 tumour suppres- on the genitalia of solitary or multiple ver-
moepidermal junction. These features sor activity may be an important mecha- ruca-like papules or plaques with histol-
are absent in BD. The vacuolated cells in nism of oncogenesis in BD {375,1075, ogy resembling full thickness epidermal
BD contain glycogen and not mucin. In 1946}. Allelic deletion of one or more 9q dysplasia as seen in Bowen disease.
malignant melanoma in situ, the basilar chromosome markers has been detected
keratinocytes are replaced by neoplastic in occasional lesions of BD. However, no Synonyms
melanocytes. The presence of intercellu- deletion of 9p markers was seen {1866}. Multicentric pigmented Bowen disease,
lar bridges and prominent dyskeratotic There have been no clonal chromosomal multifocal indolent pigmented penile
keratinocytes are features favouring the abnormalities by cytogenetic analysis of papules
diagnosis of BD. Melanoma cells do not cell cultures from BD {1003}.
contain cytokeratins of 54 and 66 kilodal- Epidemiology
tons (kd); the reverse applies with the Prognosis and predictive factors Bowenoid papulosis occurs mainly in
cells in BD. Surgical excision with complete removal young individuals and although uncom-
may cure BD. The origin of BD from pilar mon the incidence is increasing. There is
Histogenesis outer root sheath cells at the sebaceous a male predominance.
It has been suggested that BD most like- gland level explains in part the high
ly originates from germinal cells of the recurrence rate, following treatment with Etiology
pilar outer root sheath and the pluripo- superficial curettage and desiccation, The etiopathogenesis of this condition
tential epidermal cells of the acrotrichi- topical fluorouracil, and X-ray. Invasive almost certainly favours linkage to
um. This concept is substantiated by the adnexal carcinoma may develop in human papillomavirus infection particu-
findings of various types of histologic dif- untreated plaques of BD of prolonged larly oncogenic types 16, 18, 33,35 and
ferentiation in carcinoma arising in BD duration following expansile growth. The 39. DNA sequences have been identified
{1120,1203,2016}. Using immunohisto- metastatic rate in these uncommon by various workers {908,1737,2113}.
chemical localization of keratins and tumours was 18% and fatality was Consequently in females there is a high-
involucrin, the atypical cells of BD exhib- observed in 10% of cases in a large case er incidence of abnormal cervical/vagi-
it a diversity of differentiation {1093}. series {1203}. nal smears both in affected patients and
in partners of men with penile lesions.
Whilst controversies regarding the bio-

28 Keratinocytic tumours
logical potential of bowenoid papulosis (VIN) III or penile intraepithelial neoplasia mutation of TP53 observed in lesions
exist, with the possibility of invasive (PIN) III by some pathologists {570}. suggest that loss of normal TP53 tumour
malignancy, in most cases the clinical There is loss of architecture. The base- suppressor activity is likely to be an
course is benign and some lesions ment membrane is intact. Mitoses are important mechanism of oncogenesis in
regress. frequent, sometimes with abnormal bowenoid papulosis. To date, there have
forms often in metaphase. Dyskeratotic been no clonal chromosomal abnormali-
Localization cells are also seen. Typical koilocytes are ties by cytogenetic analysis of cell cul-
Bowenoid papulosis was first described uncommon {908}. The stratum corneum tures from bowenoid papulosis.
as a condition affecting the groin {1438}. and granular cell layer often contain
It was later defined {1305,2447} as an small inclusion - like bodies which are Prognosis and predictive factors
entity involving the genitalia or perigeni- deeply basophilic, rounded and sur- Bowenoid papulosis appears in many
tal areas. Isolated cases of extragenital rounded by a halo. cases to remain benign {1790} and spon-
bowenoid papulosis have been taneous regression has occasionally
described {902,1147}. Differential diagnosis occurred; however, close follow up is
The basophilic bodies, together with the essential.
Clinical features numerous metaphase mitoses, are the
The lesions are usually asymptomatic features which suggest a diagnosis of
with variable clinical presentation: multi- bowenoid papulosis rather than Bowen
ple generally small, round fleshy disease itself.
papules, isolated or confluent (2.0-20
mm), with a smooth papillomatous sur- Histogenesis
face, sometimes with desquamation A study based on histomorphology and
resembling lichenoid or psoriasiform der- DNA ploidy analysis has suggested that
matoses. The colour of lesions can vary bowenoid papulosis is a form of low-
from pink to reddish-purple to brown / grade squamous cell carcinoma in situ
black. {269}. Electron microscopy has shown
structures resembling viral particles
Histopathology {1274,1790} within the granular layer.
The histological features demonstrate
epidermal atypia ranging from partial to Somatic genetics
full thickness atypia similar to in situ Many of the atypical keratinocytes of
squamous cell carcinoma i.e. Bowen dis- bowenoid papulosis not unlike Bowen
ease. On the genitalia changes may be disease, contain large numbers of aneu-
termed vulvar intraepithelial neoplasia ploid cells. Increased expression and

Bowen disease 29
Actinic keratosis C. James
R.I. Crawford
M. Martinka
R. Marks

Definition persistent, asymptomatic erythematous

A common intraepidermal neoplasm of lesions. Most measure less than 1 cm
sun-damaged skin characterized by vari- and are hyperkeratotic. Atrophic lesions
able atypia of keratinocytes. predominate on the face. Thickening and
tenderness may indicate the develop-
Synonyms ment of invasive carcinoma.
Solar keratosis
Epidemiology Most lesions are circumscribed <1cm
Actinic keratoses (AK’s) usually present scaly macules or slightly elevated
in older individuals. The fair-skinned, the papules or plaques, ranging from erythe-
freckled and those who do not tan easily Fig. 1.24 Actinic keratosis on the face, presenting matous to grey-brown with adherent yel-
as a group of irregularly shaped small papules.
are at increased risk. Lesions have low-brown scale. Some are larger, more
developed in areas of vitiligo {2023, irregularly shaped and pigmented
2564}. The rate is higher in men because of damaged keratinocytes in cells with {1128}, whilst others, particularly on the
of greater sun exposure {1049}. In the two TP53 mutations {1150,1396,1696, dorsal hands and forearms, are hyperk-
Australian Caucasian population, AK’s 2602}. Clonal proliferations of these cells eratotic or verrucous {244}. A keratin
are discovered in 40-60% of individuals form actinic keratoses and after further horn may be produced.
over 40 {789,1515}, rising to 80% in the genetic damage, invasive SCC may
seventh decade {1049}. Patients with develop. Ultraviolet light can act as an Histopathology
Rothmund-Thompson, Cockayne and initiator and promoter of carcinogenesis Six types of AK are described: hyper-
Bloom syndromes and xeroderma pig- {2602}. Epidermodysplasia verruci- trophic, atrophic, bowenoid, acantholyt-
mentosum are at increased risk {791}. formis–associated HPV types have been ic, pigmented and lichenoid {233,1446}.
discovered in AK’s after renal transplan- Most lesions reveal parakeratosis and
Etiology tation {2354}. hypogranulosis. Disordered keratinocyte
Both cumulative and intermittent sunlight maturation with cytologic atypia is pres-
exposure is implicated {790}. Ultraviolet Localization ent, including nuclear enlargement,
B (UVB) is the most harmful, but a sup- Sun-exposed areas are involved: face, hyperchromasia, pleomorphism, nucleo-
plemental effect of ultraviolet A (UVA) is ears, balding scalp, dorsal hands, fore- lar prominence, mitotic activity, dysker-
demonstrated {694}. AK’s are increased arms and lateral neck {2218}. atosis and cytoplasmic pallor. Grading
after PUVA therapy {11}. UVB induces as Keratinocyte Intraepidermal Neopla-
DNA thymidine dimer formation, which Clinical features sia (KIN I, II and III) in a manner similar to
can target TP53, with impaired apoptosis Patients commonly present with multiple that used for the uterine cervix {506} has

Fig. 1.25 Actinic keratosis. A There is focal parakeratosis, acanthosis and basal squamous atypia overlying a dense lichenoid inflammatory infiltrate. B Actinic ker-
atosis. There are elongated rete ridges with squamous cell atypia and focal acantholysis.

30 Keratinocytic tumours

Fig.1.26 Actinic keratosis. A Atrophic variant with atypical basal keratinocytes and focal parakeratosis. B Medium power magnification shows keratinocyte atyp-
ia in the stratum malpighii with a loss of polarity, nuclear enlargement, hyperchromasia, dyskeratosis, increased mitotic activity and parakeratosis. C Downward
prolongations and buds of atypical squamous cells does not indicate true stromal invasion. Note severe dermal solar elastosis and telangiectasia. D Acantholytic
variant with suprabasal acantholysis, squamous atypia, dyskeratosis and superficial follicular involvement.

been proposed, however, invasive SCC The hypertrophic variant shows acantho- Keratinocyte atypia aids distinction from
commonly arises from KIN I or II. sis, papillomatosis and conspicuous acantholytic dermatoses. Downward
Lesions in which impaired maturation hyperkeratosis with alternating paraker- extensions of the basal epidermis can
and atypia appear to involve the full epi- atosis {244}. Elongation of rete ridges, induce pseudoducts, and acantholysis
dermal thickness have been labelled dilated vessels and vertically oriented may spread along appendages.
“bowenoid actinic keratoses” (BAK) collagen bundles in the papillary dermis The pigmented variant shows increased
{1128}. Multinucleate keratinocytes and suggest superimposed lichenification. melanization of atypical keratinocytes
a verrucous architecture, can be seen in The atrophic AK variant is easily misdi- and dermal macrophages {1128}.
AKs in the setting of immunosuppression agnosed if the basal keratinocytic atypia The lichenoid variant has keratinocyte
{294,1856}. in a parakeratotic epidermis devoid of apoptosis and vacuolation, exocytotic
The abnormal keratinization often rete ridges is missed. Budding of the lymphocytes and a band-like superficial
involves the epidermis between spared basal epidermis and extension of atypia dermal lymphocytic infiltrate including
acrotrichia and acrosyringia, which in into adnexae are common. colloid bodies {2318}. The epidermis in
contrast retain columns of normal kera- The bowenoid variant is difficult to differ- early lesions is acanthotic, but more
tinization. Some lesions show spread into entiate from Bowen disease. Whilst some advanced regressing lesions are atroph-
the infundibular and isthmic segments of claim they are identical, others empha- ic with pigment incontinence.
follicles or less commonly along eccrine size the lack of full thickness atypia, less Keratinocyte atypia exceeding that
ducts {1835}. Dermal changes include defined edge, follicular sparing and expected in a reactive process differenti-
solar elastosis, an infiltrate of lympho- acrosyringeal involvement in BAK ates this lesion from benign lichenoid
cytes and plasma cells and increased {1128,2476}. keratosis.
vascularity. Inflammation is most frequent The acantholytic variant reveals clefting, The confident identification of early SCC
in lesions of the head and neck, particu- usually suprabasal, with varying acan- in an AK can be difficult {1158}.
larly the lips. tholysis and dyskeratosis {1409}. Detachment of individual irregular aggre-

Actinic keratosis 31
gates of keratinocytes from the epider- sion rate of the former {1350}. AK {791}. Metastases from invasive car-
mis, keratin pearl formation and exten- 69% of AK were aneuploid in one image cinomas arising in AK are infrequent if
sion of atypical squamous cells into the analysis DNA-cytometry study {241}. the lip is excluded, occurring in 0.5-3%
reticular dermis are helpful {1158,2476} Recurrent chromosomal changes are of such carcinomas {1459,1630}.
numerical (+7,+20) and structural,
Immunoprofile involving the distal long arm of chromo-
Keratin and involucrin distribution is sim- some 4,1p31,3p13 and the centromeric Arsenical keratosis
ilar to normal epidermis {1093} whilst region of chromosome 3 {1143}.
CD95 (Fas) is lost in two thirds of AK Definition
{741} and retinoid receptors are reduced Prognosis and predictive factors Arsenical keratosis is a precancerous
{2554}. Expression of E-cadherin/catenin Untreated AK have been reported to lesion occurring in patients exposed
and TP53 increases in the progression to develop into invasive SCC in 8-20% of (therapeutic, environmental or occupa-
invasive SCC {1770,2170}. patients {838}. AK’s are also risk markers tional) to arsenic {2109}. This is a clinico-
for basal cell carcinoma and melanoma pathological diagnosis. Arsenic is con-
Genetics {2023}. Individual AK’s can however be centrated in a variety of tissues, includ-
There is a 2-fold risk of AK in an stable for many years, and may regress ing skin, hair, and nails {49,421,2007,
Australian Caucasian population carry- after sun protection. One estimate has 2109}.
ing the glutathione-S-transferase null suggested a rate of malignant transfor-
genotype {386}, further increased by fair mation less than 0.1% yearly {1516, Epidemiology
skin and an inability to tan. 1517}. Older patients with multiple Lesions may occur after a latent period of
Around 50% of AK’s show TP53 muta- lesions followed over 10 years demon- 2 years, but usually take 20-30 years to
tions {1696,2602} and over-expression of strate a lifetime risk of progression manifest {2568}. A study of 262 exposed
cyclin D1 {2235} whilst independent acti- between 6-10% {641} whilst 14% of individuals revealed characteristic ker-
vation of HRAS is identified in 16% patients with >10 AK’s develop invasive atoses of the palms and soles in over
{2235,2307}. SCC within 5 years {1639}. Sixty percent 40% {49}. Other skin lesions include
The majority of TP53 mutations involve of invasive SCC’s have been proposed to melanosis, Bowen disease, squamous
single cytosine to thymine substitution develop from AK’s and, more recently, cell and basal cell carcinoma {421,2007,
{1396,1696,2307}. Progression of AK into contiguous AK has been identified in 2109}. Visceral cancers, particularly
invasive SCC may involve deletion of the 82.4-97% of SCC {1085,1517,1627}. involving the lung, and genitourinary
9p21 region of the p16 (CDKN2A) Clinically hypertrophic lesions reveal tract can also occur {49,421,2007,2109}.
tumour suppressor gene {1653}. invasive SCC in 36% {2290}. There is a high arsenic content in some
Loss of heterozygosity (LOH) at four or Some classify AK as a type of SCC drinking waters and naturopathic medi-
more loci has been demonstrated in {791,994,1442} rather than a precursor. It cines {1823,2007,2109}.
>50% of AK’s in a UK Caucasian popula- cannot however be proven that AK
tion {1913} and in just under 20% of inescapably progresses to invasive SCC. Clinical features
lesions in a Japanese group {1350}. PCR The hypothesis that AK requires further Arsenical keratoses begin as yellowish
microsatellite analysis has exposed loss genetic aberrations before the expres- verrucous papules, 4-10 mm in diameter.
on 17p(64%), 13q(52%), 17q(46%), sion of clinical malignancy, is plausible These typically occur on thenar emi-
9p(39%), 3p(31%) and 9q(22%) {1914}. {1810}. nences, lateral borders of palms, base or
The higher rate of LOH in AK than inva- Immune responses and adjacent normal lateral surfaces of fingers, soles, heels
sive SCC could reflect the low progres- keratinocytes modulate the behaviour of and toes {49}. A combination of mela-

Fig. 1.27 Arsenical keratosis. A Arsenical keratosis with vacuolation of the keratinocytes. B Arsenical keratosis showing acanthotic epidermis, some vacuolation
of the keratinocytes and dysplasia.

32 Keratinocytic tumours
Fig. 1.28 Arsenical keratosis. A .Arsenical keratosis with full thickness dysplasia, resembling Bowen disease. B Hyperkeratotic type.

nosis and multiple keratoses in non-sun- PUVA keratosis high doses of UVA to epidermal ker-
exposed areas in adults is highly sug- atinocytes. PUVA is used in the treatment
gestive of chronic arsenic exposure Definition of patients with psoriasis and other disor-
{2007}. PUVA keratosis is a form of keratosis that ders.
arises in response to PUVA therapy. Patients treated with long-term PUVA
Histopathology therapy are at increased risk for develop-
A spectrum of histological appearances Epidemiology ment of actinic keratoses and squamous
exists {49,421,2007,2109}. Lesions may There are no detailed studies on the true cell carcinoma.
show compact hyperkeratosis, acantho- frequency of actinic keratoses attributa-
sis, papillomatosis, hypertrophic actinic ble solely to PUVA, but estimates have Clinical features
keratosis-like lesions and a pattern varied from 2-5% {11,1057}. There are PUVA keratoses resemble actinic ker-
resembling seborrhoeic keratosis {2007, long term epidemiological data indicat- atoses. They occur on PUVA-treated
2109,2568}. Vacuolated cells in the ing increased risk of squamous cell car- skin.
Malpighian layer suggest arsenical ker- cinoma in patients on high dose PUVA,
atosis, but this is not a reliable criterion. recorded as 300 treatments or more Histopathology
Arsenical keratoses may spare adnexae, {2265}. More recently, phototherapy PUVA keratoses are said to have less
similar to solar-related keratoses {2109}. using a narrow band of ultra-violet radia- keratinocytic atypia than sunlight-
Bowenoid arsenical keratoses may dis- tion in the UVB range has been used with induced actinic keratoses {2417}.
play vacuolated, dyskeratotic cells with increasing frequency, substituting for
abnormal mitoses and multinucleated PUVA therapy in a substantial proportion
giant cells {1823}. Arsenical-induced of patients {2264}. There are no long-
pigmentation comprises melanosis and term data published as yet on the risk of
dermal arsenic deposition {49}. actinic keratoses and squamous cell car-
cinoma in patients receiving narrow band
Histogenesis UVB phototherapy.
The exact nature of arsenical carcino-
genesis is unclear. Etiology
Arsenic and its metabolites are shown to PUVA is a photochemotherapy using
cause chromosomal abnormalities and either an oral or topical psoralen product
gene amplification {421,1823,2109}. in association with long-wave ultraviolet
Human papillomavirus may be a co-fac- radiation (UVA) {374}. This treatment is
tor in the pathogenesis {820}. locally immunosuppressive, and delivers

Actinic keratosis 33
Verrucas J.N. Breuer-McHam
M. Tommasino
C.A. Harwood
D. Weedon
M. Martinka
C. Gross

Definition prevalence of cutaneous warts is up to mous intraepithelial lesions {288}. HPV

Verrucas or condyloma are common, 10% in children 2-12 years old, occurring infection occurs by direct contact with
contagious, epithelial tumours caused by with equal frequency in both sexes and individuals who harbour clinical or sub-
human papillomaviruses (HPV). regressing spontaneously in 1-2 years clinical HPV-associated lesions, or indi-
{1282}. HPV infection of the lower genital rectly via contaminated surfaces and
Synonyms tract is one of the most common sexually objects. Autoinnoculation from the lesion
Verrucae vulgares (common warts); ver- transmitted diseases among adolescents to surrounding skin is frequently
rucae palmares (deep palmar or hand and adults. Most benign genital warts observed {1282,1641}. Impaired cell-
warts); verrucae plantares (deep foot resolve spontaneously and are usually mediated immunity is associated with
warts, myrmecia); superficial plantar caused by HPV types 6 and 11, which markedly increased incidence of viral
warts (mosaic warts); verrucae planae are considered low-risk types as they are warts, for example after organ transplan-
(plane warts, flat warts); condylomata rarely found in high-grade genital dys- tation, HIV infection, chronic lymphocytic
acuminata (genital warts); condylomata plasias and almost never in invasive can- leukaemia and lymphoma {1641}.
plana (flat cervical condylomas, plane cer. However, persistent infection with
condylomas). high-risk types, predominantly HPV-16 Etiology
and 18, represents the most important Verrucas are caused human papillo-
Epidemiology risk factor for development of anogenital maviruses (HPV), a large family of DNA
HPVs are widespread in nature and the malignancies and their precursors, squa- viruses which are epitheliotropic and
induce benign and malignant epithelial
tumours in skin and mucosa. The defini-
Table 1.01
Clinical manifestations and associated HPV types
tion of an HPV type is based upon
nucleotide sequence homology; more
Frequently Less frequently than 95 HPV types have been fully char-
Skin lesions detected HPV detected acterized to date, and additional partial
DNA sequences have been obtained
Common, palmar, plantar, mosaic 1,2,4 26,27,29,41,57,60,63,65 indicating the existence of at least 130
HPV genotypes {188,605,1738}.
Flat warts 3,10 28,29
HPV structure and lifecycle {2283,
Butcher’s warts 2,7 1,3,4,10,28 2608,2609}: HPVs are 55 nm diameter,
non-enveloped, double-stranded DNA
Epidermodysplasia verruciformis 3,5,8,10 9,12,14,15,17,19-25,36-38, viruses. The icosohedral capsid sur-
46,47,49,50 rounds the viral genome which is approx-
imately 8kb in length and is composed of
EV-squamous cell carcinoma 5,8 14,17,20,47 the upstream regulatory region contain-
ing the origin of replication and control
Periungual SCC 16 34,35 elements for transcription and replica-
tion, the early region containing the open
Other SCCs EV HPV types Other cutaneous types
reading frames for viral genes that are
principally expressed early in the papillo-
Mucosal lesions mavirus lifecycle (E1, E2, E4, E5, E6, E7),
and the late region encoding the viral
Condyloma acuminata 6,11 42-44,54,55,70, 2,27,57 capsid proteins (L1, L2). Productive
infection and induction of hyperprolifera-
High grade intraepithelial neoplasia tion are initiated when the virus enters
(including cervical tumours, bowenoid papulosis) 16,18 31,33-35,39,40,51-59,61,62 proliferating basal epithelial cells, and
this requires abrasion or other minor trau-
Buschke-Lowenstein tumours 6,11
ma to the epithelium. The HPV lifecycle is
Recurrent respiratory papillomatosis,
only completed in fully differentiated
conjunctival papillomas 6,11 squamous epithelia since the pro-
gramme of viral gene expression is inti-
Focal epithelial hyperplasia (Heck’s disease) 13,32 mately linked to the differentiation state
of keratinocytes. HPV does not encode

34 Keratinocytic tumours
the enzymes required for transcription or filamentous network by viral E4 proteins. Localization
replication of viral DNA and therefore is Host immune response {2246,2608}: Warts can occur on any skin or mucosal
entirely dependent on subverting cellular Persistent papillomavirus infections are surface. Certain HPV subtypes cause
proteins for these functions. In particular, common, indicating that HPVs have specific kinds of warts and show special
in HPV types 16 and 18, proteins E6 and evolved mechanisms to evade immune affinity for particular body locations.
E7 promote continued cell cycling of surveillance. There is no viraemic phase, Subtypes causing common warts are
suprabasal epidermal cells by abroga- low levels of viral proteins are expressed found on the hands, fingers, and palms.
tion of the functions of TP53 and pRb in the basal cell layer, and extensive viri- Periungual subtypes are often seen in
respectively. HPV genomes are thereby on production only occurs in the more nail biters. Verruca plantaris is seen on
amplified to high levels during vegetative immunologically privileged terminally dif- the sole of the feet. Condylomata acumi-
viral replication for assembly into infec- ferentiated layers. However, a successful nata lesions (genital HPV infection)
tious virions after encapsulation by L1 immune response is eventually generat- appear on the vulva, cervix, perineum,
and L2 proteins in the granular layer and ed in most cases, since two thirds of anus, or penis. Scrotal condylomata are
above. Virus assembly does not lyse ker- cutaneous warts regress spontaneously very rare and only seen in 1% of HIV pos-
atinocytes, but rather the infectious virus within 2 years and multifocal lesions itive males.
is shed with desquamating cornified often regress concomitantly. Cell mediat-
cells, and viral release is facilitated by ed immune responses appear to be pri-
disruption of the keratinocyte intracellular marily responsible.

Table 1.02
Correlation between cytopathological changes of verrucas and causal HPV types

Clinical manifestation HPV typesa Epidermal changesb Cytopathic effect (location)

Verruca vulgaris
2 Prominent Eccentric nucleus; condensed heterogeneous
keratohyaline granules (granular)

4 Prominent; endophytic Large, vacuolated keratinocytes with no keratohyaline

granules and small, peripherally located, ‘signet ring’
nuclei (granular)

7 (Butcher’s wart) Prominent Central, small, shrunken nuclei within proliferating

rete ridges (granular)

1 (Myrmecia) Prominent, endophytic Vacuolated cells with large, eosinophilic keratohyaline
granules forming ring-like and sickle-like figures. Basophilic
nuclear inclusions (spinous, granular)

60 (Ridged wart) Acanthosis and mild Eosinophilic, homogeneous and solitary inclusions
papillomatosis; endophytic

65 (Pigmented plantar wart) Prominent; endophytic Eosinophilic, homogeneous and solitary inclusions

63 Prominent; endophytic Intracytoplasmic, heavily stained keratohyaline material with

filamentous inclusions that encase the vacuolated nucleus

Verruca Plana 3 Subtle; no parakeratosis Central, pyknotic, strongly basophilic ‘bird’s eyes’ nuclei
and basket-weave like (upper spinous and granular)
appearance of stratum corneum

Epidermodysplasia 5 Nests of large, clear cells; Basophilic cytoplasm containing keratohyaline granules of
verruciformis stratum corneum loose with various shapes and sizes; clear nucleoplasm (upper
basket-weave like appearance spinous and granular)

Condyloma acuminata 6,11 Marked acanthosis, some Less prominent vacuolisation of granular cells
papillomatosis and hyperkeratosis

a Most common associated HPV genotype

b Epidermal changes comprise papillomatosis, compact hyperkeratosis, focal parakeratosis, hypergranulosis, acanthosis.

Verrucas 35
Clinical features and correlation with clinical infections are more common than HPV-4 and HPV-7. In children, HPV-6
viral genotyping visible warts {1282}. Genital warts are and/or HPV-11 are rarely found. Other
Cutaneous and mucosal HPV types form generally caused by low-risk mucosal HPV types have rarely been implicated,
two distinct groups that infect skin or HPV types rather than the high-risk types usually in immunosuppressed individuals
mucosa, although viral tropism is not associated with anogenital neoplasia {106}.
absolute {605}. Clinical manifestations {605}. Bowenoid papulosis (section
depend on the HPV type involved, the 1.5.01) may clinically resemble genital Localization
anatomical location and the immune sta- warts, but histologically resembles squa- Common warts may be solitary or multi-
tus of the host {1282}. mous cell carcinoma in situ and contains ple, and they are usually found on
Cutaneous infections: In general, classifi- high-risk HPV types. Giant condyloma exposed parts, particularly the fingers
cation of warts is based on morphology acuminata (Buschke-Lowenstein tumour) and on the dorsum of the hands.
and anatomic localization and cutaneous may also resemble genital warts but is an
warts have traditionally been classified anogenital verrucous carcinoma har- Clinical features
as verruca vulgaris or common warts, bouring low -risk HPV types {2476}. Oral They are hard, rough-surfaced papules
palmoplantar warts, including superficial warts are also associated with HPV types that range in diameter from about
and deep types, verruca plana or plane 6 and 11 and focal epithelial hyperplasia 0.2:1.5-2.0 cm. New warts may some-
warts and epidermodysplasia verruci- (Heck’s disease) resembling gingival, times form at sites of trauma (Koebner
formis (EV). Recent studies suggest that buccal and labial flat warts or condylo- phenomenon).
histological and clinical characteristics of mata usually harbours HPV 13 or 32
warts are mainly determined by viral {2476}. Histopathology
genotype, indicating that HPV typing Common warts show marked hyperker-
may allow a more accurate classification. atosis and acanthosis. There are out-
However, the use of highly sensitive PCR Verruca vulgaris growths of epidermis presenting as slen-
techniques for HPV detection and geno- der spires in filiform warts or blunter dig-
typing has highlighted the presence of a Definition itate processes in other variants.
greater diversity of HPV types than was Verruca vulgaris is a benign, squamous Columns of parakeratosis overlie the
previously appreciated {975}. These indi- papillomatous lesion caused by infection papillomatous projections. There may be
viduals often harbour multiple HPV types, with the human papilloma virus (HPV). haemorrhage into these columns.
particularly epidermodysplasia-verruci- Hypergranulosis is present where the
formis (EV)-HPV types. These HPVs were Synonym cells contain coarse clumps of kerato-
previously thought to occur only in the Common wart. hyaline granules. Koilocytes (large vac-
context of the rare genodermatosis EV, uolated cells with small pyknotic nuclei)
characterised by infection with unusual, Epidemiology are present in the upper malpighian layer
widespread, cutaneous warts and asso- Verruca vulgaris occurs predominantly in and the granular layer. Small amounts of
ciated with increased risk of non- children and adolescents, although keratohyalin may be present in the cyto-
melanoma skin cancers harbouring EV- adults are also frequently infected. They plasm of these cells. There is often some
HPV types on ultraviolet radiation have been found in up to 20% of school inward turning of the elongated rete
exposed sites {1492}. There is also students {1262}. Clinically detectable ridges at the edges of the lesion.
mounting evidence that EV-HPV types verrucae develop from a few weeks to 18 Tricholemmal differentiation and squa-
play a cofactor role with UVR in NMSCs months after inoculation {1691}. mous eddies may be seen in old warts.
arising in immunosuppressed individuals Dilated vessels are often found in the
{974}. Etiology core of the papillomatous projections. A
Mucosal infections: Over 25 HPV types Common warts are preferentially associ- variable lymphocytic infiltrate is some-
are recognized to infect anogenital and ated with HPV-2, but they may also be times seen, and this may be lichenoid in
aerodigestive mucosa {605}, and sub- caused by other types such as HPV-1, presumptive regressing lesions.

Prognosis and predictive factors

Most warts are only a cosmetic problem.
Rarely, Bowen disease or squamous cell
carcinoma may develop in a common
wart, usually in immunocompromised
patients {1611}. Thrombosis of superfi-
cial vessels, haemorrhage and necrosis
of the epidermis are rarely seen in
regressing common warts.

Fig. 1.29 Verruca vulgaris showing the Koebner Fig. 1.30 Verruca vulgaris. There is hyperkeratosis,
phenomenon. Note the linear arrangement of the papillomatosis and interning of the elongated rete
lesions as a consequence of scratching. ridges.

36 Keratinocytic tumours
Fig. 1.31 Verruca plantaris. A, B Plantar wart. Note papillomatosis, acanthosis, hyperkeratosis, viral cytopathic changes.

Verruca plantaris Clinical features nent eosinophilic intracytoplasmic inclu-

Plantar warts are sharply defined, round- sions. The nuclei are retained in the stra-
Definition ed lesions, with a rough keratotic sur- tum corneum and appear as basophilic
Verruca plantaris is a benign, human face, surrounded by a thickened horn. round bodies surrounded by a clear halo
papillomavirus (HPV)-induced epithelial They tend to grow into the foot and are {505,1055,1214}.
proliferation occurring on the sole of the covered by black dots representing Regression of palmo-plantar warts is
foot. It is characterized by the formation thrombosed capillaries {505,648,1214}. often associated with thrombosis of
of thick, hyperkeratotic lesions {505,648, They do not retain the normal fingerprint superficial vessels, haemorrhage and
1214}. lines of the feet, as calluses (corns) do. necrosis of the epidermis and a mixed
They often occur in multiples, and can be inflammatory cell infiltrate.
Synonyms painful {1055,2390}. They are traditional-
Plantar wart, deep foot warts, myrmecia ly divided into the superficial warts Pathogenesis
(mosaic), which are ordinary verrucae, HPV is the established cause.
Epidemiology and deep warts (myrmecia). Several Correlations between the variety of wart
Plantar warts are most common in chil- other variants have been recently and the HPV type are as follows:
dren and young adults; possibly described {1055,1214,1556}.
because of immaturity of the immune
system or sport-related repetitive micro- Histopathology
trauma. They are most frequent over The mosaic–type shows acanthosis,
pressure points {505,648}. Particularly in papillomatosis, hyperkeratosis, vacuolat-
children they may spontaneously regress ed cells (koilocytes) in the upper
within a few months, but in adults and Malpighian layer, vertical tiers of paraker-
immunocompromised patients they can atotic cells and clumped keratohyaline
persist for years. Rarely chronic lesions granules. Myrmecia are characterized by
are associated with the development of an endophytic proliferation of rete ridges
verrucous carcinoma {594}. covered by thickened keratin and promi-

Fig. 1.34 Flat wart.

Fig. 1.32 Verruca plantaris on the volar surface of Fig. 1.33 Plantar wart (myrmecia type). Nuclei are Fig. 1.35 Multiple flat warts on the chin of a young
the toe. Clinically, the lesion was painful. retained in the stratum corneum as basophillic female.
round bodies surrounded by a clear halo.

Verrucas 37
Fig. 1.36 Flat wart in a patient with epidermodys- Fig. 1.37 Flat wart. There are superficial vacuolated keratinocytes with perinuclear clearing.

Deep plantar wart (myrmecia) - HPV1, suppression are possible predisposing cytosis, vacuolated keratinocytes with
HPV63 {505,2390}. factors {778,909,2262}. perinuclear clearing around centrally
Common and mosaic wart - HPV2, HPV4 located nuclei (so-called “birds-eye
{1055} Localization cells”) and hypergranulosis.
Endophytic common wart - HPV4 {1055} Most lesions are located on the back of Flat wart-like lesions can be encountered
Ridged and flat warts (associated with or the hands and fingers, distal forearm, in patients with epidermodysplasia verru-
without cyst, respectively) - HPV60 {505, lower leg and face. ciformis. These lesions may show typical
1055,1214,2390} blue-grey cytoplasm {907,909,1491}.
Large plantar wart - HPV66 {1556} Clinical features Regression of plane warts is accompa-
Flat warts generally are smaller than nied by superficial lymphocytic infiltrate
common warts and typically develop as in the dermis with exocytosis and single
Verruca plana small round to oval epidermal papules epidermal cell apoptosis {2476}.
measuring 1-4 mm in diameter. Lesions
Definition are mostly skin-coloured with a smooth Prognosis and predictive factors
Verruca plana are benign, HPV-induced, and flat surface, but may be hyperpig- Flat warts commonly persist for several
slightly elevated, flat-topped, smooth mented. The number ranges from one to years. Due to immunologic rejection in
papules. several hundred and the distribution is some long-standing cases, lesions have
asymmetric, sometimes linear (Koebner disappeared almost from one day to the
Synonyms phenomenon). next showing some local inflammation
Flat wart, verruca plana juvenilis. without leaving a scar. There are no
Histopathology reports regarding recurrences in such
Epidemiology Histology reveals a loose hyperkeratosis cases. In other cases warts lose evi-
Verruca plana are relatively common. with basket-weave-pattern but little or no dence of viral cytopathic change and
Children, adolescents and young adults papillomatosis as in verruca vulgaris. persist as localized verrucous epidermal
are most frequently affected. There is plate-like epidermal hyperplasia hyperplasia {909}.
of about twice the thickness of the sur-
Etiology rounding normal epidermis with com-
HPV types 3 and 10 are most commonly pressed papillae but dilatation and tortu-
associated with verruca plana. Minor osity of capillaries in the papillary dermis.
trauma, atopic dermatitis and immuno- Superficial epidermal layers show koilo-

38 Keratinocytic tumours
Acanthomas D. Weedon
E. Haneke
R.M. Williamson
G.F. Kao
M. Martinka R.E. Wilentz
G.W. Elgart M. Morgan
R.J. Mortimore S. Chimenti
C. Gross L.L. Yu

Definition Etiology normal and intracytoplasmic amorphous

Acanthomas are benign tumours of epi- The etiology remains unknown but trau- eosinophilic bodies i.e. epidermolytic
dermal keratinocytes. The proliferating ma {2033}, sun exposure {2298} and hyperkeratosis {14}.
keratinocytes may show normal epider- PUVA {1677} have been proposed as
moid keratinization or a wide range of causes of disseminated epidermolytic Genetics
aberrant keratinization, which includes acanthoma. Based on patterns of keratin expression
epidermolytic hyperkeratosis (epider- determined by immunohistochemical
molytic acanthoma), dyskeratosis with Localiz.ation techniques, a somatic mutation involving
acantholysis (warty dyskeratoma) or They can occur at any skin site and may K1 and K10 genes has been postulated
acantholysis alone (acantholytic acan- involve oral or vaginal mucosa {515, {515}.
thoma). Seborrhoeic keratosis, melano- 601,1869,2151}. Patients with disseminated disease may
acanthoma, clear cell acanthoma, large also have germline mutations, with off-
cell acanthoma and keratoacanthoma all Clinical and macroscopic features spring at risk for congenital ichthyosiform
fulfil the criteria for an acanthoma. Epidermolytic acanthomas are generally erythroderma/generalized epidermolytic
asymptomatic, flat or elevated keratotic hyperkeratosis.
papules 2-12 mm in diameter {515,601,
Epidermolytic acanthoma 1291,1628,1677,1712,1869,2033,2151,
2298}. Lesions may be solitary, multiple Warty dyskeratoma
Definition (localized to a region), or disseminated
A benign tumour presenting as solitary or {515}. Definition
multiple discrete lesions and demonstrat- Warty dyskeratoma is a benign papulo-
ing the characteristic histologic features Histopathology nodular lesion characterized by an endo-
of epidermolytic hyperkeratosis {1628, Epidermolytic acanthoma is charac- phytic proliferation of squamous epitheli-
2151}. terised by compact hyperkeratosis, per- um typically occurring in relation to a fol-
inuclear vacuolisation of the cells of the liculosebaceous unit and showing promi-
Epidemiology stratum Malpighii sparing only the basal nent acantholytic dyskeratosis.
The reported age range is 3-72 years layer, indistinct reticulate cell boundaries
with a slight male predominance and var- and hypergranulosis with larger Synonyms
ious racial groups affected {515}. basophilic keratohyaline granules than Isolated dyskeratosis follicularis
Follicular dyskeratoma

Warty dyskeratoma occurs mostly in mid-
dle aged to elderly adults {1166}.

There are no known etiological factors. A
recent study showed no evidence of HPV
in 13 cases using PCR {1166}.

The head and neck region is most com-
monly involved {873,1166,2306,2321}.
Cases arising in oral {869} and laryngeal
{1185} mucosa and in a subungual {147}
location have been reported. It has been
suggested that lesions arising in sites
devoid of hair follicles maybe a separate
entity {1166}.

Fig. 1.38 Epidermolytic acanthoma. This lesion shows hypergranulosis and marked cytoplasmic vacuoliza- Clinical features
tion with clumps of eosinophilic material, sparing the basal layer. Most lesions are solitary flesh coloured to

Acanthomas 39
brown papules, nodules or cysts with an blance to that seen in several vesiculob- Lentigo simplex
umbilicated or pore-like centre or central ullous disorders {320,1566,1885,2476}.
keratin plug {873,1166}. Most are 1- Definition
10mm in size {873}. Occasionally the Epidemiology Lentigo simplex is characterized by a
lesions are multiple {121,2306}. In the 31 cases reported by Brownstein clinically flat epidermis with microscopic
{320}, the patients ranged in age from acanthosis and highly localized well-cir-
Histopathology 32-87 years. The median age was 60 cumscribed pigment on sun exposed
Warty dyskeratoma is a well-demarcated years; the male to female ratio was 2:1. skin.
endophytic lesion characterized by
prominent acantholytic dyskeratosis. Etiology Synonyms
This results in suprabasal clefting with Although it is known that immunosup- Solar lentigo, actinic lentigo, “ink spot”
formation of villi which protrude into a pression increases the incidence of cuta- lentigo and lichen planus like keratosis.
lacuna. There is typically abundant ker- neous neoplasms, the role of impaired
atin present within the centre of the pro- immune surveillance resulting in acan- Epidemiology
liferation forming a plug {829,873,1166, tholytic acanthoma is speculative {1885}. Lentigines are common pigmented
2306}. Keratin pearls are commonly seen lesions most frequently seen on the sun-
as are small cysts lined by infundibular Localization exposed skin of light skinned individuals.
type epithelium {1166}. Mitotic figures Truncal skin, i.e., back, chest, or flank, is
are commonly identified and may most commonly involved, followed by Localization
exceed 5 per HPF {1166}. extremities, neck, groin, axilla, ear, scro- These lesions occur essentially only on
Three architectural variants have been tum and shoulder. skin or mucosa and spare the palms and
described namely cup-shaped, cystic soles. There is relative sparing of sun-
and nodular and combinations of these Clinical features protected areas, but some lesions may
may occur {1166}. There may be an epi- Acantholytic acanthoma is a solitary, ker- occur in these sites.
dermal collarette present and the sur- atotic, asymptomatic to occasionally pru-
rounding epidermis may show papillo- ritic papule or nodule. Multiple lesions Clinical features
matosis, hypergranulosis and hyperpla- have been recorded in a renal transplant Lentigines are well-circumscribed mainly
sia {1166}. A connection to folliculoseba- patient {1885}. flat (macular) localized collections of pig-
ceous structures is commonly demon- ment. The lesions are common and are
strable {873,1166}. Macroscopy ubiquitous in light skinned individuals.
The stroma often shows a characteristic The scaly, flesh-coloured, hyperkeratotic Most are somewhat randomly distributed
appearance with dense collagen or growths range in size from 0.5-1.2 cm. on sun-exposed skin. The presence of
fibroblasts and focal intrastromal clefts. many lesions may raise the consideration
There may be an associated mixed Histopathology of a syndrome, particularly when there is
inflammatory cell infiltrate {873,1166, The tumour shows a well-defined area of extensive involvement of the lips. Peutz-
2321}. papillomatous epidermal hyperplasia. Jeghers syndrome is the presence of
There is hyperkeratosis with prominent numerous lentigines associated with mul-
Differential diagnosis acantholysis involving multiple levels of tiple hamartomatous gastrointestinal
Comedonal Darier disease shows identi- the epidermis. Suprabasal or subcorneal polyps {893}.
cal histological features and is differenti- clefts with some dyskeratotic cells (corps
ated on clinical grounds {623}. ronds and grains) and occasional villi are Macroscopy
Familial dyskeratotic comedones is a noted. The upper dermis contains a vari- Individual lesions may be smooth-
rare condition which tends to spare the able perivascular lymphohistiocytic and edged, but many have an irregular out-
scalp and face and shows less marked occasional eosinophilic infiltrate. line. Most appear entirely uniform in
acantholysis and dyskeratosis than warty colour and range from light tan to brown
dyskeratoma {941}. Differential diagnosis to black. While lesions may approach 1
Acantholytic acanthoma must be distin- cm in greatest dimension, nearly all clini-
Histogenesis guished from other acantholytic disor- cal lesions are 1-5 mm.
It has been recently suggested that this ders and from various acanthomas. In the large cell acanthoma variant, the
lesion is a follicular adnexal neoplasm Pemphigus, Grover disease, and Hailey- tumours are macroscopically very deeply
{1166}. Hailey disease are disorders with more pigmented and may simulate malignant
extensive clinical papulovesicular erup- melanoma in situ.
tions. Lichen planus like keratoses have a high-
Acantholytic acanthoma Epidermolytic acanthoma shows epider- ly variable appearance and may show
molytic hyperkeratosis, and no acanthol- pink, orange, or rust coloured hues. Most
Definition ysis is present. Clear cell acanthoma are minimally raised from the skin sur-
Acantholytic acanthoma is a rare benign contains numerous pale cells, with abun- face and have a paving stone outline that
epidermal tumour. The lesion displays a dant intracytoplasmic glycogen, which is is frequently polygonal rather than round-
striking characteristic microscopic fea- absent in acantholytic acanthoma. ed {677}.
ture of acantholysis that bears resem-

40 Keratinocytic tumours
All lentigines demonstrate a sharply cir-
cumscribed focus of epidermal hyper-
plasia. The tumours are strikingly
melanized, and many retain residual
melanin in the overlying stratum
corneum. This pigment occasionally sim-
ulates parakeratotic nuclei seen in der-
matitis, a feature referred to as “pigment-
ed parakeratosis”. Fig. 1.39 Pigmetned seborrhoeic keratosis. There are elongated interlocking retes consisting of a prolifera-
While clinically macular, the typical lesion tion of bland and pigmented basaloid and squamous cells with formation of pseudo horn cysts
of lentigo simplex demonstrates a specif-
ic form of epidermal hyperplasia charac-
terized by elongate rete ridges with
somewhat club shaped or bulbous ends.
This appearance is characteristic of
other settings of epidermal hyperme-
lanization, such as in melanocytic nevi.
However, it is so typical of lentigines that
in every circumstance where found, this
form of epidermal hyperplasia is referred
to as lentiginous epidermal hyperplasia.
In most circumstances where it is seen,
the underlying papillary dermis demon-
strates a variable amount of eosinophilic
collagen deposition (or fibrosis). This
may imply that the epidermal prolifera- Fig. 1.40 Pigmented reticulated seborrhoeic keratosis. There are slender elongated interlocking rete ridges
tion requires a scar like response in the with hyperpigmentation and no squamous cell atypia, accompanied by focal pseudo horn cyst.
underlying dermis. However, inflamma-
tion is an inconstant feature in these
lesions {277,1634}. but may relate to the marked accumula- Seborrhoeic keratosis
Because of the histologic similarity to the tion of melanin pigment {277,1033,1959}.
epidermis of melanocytic nevi, lentigines A final variant is the lichen planus like Definition
are defined partially by what is absent in keratosis. While some authors maintain Seborrhoeic keratoses are benign hyper-
the tumours: namely nevomelanocytic that a variety of lesions may develop into plastic tumours of epidermis which are
nests. The presence of even rare nests is these lichenoid proliferations, most con- more common in older individuals.
sufficient to separate the diagnosis as cur that a large proportion begin as
lentiginous junctional nevus (or “jenti- lentigines. Several lines of evidence Synonyms
go”). point to this origin and have been Seborrhoeic wart, senile wart, stucco
Thus, to make a diagnosis of lentigo the reviewed. Histologically, these lesions keratosis, melanoacanthoma.
requisite features are: localized lentigi- often suggest a solitary lesion of lichen
nous epidermal hyperplasia, marked epi- planus as they were initially described. Epidemiology
dermal hypermelanosis, and the lack of Most demonstrate hypergranulosis and a Seborrhoeic keratoses are the most com-
nevomelanocytic nests. In fact, despite band like superficial infiltrate but unlike mon of the cutaneous neoplasms and
the remarkable melanization of the routine lichen planus they may show occur in the majority of elderly Caucasian
tumour, increased numbers of melano- overlying parakeratosis or an inflamma- patients. These lesions are by no means
cytes are not found in lentigines. tory infiltrate which contains a mixture of limited to Caucasians, but are present in
Two clinical variants are known: large cell inflammatory cell types with some neu- numerous older individuals of any race.
acanthoma and lichen planus like kerato- trophils or eosinophils. Careful evaluation The lesions are unusual in children and
sis. In large cell acanthoma, the pres- of most lesions demonstrates some even young adults are rarely affected.
ence of a localized proliferation of larger- residual lentigo simplex and pigment Identical histological features are seen in
than-normal keratinocytes with marked within dermal melanophages {1373}. certain epidermal naevi.
melanization is seen. These lesions are There is no appreciable sex predilection.
strikingly dark and are often clinically Differential diagnosis In part due to the very widespread inci-
highly suspicious for malignant mela- The separation between seborrhoeic ker- dence of the lesion, most cases are spo-
noma. atosis and lentigo is somewhat arbitrary, radic although several syndromes are
The other characteristic histologic fea- but most authors describe the epidermis associated with seborrhoeic keratosis.
ture of this variant is the larger than nor- as flat in lentigo simplex while the skin Recent studies support the long held
mal appearance of the keratinocytes. surface is clearly raised in seborrhoeic belief that seborrhoeic keratosis is a
The reason for this feature is unknown, keratosis. clonal process in the skin {1679}.

Acanthomas 41
Fig. 1.41 Pigmented seborrhoeic keratosis. A and B There are elongated interlocking retes consisting of a proliferation of bland and pigmented basaloid and squa-
mous cells with formation of pseudo horn cysts

Clinical features trointestinal origin, but lymphomas and collections or nests of keratinocytes with-
Seborrhoeic keratoses are slightly leukaemias have also been reported. It in the thickened epidermis. These foci of
raised, tan to brown or black papules. should be emphasized that some enlarged keratinocytes arranged in cir-
Sun exposed skin is especially affected, authors dispute the syndrome entirely cular collections are suggestive of the
but lesions may be present on any site of and favour a coincidental association epidermal collections seen in some
the skin except for palms or soles. They due to the high frequency of seborrhoeic cases of in situ squamous carcinoma,
often have a “stuck on” appearance and keratoses in the elderly patients {955, but lack the cytological atypia inherent in
may be easily removed. Irritated lesions 2110}. malignant neoplasms.
often demonstrate a crust and prominent
hyperkeratosis which diminishes the visi- Histopathology Irritated seborrhoeic keratosis
bility of the epidermal pigment. Thus, Seborrhoeic keratoses are well-defined There is a heavy lichenoid inflammatory
many of these irritated seborrhoeic ker- proliferations of epidermal keratinocytes cell infiltrate in the upper dermis.
atoses are pink to red and quite scaly. which may be endophytic, exophytic or Apoptotic keratinocytes are usually quite
Many of these lesions appear more flat. There are seven major types of seb- numerous. Features of the hyperkeratotic
smooth-surfaced and are mistaken for orrhoeic keratosis: type (see below) may also be present.
basal cell carcinoma clinically. Sometimes there is a heavy inflammatory
While most seborrhoeic keratoses are Acanthotic (common) seborrhoeic cell infiltrate, including neutrophils, which
uniform in colour, speckled examples are keratosis may not have lichenoid features.
common. Pigmented seborrhoeic ker- The acanthotic type is composed of Squamous eddies are often present in
atoses may be mistaken clinically for broad columns or sheets of basaloid or the epidermis.
malignant melanoma. There is some cor- squamoid cells with intervening horn
relation between the many described cysts. There may be varying degrees of Hyperkeratotic seborrhoeic keratosis
histological variants of seborrhoeic ker- hyperkeratosis, papillomatosis and acan- This variant shows varying degrees of
atosis and the clinical appearance of the thosis. hyperkeratosis, papillomatosis and acan-
tumour. thosis. Some cases show inflammatory
Keratoses are generally very well circum- Reticulated seborrhoeic keratosis features similar to the irritated variant.
scribed clinically. Usual lesions are oval This common variant is often sampled
in configuration, but linear or unusually histologically because clinical examples Flat seborrhoeic keratosis
shaped lesions are common. are frequently deeply pigmented. They There is mild hyperkeratosis, often mild
Dermatosis papulosa nigra appears to form a net like or retiform pattern of acan- basal pigmentation (‘dirty feet’) and only
be a form of multiple seborrhoeic ker- thosis. minimal acanthosis. There are no horn
atoses of the face seen primarily in cysts. The cells contrast with those of the
patients of African descent. This condi- Pigmented seborrhoeic keratosis adjacent normal epidermis by being
tion is not known to be associated with Pimented seborrhoeic keratoses are in more compact.
any type of internal malady {658}. every way similar to usual seborrhoeic
keratoses, but in addition demonstrate Immunoprofile
Leser-Trélat syndrome pronounced epidermal melanin pigment. All studies confirm the presence of ker-
This syndrome is the rapid onset of mul- atins throughout the tumour. Some stud-
tiple pruritic seborrhoeic keratoses asso- Clonal seborrhoeic keratosis ies have also demonstrated the pres-
ciated with malignancy. The tumours Clonal seborrhoeic keratosis is an unusu- ence of carcinoembryonic antigen (CEA)
associated have primarily been of gas- al variant, which demonstrates whorled {314,319,665}.

42 Keratinocytic tumours
ally all layers of the lesion. The ker-
atinocytes are rich in melanin granules.

Clear cell acanthoma

Clear cell acanthoma (CCA), is a benign
epidermal neoplasm characterized by
the presence of glycogen-rich clear/pale

Degos acanthoma, pale cell acanthoma.

It is usually located on the lower extremi-
ties of middle-aged or elderly individuals.
Other sites are the upper extremities,
head and neck, trunk, buttocks and gen-
ital area.

Clinical features
It usually occurs as a solitary, slowly
growing, dome-shaped papule, nodule
or plaque. The lesion has sharp margins,
Fig. 1.42 Melanoacanthoma. There are elongated interlocking rete ridges consisting of a proliferation of
bland basaloid and squamous cells with formation of pseudo horn cysts, intimately mixed with numerous sometimes with a keratotic scale, and a
melanocytes throughout the lesion. red or pink colour, giving the tumour a
vascular appearance. Clinical variants
include multiple, pigmented, giant, atyp-
Differential diagnosis melanocytes. It is considered to be a ical, cystic and polypoid CCA {345}.
Dowling Degos disease has lesions variant of seborrhoeic keratosis. The clinical differential diagnosis may
indistinguishable from seborrhoeic ker- Melanoacanthoma of the oral mucosa is include pyogenic granuloma, irritated
atosis except for their small size and the an unrelated disorder. seborrhoeic keratosis, squamous and
presence of a reticulated network of basal cell carcinoma, melanocytic nae-
adjacent lesions. Synonyms vus and nodular amelanotic melanoma.
The hyperkeratotic form may resemble a Melanoacanthosis, deeply pigmented
verruca vulgaris. Seborrhoeic keratoses seborrhoeic keratosis. Histopathology
lack parakeratotic columns overlying the There is a circumscribed, sharply demar-
digitate hyperkeratosis and there is no Epidemiology cated epidermal proliferation with psori-
haemorrhage, dialated capillaries, koilo- Most patients are adults beyond 40 years asiform elongation of plump and inter-
cytosis or inward turning of the acanthot- of age. Sex predominance is not known. connected rete ridges. The keratinocytes
ic downgrowths. There are no reliable frequency data. differ from those of the adjacent normal
epidermis by their pale/clear cytoplasm
Precursor lesions Localization containing a large amount of glycogen,
Some believe that the solar lentigo (lenti- Most melanoacanthomas are located on best demonstrated with a periodic acid-
go senilis) is a precursor lesion of reticu- the trunk. Schiff reaction. The keratinocytes of the
lated seborrhoeic keratosis. Others basal layer and the intraepidermal por-
regard it as an early form of this lesion. Clinical features tion of the adnexae are not involved.
Clinically, the lesion resembles a darkly Parakeratosis, infiltration of neutrophils,
Prognosis and predictive factors pigmented seborrhoeic keratosis. There which may form microabscess in the
In a small number of cases Bowen dis- are no characteristic symptoms. It may stratum corneum, and the absence of the
ease coexists with seborrhoeic keratosis. resemble a melanoma with der- granular layer are additional characteris-
matoscopy. tic findings. Dilated capillaries and a
scattered inflammatory infiltrate can be
Melanoacanthoma Histopathology observed in the papillary dermis. The
Melanoacanthoma has the same archi- presence of melanophages in the papil-
Definition tecture as common seborrhoeic ker- lary dermis and an increased number of
Melanoacanthoma of the skin is a benign atoses. However, they stand out by their melanocytes provide clues to the diag-
mixed proliferation of keratinocytes and abundant dendritic melanocytes in virtu- nosis of a pigmented CCA.

Acanthomas 43
The histogenesis of CCA is not yet com-
pletely clear. Initially considered a
tumour of sweat gland or hair follicle ori-
gin, these sites were later excluded
because of the different cytokeratin
expression compared to CCA {1743}.
Some investigators hypothesized that
CCA is a benign epidermal tumour of
unknown etiology, probably caused by a
specific disturbance of keratinocyte dif-
ferentiation. The expression of involucrin
and epithelial membrane antigen further
suggest that CCA is derived from surface
epithelium. However, since CCA shows A
histopathologic findings and cytokeratin
expression similar to those observed in
psoriasis, others believe that it might rep-
resent an inflammatory disease rather
than a neoplastic process {742}.

Large cell acanthoma

Large cell acanthoma, a benign lesion, is B C
now considered to be a stage in the evo- Fig. 1.43 Clear cell acanthoma. A There are well circumscribed interlocking columns of pale to clear ker-
lution of a solar lentigo to a reticulated atinocytes with absent granular layer and no squamous cell atypia. B Note sharp demarcation between
seborrhoeic keratosis {1576,1959}. It normal epidermis (right) and tumour (left). C High power view of tumour cells showing pale cytoplasm due
was thought to represent a particular to glycogen accumulation.
type of actinic keratosis {1875,2095},
Bowen disease {2038}, or a distinct enti-
ty {69,1871,2039}. {2165}. Hypopigmentation is also seen keratoses show parakeratosis and
{69}. Dermatoscopy may rule out greater nuclear pleomorphism.
Epidemiology melanoma.
Most patients are middle-aged to elderly
persons. Sanchez Yus et al (1988) esti- Histopathology Keratoacanthoma
mated that approximately 1-2.5 LCAs are Large cell acanthoma is a sharply delim-
diagnosed per 1000 skin biopsies ited lesion standing out by its unique Definition
whereas Scholl (1982) saw only 4 cases large keratinocytes that have about dou- Keratoacanthoma is a squamoprolifera-
among > 1000 actinic keratoses and > ble the size both of their cytoplasm and tive tumour, mainly of hair-bearing skin.
3200 seborrhoeic keratoses. nuclei compared to normal ker- Although it has distinctive clinical and
atinocytes. Often, considerable numbers histological features, some regard it as a
Etiology of melanocytes are present. Three vari- variant of squamous cell carcinoma
Chronic sun exposure is the probable ants have been described: a basic pat- {190,1701}.
cause of LCA. tern with mild to moderate acanthosis, a
verrucous pattern with papillomatosis ICD-O code 8071/1
Localization and hyperkeratosis, and a flat-hyperker-
Most lesions tend to occur on the trunk atotic pattern {2039}. The granular layer Synonym
and extremities. is thick, there is usually orthohyperker- Well-differentiated squamous cell carci-
atosis and the rete ridges may be slight- noma (keratoacanthoma type).
Clinical features ly bulbous.
The lesion resembles a solar lentigo, flat The growth fraction is low {86,1576} Epidemiology
seborrhoeic keratosis or stucco kerato- although there is a considerable propor- Most cases develop in older persons,
sis. Most cases are lightly pigmented flat tion of both aneuploid and hyperdiploid particularly in the sixth and seventh
plaques or patches, usually less than 10 cells {86}. decades. There is a male preponder-
mm in diameter. Hyperkeratosis or even ance. Keratoacanthomas are more fre-
verrucous appearance has been Differential diagnosis quent in subtropical areas.
described. In Black patients, LCA may Flat seborrhoeic keratoses differ by the
present as darkly pigmented lesions smaller size of the constituent cells. Solar

44 Keratinocytic tumours
Fig. 1.44 Large cell acanthoma. A There is abrupt transition between normal epidermis (left) and large cell acanthoma (right). There is hyperkeratosis, hypergran-
ulosis and markedly enlarged keratinocytes. B The tumour cells have enlarged nuclei without hyperchromasia and a low nuclear to cytoplasmic ratio.

Etiology pink or flesh-coloured, dome-shaped Histopathology

Exposure to excessive sunlight is the nodules with a central keratin plug. They Keratoacanthomas are exoendophytic,
most frequently incriminated factor in measure 1-2 cm in diameter. They tend to squamoproliferative nodules with a cen-
their etiology. Viruses have also been grow rapidly over 1-2 months with spon- tral, keratin plug. Fully developed lesions
implicated, particularly in immunosup- taneous involution after 3-6 months. show lipping (buttressing) of the edges
pressed patients in whom DNA Uncommonly, lesions persist for more of the lesion which overlap the central
sequences of HPV have been detected than 12 months. Because local tissue keratin-filled crater, giving it a symmetri-
in 20% of cases {2270}. Chemical car- destruction can occur during growth and cal appearance. Blunt downgrowths of
cinogens produce similar tumours in involution, active treatment is usually squamous epithelium extend into the
some animals, but their role in humans is advocated. dermis with an irregular lower border to
speculative. Several clinical variants occur: the tumour. The cells at the periphery of
Giant keratoacanthoma, a lesion greater the squamous islands are basaloid in
Localization than 2-3 cm in diameter type. As they mature, they become large
In temperate climates, up to 70% of Keratoacanthoma centrifugum margina- squamous cells with a distinctive pale
lesions develop on the face. In subtropi- tum, which undergoes progressive eosinophilic cytoplasm. Mitoses may be
cal areas, there is a much greater ten- peripheral growth with coincident central seen, but atypical mitoses and stromal
dency for lesions to arise on the arms, healing {1740} infiltration suggest a squamous cell car-
dorsum of the hands and the lower Subungual keratoacanthoma, a destruc- cinoma. SCCs are acknowledged to
extremities. tive form that may produce pressure ero- occur in less than 1% of keratoacan-
sion of the distal phalanx. They usually thomas found in subtropical regions. In
Clinical features fail to regress spontaneously {146} one series, the reported incidence of a
Keratoacanthomas are usually solitary, Multiple keratoacanthomas, which may supervening squamous cell carcinoma
be eruptive (Grzybowski type), self-heal- was approximately one-quarter of all ker-
ing (the Ferguson Smith type, which is atoacanthomas {2040}.
autosomal dominant in inheritance and A mixed inflammatory cell infiltrate, often
caused by an abnormality on chromo- including eosinophils and neutrophils
some 9q22-q31), and a mixed eruptive may be present in the stroma.
and self-healing type (Witten and Zak Neutrophils may extend into the epithelial
type). nests, producing small microabscesses.
Multiple lesions can also occur in Hyperplasia of sweat duct epithelium
immunosuppressed patients {625}, in the may be present in some cases.
Muir-Torre syndrome (see below) and at Perineural invasion is an incidental and
sites of trauma {1789}. infrequent finding, often in facial lesions.
It does not usually affect the prognosis or
Fig. 1.45 Keratoacanthoma. Typical clinical appear- Macroscopy behaviour of the lesions, although local
ance of exophytic tumour with central crateriform They are usually pale nodules with a cen- recurrence has been reported in such
ulceration filled with keratin plug. tral keratin plug. cases. Several cases with intravenous

Acanthomas 45
Fig. 1.46 A A low power view of keratoacanthoma demonstrating a central crateriform lesion filled with a keratotic plug and flanked by epidermal buttresses and
consisting of tongues and lobules of squamous cells pushing into the deep dermis. B Regressed keratoacanthoma. The crateriform architecture remains but the
tumour cells are replaced by flattened epidermal keratinocytes, accompanied by dermal fibrous scarring, a lichenoid inflammatory infiltrate and focal foreign body
giant cell reaction to keratin in the dermis.

Fig. 1.47 Keratoacanthoma. A The tumour cells have abundant pale eosinophilic cytoplasm and pleomorphic nuclei, accompanied by a dermal lymphocytic and
eosinophilic infiltrate. B Focal neutrophilic aggregates in tumour nests are characteristic of keratoacanthoma.

growth and a favourable outcome have The differential diagnosis from squamous Genetics
been recorded {842}. cell carcinoma may be difficult or impos- A genetic defect has been reported in
Regressing keratoacanthomas are shal- sible in superficial shave and punch patients with the Ferguson Smith type of
lower lesions with a large keratin plug biopsies. Features favouring keratoacan- “multiple self-healing epitheliomas” (ker-
and buttressing at the margins. There is thoma include the flask-like configuration atoacanthomas). The Muir Torre syn-
progressive dermal fibrosis and disap- with a central keratin plug, the pattern of drome, in which sebaceous tumours
pearance of tumour nests in the dermis. keratinization, the large central squa- develop in association with visceral
Foreign body giant cells may be present mous cells, the lack of anaplasia and a tumours, usually gastrointestinal can-
around residual keratin fragments. sharp outline between tumour nests and cers, and often with keratoacanthomas,
(PCNA / MIB-1 labelled proliferating cells the stroma {555,2477}. epidermal cysts and colonic polyps, is
are found in the periphery of the squa- inherited as an autosomal dominant trait.
mous nests in keratoacanthoma, in con- Histogenesis Mutations have been found in some
trast to a more diffuse pattern in squa- The great majority of keratoacanthomas cases in one of the DNA mismatch repair
mous cell carcinoma. Expression of TP53 develop on hair-bearing skin {474} and genes MLH1 and MSH2.
is found in both tumours. Subungual ker- are presumed to be derived from follicu- Prognosis and predictive factors
atoacanthomas have characteristic lar keratinocytes, perhaps with a pro- Most lesions regress spontaneously over
dyskeratotic cells, some showing dys- grammed life span. Those rare tumours several months {260}. This regression
trophic calcification, towards the centre that arise on glabrous skin and mucous may, in part, be immunologically mediat-
of the tumour nests. This variant has membranes presumably derive from ed {1782}. Even lesions with perineural
fewer neutrophils and eosinophils. epithelial keratinocytes. and intravenous invasion have a

46 Keratinocytic tumours
favourable outcome. Keratoacanthomas Epidemiology hyperkeratosis, frequently with parakera-
can recur in up to 8% of cases. This is LPLK is a relatively common lesion. Most totic foci. Actinic elastosis is often pres-
more likely with lesions on the fingers, patients are middle-aged to elderly. ent {785}. Features of solar lentigo, large
hands, lips and ears. Trauma may be There is a female predominance. cell acanthoma or early seborrhoeic ker-
responsible for recurrent lesions in some atosis may be present at the margins.
cases. Rare cases that have developed Etiology The inflammatory infiltrate often extends
metastasis have been reported {1038}. The cause of the lesion is not exactly around the superficial vascular plexus.
Possible explanations include misdiag- known. However, chronic sunlight expo-
nosis of the original lesion, the develop- sure appears to be an important factor. Differential diagnosis
ment of a supervening squamous cell Localization Lichenoid solar keratosis shows atypia of
carcinoma not recognized in the original Most LPLKs are located on the upper epidermal keratinocytes. In lichen
material, genuine ‘rogue’ variants or trunk and upper extremities. planus, the inflammatory cells do not
transformation of the initial lesion into a usually extend around the superficial
squamous cell carcinoma in immunosup- Clinical features vascular plexus. Furthermore paraker-
pressed patients {2476}. Clinically, LPLK presents as a flat, irregu- atosis, plasma cells and/or eosinophils
larly hyperkeratotic plaque with often may be present in LPLK. Similar changes
irregular borders. It may be irregularly may be seen in lichenoid drug eruptions.
Lichen planus-like keratosis pigmented or pale in colour. The lesion Clinical information may be required to
resembles a basal cell carcinoma, separate these entities.
Definition Bowen disease, actinic keratosis or flat
Lichen planus-like keratosis (LPLK) is a seborrhoeic keratosis. Itching and some
benign lesion of the skin that represents pain may occur {1373}. Dermatoscopy
the attempted immunologic regression of can rule out melanocytic lesions.
a solar lentigo, seborrhoeic keratosis,
large cell acanthoma or other epidermal Histopathology
proliferative lesion {1569,2150}. LPLK is characterized by a lichenoid
lymphocytic infiltrate leading to basal
Synonyms vacuolar change and numerous apoptot-
Benign lichenoid keratosis. ic cells. There is hypergranulosis and

Acanthomas 47

Melanocytic Tumours

Melanocytic skin tumours include a large variety of benign and

malignant neoplasms with distinct clinical, morphological and
genetic profiles. From a clinical and public health point of view,
the malignant melanomas are the most important group of skin
cancers. Although less common than the familiar basal and
squamous cell tumours of the skin, they are much more fre-
quently fatal, due to their intrinsic tendency to lymphatic and
haematogenic metastasis.
Intermittent high-dose UV radiation is the major environmental
risk factor, often in combination with endogenous factors,
including genetic susceptibility. Malignant melanoma affects
predominantly fair-skinned caucasians, although they also
occur in ethnic groups characterized by a more pigmented
skin. The sharp increase in incidence rates largely reflects
lifestyle attitudes towards vacational sun exposure, but recent
data indicate that this trend is now levelling off. Primary pre-
vention and screening for early lesions are considered the most
promising approach to a reduction of melanoma mortality.
WHO histological classification of melanocytic tumours
Malignant melanoma 8720/3 Dermal melanocytic lesions
Superficial spreading melanoma 8743/3 Mongolian spot
Nodular melanoma 8721/3 Naevus of Ito and Ota
Lentigo maligna 8742/2 Blue naevus 8780/0
Acral-lentiginous melanoma 8744/3 Cellular blue naevus 8790/0
Desmoplastic melanoma 8745/3 Combined naevus
Melanoma arising from blue naevus 8780/3 Melanotic macules, simple lentigo and lentiginous naevus
Melanoma arising in a giant congenital naevus 8761/3 Dysplastic naevus 8727/0
Melanoma of childhood Site-specific naevi
Naevoid melanoma 8720/3 Acral
Persistent melanoma 8720/3 Genital
Meyerson naevus
Benign melanocytic tumours Persistent (recurrent) melanocytic naevus
Congenital melanocytic naevi Spitz naevus 8770/0
Superficial type 8761/0 Pigmented spindle cell naevus (Reed) 8770/0
Proliferative nodules in congenital melanocytic naevi 8762/1 Halo naevus 8723/0

Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, /2 for non-invasive tumours, and /1 for borderline or uncertain behaviour.

50 Melanocytic tumours
TNM classification of malignant melanoma
TNM classification 1,2 pT – Primary tumour (pathological classification)
pTX Primary tumour cannot be assessed*
T – Primary tumour pT0 No evidence of primary tumour
The extent of the tumour is classified after excision, see pT. pTis Melanoma in situ (Clark level I) (atypical melanocytic hyperplasia,
severe melanocytic dysplacia, not an invasive malignant lesion)
N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed pT1: Tumour 1mm or less in thickness
N0 No regional lymph node metastasis pT1a: Clark level II or III, without ulceration
N1: Metastasis in one regional lymph node pT1b: Clark level IV or V, or with ulceration
N1a: only microscopic metastasis (clinically occult) pT2: Tumour more than 1mm but not more than 2mm in thickness
N1b: macroscopic metastasis (clinically apparent) pT2a: without ulceration
N2: Metastasis in two or three regional lymph nodes or intralymphatic pT2b: with ulceration
regional metastasis pT3: Tumour more than 2mm but not more than 4mm in thickness
N2a: only microscopic nodal metastasis pT3a: without ulceration
N2b: macroscopic nodal metastasis pT3b: with ulceration
N2c: satellite or in-transit metastasis without regional nodal pT4: Tumour more than 4mm in thickness
metastasis pT4a: without ulceration
N3: Metastasis in four or more regional lymph nodes, or matted pT4b: with ulceration
metastatic regional lymph nodes, or satellite or in-transit metasta
sis with metastasis in regional lymph node(s) Note: *pTX includes shave biopsies and regressed melanomas.

Note: Satellites are tumour nests or nodules (macro- or microscopic) within 2cm of Stage grouping3
the primary tumour. In-transit metastasis involves skin or subcutaneous tissue more Stage 0 pTis N0 M0
than 2 cm from the primary tumour but not beyond the regional lymph nodes. Stage I pT1 N0 M0
Stage IA pT1a N0 M0
M – Distant metastasis Stage IB pT1b N0 M0
MX Distant metastasis cannot be assessed pT2a N0 M0
M0 No distant metastasis Stage IIA pT2b N0 M0
M1 Distant metastasis pT3a N0 M0
M1a: Skin, subcutaneous tissue or lymph node(s) beyond the Stage IIB pT3b N0 M0
regional lymph nodes pT4a N0 M0
M1b: Lung Stage IIC pT4b N0 M0
M1c: Other sites, or any site with elevated serum lactic dehydro Stage III Any pT N1, N2, N3 M0
genase (LDH) Stage IIIA pT1a-4a N1a, 2a M0
Stage IIIB pT1a-4a N1b, 2b, 2c M0
pT1b-4b N1a, 2a, 2c M0
Stage IIIC pT1b-4b N1b, 2b M0
Any pT N3 M0
Stage IV Any T Any N M1

UICC (2002). TNM classification of malignant tumours. Sixth edition. Wiley, New York
AJCC (2002). Cancer staging manual. Sixth edition. Springer, New York
A help desk for specific questions about the TNM classification is available at http://www.uicc.org (activities, TNM)
Clinical staging includes complete excision of the primary melanoma [pT] with clinical/radiological assessment for regional and distant metastases.
Pathologic staging includes complete excision of the primary melanoma [pT] and pathologic assessment of the regional lymph nodes [pN] after partial or
complete lymphadenectomy. Stage 0 or stage IA patients do not require pathological evaluation of their lymph nodes.

TNM classification of malignant melanoma 51

Malignant melanoma: Introduction E. de Vries
F. Bray
D.E. Elder
J.F. Thompson
J.W. Coebergh R.L. Barnhill
L. Cerroni G.N.P. van Muijen
D.J. Ruiter R.A. Scolyer
P.E. LeBoit

Incidence and mortality ing. Survival has improved substantially, melanoma is observed with relatively low
mainly in countries with high incidence mortality rates, due to the fact that
Approximately 79,000 males and 81,000 rates. This is mainly due to early detec- melanomas are diagnosed in early
females were diagnosed with melanoma tion of melanomas as a result of an stages {609}.
world-wide in 2002, of which about 80% increasing awareness of the disease,
occurred in the predominantly white pop- probably partly owing to the success of Migrant studies
ulations of Northern America, Australia, primary and secondary prevention cam- Groups of migrants from regions of low
New Zealand and Europe. On a global paigns. melanoma incidence to high incidence
scale, malignant melanoma was the 16th regions acquire higher rates of
and 15th most commonly diagnosed Geographical differences melanoma than in their home country, but
cancer in males and females respective- The levels of both melanoma incidence lower than those in the host country, in
ly and occurred most frequently in and mortality vary considerably world- both sexes {96,689}. Incidence and mor-
Australia and New Zealand (4th most wide. Rates are high in populations tality rates of native Australians and New
common males, 3rd in females), North- where Caucasians predominate, and Zealanders, who are largely of British ori-
America (6th in males, 5th in correspondingly low in countries where gin, are estimated to be roughly twice
females),and Europe (16th in males, 8th inhabitants are of mainly Asian or African those of recent British immigrants to
in females) {724}. origin. these countries {96,1255}. Likewise,
In 2002, around 22,000 males and native Israelis experience a twofold
19,000 females died of the disease Melanoma in Caucasians increased risk of incidence compared to
worldwide {724}. Melanoma is one of the As the most important environmental risk immigrants to Israel from Europe, a risk
most important cancers when consid- factor in Caucasians is exposure to ultra- that remains at least three decades fol-
ered as a cause of loss of life as it is com- violet radiation, incidence within white lowing immigration {2260}. The risk of
monly diagnosed in relatively young peo- populations generally increases with immigrants has been shown to approach
ple {54,310,350,1761}, and can be fatal if increasing proximity to the equator. The that of the native populations in both
untreated. It has been calculated that, in highest rates are observed in Australia, Australia and Israel with increasing dura-
the United States, a person dying of where many inhabitants are of Northern tion of residence in the host country {96,
melanoma would die, on average, some European descent and live in a climate 533,689,1255,2260}.
17 years before the age of 65, whereas in with substantially more sunshine than the Amongst Northern European migrants to
Denmark, the mean figure is put at 14-15 norm in Northern Europe. Australia, the incidence rates of
years, and in Belgium 6-8 years {54, In Western Europe, a diverging pattern is melanoma have been observed to
310,1761}. observed: incidence rates are higher in increase with duration of residence, but
Melanoma had a poor prognosis in the Northern Europe (more distant from the decrease with later age of arrival, sug-
1950’s and 1960’s, but from the mid equator) than in the South, reflecting a gesting that exposure at young ages is
1970s, mortality rates have been stabilis- combination of lighter skin type and high- important in determining risk {1255}. The
ing in many high-risk populations, er wealth in the North of Europe. In lowest risk in immigrants to Australia has
although incidence rates are still increas- wealthy populations, a high incidence of been found to be for Southern European
and Eastern Asian migrants, reflecting
the protective effect of a higher degree of
skin pigmentation {1255}. Differences in
skin colour are also assumed to be the
reason underlying the higher incidence
of melanoma in white immigrants to
Hawaii from the United States mainland

Melanoma in non-Caucasians
U.S. Whites have rates 15 times higher
than U.S. Blacks, and a similar contrast
in risk is observed in the White and Black
populations of South Africa and
Fig. 2.1 Age-specific incidence of cancer. All data are based on data from Europe 1990-1997. Zimbabwe {1780}. Melanoma is also rel-
Source: European Network of Cancer Registries. EUROCIM 4.0, Lyon 2001. atively uncommon among Asians {1295,

52 Melanocytic tumours
In the United States, Australia and
Northern Europe, where incidence rates
were very high during the 1980s, the
rates have been rising less sharply or
levelling off since the mid-1990’s, espe-
cially in younger age groups {516,609,
1137,1353,1472,2144,2244,2245}. In
contrast, in Southern and Eastern Europe
and in Latin America, rates are increas-
ing {7,609,1353,1579,2144}. Incidence
rates in Asia have been rather stable
{1142,1295}. There is insufficient data at
present to report on time trends in
melanoma incidence among African
populations. Over the last decades,
increases in incidence have mainly been
observed for thin melanomas, whereas
the rate of thick melanomas seems to be
relatively stable {618,1433}. This
increase in the number of thin mela-
nomas is mainly observed in countries
with high incidence rates, where increas-
es in rates are mainly seen in the super-
ficial spreading melanomas {414,
560,1052,1137,1472,1501}. In countries
with lower incidence rates, increases are
generally more evenly spread across
thickness categories.
Fig. 2.2 Age-standardized incidence rates for malignant melanoma of skin, per 100 000 population and year, Although trends in incidence rates of
adjusted to the world standard population. From D.M. Parkin et al. {1779}. melanoma vary greatly, mortality rates
show less variation. Mortality rates have
been levelling off in many populations
1746} and Middle- and South-American considered beautiful to have a light skin. with high melanoma incidence rates,
populations {891}, probably due to a bet- The avoidance of sun-exposure and such as Australia, the United States, and
ter protection afforded by a larger even more extreme measures, such as North-western Europe {516,609,827,
amount of pigment in the skin and possi- bleaching of the skin, have been report- 1353,1411,1412}. In some countries, a
bly different (‘wiser’) sun-exposure pat- ed {952,2081}. levelling off of incidence rates is now also
terns. Melanomas appear more often on observed, starting in younger age
the non-pigmented areas of the skin in Time trends groups {609}.
non-Caucasians {940}, are often of the Since the 1970’s there have been reports
acral lentiginous melanoma type and of alarming increases in melanoma, ini- Stabilisation of melanoma incidence
appear on the palms of hands, soles of tially in terms of mortality {1393} and then rates
the feet and under the nails {200,554}. A in incidence {1481}. These reports Age-period-cohort analyses indicate that
common problem in these populations is observed a doubling in rates every one in Western populations (USA, Australia,
that pigmented lesions in the skin are or two decades (mean annual incre- New Zealand, Sweden, the Netherlands,
often more difficult to notice, and are ments of between 3% and 7%) per Germany) the increasing mortality rates
therefore often detected at relatively late annum in populations of European origin have started to level off, starting in
stages, which, at least in part, explain the for both genders {1761}. The incidence cohorts born in the 1930s and 1940s
high case-fatality rates {200,554}. In rates increased markedly for intermittent- {534,827,1050,1136,1692,1983,2244,
many African and Asian societies it is ly exposed body sites (trunk, legs, etc.) 2352}. In Southern Europe, generally
whereas increases in the face and neck those with lower incidence rates (e.g.
were moderate. In males, the largest Italy and Spain) there has been no sign,
Table 2.01 increases were found on the trunk, and in as yet, of a downwards trend {1480,
Age-standardized incidence rates per 100 000 per-
females on the legs and arms {332,459, 1849,2144}.
son / year in the SEER registry (USA) {1781A}.
1007,1472,1482,1699,2120,2245,2350}. A recent plateau in melanoma mortality
Population Males Females In an analysis of the SEER data, it was rates (in some cases followed by inci-
found that melanomas of all stages dence rates) is reported in high-inci-
Blacks 1.00 0.5 increased from 1988-1997, but that local- dence countries, such as Australia, USA,
Whites 15.4 11.6 ized and in situ lesions increased the Sweden, Norway and Germany {609,
most {1137}. 1353,1761,2120,2245}. Only the mortali-

Malignant melanoma: Introduction 53

main risk factor for the development of
melanoma, although exposure in adult-
hood also plays a part. The relative risk
of UV exposure for the development of
melanoma is around 2, but when skin
characteristics are taken into account,
the relative risks increase markedly for
those with a sun-sensitive skin. As
sunbeds also emit UV-radiation, they
most likely also confer a risk for the
development of melanoma, as was
recently confirmed in a large prospective
study {2426}.
Although high sun exposure in childhood
is a major determinant {2509}, multiple
sunburns {683} and high exposure
throughout life {117} raise risk of disease
significantly. Cutaneous melanomas
appear to arise by different pathways.
Those on the head and neck relate main-
Fig. 2.3 Melanoma of the skin in Whites. SEER Incidence, delay adjusted incidence and US death rates. ly to chronic sun exposure while those on
Despite rising incidence rates, mortality is now stable in men and shows a recent decrease in women. From: the trunk occur in people with many
L.A.G. Ries et al. {1936}. http://seer.cancer.gov/csr/1975_2001/ melanocytic naevi {2508}. High numbers
of naevi reflect an innate propensity to
melanocytic proliferation {2196,2197}
ty rates levelled off initially, starting in the ically benign form of melanoma. and stimulation by sun exposure {591}.
late 1970s, with increasing incidence Although some artefacts may have con- The risk of acral melanoma is also
rates. This was most likely because of tributed to the increases, a substantial increased by exposure to high cumula-
improving survival {1472, 2245,2351} part of the increases is assumed to be tive UVR and to agricultural chemicals
due to earlier detection, as there were no genuine {610}. {890}. Occupational sun exposure, espe-
major advances in systemic treatment. Both familial and environmental factors cially farming, is associated with risk of
Melanoma incidence rates have been play a role in the etiology of melanoma. ocular melanoma {2401}. Inherited muta-
reported to be levelling off, or even The familial/genetic components include tions of tumour-suppressor genes (eg
decreasing in younger age groups, start- skin type, number of naevi, having clini- CDKN2A) are strongly associated with
ing in the 1980s {609}. Furthermore, the cal atypical naevi, and having a family familial melanoma but probably underlie
mean and median stage or thickness at history of skin cancer. They are the most less than 1% of all cutaneous melanoma
diagnosis is decreasing {560,618,1433, important predictors of melanoma risk. {42}.
1472,2351}, with an increasing registra- As it is not likely that there has been a
tion of thin, superficial spreading mela- substantial change over time in famil- Occupational vs. recreational exposure
nomas. ial/genetic risk factors in most popula- Before the Industrial Revolution, many
Changes in the biology of melanoma, tions, these cannot have contributed wealthy people had a pale skin: they
characterized by a tendency towards substantially to the observed increases worked or stayed indoors, whereas the
less aggressive lesions being observed in melanoma incidence over the past 50 lower classes tended to work mainly out-
{353} could also be consistent with a years. doors. During the industrialisation of
continuing rise in melanoma incidence, society (1750-1800), working class peo-
and a corresponding moderation or sta- Exposure to UV radiation ple started working indoors and only the
bilisation in the mortality rates. Intermittent exposure to UVR is the major rich had the time and money to afford
environmental risk factor for melanoma, recreational outdoor life. By the early
especially in combination with endoge- 1920s, daily exposure to sunlight was
Etiology nous factors (skin types I and II, immune also advised as a cure for many diseases
deficient status, genetic predisposition) (acne, rickets, tuberculosis), especially
There has been much discussion and {95}. The association between UVR and for children. By the 1930s a suntan had
debate as to the reasons underlying the melanoma is ambiguous, with differ- become a symbol for wealth and health
dramatic increases in melanoma inci- ences in risks associated with the dose, and since the 1950s, holidays to sunny
dence and mortality, and in particular, the way it is delivered (intermittent vs. destinations became popular and affor-
whether they are real or due to artefacts, chronic exposures) and critical time peri- dable to many.
via, for example, increased efforts at ods (childhood vs. cumulative exposure The rising melanoma incidence is most
screening and diagnosing the disease, during life). Intermittent exposure to UVR commonly attributed to changes in
changes in diagnostic criteria, or the in white people, especially during child- lifestyle with increasing intermittent expo-
existence of a non-metastasizing biolog- hood, has been postulated to be the sure to ultraviolet radiation (UVR), due to

54 Melanocytic tumours
the popularity of sunbathing and tanning. increase the risk of melanoma develop- being frequently observed in young
Given an induction time of some 20-40 ment by increasing sunbathing-time. Of patients, and on body sites that are inter-
years between exposure and melanoma fifteen case-control studies examined by mittently exposed to sunlight.
occurrence, these factors are in accor- an expert panel, only 3 showed a signifi-
dance with the continuing increases - cantly reduced risk of melanoma, with Nodular melanoma
mainly on the trunk in men and on the relative risks between 0.2 and 0.6, the It usually presents as a rapidly growing
legs in women {331,332,619,620,682, others observing no significant effect (4 pigmented nodule (amelanotic nodular
772,2409}. studies) or an increased risk (8 studies, melanomas are rarely observed), which
RR between 1.7 and 3.5) {2400A}. The bleeds or ulcerates. This is the most
Ozone layer increasing use of sunscreens may there- aggressive type of melanoma. It often
Another explanation for the increases is fore have contributed to the increases in presents on body sites that are intermit-
the depletion of the ozone layer, which melanoma incidence. tently exposed to sunlight.
protects the earth’s surface against UVR
by filtering out a large part of the UVR Vaccination Acral lentiginous melanoma
from the sunlight before it reaches the Vaccination during childhood against These lesions are pigmented, arising on
earth’s surface. Chemical substances tuberculosis with the Bacille Calmette- the palm of the hand, sole of the foot or
released in the earth’s atmosphere are Guérin (BCG) vaccine or against small- under the nails. They often present late
slowly breaking down the ozone layer pox with the vaccinia vaccine, or having and represent the most common type of
{2199}, increasing the amount of UVR experienced one or more infectious dis- melanoma in heavily pigmented people.
that reaches the earth’s surface and like- eases may decrease the risk of develop-
ly increasing the risk of skin cancer. ing melanomas (odds ratios between Age distribution
Estimates indicate that skin cancer inci- 0.29 and 0.44) {1303,1330,1331,1821, Malignant melanoma (hence referred to
dence rates could increase dramatically 1822}. Part of the increases in melanoma as melanoma) is a tumour affecting pre-
by the end of this century compared to incidence could be due to the abolish- dominantly adults and elderly patients,
the situation around 2000 {1240}. ment of this type of vaccination in with a peak of incidence around the sixth
Europe. decade of life. In recent years, however,
Socio-economic status it has been increasingly recognized in
Melanoma is more common among peo- middle-aged and young adults, and can
ple with a higher socio-economic status, Clinical features be observed in children and adolescents
probably due to a higher excessive inter- as well. Thus, no age group is spared,
mittent exposure to UVR (outdoor sports, Sites of involvement and a high level of suspicion should be
winter sports, sunbathing, getting a tan) Most commonly affected site per unit sur- exerted in examination of any dubious
in this group. Increasing wealth over the face area of skin in both sexes is the face pigmented lesion regardless of the age
past 6 decades in large parts of the and male ear head and neck {772,890}, of the patient.
Western (i.e. predominantly Caucasian) with back and shoulders in men and the
populations may indirectly have contribu- lower limbs in females also having high Origin
ted to the increases in incidence rates of rates per unit area. The clinical features of melanoma are
melanoma and other skin cancers. variable and depend on type and stage
Major subtypes of evolution of the tumour, and on loca-
Most classification schemes of mela- tion of it. Melanoma may occur de novo,
Melanoma prevention noma categorize them clinically into four that is, without a precursor lesion, or may
major types, but such classification has develop within a pre-existing benign
Sunscreens little prognostic value and diagnostic rel- melanocytic naevus {1168,1750}. It has
An international group of experts con- evance, thus being of very limited useful- been estimated that 20-30% of
vening at the International Agency for ness in clinical practice. melanomas arise within a pre-existing
Research on Cancer investigated the melanocytic naevus, but this figure in
preventive effects of sunscreen use on Lentigo maligna melanoma. truth may be higher, as in many
the development of skin cancer: They This type of melanoma develops when instances it is very difficult to distinguish
concluded that the use of protective an invasive tumour arises in a lentigo histopathologically residual complexes
cream could indeed prevent erythema maligna. It is most common in the head of a benign naevus from those of the
and squamous cell carcinoma after non- and neck region and in elderly people, melanoma. All types of melanocytic
intentional sun-exposure (i.e., exposure and has a relatively favourable progno- naevi can give rise to a melanoma, but
to the sun without the objective of getting sis. some are more frequently involved, such
exposed, for example, work-related as congenital melanocytic naevi.
exposure). Its protective effect for basal Superficial spreading melanoma. Melanoma has only rarely been
cell carcinoma and melanoma, however, This type of melanoma grows laterally observed in association with Spitz naevi
is not yet determined, as it is difficult to before vertical invasion develops. {1380}, but this may be due also to the
study due to a long latency period. Increasingly, this is the most common difficulty in discerning histopathological-
Paradoxically, there is inconsistent evi- type of melanoma in Caucasians, and ly melanocytes of a melanoma from the
dence that the use of sunscreens may has a relatively favourable prognosis atypical melanocytes frequently found in

Malignant melanoma: Introduction 55


Fig. 2.4 Clinical presentation of melanomas. A Malignant melanoma arising in a congenital naevus. B Stereotypical cutaneous melanoma characterized by asym-
metry, uneven pigmentation, and irregular margins. C "Small" melanoma (< 3 mm) characterized by a relatively symmetrical, evenly pigmented small papule.
D Melanoma in situ. Note flat pigmented lesion with different hues of brown and slightly irregular margins. E Early "invasive" melanoma characterized by marked
asymmetry and variegations in colour. F A nodule of melanoma arising within an in situ component. Note the irregular pigmentation and asymmetry of the flat part
of the lesion.

Spitz naevi. Melanoma arising within a pathologically {282}. In addition, when lar growth from the outset without hori-
pre-existing blue naevus is commonly assessed with the ABCD rule many zontal spread, usually within a few
referred to as malignant blue naevus, an benign melanocytic naevi have atypical months (so-called nodular melanoma).
imprecise term that should be avoided. features, thus decreasing specificity of Finally, exceptional cases of dermal
Melanoma may arise at the site of pre- this diagnostic criteria, too. melanomas without any intraepidermal
existing scars (e.g., burn scar) {1758}. component have been recorded {2305}.
Recurrence at the site of a scar from pre- Pigmentation and growth
vious biopsy or narrow excision is a sign Most (practically all) de novo melanomas Regression
of incomplete excision of the primary are pigmented lesions that begin as a flat Partial regression of part of the lesion
tumour. Recurrence at the site of a com- macule, representing the neoplastic takes place commonly during the entire
plete excision (with negative margins growth of malignant melanocytes con- process of growth of melanoma, resulting
verified histologically) represents locally fined to the epidermis (melanoma in situ) in the presence of whitish-grey areas that
metastatic disease rather than persist- . Lesions in this stage are characterized accentuate the asymmetry and uneven
ence {1000}. by a relatively homogenous brown pig- pigmentation of the lesion. In rare cases,
mentation with slightly irregular borders. complete regression can be observed,
ABCD rule Over time (in most instances probably leading to the disappearance of all neo-
The most useful criteria for clinical diag- several years) lesions spread horizontal- plastic melanocytes. Usually, these
nosis of melanoma are asymmetry and ly showing more irregular contours and lesions show uneven pigmentation with
uneven pigmentation of the lesion, and variegations of the pigmentation, and whitish, grey and black areas correspon-
have been integrated in the acronym revealing histopathologically involvement ding to the presence of variable fibrosis
“ABCD” (Asymmetry, irregular Border, of the superficial (papillary) dermis. and infiltrates of melanophages in the
uneven Colour, Diameter > 6 mm) {1552}. When the papillary dermis is filled by dermis. With time, the pigmentation may
Although the “ABCD” mnemonic is con- neoplastic melanocytes the lesions disappear almost completely. Although
sidered the standard approach for the appear as irregular, unevenly pigmented regression is an immune-mediated phe-
clinical diagnosis of melanoma, it has plaques. In later stages the neoplasms nomenon corresponding to the elimina-
severe limitations when applied to early exhibit vertical growth resulting in the for- tion of malignant melanocytes by cyto-
lesions of it, that may have a relatively mation of papules or nodules, usually toxic lymphocytes, complete regression
homogenous pigmentation, sharp mar- confined to one area of the lesion. The of a melanoma can be associated with
gins, and small diameter. Melanomas papules and nodules represent areas metastatic spread, thus being a bad
less than 5 mm in diameter have been where the tumour grows vertically rather than a good prognostic sign. The
referred to as “small melanomas” in the through the dermis, eventually involving prognostic role (if any) of partial or focal
literature, and may be the source of diag- the subcutaneous tissues. In a minority of regression has not yet been elucidated,
nostic pitfalls both clinically and histo- cases, melanoma exhibits a rapid nodu- but it seems negligible {764}.

56 Melanocytic tumours

Fig. 2.5 Clinical presentation of melanomas. A Nodular melanoma. Large, darkly pigmented tumour practically devoid of a flat component. B Melanoma with promi-
nent regression resulting in almost complete disappearance of large part of the lesion. C Complete regression of melanoma. The grey pigmentation is due to the
presence of heavy infiltrates of melanophages within a fibrotic papillary dermis. The patient had regional lymph node metastases at presentation. D Ulcerated nodu-
lar melanoma resembling a granuloma pyogenicum. Note focally small areas of slight pigmentation at the margins. E So-called "lentigo maligna" (melanoma in situ
on sun-damaged skin) arising on the nose. F Acral melanoma. Note the marked irregularity of the margins, confering a "multifocal" appearance to the lesion.

Melanoma is more frequent in particular uneven pigmentation {670,1963}. atoses or common warts (verrucous
settings (so-called “markers”) including Differentiation of early lesions of mucosal melanoma) {101}. These cases may be
a familial history of melanoma, a previous melanoma from so-called melanosis (a misinterpreted clinically as pigmented
melanoma in the same patient, presence benign condition characterized by seborrhoeic keratoses or other verrucous
of many melanocytic naevi, presence of prominent hyperpigmentation of the tumours.
giant congenital naevi, skin type 1 or 2, mucosa without or with only slight
as well as in rare conditions such as increase of melanocytes at the dermo- Dermatoscopy
xeroderma pigmentosum among others epidermal junction) may be very difficult Besides clinical examination, der-
{53,901,1196,1202,2231,2481}. Patients or even impossible clinically as well as matoscopy (dermoscopy, skin surface
presenting with one or more of these fea- histopathologically. microscopy, epiluminescence micros-
tures should be monitored closely, and copy) has been increasingly regarded as
suspicious lesions should be biopsied. It Subungual melanomas a valuable aid in diagnosis of early
is important to remember that multiple In early stages these are sometimes melanoma clinically. Dermatoscopic
primary melanomas may be observed characterized by the presence of a well instruments enlarge the lesion 6-100-
rarely in some patients {1196}. demarcated, pigmented longitudinal fold, thus allowing detection of structures
streak (longitudinal melanonychia) {263}. and signs not visible to the naked eye. In
Clinical variants The so-called Hutchinson sign (periun- addition, connection of the dermato-
Amelanotic melanoma gual spread of the pigmentation on the scopic devices to a computer allows one
Although melanoma is a tumour charac- proximal or lateral nail fold) may be to take standardized digital pictures that
terized by variable degrees of pigmenta- absent in early lesions, thus representing can be compared over time, thus being
tion, in rare instances the pigment may a pitfall in the clinical diagnosis. much more sensitive for detection of min-
be missing altogether (so-called amelan- imal structural changes of the examined
otic melanoma). Amelanotic melanomas Ulceration lesion {719}. Finally, computer-assisted
are more frequent on the face, where Rapidly growing, ulcerated melanomas diagnostic systems based on dermato-
they often display the histopathologic may be misdiagnosed clinically as gran- scopic images are available as aids for
features of desmoplasia (desmoplastic uloma pyogenicum. Pigmentation in the evaluation of suspicious pigmented
melanoma), but can be observed also on these cases may be scant and confined lesions {91}.
other parts of the body {77,2285}. only to small areas of the tumour. Several dermatoscopic diagnostic
approaches have been proposed, all of
Mucosal melanoma Verrucous phenotype them relying on the examination of dis-
Melanomas arising within a mucosa (oral In rare cases, melanoma may present tinct patterns and structures. Of particu-
mucosa, genital mucosa) are often multi- with a verrucous surface similar to what lar value in the diagnosis of melanoma
focal, and are characterized by dark, can be observed in seborrhoeic ker- are the presence of an irregular pigment

Malignant melanoma: Introduction 57

network (uneven thickness of the lines,
presence of broad lines at the periphery
of the lesion), of black or brown dots
irregularly distributed within the lesion, of
irregular lines at the periphery of the
lesion that are not clearly combined with
the pigment network (streaks), of a blue-
whitish veil corresponding to infiltrates of
melanophages below a thick epidermis
with hypergranulosis, of an atypical vas- A B
cular pattern, and of regression struc-
Fig. 2.6 Clinical presentation. A and dermatoscopic picture B of an early melanoma developing within a
tures. A 7-point checklist for dermato- "dysplastic" naevus. Note the marked asymmetry of the lesion and the presence of an area with irregular
scopic scoring of atypical melanocytic pigment network and broad lines at the periphery, representing melanoma in situ.
lesions using the aforementioned criteria
has been proposed, and it has been sug-
gested that this approach allows diagno- finding favouring melanoma, there are nosis of melanoma {8}. The distribution of
sis of melanoma with a sensitivity of 95% many exceptions. melanophages also affects pigmenta-
and a specificity of 75% {91,1671}. Other tion.
proposed approaches include the Symmetry of changes in the epidermis
Menzies method and the ABCD rule {91}. The most important attribute of symmetry Circumscription
Besides dermatoscopy, the use of sever- is in reference to that of melanocytes Most melanocytic naevi have sharp bor-
al other devices has been proposed for themselves. The symmetry or lack there- ders, and melanomas indistinct ones. A
the early in vivo diagnosis of melanoma, of in terms of the distribution of melanocytic neoplasm is easiest to judge
including confocal laser microscopy melanocytes in the epidermis is more dif- as well circumscribed if the edge of the
{1509}. ficult to judge than is the overall silhou- lesion is defined by a nest, rather than by
ette of the lesion. It is evaluated by com- single melanocytes. In such cases, care
Staging paring the density of melanocytes on one must be taken that the distances
Staging investigations depend on stage side of the lesion with the other; pattern between nests do not exceed or even
and extent of the disease and should of distribution of melanocytes (are they at approximate those between the most
always include a complete clinical exam- the junction or above it) on one side of peripheral nest and the edge of the sec-
ination {2218A}. Sonography of the the lesion with the other; disposal as tion (in other words, one must be sure
superficial lymph nodes and of the nests or as single cells on one side of the that the “last” nest is truly the last one).
abdomen, radiography of the thorax and lesion with the other; cytological findings One should also assess whether the
evaluation of serum markers such as lac- (are melanocytes on one side of the nests at the periphery of the lesion are at
tate dehydrogenase (LDH), S-100-beta lesion different cytologically with those irregular intervals. A lesion can have an
or melanoma-inhibiting activity (MIA) on the other side). Asymmetry in any of entirely nested junctional component,
seem to be of little value in asymptomatic these attributes favours melanoma. with small nests at increasingly long
patients. Computer tomography (CT) Secondary forms of asymmetry, less intervals at its edges. This is often the
scan, magnetic resonance imaging important that that of the distribution of cause of a “fuzzy” border in a dysplastic
(MRI), bone scintigraphy and positron melanocytes include asymmetry in pig- (Clark) naevus.
emission tomography (PET) are useful mentation, epidermal thickness and
methods for evaluation of patients with inflammatory infiltrates. Most of these Predominance of single cells vs. nests
metastatic disease. attributes are not decisive {2506}. At an early stage in the intraepidermal
Pigmentation in the epidermis in development of a melanocytic prolifera-
melanocytic neoplasms is usually in the tion, benign or malignant, single
Histopathology basal layer (exceptions are particularly melanocytes in increased number will be
dark lesions, such as so-called hyperme- present. Therefore, a 1 or 2 mm lesion, as
Architectural criteria in the epidermis lanotic naevi) {513}. In such naevi, and in noted above in which single melanocytes
Lesional breadth very dark foci of some melanomas, there predominate is not necessarily aberrant.
A proliferation of melanocytes wholly may be copious melanin in keratinocytes In the evolution of most acquired
within the epidermis can range in size not only in the basal layer but also in the melanocytic naevi, the single melano-
from >1 mm to a patch many cm in width. spinous and cornified layers. Either an cytes aggregate into nests by the time
Both melanocytic naevi (conventional asymmetrical distribution of melanoma in the lesion is 2 or 3 mm. in diameter.
and Spitz) and melanoma begin as pro- the basal layer of the epidermis, or The distribution of single melanocytes is
liferations in which single melanocytes melanin above the basal layer on one also noteworthy. One can imagine a dot-
predominate. side of the lesion but not on the other ted line connecting the tops of dermal
By the time most melanomas can be rec- raises the possibility of melanoma. An papillae with one another. Very few
ognized as such clinically they are over 4 irregular distribution of epidermal pig- melanocytes should reside in the epider-
mm in diameter, and often far broader ment is the cause of one of the “ABCD” mis above that line.
{730}. While a large lesional diameter is a rules (variegated colour) of clinical diag- Confluence of melanocytes is another

58 Melanocytic tumours
clue to the diagnosis of melanoma.
Confluent single melanocytes replace
the basal layer in a manner such that, at
least focally, keratinocytes do not seem
to intervene between them. Confluence
of nests of melanocytes is a more sub-
jective determination.

Scatter of melanocytes above the

junction A
If any criterion expounded herein
emblemizes intraepidermal melanoma in
the minds of pathologists, it is supra-
basal scatter of melanocytes. Pagetoid,
buckshot and birdshot scatter also
describe this distribution of neoplastic
cells. It can be difficult to tell if “slight”
suprabasal scatter of melanocytes is
Physical trauma, such as excoriation or
abrasion or by ultraviolet light exposure B C
provokes scatter of melanocytes above Fig. 2.7 A Melanoma with asymmetry. Asymmetry in the distribution of nests and of pigment- which can be
the epidermis {2374}. Signs of physical within keratinocytes, melanocytes or melanophages is typical of intraepidermal melanoma. B Pagetoid
trauma include erosion, necrosis of scatter of melanocytes is practically emblematic of intraepidermal melanoma. C Consumption of the epi-
superficial keratinocytes, parakeratosis, dermis in melanoma. The epidermis is thinned, with squamous rather than cuboidal cells in the basal layer.
subepidermal fibrin deposits and
extravasation of erythrocytes in the pap- Kamino bodies occur in some dysplastic by the use of some alcohol-based fixa-
illary dermis. Suprabasal scatter of (Clark) naevi, and in some halo naevi tives instead of formalin.
melanocytes is typical of naevi on acral Large round or oval, or epithelioid
skin {292}. Cytological features of melanoma in melanocytes occur in both benign prolif-
the epidermis erations and in melanoma. Such cells
Configuration of the epidermis Cytologic findings are less of a link to the often have abundant pale cytoplasm,
An uneven epidermal contour is more apt correct diagnosis in the realm of with “dusty” (fine and evenly dispersed)
to be present in melanoma than in a nae- melanocytic neoplasia than in other melanin. These cells are typically seen in
vus. The most typical diagnostic alter- tumours. Melanocytes can be large or the intraepidermal components of
ation is a thinned epidermis in the area of small, deeply pigmented or amelanotic, melanomas of all types. Large, pale
the melanoma (or melanoma in situ) and and vary from appearing to be round to melanocytes are also present in naevi of
elongated rete ridges in an area in which oval to spindled to thin and dendritic. the scalp (especially in children and
a pre-existent naevus is present. In the Most acquired naevi feature small round, teens), breast and genitalia, and in some
case of melanomas in which a large oval or small spindled melanocytes with- dysplastic naevi {1532}.
mass of neoplastic cells is present in the in junctional nests. There may be no visi- Spindled melanocytes occur within the
dermis, a finding known as “consumption ble pigment, or some may be intracyto- epidermis in the junctional nests of dys-
of the epidermis” can occur. The epider- plasmic. In general, the amount of cyto- plastic naevi and in Spitz naevi, as well
mis is thinned, and instead of small plasm is scant in most “common” and as in melanoma, where their orientation is
cuboidal keratinocytes in the basal layer, even in most dysplastic naevi. The nuclei haphazard (some nests may be vertical
one sees large, flat squamous ones, of such cells are usually monomorphous, and some horizontal). The nuclei of spin-
often with vacuolar change. This finding allowing for different shapes due to vari- dled melanoma cells are more often
is much more common in melanoma than ous planes of sectioning if the cells are pleomorphic, and there is heterochroma-
in naevi {947}. elongated. Melanomas with similar cyto- sia, i.e. some may be vesicular and some
logically bland cells do occur, and the stain darkly.
Kamino bodies diagnosis in such cases must be made Dendritic melanocytes are present in
The finding of many large, well formed via the architectural features of the melanomas in dark skin patients in
Kamino bodies favours a Spitz naevus lesion. diverse settings, and light skinned ones
over melanoma. There are few convinc- Small melanocytes with scant cytoplasm in so-called lentigo maligna and the lenti-
ing reports of melanomas with Kamino and angulated, darkly stained nuclei are go maligna pattern of melanoma, and in
bodies, and these describe few, and particularly apt to be found in melano- melanomas of acral-volar skin, the nail
smaller bodies. In some such reports, the mas in severely sun-damaged skin (lenti- bed and of mucous membranes. The
bodies are not PAS-D positive, suggest- go maligna and lentigo maligna nuclei of dendritic melanocytes may be
ing that dyskeratotic cells were mistaken melanoma). A similar appearance can inconspicuous. The findings of dendrites
for them. In addition to Spitz naevi, small be induced by processing artefact, and that ascent to the mid-spinous zone, and

Malignant melanoma: Introduction 59

Fig. 2.8 A Melanoma, invasive radial growth phase (invasive but non-tumorigenic melanoma). Clusters of cells are present in the dermis (see bottom left) that are
not larger than the largest intraepidermal clusters. B A thin invasive and tumorigenic melanoma. The cluster of cells in the dermis is slightly larger than the largest
cluster in the epidermis, constituting a pattern consistent with a very early tumorigenic melanoma.

especially variability in the widths of den- Contour amount of cytoplasm is less at the base
drites at the same level of the epidermis Dysplastic naevi have a flat base at the of a benign melanocytic neoplasm than
(anisodendrocytosis) are useful clues to interface between the papillary and retic- in its upper nests. If the cytoplasm of the
melanoma in these settings. ular dermis, Spitz naevi have flat or upper cells of a naevus is pigmented, its
The extreme cytologic atypia typically wedge shaped bases, superficial blue lower cells tend to be less pigmented or
seen in thick melanomas in the dermis naevi are wedge shaped, congenital and achromic. The sizes of aggregations of
and in metastases of melanoma, with congenital-like naevi have an uneven melanocytes also should be smaller
very large, irregularly shaped and bright- base, with melanocytes clustered around toward the bottom of a benign neoplasm
ly eosinophilic nucleoli is not usually to adnexa and sometimes around vessels, of melanocytes.
be found in the intraepidermal compo- and deep (often cellular) blue naevi have The scientific basis of maturation rests on
nent of a melanoma. a lobulated base, with blunt masses of changes in metabolism (less tyrosinase
cells that protrude into the subcutis . activity and more acetylcholinesterase
Architectural criteria in the dermis Melanomas that involve the dermis typi- activity) and telomeric exhaustion
The presence of the intraepidermal cally have uneven, sometimes jagged {865,1620}.
changes of melanoma is of course a clue bases. Maturation occurs to a limited extent in
that the dermal component of a some melanomas, but in most there are
melanocytic neoplasm might represent Maturation cells at the base of the lesion nearly as
melanoma as well. Again, architectural Maturation of melanocytes is in some large as those at the top, and dispersion
criteria are more important than cytolog- ways a misnomer- a mature melanocyte from large nests to small ones and single
ic ones, although the balance is more is dendritic, and synthesizes pigment cells is often absent {1989}. Pigmentation
even than in assessing the intraepider- within an epithelium. The process com- near the base of a melanocytic neoplasm
mal portion of a melanoma. monly referred to as maturation is really can also be a clue to melanoma, but it
senescence; it reflects a loss of metabol- commonly occurs in blue naevus.
Symmetry ic activity, reproductive capacity and in
The most important aspect of symmetry some cases a tendency to become fat- Mitotic activity
of the dermal component of a melanocyt- just as mammalian senescence does. Mitoses in the dermal portion of a lesion
ic neoplasm pertains to its outline, or sil- Maturation of melanocytes occurs in do not mandate a diagnosis of
houette. most naevi, with the exception of blue melanoma. As a rule, the mitotic figures
Other forms of symmetry pertain to what naevi (including deep penetrating naevi). in benign naevi are found in melanocytes
lies within the silhouette- the composition The best-known form of maturation is the within the papillary or superficial reticular
of the neoplasm. The sizes and shapes progressive diminution in the size of the dermis. If the lesion in question only
of nests, the pigmentation and cytologic nuclei of melanocytes at increasing extends to this depth, the number of
features of the melanocytes and infil- depth within a lesion. Nucleoli also dimin- mitoses becomes important, as does the
trates of lymphocytes and melano- ish in size, and if they are eosinophilic in question of whether the mitoses are in
phages ideally are the same on both the upper part of a lesion they tend to clusters (reflecting “hot spots”) or are
sides of the lesion, at the same level of become basophilic at its base. Nuclear atypical. Atypical (asymmetric, tripolar or
the dermis. A disproportionately large maturation in melanocytic lesions can be ring) mitotic figures can occur in Spitz
nest of cells with cytologic features that quantified by morphometric studies naevi, but are rare in other forms of nae-
contrast with those on the other side of {211,1398}. vus. Ki67 / MIB-1 marks cells that are
the lesion may be a clue to melanoma. In addition to nuclear maturation, the actively cycling, and the number of such

60 Melanocytic tumours
cells should diminish toward the bottom melanomas may migrate into the papil-
of a benign melanocytic neoplasm. The lary dermis. In the dermis, these cells
finding of a low proliferation rate is no may either undergo apoptosis and dis-
guarantee of benignancy. A high rate in a appear {1070}, or may survive without
lesion thought to be benign should trig- proliferating. In the latter case, the lesion-
ger reassessment. al cells may persist in the dermis, but
they do not expand to form a tumorigenic
Cytologic features of melanoma in the nodule.
The cells of a melanoma may be large or Vertical growth phase (tumorigenic)
small melanocytes, round or spindled, In the next phase of progression, a tumor
Fig. 2.9 Lymphoscintigraphy in a patient with a
amelanotic or deeply pigmented. nodule appears either within the confines melanoma on the central upper back.
Large spindled melanocytes comprise of a pre-existing plaque, or, sometimes, Top: summed 10-min dynamic images in posterior
the dermal component in some de novo in a lesion which is then termed and anterior projections after injection of tech-
melanomas. They often are not reliably “nodular melanoma” {675} cells. netium-99m antimony sulphide colloid intradermal-
demarcated from each other by clefts, as The key biological feature of vertical ly at melanoma site. Dominant lymphatic channels
is the case in Spitz naevi. They can form growth phase is the ability of the lesional pass laterally to both axillae and upwards to inter-
elongated, sometimes sinuous fascicles, cells to survive and proliferate in the der- val nodes on back. Delayed scans 2 h later show a
especially in melanomas with neuroid dif- mis. This ability may be manifested by single sentinel node in each axilla and three inter-
val nodes (also sentinel nodes in this patient) on
ferentiation and in desmoplastic melano- growth to form a true “tumour” or
upper back. From J.F. Thompson et al. {2348A},
mas. The spindled melanocytes of swelling, or by the presence of mitotic
with kind permission of The Lancet.
desmoplastic melanoma can also be activity. Tumorigenic vertical growth is
found singly between thickened collagen easily recognized when there is a bulky
bundles. They tend to be hyperchromat- nodule present. In thin lesions, such as 2088}. The reason why “dormant” metas-
ic, and have irregular nuclear mem- AJCC stage I melanomas, either of two tases begin to grow after such a long
branes and small nucleoli. criteria suffices for the diagnosis of verti- time is yet unknown.
Melanocytes with abundant pale cyto- cal growth phase, namely the presence In most patients with metastatic disease,
plasm and dusty melanin (large, pale of either “tumorigenicity” or “mitogenici- the regional lymph nodes are affected
melanocytes) are typically present in the ty”. The term "mitogenic" refers to the first, but distant metastases may be
dermis in some dysplastic naevi, naevi at presence of any mitotic figures in lesion- observed in patients who do not have
special sites (scalp, breast and genitalia) al cells in the dermis. The term “tumori- obvious lymph node involvement.
and in deep penetrating naevi. They are genic” is here defined as the presence of Besides lymph nodes, the most common
a common cytologic type in melanoma, a cluster of cells in the dermis larger than site of metastatic spread is the skin.
especially in the superficial spreading the largest intraepidermal cluster. Visceral metastases are more frequently
and nodular patterns. located in the lungs, liver, central nerv-
Small round melanocytes with scant ous system, and bones, but any organ
cytoplasm, resembling those of the Metastatic spread may be affected.
mature portion of a naevus can predomi- In 1992, sentinel node (SN) biopsy was
nate in naevoid melanomas Most distant metastases from melanoma proposed as a minimally invasive proce-
become evident clinically or are detect- dure that provided accurate assessment
Radial and vertical growth ed during follow-up visits within a few of regional node status in melanoma
Radial growth phase years from excision of the primary patients {1655}, allowing full regional
Most melanomas evolve through an initial tumour. However, it is important to node dissection to be avoided in the
stage of tumor progression, as a flat or remember that late metastases (> 10 80% of patients who had negative SNs.
plaque - like lesion which expands along years, sometimes even over 25 years The SN concept is simple: lymph drain-
the radii of an imperfect circle. Because after excision of the primary tumour) are ing from a tumour site passes first to a
of this clinical analogy, this phase has not uncommon in this neoplasm {566, so-called sentinel node before onward
been termed the “radial growth phase”
Table 2.02
The radial growth phase may be in situ Melanoma antigens
(confined to the epidermis), or in situ and
invasive, but in the latter case the cells Type of antigen Antigen
do not have capacity for proliferation in
the dermis {674,832}. Proliferation in the Differentiation antigens Tyrosinase, gp100, Melan-A/MART-1, TRP-1,
TRP-2, MC1R, AIM-1
epidermis may give rise to a pattern of
Gangliosides GM3, GD3, GD2, GM2, 0-acteyl GD3
single cells, or of clusters or nests of
Mutated proteins CDK4, ß-catenin, CDC27, MUM-2,
atypical neoplastic melanocytes. Like the triosephosphate isomerase
cells of junctional nevi, which may Products of unusual DNA transcrips TRP-2, N-acteylglucosaminyl transferase
migrate into the dermis to form com- Cancer / testis antigens (CTAs) MAGE, BAGE, GAGE, RAGE, NY-ESO-1
pound nevi, the cells of in situ

Malignant melanoma: Introduction 61

Table 2.03 many melanoma patients before SN
Melanoma markers biopsy provided important new insights
Type of marker Marker1
into cutaneous lymphatic drainage path-
ways {2348,2396} and this new informa-
Differentiation Tyrosinase, TRP-1, AIM-1 Mitf, tion highlighted the importance of preop-
gp100, TRP-2, S-100 HMW-MAA erative lymphoscintigraphy before
Melan-A/MART-1 MC1R undertaking a SN biopsy procedure.
Progression The prognostic value of determining SN
Proliferation Cyclin A ↑ Cdk2 ↑ p21 ↑ PCNA ↑ status has now been shown in several
Cyclin B1 ↑ p15 ↓ p27 ↓ mdm-2 ↑ large studies. All show a large difference
Cyclin D1/D3 ↑ p16 ↓ Ki67 ↑ telomerase ↑ in probability of 5-year survival between
Cyclin E ↑
patients who are SN positive and those
Signaling c-Kit ↓ N-ras ↑ EGFR ↑ PTEN ↓
c-Myc ↑ α-catenin ↓ Transferrin
who are SN negative, independently of
receptor ↑ other prognostic variables. Results from
Transcription ATF-1 ↑ AP-2 ↓ the Sydney Melanoma Unit {2565} are
Adhesion E-Cadherin ↓ ICAM-1 ↑ ALCAM ↑ α4ß1 ↑ typical, with a 5-year survival rate of 56%
N-Cadherin ↑ MCAM ↑ αvß3 ↑ CD44 v6 ↑ for SN positive patients (n=145) and 90%
VCAM-1 ↓ for SN negative patients (n=846).
Proteases MMP-1 ↑ MMP-13 ↑ TIMP-3 ↑ PA-system ↑ Prognostic information from SN biopsies
MMP-2 ↑ MT1-MMP ↑ EMMPRIN ↑ Cathepsin B, may be further refined by PCR to detect
MMP-9 ↑ TIMP-1 ↑ D, H, L ↑ melanoma-specific mRNA in lymph
Other ME491/CD63 ↓ HLA class I ↓ Osteonectin ↑ Fas/Fas ligand
nodes that are negative by standard
HLA Class II ↑ CTAs ↑ ↑
histopathological techniques {1916}.
↑ Upregulation with tumour progression; ↓ downregulation with tumour progression SN assessment not only provides impor-
tant prognostic information; resent clini-
cla trials suggest that as an removal, with
complet regional node field dissecion if
passage to other nodes in the regional the USA {1915} and Australia {2347}. micrometastatic melanoma is found,
node field. Thus the SN is most likely to It soon became clear that identification of improves the survival of patients
contain tumour cells, and if none are this node was most accurate if three {1655A}.
present in this node, tumour cells are methods were used: a preoperative lym-
unlikely to be present in other nodes in phoscintigram, injection of blue dye Stage distribution
the node field. Within 3 years of the land- around the primary melanoma site imme- Survival from melanoma is related to
mark publication by Morton et al {1915}, diately preoperatively, and the use of a stage at diagnosis. The stage distribution
confirmation of the accuracy of such hand-held gamma probe intraoperative- is generally more favourable in high-
assessment was provided by studies in ly. Preoperative lymphoscintigraphy for resource settings, and thus countries
with high incidence rates tend to also
have better survival than lower incidence
(and lower resource) countries {608,
Most melanomas are localized in high
incidence countries and the proportion
that are localized continues to increase
with time. Of the cases reported in the
U.S. SEER program 1992-1998, 82% had
localized disease, 9% regional disease,
4% distant metastases, and 6% were
unstaged {186}.
Young patients and women are often
diagnosed with melanomas that have a
thinner Breslow thickness than older
patients and men. Because of the shift in
the stage distribution of melanomas
towards thinner lesions, together with a
disproportionate increase in incidence
relative to mortality, some have ques-
tioned whether some of these thin lesions
A B that were removed would have ever pro-
Fig. 2.10 Immunoreactivity of melanoma. A Immunohistochemical staining for S-100 of dendritic cells in gressed to metastatic disease {353}.
reactive lymphadenopathy and B Melanoma micrometastasis in a sentinel lymph node.

62 Melanocytic tumours
also ectopic melanin synthesis in cells of markers for the other diagnostic options
other lineages. Differentiation markers are negative. Given the low specificity of
show a broad expression in many benign S-100 for melanocytic differentiation the
melanocytic lesions and (most) primary diagnosis has to be substantiated. For
melanomas. However, in melanoma this purpose MART-1 (syn. Melan-A) is a
metastases expression decreases which powerful marker both having a high sen-
is accompanied by heterogeneity. sitivity and specificity. Its sensitivity is
higher than gp100 (recognized by
Progression markers HMB45) in cutaneous melanoma and
These markers are preferentially metastasis, although in non-cutaneous
expressed in one or few stages in melanoma it may be the reverse.
melanocytic tumour progression. Based
on their tissue distribution, early, interme- Immunotherapy
diate and late progression markers are Vaccination trials have been started
discerned. Progression markers include using gp100 and tyrosinase presented
molecules that are involved in key by dendritic cells, and MAGE3. Patients
A B processes in the pathogenesis of metas- are selected on the basis of an appropri-
Fig. 2.11 Immunoreactivity for A gp100 and B tasis, i.e. proliferation, migration and ate HLA haplotype and extent of antigen
MART-1 of metastatic melanoma cells. Note the
matrix degradation. They may be derived expressed {611}. Expression of gp100
extranodal tumour embolus in A (arrow).
from the neoplastic cells and/or the stro- and tyrosinase is estimated on immuno-
mal cells, and serve as targets for vari- histochemically stained melanoma
Immunoprofile ous clinical interventions. slides; for MAGE3 RT-PCR is used.

Melanoma antigens Other markers

The term “melanoma antigen” is used These represent molecules that cannot Genetic susceptibility
two-fold. Firstly, it refers to a large variety be incorporated into either of the above
of molecules recognized by (monoclon- groups. If melanoma runs in the family (i.e. if a
al) antibodies, that were generated to parent or sibling was diagnosed with a
explore their potential as biological Clinical applications malignant cutaneous melanoma), the rel-
and/or clinical markers. Secondly, The markers mentioned can be used for ative risk of developing a melanoma
melanoma antigen in a strict sense several clinical applications {392}. For compared to persons without a family
implies a tumour molecule that evokes an this purpose currently immunohisto- history of melanoma is 2-3 {1006} and
immune response in the autologous host chemistry on paraplast embedded tissue some melanoma pedigrees have been
{1944}. Some overlap exists between sections is applied, preferentially discovered. Clustering of melanoma in
genuine melanoma antigens and employing a red chromagen in order to families is however not frequent and the
melanoma markers. Melanoma antigens contrast with the brown colour of genes implicated in large melanoma
currently are used in vaccination trials. melanin. For some applications RT-PCR families probably only play a small role in
is used. population-based melanomas. Two
Melanoma markers genes have been discovered in
Three groups of markers can be distin- Differential diagnosis of poorly melanoma families: CDKN2A (p16) on
guished: differentiated malignant tumours chromosome 9p21, and CDK4 on chro-
In case of a differential diagnosis mosome 12. Mutations in the CDKN2A
Differentiation markers between poorly differentiated carcinoma, gene have been found in up to 25% of
These markers indicate melanocytic dif- sarcoma, lymphoma and melanoma a melanoma families worldwide, whereas
ferentiation which is manifested by signs panel of various differentiation markers is CDK4 has only been observed in a few
of melanin synthesis. Hereby cells of the applied. Melanoma is likely if the tumour rare families. The CDKN2A/p16 gene
melanocytic lineage are identified, but is diffusely staining for S-100 and the acts as a tumour suppressor gene and
plays a crucial role in cell cycle regula-
Table 2.04 tion and senescence. The p16 protein is
Prognostic indicators for melanoma. a cyclin-dependent kinase inhibitor
which works by binding to CDK4.The
Prognostic factor Most favourable when: p16 gene tends to be transmitted in an
autosomal dominant fashion. Its pene-
Breslow thickness Thin (<1.51 mm) trance varies with population incidence
Histology Superficial spreading melanoma rates, indicating that the same factors
Age Young
that affect population incidence of
Sex Female
Body site Not on the trunk, hands, feet
melanoma may also mediate CDKN2A
Ulceration Absent penetrance. The frequency of mutated
Mitotic index Low p16 in the general population is estimat-
ed to be 0.01% {176}.

Malignant melanoma: Introduction 63

Other genes, such as MC1R (Melano-
cortin 1 Receptor) and DNA repair
genes, are likely to be more important in
determining susceptibility for melanoma
in the general population. The MC1R
gene is involved in skin and hair pigmen-
tation and in senescence and immunity
{176,251,2385}. Patients with inherited
abnormalities in the DNA repair system,
like xeroderma pigmentosum patients,
are at a 1000-fold increased risk {891}.

Prognosis and predictive


Melanoma thickness, body site, histolog-

ical type of the melanoma, gender of the
Fig. 2.12 Thickness and prognosis. Kaplan-Meier ten year survival curves by thickness, SEER cohort.
patient and ulceration are important indi-
Thickness groups presented in various colours are from top to bottom <1.00mm, 1.01-2mm, 2.01-3.0 mm, 3.0-
cators of patient prognosis {130}.
5.0 and >5mm, respectively. Adapted from Gimotty et al, 2005 {830}.
Generally, older patients do less well
than younger patients for the same
tumour thickness, while females do bet- Clark’s levels of invasion tion. For any given thickness level, the
ter than males. Superficial spreading First described in 1967, these attributes prognosis is significantly worse when
melanomas generally have a better prog- along with Breslow’s thickness measure- ulceration is present. In “thin”
nosis compared with other histological ments are the best known prognostic melanomas (Breslow thickness less than
subtypes, because they usually have a attributes for melanoma {492}. In Clark’s 1 mm) this remains true however only a
thin Breslow thickness {1471}. One level I, the melanoma is confined to the few melanomas are ulcerated. Ulceration
report suggests that sun exposure is epidermis (melanoma in situ). In level II, loses its significance when mitotic rate is
associated with increased survival from melanoma cells are present in the papil- included in a population based multivari-
melanoma {224}. lary dermis, which may be expanded but able prognostic model {160}.
Reports on prognosis from specialized has not filled by tumour. Most level II
centres {130}, may contain survival rates melanomas are non-tumourigenic, but a Mitotic rate
lower than reported by population based few meet criteria for tumourigenicity dis- Mitotic rate was the single strongest
cancer registries {2051}, possibly cussed above. In level III, there is a attribute in the 1989 Clark prognostic
because patients with less favourable tumour that fills and expands the papil- model, which was developed in a cohort
prognosis are being referred to special- lary dermis. In level IV, tumour cells infil- of patients all of whom had vertical
ized centres. trate to the collagen fibres of the reticular growth phase. Patients with a mitotic rate
dermis which unlike the papillary dermis of six or greater were at approximate
Morphological prognostic factors are not specialized maintain epithelium. twelve-fold greater risk of metastasis
Several clinical and histologic attributes In level V, the subcutaneous tissue is infil- than patients whose tumours had no
are useful in predicting the probability of trated. mitoses {491}. In addition, the presence
survival for patients with melanoma, and, of any mitoses at all in the dermis (“mito-
as targeted therapies begin to be devel- Breslow’s thickness genicity”) is predictive not only of survival
oped, no doubt these or similar attributes According to Breslow’s definition, pub- {831} but also of sentinel lymph node
may be useful in predicting therapeutic lished in 1969, thickness is measured positivity {1251}.
responsiveness. Staging of melanoma from the top of the granular layer to the
has been discussed above, and in the deepest invasive tumour cell. This can Tumour infiltrating lymphocytes
2002 AJCC classification, this staging occasionally be misleading, for example First demonstrated in the 1989 Clark
includes clinical as well as histologic when there is marked epithelial hyperpla- model {491} and later confirmed by oth-
attributes {130}. The basic purpose of sia but only a few tumour cells are pres- ers {502,1609}, the presence of “brisk”
staging is to describe the clinical extent ent in the dermis. In the 2002 AJCC stag- tumour infiltrating lymphocytes (lympho-
of disease. This may be done by physical ing system, thickness is grouped in 1 mm cytes present among and in contiguity
exam, by clinical investigations, and by intervals {130}. If only one attribute is with tumour cells) is almost as powerful
gross and microscopic pathologic exam- known, thickness is the single strongest an attribute as mitotic rate.
ination. The process of predicting prog- prognostic attribute for melanoma.
nosis using pathological attributes may Lymphovascular invasion
be referred to as “microstaging”. Some of Ulceration Although not commonly observed, and
these attributes useful in prognostication Ulceration is a significant stage modify- therefore not found to be an independent
are discussed below. ing factor in the 2002 AJCC classifica- factor in most prognostic models, vascu-

64 Melanocytic tumours
lar invasion when present appears to be tumour thickness and ulceration. A list of
associated with a worse prognosis prognostic markers is presented in Table
{1213}. 2.5. It should be noted here that the clin-
ical relevance of these markers is
Radial growth phase regression increasing as the primary melanomas
Several studies have demonstrated currently diagnosed are relatively thin
worse prognosis when radial growth (1.0-1.5 mm) and rarely show ulceration.
phase regression is present {491}. It is expected that a set of prognostic
Possibly in these cases, a small area of markers may help to select melanoma
tumourigenic vertical growth phase was patients for adjuvant therapy. Such a set
present before the regression obliterated may be designed on the basis of the out-
it. come of ongoing expression array stud-
Microscopic satellites 2. Microstaging. The presence of
Like clinical satellites, microscopic satel- melanoma deposits in various stages of
lites are indicative of a lesion with com- the disease is assessed by the demon-
petence for metastasis and are associat- stration of differentiation markers.
ed with a worse prognosis {962}. However, they may decrease during
tumour progression and do not reveal the
Patient gender and lesional cell location aggressiveness of the tumour cells.
In most series, even when other prog- Nevertheless, the extension of the pri-
nostic factors are controlled, female mary tumour that includes thickness
patients have better survivals, and the measurement and identification of
survival is better for patients whose microsallelites, can be facilitated by S-
lesions are on the limbs compared to the 100 or MART-1 immunohistochemistry.
trunk or extremities {491}. This also is applicable for the detection
of melanoma cells in sentinel nodes.
Immunoprofiling for the assessment Immunohistochemistry on serial sections
of prognosis is preferred to molecular staging of sen-
Two strategies are followed: tinel nodes as it has a similar sensitivity,
1. Identification of markers suggestive of a higher specificity and it preserves mor-
aggressive subpopulations in primary phology.
melanoma {1990}. For this purpose late
progression markers are used. Only a
limited number of progression markers
have prognostic implication independent
of the conventional dominant factors, i.e.

Table 2.05
Prognostic markers in malignant melanoma

Marker Expression Prognosis1

Ki67 ↑ _
PCNA ↑ _
Cyclin A ↑ _
p16 ↓ _
αvβ3 ↑ _
ICAM-1 ↑ _
CD44 ↑ +
MMP-2 ↑ _
t-PA ↑ +
gp100 ↓ _
Mitf ↑ +
c-kit ↓ _
c-myc ↑ _
p53 ↑ +
Osteonectin ↑ _

-: Unfavourable: +: favourable

Malignant melanoma: Introduction 65

Superficial spreading melanoma E. Haneke
B.C. Bastian

Definition Localization matic, but can present with bleeding

Superficial spreading melanoma (SSM) SSM may appear on almost the entire once the lesion ulcerates.
is a subtype of melanoma which tends to body, particularly on sites with acute-
occur on usually covered skin and is intermittent sun exposure. SSM in women Histopathology
characterized by a radial growth phase is most frequently observed on the legs, SSM in situ or the intraepidermal part of
comprised of large neoplastic in men more commonly on the trunk. an invasive lesion stands out by pagetoid
melanocytes that extend among ker- spread throughout the epidermis of atyp-
atinocytes in a “buckshot” or pagetoid Clinical features ical melanocytes that often have large
pattern {493,494}. It is controversial Signs and symptoms nuclei and nucleoli and abundant pale
whether SSM is truly different from other SSM in situ begins as an irregularly pig- cytoplasm. Mitoses are frequently
melanoma forms of the skin or whether mented and outlined macule. With the absent. The melanocytes may be distrib-
the differences are only due to differ- onset of invasion, it develops into a uted singly or in nests. The distribution is
ences in the skin architecture {22}. slightly raised plaque. Its borders are often irregular and the nests may have
usually sharply delimited, often irregular irregular shapes or show confluence.
ICD-O 8743/3 indicating progressive peripheral exten- Poor lateral circumscription is often pres-
sion, but they may also be ill-defined. ent, with single enlarged melanocytes
Synonym The pigmentation within an individual found lateral to the last nest. Hair follicles
Pagetoid melanoma. lesion varies from light to dark brown to and eccrine duct epithelium can be
even jet-black. Grey or white areas indi- involved in a similar pattern. To one side
Epidemiology cate regression. White vitiliginous areas, or in the subjacent dermis there may be
SSM makes up almost two thirds of all sometimes even poliosis (white hair) may a residuum of a naevus. In MIS the stro-
melanomas in light-skinned people be observed. Red areas are due to mal and inflammatory reaction tends to
(Fitzpatrick skin types 1–3) and is thus inflammation or increased vascularity. be inconspicuous and can be absent. An
the most frequent subtype of all Some SSMs are amelanotic, resembling irregular distribution of lymphocytes
melanomas. The sex incidence is identi- Bowen or Paget disease. The tumour and/or melanophages may be a diag-
cal in most areas. may reach a considerable diameter until nostic clue that the lesion is a melanoma.
it develops a papule representing the Actinic elastosis may or may not be
Etiology transition from the radial growth to verti- present.
Its etiology is not exactly clarified, how- cal growth phase of SSM. These papules With development of invasive melanoma,
ever, repeated severe sunburns in child- tend to become erosive, ulcerated and an asymmetric outline becomes a major
hood appear to play an important role. crusted with a tendency to easy bleed- characteristic. Extensive and highly
Intermittent sun exposure in adult life is ing. In rare instances satellite nodules irregular junctional tumour nests are
also important. are present. Most lesions are asympto- found at a variable distance to each

Fig. 2.13 Superficial spreading melanoma. A Low power magnification of the papular component. B Pagetoid spread of single melanocytes as is typically found in
many examples.

66 Melanocytic tumours
Fig. 2.14 Superficial spreading melanoma. A Single cells and small nests are irregualrly arranged along the junction. Toward the centre a large melanocyte is pres-
ent in mid-spinous layer. A Langerhans cell is in nearly the same position toward the edge but is much smaller. B The invasive portion of the melanoma, showing
nuclear pleomorphism. At the base there is a lymphocytic infiltrate.

other and may merge. There is often a of the lesion. In both forms there is fibro- somal aberrations in SSM are losses of
lack of maturation, manifested by a fail- sis of the papillary dermis, vascular pro- chromosomes 9, 10, 6q, 8p and gains of
ure of nests, cells, nuclei or nucleoli to liferation and ectasia, and variably dense chromosomes 1q, 6p, 7, 8q and 20 {173}
become smaller towards the base of the infiltrates of lymphocytes and melano- Melanomas with increased copies of
lesion. Pigment is often irregularly distrib- phages. The epidermis may show loss of chromosome 7 that show mutations of B-
uted. Mitoses, sometimes atypical, are rete ridges. The type of regression raf selectively increase the copy number
often seen whereas necrotic melano- described above affects the radial of the mutated allele suggesting that the
cytes are rarely identified. A lymphocytic growth phase. Occasionally, a vertical mutation precedes the chromosomal
infiltrate may be present at the base of growth phase may undergo regression, aberration {1493} The minimal deleted
the neoplasm or may infiltrate among its and sometimes the regressed portion region on chromosome 9 includes the
cells (so called tumour infiltrating lym- may be replaced by a large mass of CDKN2A locus on 9p21 as can be seen
phocytes or TILS). Melanoma may melanophages, representing a phenom- by high-resolution comparative genomic
undergo regression, which clinically and enon called “tumoural melanosis”. hybridization (CGH) {876}
grossly most often involves a portion of
the lesion, or occasionally its entirety. Immunoprofile Prognosis and predictive factors
Histologically this regression may be There are no specific differences in the The prognosis of SSM does not differ sig-
complete or partial within a given area. immunophenotype of SSM and other nificantly from other forms of melanoma
Complete regression of a portion of a forms of melanoma. (see Introduction).
melanoma (“segmental regression”) is
manifested by absence of melanocytes Somatic genetics
in the affected area. In partial regression, SSM has a high incidence of mutations in
there is a strikingly diminished number of the BRAF oncogene on chromosome
melanocytes compared to the remainder 7q34 {1493}. The most common chromo-

Superficial spreading melanoma 67

Nodular melanoma R. Bergman
S. Brückner-Tuderman
J. Hercogova
B.C. Bastian

Definition Localization ence and location of any metastases

Nodular melanoma (NM) is a subtype of NM may occur in any location, but as for (TNM staging) {130}.
malignant melanoma (MM) exclusively in SSM, it is more common on the trunk,
vertical growth phase. head and neck, and lower legs {163}. Histopathology
Scanning magnification discloses a
ICD-O code 8721/3 Clinical features raised, dome-shaped, or polypoid
NMs typically present as a rapidly tumour, often, but not always, exhibiting
Epidemiology expanding papule, nodule or plaque. some asymmetry. The overlying epider-
In most parts of the world, NM is the sec- They are occasionally polypoidal and mis may be thin, effaced or ulcerated.
ond most common subtype of MM, and even pedunculated. They are usually Melanoma cells may be present in the
accounts for 10 to 15% of all melanomas well circumscribed and symmetric and overlying epidermis but not beyond the
in Caucasian people {163,436}. NM frequently reach a size of approximately margins of the dermal component (some
appears on the average, in older individ- 1 cm before diagnosis. The skin mark- allow an extension up to 3 adjacent epi-
uals than the common superficial ings are often obliterated with frequent dermal rete ridges beyond the dermal
spreading MM (SSM) {436,493}. ulceration and crust. The colour is often component). The dermal component is
black or blue, although a subset of NM is typified by a cohesive nodule or small
Etiology amelanotic. The amelanotic variety fre- nests of tumour cells that have a “push-
Most of the skin characteristics and risk quently has a subtle blush or peripheral ing” or “expansile” pattern of growth. The
factors associated with the development rim of pigment {163,436}. tumour cells most frequently are epithe-
of NM are similar to those of SSM {1364}, lioid, but other cell types, including spin-
including fair or red hair, blue eyes, fair Macroscopy dle cells, small epithelioid cells resem-
skin, tendency to develop freckles and As in the clinical features bling naevus cells, and giant mononu-
sunburns, excessive exposure to ultravi- clear or multinucleate forms, may pre-
olet radiation, numerous common naevi, Tumour spread and staging dominate or be admixed with other cell
giant congenital naevi, atypical (dysplas- The tumour spreads first to the local types. The cell population usually
tic) naevi, melanoma in a first degree rel- lymph nodes and then to internal organs. appears monomorphous but closer
ative, familial atypical mole-melanoma The staging system devised by the examination reveals frequent cellular
syndrome, immunosuppression, xeroder- American Joint Committee on Cancer enlargement, nuclear enlargement, vari-
ma pigmentosum and prior melanoma includes aspects of the primary tumour, ation in nuclear size and shape, hyper-
{624,2304}. the status of lymph nodes, and the pres- chromatism, and prominent nucleoli.

Fig. 2.15 Nodular melanoma. A On scanning magnification the tumour has a polypoid configuration with slight asymmetry. Cohesive nodules of tumour cells fill the
dermis. B Superficial portion of the tumour. Epithelioid melanoma cells are present as single units and in nests that vary in size and shape along the dermoepider-
mal junction and above it. Similar nests are present in the upper dermis along with numerous melanophages and lymphocytic infiltrates. Some of the epithelioid
melanoma cells contain fine melanin granules.

68 Melanocytic tumours
Fig. 2.16 A Nodular melanoma with asymmetrical distribution of lesional cells, lymphoctic infiltrates and melanophages. B The tumour is composed of melanocytes
with large, pleomorphic, vesicular nuclei, some in mitosis.

High nuclear-to-cytoplasmic ratios are found in other tumours. Other frequent Prognosis and predictive factors
often noted. The tumour cells fail to findings are nuclear pseudoinclusions, In the T (tumour) category, tumour thick-
“mature” with progressive descent into prominent nucleoli and cytoplasmic inter- ness increased mitotic rate and ulcera-
the dermis. The cytoplasm of the epithe- mediate filaments corresponding mor- tion are the most powerful predictors of
lioid cells often has eosinophilic granular phologically to vimentin filaments. In a survival, and the level of invasion has a
qualities. It may contain melanin gran- minority of melanomas poorly developed significant impact only within the sub-
ules that vary in size, or appear fine and intercellular junctions may be present group of thin (≤1 mm) melanomas {131}.
“dusty”. There is absence of melanin in {1016}. Other adverse prognostic factors include
the amelanotic tumours. The surrounding increased tumour vascularity, vascular
stroma may demonstrate variable Precursor lesions and histogenesis invasion, microscopic satellites, male
mononuclear cell infiltrates, fibroplasia, It is more common for NM to begin de gender, increased age, and anatomic
telangiectasia, and melanophages novo than to arise in a pre-existing nae- location on the head, neck and trunk
{154,163}. vus {163}. One hypothesis holds that NM {122,1528,2597}. In the N (nodes) cate-
represents a final common pathway of gory the following three independent fac-
Immunoprofile very rapid tumour progression from a tors have been identified: the number of
S-100 protein, HMB-45, Melan A (MART- brief intraepidermal proliferative phase of metastatic nodes, whether nodal metas-
1), MAGE-1, NKI/C-3, tyrosinase, SSM, lentigo maligna, or acral lentigi- tases were clinically occult or clinically
melanoma cell adhesion molecule (Mel- nous MM {154,163}. apparent, and the presence or absence
CAM) MUC18 and microphthalmia tran- of primary tumour ulceration. In the M
scription factor (MITF), are expressed by Somatic genetics (metastases) category, nonvisceral
most melanomas {732,1500,1855}. Comparative genomic hybridization and metastases are associated with a better
Melanoma cells also express bcl-2 pro- mutation analyses have revealed marked survival compared with visceral metas-
tein, neuron specific enolase and differences between melanomas tases {131}.
vimentin {626,1861,2131}. Antigens depending on the anatomic site and sun-
which may demonstrate higher rates of exposure patterns {173,1493}. These
expression in melanoma cells than in studies did not find unique genetic fea-
naevus cells include Ki-67 (MIB-1), prolif- tures in nodular melanomas that justify
erating nuclear antigen (PCNA), p53, regarding them as a unique type, sup-
cyclin D1, and p21 WAF1(9). The loss of porting the ‘common pathway hypothesis
expression of CDKN2A (cyclin depen- {154,163}.
dant kinase inhibitor), and the increased
expression of ß3 integrin, have been Genetic susceptibility
associated with vertical growth phase The proportion of melanomas that have a
and more invasive forms of melanomas familial basis ranges from 6% to 14%.
{1029,1500,1904,2277,2278,2406}. Approximately 20% of all individuals with
a family history of melanoma have muta-
Electron microscopy tions in CDKN2A which maps to chromo-
The demonstration of stage II some 9p21. In a very few families CDK4
melanosomes is the hallmark of mapping to chromosome 12q14 has
melanoma diagnosis. They are rarely been found to be mutated {1851}.

Nodular melanoma 69
Lentigo maligna P. Heenan
A. Spatz
R. Cerio
B.C. Bastian

Definition described it as “senile freckle” in 1892 of melanoma in situ on the head and
Lentigo maligna (LM) is a form of {1090} and subsequently as “lentigo- neck and that patients with LM are less
melanoma in situ that occurs on the sun melanosis” {1089}. Dubreuilh {652} likely than patients with melanomas of
exposed skin of elderly people, mainly described these lesions as “mélanose the trunk to have more than 60 naevi
on the face but also, less often, at circonscrite précancereuse” which sub- whereas they had a stronger association
extrafacial sites including the neck, sequently came into common use as with the number of solar keratoses
upper back and forearm. It is character- melanosis circumscripta precancerosa {2508}.
ized histologically by linear and nested until the classification of Clark {492} in
proliferation of atypical melanocytes 1967 introduced the category of Pathogenesis
along the dermo-epidermal junction and melanoma commencing in lentigo According to some authorities, the term
down the walls of hair follicles and sweat maligna (Hutchinson’s melanotic freckle). LM encompasses a phase regarded as a
ducts. The melanocytic lesion is associ- That classification was widely but not uni- melanoma precursor in which there is
ated with severe actinic damage, mani- versally accepted; the World Health proliferation of melanocytes in severely
fested by epidermal atrophy and solar Organisation (WHO) classification of sun damaged skin in intermittent pattern
elastosis. When dermal invasion by atyp- 1974 classified superficial spreading without the confluent growth, pagetoid
ical melanocytes occurs in association melanoma and melanoma arising in spread and nesting of atypical melano-
with (LM), the term lentigo maligna Hutchinson melanotic freckle (lentigo cytes that, according to this concept,
melanoma (LMM) is used. maligna melanoma) in one category represent malignant melanoma in-situ of
{2337}. The World Health Organization LM type, whereas the lesions with less
ICD-O code 8742/2 (WHO) classification of 1996 separated severe, intermittent junctional prolifera-
melanoma in-situ into superficial spread- tion are termed atypical melanocytic
Synonyms and historical annotation ing or pagetoid type and lentigo maligna hyperplasia {759} or, preferably, atypical
LM has also been known as Hutchinson melanoma, whilst acknowledging that lentiginous melanocytic proliferation.
melanotic freckle, after Hutchinson first there may be no essential biological dif-
ference between some or perhaps all Localization
categories of melanoma {999}. Head and neck are by far the most com-
mon sites in both sexes. Extrafacial LMM
Etiology differs in its site distribution between
The strong association between LM and women and men {549}. A study in
its occurrence in the severely sun dam- Scotland showed that extrafacial LMM in
aged skin of elderly people has been men occurred mainly on the trunk where-
widely accepted as evidence that LM as in women 80% occurred on the limbs,
and LMM represent a distinctive form of mainly the lower leg. The mean age of
melanoma, resembling etiologically the patients with extrafacial LMM was signif-
non-melanocytic skin cancers, and sug- icantly lower than that of patients with
gesting that LM arises in response to head and neck LM, suggesting that the
accumulated sun exposure, in contrast association between LMM and sunlight
with the more common forms of may not be related only to the cumulative
melanoma that appear to be related to effects of solar exposure.
intermittent sun exposure {1048}. It has
also been suggested, however, that dif- Clinical features
ferences in body site distribution LM may be recognized as a small lesion,
between the commonly accepted differ- usually as a mottled light brown macule
ent types of melanoma, through their with irregular margins on the face of a fair
interaction with amount and pattern of skinned elderly patient with evidence of
sun exposure, can explain virtually all the severe solar skin damage, only a few mil-
observed pathological and epidemiolog- limetres in diameter, but usually greater
ical differences between LM and the than 10 mm. The classical lesions are
more common types of melanoma that broad, flat zones of varied pigmentation
Fig. 2.17 Lentigo maligna. Broad, flat, variably pig- occur in widespread anatomical distribu- with an irregular border. With increasing
mented lesion with a very irregular, ill-defined bor- tion {16,996}. Recent studies have found size of the lesion, variation in pigment
der on the cheek of a 78-year-old patient. that LM remains the main histologic type and irregularity of the border also

70 Melanocytic tumours
become more pronounced, nodules may
develop within the lesion and the borders
may become difficult or impossible to
define where zones of pallor or mottled
pigmentation merge imperceptibly with
the surrounding skin.

LM is characterized by a predominantly
junctional proliferation of atypical
melanocytes, frequently extending down
the walls of hair follicles and sweat ducts,
in association with epidermal atrophy
and severe solar elastosis. Although the
junctional proliferation may form conflu-
ent linear pattern in some areas, else-
where the atypical melanocytes may be
distributed as single units separated by
basal cells. Irregular junctional nests of A
atypical melanocytes are frequently
present, as are multinucleate giant cells
including those of starburst type {512}.
Marked pleomorphism is a feature of the
atypical melanocytes which show cyto-
plasmic retraction artefact and nuclei of
stellate, ovoid and crescentic forms,
some of them pressed against the cell
wall, with a variable chromatin pattern
and clear or variably pigmented cyto-
plasm. Pagetoid foci of atypical epithe-
lioid melanocytes present an appear-
ance indistinguishable from melanoma in
situ of so-called superficial spreading
A lymphocytic infiltrate and focal fibro-
plasia are frequently present in the papil- B
lary dermis underlying LM, with severe Fig. 2.18 Lentigo maligna. A Atypical melanocytes, mainly epithelioid cells with clear cytoplasm, are
solar elastosis and telangiectasia. arranged in confluent pattern along the dermo-epidermal junction and extending down the wall of a central
hair follicle. A few single atypical melanocytes are also present above the basal layer. The epidermis is
Regression, shown by fibrosis, hypervas-
atrophic overlying severe elastosis. B Severe nuclear pleomorphism and scattered multinucleate giant
cularity, melanophages and a patchy
cells are present in the junctional proliferation and down the walls of adnexal structures including a sweat
lymphocytic infiltrate, is a common fea- duct.
ture and should prompt a careful search
for invasion by atypical melanocytes. The
presence of regression at a lateral mar- degree of pigmentation varies, including The degree of pigmentation in LM may
gin of excision should be emphasized in cells with abundant clear cytoplasm vary markedly between different exam-
the report as an indication for re-exci- adjacent to cells in which the morpholog- ples of the tumour and within one tumour.
sion, even when the margins appear ic detail may be obscured by coarse Zones of amelanosis at the periphery of
clear of atypical melanocytes. melanin granules. the lesion may lead to failure by the
In LMM, dermal invasion occurs in asso- The invasive component in LMM may be pathologist to detect atypical cells at the
ciation with LM. The invasive component desmoplastic and/or neurotropic with margin of excision, thus leading to per-
may consist of atypical melanocytic spin- very subtle, diffuse invasion that predis- sistent growth and “local recurrence” of
dle cells more frequently than is seen in poses to incomplete excision and true the tumour.
the other common forms of cutaneous local recurrence. Dermal invasion may
melanoma, but epithelioid, small naevoid also originate from atypical melanocytes Differential diagnosis
and tumour giant cells may also be pres- in the walls of hair follicles and sweat In cases of extensive amelanosis (ame-
ent in varied proportions. The cells of ducts, thus creating a problem in meas- lanotic LM) {60}, the distinction between
these various types may occur in cohe- urement of tumour thickness because it in-situ squamous cell carcinoma or extra-
sive groups, strands or as single cells in is inappropriate to measure tumour thick- mammary Paget disease may be difficult
a diffuse pattern, often associated with ness from the granular layer of the epi- in routine sections, necessitating the use
lymphocytes and melanophages. The dermis in this instance. of special stains to demonstrate epithe-

Lentigo maligna 71
Somatic genetics
A recent study has shown an association
between DNA repair-deficiency and a
high level of TP53 mutations in
melanomas of xeroderma pigmentosum
patients {2231}. The LMM found in xero-
derma pigmentosum patients of the XP
complementation group, group XP-C,
were associated with an accumulation of
unrepaired DNA lesions. Lentigo maligna
melanomas have been found to rarely
show mutations in BRAF {1493}.
Comparative genomic hybridization
shows more common losses involving
chromosome 13 and less common loss-
es of chromosome 10, when compared
to other melanoma types {173}.

Prognosis and predictive factors

Complete excision of lentigo maligna, as
a form of melanoma in situ and, there-
fore, incapable of metastasis, is curative.
Prognosis for LMM has been a con-
Fig. 2.19 Lentigo maligna. Focal pagetoid growth is present in addition to junctional proliferation including tentious issue. For many years, it was
small nests of atypical melanocytes. commonly believed that the prognosis
for melanomas of LMM type is better than
for other types of melanoma. Most evi-
lial mucin in extra-mammary Paget dis- Histogenesis dence, however, suggests that for
ease, and immunostaining, including the LM develops from epidermal melanomas classified as different types
use of antibodies to cytokeratins, melan- melanocytes, most likely due to the according to their histological features,
A and S-100 protein and, as further aids cumulative DNA damage resulting from their differences in survival correspond to
to the diagnosis of Paget disease, carci- long-term sun exposure {1048}. A recent differences in tumour thickness rather
noembryonic antigen, and BerEP4. study of the differential expression of pro- than to their differences in histologic type
The distinction between LM and benign liferation- and apoptosis-related markers {20,1296}.
forms of junctional melanocytic prolifera- in lentigo maligna and the keratinocytes
tion is made on the basis of the charac- in solar keratosis has found that the epi-
teristic cytologic atypia, confluent growth dermis in LM shows overall low prolifera-
of atypical cells along the junction with tion and a low apoptotic tendency, per-
frequent extension down the walls of haps aiding aberrant melanocyte prolif-
adnexal structures and, commonly, eration in the early stages of melanoma
extension of growth above the basal development {718}.
layer in pagetoid pattern.

72 Melanocytic tumours
Acral-lentiginous melanoma Y. Tokura
B.C. Bastian
L. Duncan

Definition gal-mucosal melanoma (P-S-M mela- an anatomic nomenclature, its use is dif-
Acral lentiginous melanoma (ALM) is a noma) {2129}, or unclassified plantar ferent among articles. We define it as a
distinct variant of cutaneous melanoma, melanoma {100}. Although often consid- melanoma located on the non-hair bear-
which occurs on the palms, soles, and ered to be interchangeable, ALM and ing skin of the palms and soles or under
subungual sites, and has a characteristic acral melanoma embody distinct con- the nails because of presentation of the
histologic picture. Following the three cepts that must be distinguished from genetic data. Although P-S-M melanoma
other major clinicopathological subtypes each other. ALM is a histologic designa- was described on the basis of clinical
of melanoma, i.e. superficial spreading tion that shows similarities to lentigo and histologic similarities between the
melanoma, lentigo maligna melanoma, maligna melanoma, while acral tumours on these sites, the acral
and nodular melanoma, ALM was pro- melanoma is an anatomic designation melanomas and mucosal ones are rec-
posed as the fourth subtype by Reed in that refers to melanoma located on the ommended to be treated separately,
1976 {1905}. In this article, we also use acral sites. Acral melanoma, thus, because of their different clinical behav-
the term acral melanoma and define it as encompasses both ALM and such sub- iours {494}.
a melanoma located on the non-hair types as superficial spreading
bearing skin of the palms and soles or melanoma and nodular melanoma that Epidemiology
under the nails. The reason for this usage may develop in acral locations. Racial differences are quite pronounced
is described below. Occasionally, the terms acral melanoma in the incidence and predilection sites of
and acral lentiginous melanoma are melanomas. This is particularly true for
ICD-O code 8744/3 used interchangeably, since the majority acral melanoma wherein acral melanoma
of cases of acral melanoma are ALM comprises 2% and 80% of cutaneous
Synonyms {1071,1592,1905} and the histological melanomas in Caucasian and dark-
Historically, this type of melanoma has distinction between ALM and superficial skinned patients respectively. In a
been designated as ALM {1905}, acral spreading melanoma is not always pos- German study approximately 7% of
melanoma {494}, palmar-plantar-subun- sible {2220}. Even if acral melanoma is patients with cutaneous melanoma had

Fig. 2.20 Acral-lentiginous melanoma (ALM). A ALM on the heel, showing varying shades of tan to brown pigmentation. B ALM on the lateral aspect of the foot,
showing irregularly bordered pigmentation with a slightly ulcerated lesion. C ALM on the sole, showing an irregularly pigmented macule with notched borders.
D ALM on the second toe, showing subungual pigmented lesion extending to adjacent skin.

Acral-lentiginous melanoma 73
Fig. 2.21 Acral-lentiginous melanoma. A ALM, showing marked acanthosis, elongation of the rete ridges, broadened horny layer, and large, atypical melanocytes
with large, often bizarre nuclei and nucleoli, and cytoplasm filled with melanin granules. B ALM, showing lentiginous proliferation of atypical melanocytes at the
border of the tumour.

tumours located on acral sites {1337}. effected twice as often as women {1220, occurrence on the thumbs and great
Whereas 77% of cutaneous melanoma in 1268,1428,2130}. On the other hand in toes may suggest a role for trauma in the
Japanese patients occurs on acral sites western countries, there is less of a male etiology of subungual melanoma {2130}.
{2130}. In African and African- predominance in patients with ALM Since sun exposure obviously plays little
Americans, the highest incidence of {1337,2220}. role in palmoplantar sites, the causative
cutaneous melanoma has been reported role of ultraviolet light is presumed to be
on relatively non-pigmented areas, such Localization negligible in ALM.
as the soles, nail plates, and mucous The term acral has been used differently
membranes {1417}. Thus, ALM is the throughout the literature. Most publica- Clinical features
most common type of melanoma in dark- tions use acral for the non-hair bearing, Acral melanomas in the early stages
skinned peoples and Asians {1268, i.e. glabrous skin of the palms and soles, appear as a pigmented macule similar to
2129}. Nevertheless the absolute inci- and the nail bed, whereas others also lentigo maligna. Acral melanomas com-
dence of acral melanoma in dark- include the dorsal aspect of the hands monly exhibit clinical evidence of a
skinned African and light-skinned and feet under this term. In a German biphasic growth pattern, with a more
Caucasian populations in North America study, using the latter definition, acral rapid evolution from an entirely flat clini-
is similar, suggesting that the observed melanoma occurred on the feet in 87% cal lesion to a lesion containing an ele-
racial difference may relate to a cases (plantar sites, 57%; subungual, vated focus than is observed in the other
decreased incidence of non-acral 5%; and dorsum, 9%) and on the hands types of melanoma. The radial growth
melanoma in African American popula- in 23% (palm, 1%; subungal, 14%; and phase of ALM is characterized by a mac-
tions {2268}. Compared with the escalat- dorsum, 9%) {1337}. Thus, the plantar ular pigmented lesion with highly irregu-
ing incidence that typifies other sites were greatly more often affected lar, notched borders and varying shades
melanoma subtypes, the incidence of than the palmar sites {1337,2130,2201, of pigmentation. Within a background
ALM has remained static {661}. 2220,2296}. In contrast to ALM, superfi- pigmented macule, acral melanomas
Overall, ALM occurs in an older patient cial spreading melanoma occurs more often develop a clinically apparent verti-
population than does superficial spread- commonly on the sun-exposed dorsal cal growth phase. This is manifest as an
ing or nodular melanoma, and, in popu- aspects of the hands and feet, whereas elevated papule or nodule, sometimes
lations where ALM is common, this nodular melanoma occurs on all acral with a verrucous surface, and corre-
tumour more often afflicts men than sites with relatively equal frequency sponds to the histological vertical growth
women. Overall, the age distribution of {1337}. In addition to the sole, nail plate phase of malignant melanocytes.
ALM is similar to that of lentigo maligna is an especially frequent site with a fre- Ulceration is more often seen in ALM
melanoma, peaking in the seventh quency of 16-19% in ALM {1337,2130}. than in other types of melanoma.
decade of life, whereas superficial In contrast to the palmar/plantar Subungual melanomas often begin as
spreading melanoma and nodular melanomas, subungual melanomas brown to black discolouration of the nail
melanoma peak in the sixth decade occur more often on the hands than on that frequently become bands or streaks
{1337}. The mean age of ALM ranges the feet {745,1221,2130,2315}. In the of pigmentation. Thickening, splitting, or
from 55 to 68 years in European coun- Japanese series, the number of subun- destruction of the nail plate may occur.
tries {767,1337,2123}. In Japanese gual melanomas on the fingers is 62-72% The irregular macular hyperpigmenta-
patients, there is a peak in the sixth and on the toes 28-38%, with an 82% tion, coloured tan to dark brown, is also
decade in both males and females. In incidence on the thumbs and great toes recognized around the nail plate {2130}.
Japan, Korea, and Taiwan, men are {1221,2130}. The high percentage of In one study, 17% of the patients noticed

74 Melanocytic tumours
the pre-existence of some pigmented cases, 95%) is a more sensitive marker fications in acral melanoma preferentially
skin lesions, and 21% related a history of than either HMB-45 (80%) or MART-1 involving chromosome 11q13. In addi-
trauma {2130}. Pigmented streaks are (70%) {1268}. However, S-100 protein- tion, the studies revealed that all
not uncommon in patients with deeply negative ALM has been reported {83}. melanomas showed these features, inde-
pigmented skin, nevertheless, a history The intesitity of HMB-45 but not of S-100 pendent of their histological growth pat-
of a new or recently changing pigmented protein is correlated well with the melanin tern, as long as they were located on
lesion should prompt the consideration content. HMB-45-negative cases are all glabrous, i.e. non-hair bearing skin of the
of a biopsy for histological evaluation of amelanotic, but amelanotic cases are not palms and soles or subungual sites
the lesion. In this case, reflection of the all negative for HMB-45 {1268}. The (Bastian et al, to be published). In addi-
proximal nail fold to enable biopsy of the melanoma cells also express vimentin tion, melanomas involving these anatom-
nail bed may be necessary for definitive {1268}. Focal staining for CAM5.2 or ic sites also had a significantly lower
diagnosis. epithelial membrane protein may occa- mutation rate of the BRAF oncogene
Unfortunately, clinical misdiagnosis is not sionally be found {1268}. (6/39, 15%) than melanomas on the trunk
uncommon in patients with ALM {409, (23/43, 53%) {1493}. The molecular
767,1327,1592,2222}. Therefore, aware- Somatic genetics genetic analyses therefore suggest
ness of atypical presentations of ALM Comparative genomic hybridization melanomas of the palms of soles and
that may contribute to misdiagnosis or (CGH) of melanomas on acral non-hair subungual sites represent a genetically
diagnostic delay assumes particular bearing skin showed distinct differences distinct form of melanoma, independent
importance. ALM lesions are frequently to melanomas on non-acral skin {171}. A of their histological growth pattern.
treated or followed for considerable time study of 15 acral melanomas and 15
under the clinical diagnosis of wart, cal- superficial spreading melanomas from Prognosis and predictive factors
lus, fungal disorder, subungual non-acral sites showed that all (100%) In general, the prognosis of invasive
haematoma, keratoacanthoma, nonheal- acral cases had gene amplifications, acral melanoma is poor. This can party
ing ulcer, foreign body, naevus, ingrown whereas amplifications were found in two be explained by the above described
toenail, etc {2222}. of the superficial spreading melanomas diagnostic delay and increased tumour
(13%). The most common amplified thickness at the time of diagnosis.
Histopathology region is chromosome 11q13 which However, there are some studies sug-
The histology of ALM is characteristic but occurred in 50% of these types of gesting that acral melanomas may
not distinct. In the radial growth phase, melanoma. A recent study has shown undergo a more aggressive course inde-
the lesions are characterized by marked that cyclin D1 is one of several candidate pendent of tumours thickness {151,308,
acanthosis, expanded cornified layer, genes in this region. This conclusion was 661,1337}. In a study from Germany, 63
elongation of the rete ridges, and lentigi- based on the observation that amplifica- out of 64 patients (98.5%) with melanoma
nous proliferation of atypical melano- tion of the cyclin D1 gene was always of the sole subsequently developed
cytes along the basal epidermis at the accompanied with overexpression of the metastases {775}; a corresponding fig-
border of the tumour {1337,1767}. The cyclin D1 protein, and that inhibition of ure from Japan in 1983 was 35% {2130}.
intraepidermal component of acral cyclin D1 expression in vitro and in The same hospital recorded that the 5-
melanoma includes large, atypical xenograft models led to apoptosis or year survival rate of subungal melanoma
melanocytes with large, often bizarre tumour shrinkage {2072}. increased from 53% in 1969-82 to 83% in
nuclei and nucleoli, and cytoplasm filled FISH studies on primary lesions of acral 1983-93 {1221}, presumably because of
with melanin granules {2130}. These melanoma showed that the amplifica- early awareness of lesions and develop-
melanocytes in the basal layer often tions arise early in acral melanoma and ment of treatment {2012}. However, oth-
exhibit long, elaborate dendritic process- can already be detected at the in situ ers have reported that ALM is not a sig-
es {2130}. stage {171}. The in situ portion of acral nificant prognostic indicator {661,2201},
Atypical melanocytes can extend along melanoma may extend beyond what is and adjustment for histologic and clinical
the sweat ducts into the deep dermis. recognizable histopathologically. FISH stage renders the prognostic importance
In the vertical growth phase, tumour nod- detected gene amplifications were iden- of anatomic location insignificant {151,
ules often contain predominantly spindle- tified in single basal melanocytes imme- 308}. These conflicting results can in part
shaped cells and are associated with a diately adjacent to the in situ component be explained by the different definitions
desmoplastic reaction {2130}. The junc- of acral melanoma; they were equidis- used for acral melanomas in the studies.
tional component of thicker tumours tantly spaced and looked histopathologi- Future studies using refined criteria
often shows nesting of tumour cells and cally inconspicuous {171}. Based on the including genetic information are neces-
upward migration to the cornified layer observation that these “field cells” were sary to assess the prognosis of this
{1337}. found at the histopathologically unin- melanoma type.
volved excision margins of an acral
Immunoprofile melanoma that recurred multiple times
As in the other types of melanomas, the authors propose that field cells may
immunohistochemical stainings for S-100 be a form of minimal residual melanoma
protein, HMB-45, and MART-1 (also that leads to persistence if not removed.
known as Melan-A) are of great diagnos- More recent studies using array CGH
tic value in ALM. S-100 protein (positive have confirmed the frequent gene ampli-

Acral-lentiginous melanoma 75
Desmoplastic melanoma and S.W. McCarthy
K.A. Crotty
desmoplastic neurotropic melanoma R.A. Scolyer

Definition rineural or intraneural and often extends junctional component, preceding the
Desmoplastic melanoma (DM) is a spin- beyond the desmoplastic component. development of a bulky dermal and sub-
dle cell melanoma in which the malignant DM may also present as a recurrence or cutaneous tumour. The latter was com-
cells are separated by collagen fibres or occasionally as a metastasis from other posed of atypical melanocytes and spin-
fibrous stroma. It displays variable cyto- types of melanoma. dle cells often with elongated nuclei and
logical atypia, cellularity and stromal a dense collagenous ground substance.
fibrosis and more often than not has an ICD-O code 8745/3 Many others subsequently highlighted
accompanying junctional component. the frequent neurotropism of DMs.
Neurotropism is a common associated Historical annotations
feature (in at least 30% of cases) and DM was first described by Conley et al. Epidemiology
when it occurs such tumours are termed in 1971 {526} as a clinically inconspicu- Desmoplastic melanomas represent
desmoplastic neurotropic melanomas ous superficial melanocytic lesion, main- between 1-4% of melanomas. In a large
(DNM). The neurotropism may be pe- ly on the head and neck, with an atypical series from the Sydney Melanoma Unit


Fig. 2.22 Desmoplastic neurotropic melanoma. A Male, 73 yrs, cheek. A few atypical enlarged melanocytes are present in the junctional zone. The fibrohistiocytic
pattern is accompanied by scattered lymphocytes, some in clusters. Mitoses are hard to find. B Female, 24 yrs, lip. There are "neural transforming" areas with thick
neuroid bundles in the upper dermis. Note occasional atypical junctional melanocytes, a few subepidermal spindle cells and scattered lymphocytes. C Male, 73 yrs,
cheek. Malignant spindle cells with elongated nuclei appear to be within and between collagen bundles. D Female, 24 yrs, lip. "Neural transforming" areas with
neuroid bundle (top of picture) containing atypical elongated spindle nuclei. Intraneural and perineural involvement of a small nerve is also present. There is a
prominent infiltrate of lymphocytes.

76 Melanocytic tumours
Fig. 2.23 Desmoplastic melanoma. A Male, 57 yrs, upper lip. Abnormal junctional melanocytes, spindling dermal melanocytes and a patchy lymphocytic infiltrate.
B Female, 76 yrs, forearm. Abnormal junctional melanocytes and dermal spindle cells with patchy lymphocytes.

(SMU) the median age at diagnosis was (LM)/Hutchinson melanotic freckle (HMF) usually non-pigmented, are found in and
61.5 years (range 24-91) {1867,1868}. or superficial spreading melanoma. between mature collagen bundles. The
As in other histogenetic types of Unusual presentations include a young latter may be thickened and/or associat-
melanoma, males are more often affect- age {439,1077}, an erythematous nodule ed with a mild to marked stromal fibrosis.
ed (M:F = 1.75:1) {358A,1867,1868}. {1326} and alopecia {563}. The distribution of spindle cells is usually
haphazard but occasionally they form
Etiology Macroscopy parallel bundles or storiform areas. The
The etiology is unknown, but the majority Ulceration is uncommon although it was spindle cells often extend into the sub-
occurs in sun-exposed skin. Some have found in 17% of the SMU cases {1868}. cutis diffusely or in fibrous bands and
occurred in irradiated areas {1125}. may involve deep fascia, especially peri-
Tumour spread and staging cranium. The overlying epidermis may
Localization The tumours usually infiltrate deeply into be thinned or thickened. Charac-
DM may be found in many sites but most the reticular dermis but local spread may teristically there are accompanying small
commonly involves the head and neck involve subcutaneous tissue, deep fas- islands of lymphocytes and plasma cells
region (37%), including ear, nose and lip cia including periosteum and pericrani- within and/or at the edge of the tumour.
{1077}. Males predominate except on the um, bone and salivary gland. Neuro- The cytological atypia of the spindle cells
lower limbs. The vulva is a rare site for tropic foci may be found well beyond the usually varies from mild to moderate.
DM {1664}. main tumour. In the SMU series, neu- However, even in cases with mild atypia,
rotropism was found only in tumours there are usually a few larger or more
Clinical features exceeding 1.5 mm in thickness and Clark elongated hyperchromatic nuclei. The
Most present as a painless indurated level 4 or 5 {1867,1868}. Initial metas- cytoplasm of the spindle cells is often
plaque but some begin as a small papule tases from DM may involve regional poorly defined. In examples where the
or nodule {2501}. Almost half lack pig- lymph nodes or distant sites. spindle cells are small, well scattered
mentation {1867}. Pale lesions are often and associated with solar elastosis, the
mistaken for basal cell carcinoma, der- Histopathology lymphoid islands may be the main clue to
matofibroma or a scar. Pigment is usual- In DM the spindle-shaped melanocytes, the diagnosis. Paucicellular variants are
ly due to an associated lentigo maligna which often resemble fibroblasts and are easily missed on punch and shave biop-

Fig. 2.24 Desmoplastic melanoma. A The spindle cells stain poorly with S100 unlike the Langerhans cells and interdigitating cells. B Variable S-100 positive nuclear
and cytoplasmic staining. C Crowded abnormal spindle cells and atypical mitoses.

Desmoplastic melanoma and desmoplastic neurotropic melanoma 77

tumour cells {2476}. Ultrastructurally,
premelanosomes and melanosomes are
rare and the spindle cells have the fea-
tures of fibroblasts. There is abundant
rough endoplasmic reticulum and some-
times intracytoplasmic collagen and
macular desmosomes {2476}.

Somatic genetics
A B Chromosomal aberrations and gene
mutations have been found in sporadic
Fig. 2.25 Desmoplastic melanoma. A Firm, skin-coloured plaque. B Male, 68 yrs, scalp. This punch biopsy
was initially diagnosed as a scar. Only an occasional spindle cell was S-100 positive and no abnormal junc- and familial melanoma {799}. Allelic loss
tional melanocytes were found. A larger desmoplastic melanoma was removed from the same site 6 months at the neurofibromatosis type 1 (NF1)
later. Clues to the diagnosis are the small foci of lymphocytes and permeation of the band of dermal elas- gene locus is frequent in DM {931}. Basic
tosis by spindle cells. fibroblast growth factor (bFGF) and other
fibrocytokines are often present in the
sies. Junctional change is sometimes factor (MTF) is not a sensitive or specific nuclei of DMs {1335}. Loss of heterozy-
minimal or absent {1125}. Occasionally marker {356,885,1294}. Type IV collagen gosity of matrix interacting protein 1
there is an associated banal naevus. and laminin are frequently expressed in (MXI1) is frequent {1893}. No BRAF
Vascular invasion is rare. Even rarer DM {1857}. Vimentin is usually positive mutations were found in 12 desmoplastic
cases show heterotopic bone and carti- although positive staining does not usu- melanomas {596}, consistent with the
lage {1644}. ally assist in diagnosis. finding that melanomas on chronically
The median Breslow thickness in the sun-exposed skin only rarely have BRAF
SMU series was 2.5 mm (0.2-18 mm) Differential diagnosis mutations {358B,596,1493}.
{1867,1868}. The thickness and extent of The differential diagnosis includes
invasion is usually best determined in S- desmoplastic naevus {958}, which like Prognosis and predictive factors
100 stains. The mitotic rate is variable but DM may have perineural extension but Recurrences are common especially
is often low. Abnormal mitoses are com- lacks asymmetry, mitotic activity, marked after incomplete excision {526}, marginal
mon in the more cellular tumours. nuclear atypia and lymphoid infiltrates. excision <10 mm or if neurotropism is
The neurotropism is characterized by the Well established desmoplastic Spitz present {1867,1868}. The conflicting
presence of one or more foci in which the naevi may have many HMB45 negative results regarding the risk of regional
spindle cells extend in a circumferential spindle cells but these naevi are usually node field metastases and prognosis of
fashion around nerves in the dermis or symmetrical with epidermal thickening, DM patients may be due to a hetero-
deeper and/or thickened nerves contain- include at least a few plump cells and geneity of tumours classified as DM and
ing abnormal cells within their nerve have rare or absent mitoses. Sclerosing failure to account for tumour thickness
sheath. Spindle cells may also form cellular blue naevi, which are most fre- {2115A}. Regional nodal metastases
structures resembling nerves (“neural quent on the scalp, also lack mitoses appear to very uncommon in paucicellu-
transforming”). Neurotropism may be and are more or less diffusely HMB45 lar DMs with prominent fibrosis and are
present in melanomas without desmopla- positive. Immature scars, especially in associated with longer survival {358A,
sia. re-excision specimens, may focally 932A, 985A}. Otherwise, disease free
Melanomas of any histogenetic type may resemble DM as they may have some S- survival rates are similar to other
have desmoplastic areas. The proportion 100 positive spindle cells {476,1951}, melanomas of comparable thickness
of desmoplasia in a melanoma neces- foci of lymphocytes and mitoses. {126}. Neurotropism, HMB45 positivity,
sary for the diagnosis of DM has been ill Other differential diagnoses include der- high mitotic rate, male gender, thickness,
defined in several studies, but proposals matofibroma/fibrous histiocytoma, fibro- ulceration and site all appear to affect
for diagnostic criteria have been made sarcoma, “malignant fibrous histiocy- survival which overall is 79% at 5 years
{358A,985A,1546A}. toma”, malignant peripheral nerve {1868}. Of patients with a recurrence,
Metastases in lymph nodes may be sheath tumour and leiomyosarcoma. 78.2% experienced it within 2 years.
epithelioid cells, or spindle cells with or These tumours can usually be separated Wide local excision is the treatment of
without desmoplasia. by morphology and appropriate immuno- choice {99A}. Radiation therapy has
histochemistry. been effective in some cases {71,1125}.
The spindle cells are positive with S-100 Histogenesis
although only a few nuclei are positive in It is most likely that the desmoplastic
some otherwise typical cases. HMB45 is cells are derived from melanocytes that
usually negative except for any foci of have undergone adaptive fibroplasia.
epithelioid cells {2476}. NSE, NKI/C-3 Some authors have suggested that the
and smooth muscle actin {1929} may be desmoplasia occurs because of a fibrob-
positive. Melan A (MART-1) is usually lastic stromal response and neurofi-
negative. Microphthalmia transcription brosarcomatous differentiation of the

78 Melanocytic tumours
Melanoma arising from blue naevus L. Requena
J. A. Carlson

Definition Clinical features can also represent the well-known phe-

A melanoma that arises in association Most melanomas associated with blue nomenon of satellitosis associated with
with dermal melanocytosis, most fre- naevus (93%) develop in a pre-existing the common and cellular blue naevus
quently cellular blue naevus. dermal melanocytosis that was congeni- (agminated blue naevus) {616,1059,
tal (35%), acquired during infancy or 1195,2008}. Similarly, cellular blue nae-
Synonyms childhood (15%) or identified during their vus can also present with regional lymph
“Malignant blue naevus” or “blue nae- adult years (43%). These associated node deposits {143,1357,2261}. In the
vus-like melanoma” are terms used to lesions were cellular blue naevi (52%), former cases, histopathologic examina-
describe melanomas arising in associa- common blue naevus (16%), naevus of tion of the satellite lesions reveals fea-
tion with a cellular blue naevus or those Ota (14%), naevus of Ito (1%) {2066, tures of benign blue naevus and the
primary melanomas that resemble blue 2414}, or ocular melanocytosis {542, lesions present benign biological behav-
naevi and lack an in situ component. 1127,2332,2431}. On average, these iour with no development of distant
melanocytoses were present for 24 years lesions.
ICD-O 8780/3 before melanoma developed, with a
range of 3 months (infant with congenital Etiology
Epidemiology facial blue naevus {2066}) to 78 years The etiology of melanoma associated
Melanoma associated with blue naevus (naevus of Ito {2414}). For congenital and with blue naevus is unknown, but the
is an exceedingly rare tumour with over childhood onset melanocytoses, melano- presence of longstanding dermal
165 reported cases. It affects predomi- ma developed after a mean duration of melanocytosis is likely a risk factor.
nately Caucasians and all age groups 34 years (range 3 months to 78 years) Ocular and oculodermal melanocytosis
with the majority of cases occurring whereas for adult onset common or cel- (naevus of Ota) is strongly associated
between 20 and 60 years, with a mean lular blue naevi, melanoma developed on with uveal melanoma {2192,2193} and
age at diagnosis of 44 years {2066, average after 14 years (range 1 – 56 has been reported with meningeal
2332}. Slightly more females than males years). The majority (83%) of affected melanocytoma (blue naevus) of the brain
have been reported (82 females; 76 patients described recent, often rapid, {1877} and primary melanomas of the
males). Occasionally, dark-skinned growth or presented with proptosis in the central nervous system {253,569,1104,
patients develop melanoma in associa- case of orbital melanomas within a year 1713,1930,2046}. Based on this associa-
tion with a blue naevus {548,1352,1629}. of diagnosis. Other symptoms include tion and numerous reports of melanoma
colour change or ulceration, and in the of the face, orbit or brain associated with
Localization case of orbital melanomas, diplopia and oculodermal melanocytosis patients pre-
In decreasing order, the sites most fre- blurred vision. The melanoma is typically senting with naevus of Ota should be
quently affected are the scalp (33%), a large black nodule with mean diameter considered at lifetime risk for melanoma
orbit and face (32%), trunk- mostly back of 2.1 cm (range 0.5–8.0 cm). In some of the skin, orbit or central nervous sys-
and buttocks (19%), extremities (7%) cases, satellitosis due to cutaneous tem, a risk that maybe similar in nature to
and hands or feet (7%). Involvement of metastatic deposits appear around the that identified for large congenital
the vulva and vagina have also been primary nodule {64,276,364,856,1018, melanocytic naevi with melanoma and
reported {422,2233}. 1588,1981,2066}. However, this feature neurocutaneous melanocytosis {254}.

Fig. 2.26 Melanoma arising from blue naevus. Fig. 2.27 Melanoma arising from blue naevus. A Scanning magnification showing a blue naevus with a nod-
Note the presence of satellitosis (Courtesy of Dr. H. ule of malignant melanoma in deeper areas. B In deeper areas the nodule of malignant melanoma was
Kerl). composed of sheets of cells destroying pre-existing structures of the dermis.

Melanoma arising from blue naevus 79

Fig. 2.28 A Superficial areas showing stereotypical histopathologic features of a common blue naevus. B Higher magnification demonstrated that neoplastic
melanocytes of the melanoma showed epithelioid appearance and marked atypia, with large eosinophilic cytoplasm, pleomorphic nuclei and prominent nucleoli. C
Neoplastic melanocytes of the blue naevus showed small monomorphous nuclei. Note the striking collagenization of the dermis and the abundant number of

Additional associations of unknown influ- naevi of Ota and Ito, and ocular Although the malignant component may
ence include subacute cutaneous lupus melanocytoses attest to this latter possi- involve the superficial dermis and ulcer-
erythematosus, leukoderma, Becker’s bility of under-reporting {542,660,1783, ate the epidermis, more often it appears
naevus and prostate adenocarcinoma in 2332,2414}. as a deep-seated expansile asymmetric
one patient {1629}, papillary thyroid car- At scanning magnification, two nodule involving the reticular dermis and
cinoma {94}, acute lymphocytic histopathologic patterns are evident. subcutaneous fat. Usually, there is an
leukaemia {2119}, psoriasis {238}, and One is represented by the benign com- abrupt transition from the benign blue
oral contraceptives {1404}. Phototherapy ponent of the blue naevus, which may naevus component to the nodule of
has been associated with cellular blue range from very focal to comprising the melanoma. The nodule or nodules of
naevus development {810}. main bulk of the neoplasm. Often this melanoma show both architectural and
benign component is represented by a cytological features of malignancy. The
Histopathology cellular blue naevus and less frequently melanomatous component consists of
By definition, a melanoma that develops the lesion contains a common blue nae- sheets of cells that involve diffusely the
in a pre-existing blue naevus is a dermal vus. Most cases, however, show a com- deep dermis destroying the pre-existing
melanoma without the features of bination of the so-called cellular and structures with pushing margins and
melanoma in situ involving the dermo- common blue naevi, making this distinc- sharp demarcation between the neo-
epidermal junction or adnexal epitheli- tion useless. The areas of cellular blue plasm and adjacent dermis or subcuta-
um. In fact, 82% of all reported cases naevus consist of solid aggregations of neous tissue. Neoplastic melanocytes
described an adjacent common and/or closely arranged monomorphous ovoid appear as large spindled to epithelioid
cellular blue naevus. The absence of an cells with abundant pale cytoplasm con- cells with abundant cytoplasm and pleo-
identifiable benign naevus component in taining little or no melanin and round morphic and hyperchromatic nuclei, with
some reports may be the result of vesicular nuclei with inconspicuous prominent nucleoli and frequent mitotic
replacement of it by the melanoma or nucleoli. In contrast, the areas of com- figures. Usually they contain little or no
incomplete sampling of the benign ele- mon blue naevus are made up of elon- melanin. Without the associated benign
ment. Although these cases could repre- gated spindled bipolar melanocytes, component, these dermal nodules would
sent de novo melanomas, a subtle, with long branching dendritic processes be histopathologically indistinguishable
hypocellular dermal melanocytosis as most of them filled with abundant gran- from typical nodular or metastatic
seen in naevi of Ota and Ito, and ules of melanin. Melanophages and scle- melanoma. Necrosis of individual cells
Mongolian spots may not have been rotic bundles of collagen are also fre- as well as necrosis en masse may be
observed. Reports of orbital, facial and quently observed between the fascicles also seen in the melanoma component,
shoulder melanomas associated with of dendritic melanocytes. although this finding seems to be less

80 Melanocytic tumours
frequent than in melanomas arising de Animal type melanoma (epithelioid Immunoprofile
novo (“malignant blue naevus”) {973}. A melanocytoma) is a rare variant of pri- Immunohistochemical studies in lesions
perivascular inflammatory infiltrate, most- mary cutaneous melanoma that may also of melanoma associated with blue nae-
ly composed of lymphocytes, which is mimic melanoma associated with blue vus have demonstrated a strongly posi-
usually lacking in blue naevus, is often naevus {567,1917}. Sheets and nodules tive reaction of the neoplastic cells, both
seen around the melanoma arising in of heavily pigmented epithelioid melano- of the benign and malignant compo-
blue naevus. cytes that tend to aggregate along hair nents, for vimentin, S-100 protein, HMB-
Melanoma arising in the setting of blue follicles and involve the entire thickness 45 and NKI/C-3 {280,1708,1996}.
naevus should be differentiated from the of the dermis with extension into the sub- However, the number of silver positive
so-called atypical cellular blue naevus cutaneous tissue histopathologically nucleolar organizer regions (AgNOR
{118,2371}. These lesions show clinico- characterize animal-type melanoma. score) {813,1826} and growth fraction as
pathologic features intermediate Epithelioid melanocytes in deeper areas measured by proliferating cell nuclear
between typical cellular blue naevus and show abundant, heavily pigmented cyto- antigen (PCNA) and Ki-67 (MIB-1) are
malignant melanoma associated with plasm and pleomorphic nuclei with significantly lower in the benign compo-
blue naevus. The lesions show architec- prominent eosinophilic nucleoli and nent of blue naevus than in the nodule of
tural atypia, characterized by asymmetry mitotic figures. Histopathologic features melanoma {1708,1826}.
and infiltrative margins, as well as cyto- of melanoma in situ at the dermo-epider-
logic atypia, which consist of hypercellu- mal junction are few or absent, and neo- Electron microscopy
larity, nuclear pleomorphism, hyperchro- plastic cells do not show evidence of Although some authors have interpreted
masia, mitotic figures and necrosis. maturation from superficial to deeper the neoplastic cells of melanoma associ-
However, follow-up data of patients with dermal areas. The overall architectural ated with blue naevus as being related
atypical cellular blue naevus demonstrat- and cytologic features of animal-type with Schwann cells {1588}, electron
ed that no patient experienced either a melanoma closely resemble those of microscopic studies have demonstrated
local recurrence or lymph node or viscer- melanoma associated with blue naevus, the presence of melanosomes in the
al metastasis. but animal-type melanoma lacks the cells, as well as the lack of cytoplasmic
Melanoma associated with blue naevus benign component of blue naevus or his- enclosures of unmyelinated axons, which
should be also distinguished from large tory of a pre-existing melanocytosis. rule out the possibility of Schwann cell
plaque-type or giant cellular blue naevus differentiation. Although the melano-
with subcutaneous cellular nodules {358, Metastatic spread somes in many cells of the malignant
1059}. Large pigmented plaques of Melanoma associated with blue naevus component are devoid of melanin {1014},
childhood onset that show slow enlarge- is an aggressive tumour with frequent incubation with dopa demonstrates that
ment during adolescence and subse- metastatic disease to regional lymph they are strongly dopa-positive {1625},
quent nodule formation clinically charac- nodes (31% of reported cases) and dis- thus confirming their melanocytic nature.
terize this rare plaque variant of cellular tant sites (42%). Sites of metastasis, in
blue naevus. Histopathologically, they decreasing order of frequency, include Somatic genetics
exhibit multifocal dermal and subcuta- liver (36%), lung (22%), brain (16%), skin Results of DNA flow cytometry studies in
neous proliferations of fusiform and den- (13%), bone (9%), and in less than 6% of melanoma associated with a blue naevus
dritic pigmented melanocytes, with high- reported cases, spleen, heart, kidney, are variable revealing diploid cell popu-
ly cellular nodules located in deeper pancreas, adrenal, thyroid and parotid lations in 4 cases {1574,1826} and aneu-
areas of the plaque. The follow-up of glands, ovary, and gastrointestinal tract. ploid populations in 2 cases {1826}. A
patients with large plaque-type blue nae- Melanuria and generalized melanosis molecular analysis failed to demonstrate
vus with subcutaneous cellular nodules have also been described in its terminal loss of heterozygosity on microdissected
indicates that these lesions behave in a stage {2185}. Metastases can appear as samples in one case of melanoma asso-
benign fashion. late as 20 years after diagnosis {813}, but ciated with blue naevus, using a panel of
Metastatic melanoma mimicking blue the median and mean time of discovery eight genes (MTS1, MXI1, CMM1, p53,
naevus can also be confused with is 1.75 and 3.6 years after diagnosis. NF1, L-myc, hOGG1, and MCC), many of
melanoma associated with a blue naevus Metastasis to lymph nodes should be dif- which are commonly associated with
{354,2517}. These blue-naevus like ferentiated from the presence of blue conventional melanomas {94}. These
metastases occurred in the same naevus cells in the capsule of the node findings suggest that melanoma associ-
anatomic region as the primary tumour or {181,392,405,1357,1358}. This well- ated with blue naevus may represent a
near the skin scar of a dissected lymph known pseudo-metastasizing phenome- distinct entity with a different molecular
node metastasis and were histopatholog- non seems to be the result of migration pathway to tumourigenesis than that of
ically characterized by atypical epithe- arrest during embryogenesis and is conventional melanomas. However, in a
lioid melanocytes, mitotic figures, and an characterized by monomorphous comparative genomic hybridization
associated inflammatory cell infiltrate at melanocytes of blue naevus involving study comparing common blue naevi,
the periphery of the lesions. In contrast only the capsule and the marginal sinus- cellular blue naevi, and atypical cellular
with melanoma arising in a pre-existing es of the lymph node. In authentic metas- blue naevi with melanoma associated
blue naevus, metastatic melanoma to the tases, nests of atypical melanocytes with a blue naevus, melanomas associat-
skin simulating blue naevus lacks the replace most of the parenchyma of the ed with blue naevus showed chromoso-
benign blue naevus component. node, effacing its architecture. mal abnormalities similar to that of con-

Melanoma arising from blue naevus 81

ventional melanoma whereas cellular
and atypical cellular blue naevi exhibit
infrequent numerical chromosome aber-
rations similar in character to that identi-
fied in proliferative nodules found in con-
genital melanocytic naevi {1490}.

Prognosis and predictive factors

Some authors have proposed that
melanoma associated with blue naevus
is a low-grade malignancy {1574}.
However, the literature review does not
support this opinion. For instance, in a
series of 12 cases, metastases devel-
oped in 10, and 8 died of metastatic dis-
ease {527}, and in another series of 10
cases, 4 patients developed metastases
and 3 of them died of disease {883}. Of
the 160 cases reported with follow up
data, 34% of patients have died due to
locally invasive or metastatic melanoma Fig. 2.29 High Ki-67 labelling index in hyperchromatic spindle nuclei of the melanoma arising from blue nae-
20 months median, 41 months mean time vus. The benign portion of the lesion (not shown) had a very low labelling index.
from diagnosis (range 2–240 months).
Therefore, melanoma arising in blue nae-
vus is a highly aggressive tumour with lioid melanocytes), older age, high mean lymph node dissection in the staging of
poor prognosis similar to that of thick mitotic count (>4/40 high power field), melanoma associated with a blue naevus
(>4.00 mm), AJCC stage IIB convention- and lymphocyte count (>100 per 20 high is advocated by some authors {2173}
al melanomas {392}. Indeed, the Breslow power field) {2332}. These prognostic and one patient with metastatic disease
thickness for this melanoma variant typi- factors were identified in a study of pri- to the lymph nodes was alive and without
cally is much greater than 4 mm with a mary orbital melanoma where 90% of the evidence of disease two years after sur-
mean tumour thickness of 10 mm (range patients had an associated blue naevus gery followed by therapy with interferon
2.8–45mm){64,640,813,883,1844}. and 47.5% had congenital melanocyto- {640}.
Possible prognostic factors indicative of sis (naevus of Ota or ocular melanocyto-
a poor outcome include the presence of sis). The role of sentinel lymph node dis-
congenital melanocytosis, mixed mela- section and postoperative adjuvant ther-
noma cell type (both spindle and epithe- apy remains to be determined. Sentinel

82 Melanocytic tumours
Melanoma arising in giant congenital H. Kerl
C. Clemente
I Sanchez-Carpintero
M.C. Mihm
naevi P.E. North B.C. Bastian

Definition appears as a rather rapidly growing

A proliferation of malignant melanocytes asymmetrical nodule or plaque of blue-
arising either in the epidermal compo- black, reddish or even rarely flesh
nent or the dermal component of a giant colouration {568,1009}. Melanoma can
congenital naevus associated with risk of occasionally present as a cystic lesion.
metastasis and death. Therefore, any GCN that develops an
apparent subcutaneous cyst must be
ICD-O code 8761/3 biopsied. Melanoma is only one of many
benign and malignant tumours that may
Synonyms occur in GCN {1009,1928}.
Malignant melanoma arising in a gar-
Fig. 2.30 Malignant melanoma presenting as a red-
ment naevus; dish brown nodule in the midst of the congenital
malignant melanoma arising in a bathing naevus. The lesion usually appears either as a
trunk naevus; firm nodule, or as a boggy discoloured
malignant melanoma arising in a giant area, usually dark brown or black in the
hairy naevus. Sites of involvement midst of the naevus. If the lesion arises in
Malignant melanoma can occur any- the dermis, the tumour can sometimes
Epidemiology where in a giant congenital naevus. The only be seen on cut surface as a sepa-
About 1% of all infants have some kind of lesion most commonly arises in lesions rate nonencapsulated nodule amidst the
a congenital pigmented skin lesion {568}. on the trunk but can appear in any area otherwise tan or pale tan coloured nae-
The giant congenital naevus (GCN) is even in congenital naevi of the meninges vus in the dermis or subcutis.
estimated to occur in around 1 per {568,1306,1927}.
20,000 infants {67,411,1306}. The risk of Histopathology
malignant transformation of a GCN has Clinical features Histologically, the tumours are often
been estimated at from 5-20% but more The definition of GCN varies and asymmetrical and sharply demarcated
recent studies based on statistical analy- includes a naevus with a diameter larger from the adjacent congenital naevus. If
ses suggest a figure of 6%. The GCN is than 20 cm. Frequently large areas of the superficial, there is effacement of the rete
a direct precursor of melanoma {1197, body (more than 2% of the body surface) ridges of the epidermis and often ulcera-
1207,1927,2218}. There is a bimodal dis- are covered in a garment-like fashion tion. The intraepidermal component usu-
tribution to the occurrence of melanoma {1306,1927}. The trunk and head and ally is composed of epithelioid cells with
in GCN. Most develop in childhood neck are the most common sites for pigmentation. Pagetoid spread is com-
before the age of 10 {1508} with a sec- these naevic lesions. The melanoma, monly noted. The tumour cells of the der-
ond peak of incidence in adult life. very rarely present at birth, usually mal component usually form expansile

Fig. 2.31 Melanoma arising from large congenital naevus. A The melanoma is clearly separate from the naevus cells that are on the left. B A protuberant nodule
shows the small dark naevus cells to the left and at the base of the melanoma that is composed of nests with dyscohesion.

Melanoma arising in giant congenital naevi 83

Fig. 2.32 Melanoma arising from large congenital naevus. A There is a distinctive proliferation of malignant melanocytes invading the dermis. Note thinning of the
rete ridges with a proliferation of malignant melanocytes invading the dermis as spindle cells with an admixed population of melanophages. B Reveals epithelioid
cells in nests invading the epidermis giving rise to spindle cells in the dermis. C The malignant spindle cells show nuclear hyperchromasia and mitoses.

nodules. They exhibit fully transformed response may be observed as well as Somatic genetics
malignant characteristics with very irreg- focal mucinosis. In our experience, the Comparative genomic hybridization
ular chromatin patterns and prominent vertical growth phase dermal nodules shows that melanomas arising in con-
nucleoli. There is variable pigmentation. may exhibit prominent areas of different genital naevi show similar chromosomal
Both single cell and zonal necrosis may cell types with different degrees of pig- aberrations as melanoma arising inde-
be observed. The melanoma cells as mentation {568,703,1197,1928}. pendently {175}. By contrast, the prolifer-
they abut or infiltrate as cords into the Histologically, the presence of a residual ative nodules arising in early life do not
adjacent naevus show no evidence of dermal naevic component with congeni- show chromosomal aberration support-
maturation but maintain their fully malig- tal features may be quite difficult to find, ing the view that they are benign {175}.
nant characteristics. Mitoses are com- particularly, if present in the wall of a ves-
mon and atypical forms are usually pres- sel.The differential diagnosis includes
ent. A lymphocytic host response is often the proliferative nodules that also arise in
noted. Occasionally, a desmoplastic host large congenital naevi.

Childhood melanoma R.L. Barnhill

Definition doubled in patients aged 15 to 19 years (15%), and upper limbs (15%).
Melanomas developing in individuals over the past decade but has remained
prior to the onset of puberty are child- unchanged in younger individuals Clinical features
hood melanomas and thereafter they are {204A,1037A}. Less than 80 well docu- Melanomas in individuals under the age
designated as melanomas in adoles- mented cases of melanoma in children of 20, particularly in adolescents, show
cents with the age limitation of 18 to 20 younger than 10 years have been fairly similar clinical features as com-
years. Childhood melanomas can be fur- recorded in the literature over a period of pared to melanomas in adults
ther subcategorized as 1) congenital 30 years. As in adults, childhood mela- {123A,1916A}. However melanomas in
melanoma (onset in utero to birth), 2) nomas have a predilection for Cauca- prepubertal individuals are so rare that
infantile melanoma (birth to one-year of sians. Individuals with congenital naevi they are usually unsuspected. Features
age), and 3) childhood melanoma (one especially large varieties, atypical naevi, suggesting melanoma in a pigmented
year to onset of puberty). family history of melanoma, xeroderma lesion such as a congenital naevus are
pigmentosum, and immunosuppression rapid increase in size, bleeding, devel-
Epidemiology are at increased risk for childhood opment of a palpable nodule (e.g., in a
The incidence of melanoma is excep- melanoma. giant congenital naevus), colour change
tionally rare in prepubertal individuals of a nodular lesion, surface changes
(estimated incidence approximately Localization such as ulceration, and loss of clearly
0.4% among all melanomas) {269A, Melanomas developing in patients up to defined margins. Recognition of
1487A} and uncommon under the age of 16 years of age most commonly involve melanoma appearing de novo requires a
20 years (incidence approximately 2%) the trunk (50%), followed by the lower high index of clinical suspicion, espe-
{123A}. The incidence of melanoma has extremities (20%), head and neck cially for amelanotic lesions. Utilizing the

84 Melanocytic tumours
conventional ABCDE criteria (Asymme-
try, ill-defined Borders, irregular Colour,
and large Diameter, Elevation) the clini-
cal detection of melanoma in adults, all
such suspicious lesions in children
should be evaluated for biopsy and
histopathological examination. Melano-
ma in children also may be associated
with pain or pruritus {155,417A,530A,
1037A,1619A,1859A,1930A,1990A, A B
Fig. 2.33 Small-cell melanoma from the scalp of a prepubertal individual. A The lesion resembles a con-
ventional melanocytic naevus at scanning magnification. B High magnification shows a highly cellular
Histopathology dermal component without maturation. There is a monomorphous population of small round melanocytes
The same histopathological criteria with scant cytoplasms resembling the neoplastic cells in lymphoma or neuroendocrine carcinoma. The
should be utilized for diagnosis as have nuclei are pleomorphic.
been developed for adult melanomas
{155,159A,417A,1990A,2232}. However,
clinical information must be strongly con- patients with XP are histologically often Differential diagnosis
sidered, particularly age, since cuta- similar to solar melanomas except that Childhood melanomas must be distin-
neous melanoma is almost nonexistent the actinic damage characteristic of guished from congenital and other naevi
under the age of two years and especial- adult tumors is absent {159A,2232}. exhibiting pagetoid melanocytosis,
ly in the neonatal period. lentiginous melanocytic proliferation,
The important stimulants of melanoma Small-cell melanomas atypical nodular melanocytic prolifera-
must be excluded: 1) atypical nodular Small-cell melanomas are comprised of tion, and from Spitz naevi. Conventional
proliferations developing in congenital monomorphous small cells, reminiscent criteria such as age, clinical presenta-
naevi in infants and young children and of small round cell malignancies such as tion, size, asymmetry, circumscription,
2) Spitz naevi. lymphoma, or a melanocytic naevus degree of cellular density, maturation,
Great attention should be given to avoid- {155,159A,2232}. These cells are often degree of cytological atypia, and mitotic
ing over diagnosis melanoma and at the arranged in sheets or in organoid config- rate should facilitate this discrimination in
same time to the under recognition of urations. The melanocytes contain most cases.
atypical and borderline lesions that basophilic round nuclei and condensed Pagetoid melanocytosis and lentiginous
require adequate surgery and follow-up chromatin. The high cellular density, lack melanocytic proliferation and are fea-
for disease recrudescence. Lesions not of maturation, and often prominent mitot- tures commonly observed in naevi devel-
clearly meeting sufficient criteria for ic rate are features suggesting melano- oping in children, particularly in glabrous
melanoma should be designated as bio- ma. In children, small cell melanomas skin. These changes must not be overin-
logically indeterminate. Features appear- may appear de novo or may develop in a terpreted unless architectural disorder is
ing to be most useful for the distinction of congenital naevus. Such melanomas prominent and cytological abnormalities
melanomas from naevi are large size with small-cell phenotypes have often are present throughout the breadth of the
(i.e., >7 mm), ulceration, high mitotic rate been localized to the scalp, shown strik- lesion.
(>4 mitoses/mm2), mitoses in the lower ing Breslow thicknesses, and fatal out- Virtually all atypical nodular melanocytic
third of the lesion, asymmetry, poorly come in most patients {159A}. proliferations developing in congenital
demarcated lateral borders, lack of mat- naevi are biologically benign. Exami-
uration, finely-divided melanin, and Melanomas simulating Spitz naevus nation of these atypical tumors with refer-
marked nuclear pleomorphism {155, On occasion melanomas in both children ence to karyotype, expression of cell-sur-
159A,2232}. Melanomas in children can and adults may exhibit features strongly face antigens, growth in soft agar, chro-
be (somewhat artificially) categorized suggesting a Spitz naevus. These fea- mosomal aberrations, and other parame-
into three principal groups {155, tures include both architectural and cyto- ters has shown that they have the prop-
159A,2232}. logical attributes such as epidermal erties of an immature proliferative but
hyperplasia, wedge-shaped configura- benign tumor {71A,175,1496A}.
Conventional melanomas tion, epidermal clefting about intraepi- Various authors have proposed criteria
About 40 to 50% of melanomas in chil- dermal nests, large epithelioid cells and for distinguishing Spitz naevi from
dren are similar histologically to those in spindle cells arranged in fascicles, etc. melanomas. Criteria favoring melanoma
adults {159A,2232}. The intraepidermal {155,159A,2232}. include asymmetry, ulceration, deep
components of such melanomas conse- extension (particularly subcutaneous
quently may be pagetoid, lentiginous, or In addition to conventional melanomas fat), large size (>1 cm), prominent cellu-
nested. Melanomas of glabrous skin are and typical Spitz naevi, there is also an lar density, lack of maturation, deep
exceedingly rare in childhood {159A, intermediate group of Spitz-like lesions mitoses (i.e., more than 3 mitoses in the
2232}. Solar (so-called lentigo maligna) that demonstrate not only some features lower third), high mitotic rate (i.e., >4 to
melanomas do not occur in childhood. of Spitz naevi but also varying degrees of 6/mm2), abnormal mitoses, and marked
However, melanomas diagnosed in atypicality. nuclear atypia.

Melanoma of childhood 85
Naevoid melanoma N.S. McNutt
S. Kossard

Definition Table 2.06

Naevoid melanoma is a subtype of Sex and ages in series of patients with naevoid melanomas.
malignant melanoma of the skin that is
Reference Number of subjects M/F Ratio Mean Age
distinctive in that the primary lesion mim-
Females Males
ics many of the architectural features of a
common compound or intradermal nae- McNutt {1563} 5/16 11/16 2.2 M 47 (26-75); F 45 (44-57)
vus when composed of small melanoma
cells, or with Spitz naevus when com- Schmoeckel {2092} 25/33 8/33 0.32 M 43 (22-52); F 49 (16-76)
posed of medium-sized to large
melanoma cells. These lesions are Zembowicz {2596} 10/20 10/20 1 M 41 (19-61); F 44 (26-81)
defined not as atypical naevi but as
melanomas because they involve the Blessing 2000 {262} 10/14 4/14 0.4 48.6 (30-77) (small cell MM)
dermis and have the potential for metas-
Blessing 1993 {261} M>F 57 (verrucous MM)

ICD-O code 8720/3

was mostly on the trunk and proximal Etiology
Synonym extremities, specifically on the leg Unknown. The tumour may arise in clini-
The term minimal deviation melanoma (38.5%), trunk (26.1%), arm (18.5%), cally normal skin, or in a pre-existing
has been used for some examples. head (12.3%), and neck (4.6%) {261, naevus that maintains a naevus pattern
262,1563,2092,2596}. of differentiation, or in a lentigo.
Naevoid melanoma is uncommon, being Clinical features Histopathology
estimated to be approximately 1–2% or The lesions are generally small papular, The microscopic features of naevoid
less of melanomas {2096,2255}. Due to nodular, or verrucous, with tan to dark melanoma are at present restricted by an
the low incidence, the small size of series brown colour. The colour may be uniform arbitrary definition to lesions that do not
of studies of these tumours, and the or irregular. The borders of the lesion are have much intraepidermal spread of
slightly different definitions of the lesion, sharp and not very irregular. The lesions tumour cells (pagetoid upward migra-
the demographic profiles are not well- often are approximately 5-10 mm in tion) and have a relatively symmetrical
established. Naevoid melanomas can diameter {568}. Clinically apparent profile at low magnification.
occur at any age but often are in young inflammation is uncommon. The patient There is sharp lateral demarcation of the
to middle-aged adults. Both men and may report that there was a pre-existing lesion. Usually there are areas of sheet-
women are affected, but there is a slight macular pigmentation, which became a like confluent melanocytic proliferation in
female predominance, perhaps due to papule. The lesions are soft and non-ten- the dermis. Some lesions have only large
early detection in women. In combining der. They are usually solitary lesions that nests of cells in the dermis, often larger
data from three similar studies with a total often are removed because of recent in the deep portion of the lesion when
of 65 patients, the distribution of lesions growth or for cosmetic purposes. compared to the upper portion. Mitotic

Fig. 2.34 Naevoid melanoma. A Naevoid melanoma, papular lesion. (A) At low magnification, note the lack of maturation and the lack of good naevus nest forma-
tion in the dermis. B Naevoid melanoma, papular lesion. (B) At intermediate magnification, many of the cells are hyperchromatic and atypical. C Naevoid
melanoma, papular lesion. Perivascular infiltration is at the base of the lesion.

86 Melanocytic tumours

Fig. 2.35 Naevoid melanoma. A Verrucous type. Note the crowding of the cells in the dermal papillae. B Naevoid melanoma, verrucous type. Note the atypical
mitosis in the dermis. C Naevoid melanoma, verrucous type. There is vascular invasion at the base of the lesion. D Naevoid melanoma with spindle and epithelioid
cells. The diffuse dermal pattern with scattered atypical cells, without dermal maturation, shares some features with early desmoplastic melanomas. E Naevoid
melanoma with spindle and epithelioid cells. Note the nuclear atypia. F Naevoid melanoma with spindle and epithelioid cells. Note the lack of maturation of cells
in the base of the lesion.

figures can be found in the dermis in tion. A103 antibody, which binds to the showed an average number of 5.83
most lesions and often multiple mitoses antigen Melan-A, reacts with the (SD+/- 1.69) AgNORs per nucleus. This
are noted. However, small lesions may melanocytic cells throughout the lesion provided some separation from benign
have very few mitoses. Naevoid {265}. small dermal naevus cells, which had an
melanomas can occupy a portion of a The reactivity of the tumour cells with the average of 2.71 (SD+/- 0.50) AgNORs
pre-existing intradermal or compound antibody MIB-1 to detect the protein Ki- per nucleus. The comparison mean num-
naevus. The melanomas have a relative- 67 in cycling cells is positive in both the ber in 10 superficial spreading
ly uniform population of small cells with upper and lower portions of the tumour. melanomas was 8.49 (SD+/- 1.58)
hyperchromatic angulated nuclei or a In some lesions, the reactivity is slight but AgNORs per nucleus {1316}.
population of medium-sized to large greater in the deep portion than in the
melanoma cells with more open nuclear superficial portion of the lesion. Under Histogenesis
chromatin and pale cytoplasm. controlled conditions, antibodies to Naevoid melanomas may arise from the
Inflammatory reaction usually is slight detect proliferating cell nuclear antigen dermal component of small compound or
and may be absent. The lesions often are (PCNA) have been used to grade intradermal naevi or from the junctional
dome-shaped, polypoid, or verrucous in melanomas {1160,1934}. In specimens component of melanocytes in normal
profile {261,568,1562,1563,2092,2543, with varied fixation conditions, PCNA has skin, or a pre-existing small naevus or
2596}. not been found to be reliable because it lentigo. It is possible that some naevoid
is sensitive to underfixation and to over- melanomas represent early nodular
Immunoprofile and other special stains fixation in formalin {1563}. Silver staining melanomas lacking an evident junctional
HMB-45 reactivity is variable and may be of nucleolar organizing regions component.
negative or positive {265,1562,1563}. (AgNORs) in 10 small cell melanomas
When positive, aberrant patterns of reac- Prognosis and predictive factors
tivity are common. HMB-45 reactivity Table 2.07 Histological criteria for metastatic Predictive features of naevoid melanoma
may be uniform throughout the dermal spread of naevoid melanoma. prognosis are tumour thickness, mitotic
portion of the lesion even though there is rate, and large cell type. From 3,500
Metastases Mean Mean
no junctional component. This reactivity melanomas, Schmoeckel et al. {2092}
thickness mitotic index
pattern can also be found in blue naevi, selected naevoid melanomas with at
some Spitz naevi, and in so-called deep Without least 5 years of follow-up unless there
penetrating naevi, and combined naevi (n=18) 2.24 mm 0.99/mm2 was earlier metastasis. Thirty-three
{1563,2198}. HMB-45 antibody reacts cases were selected: 18 were disease
with the premelanosomal glycoprotein, With free for at least 5 years. Fifteen had
gp100, and indicates an immature status (n=15) 1.82 mm 2.96/mm2 developed metastases. Eight had died of
of the cell with regard to melanin produc- disseminated melanoma. The “most

Naevoid melanoma 87
important criterion was tumour thick-
ness” (but mitoses also seem important
McNutt et al. {1562} studied 16 naevoid
melanomas and observed that 2 died of
melanoma (both large cell type), and one
was alive with metastases (10 years,
small cell type). Thirteen had wide exci-
sions with no evidence of residual dis-
ease or were lost to follow-up. A B
Zembowicz et al. {2596} selected 20
cases of naevoid melanomas from their
files. Three had died and 6 had metas-
tases. There was a three-year follow-up
on 8 cases, with a mean follow-up period
of 2 years. They conclude: “Naevoid
melanoma, as currently defined in the lit-
erature and in the present study, seems
to have a prognosis similar to that of clas-
sical melanoma.”
Wong et al. {2543} studied 7 cases of C D
naevoid melanoma (two dome-shaped Fig. 2.37 Naevoid melanoma. A The melanocytes are arranged as a sheet rather than as discrete nests.
and five verrucous types) and found B The aggregates of melanocytes do not disperse very much at the base of the lesion, where there is a
local recurrences in 3 and regional dense lymphocytic infiltrate. C Naevoid melanoma and its recurrence. Atypical spindle and epithelioid cells
metastasis in one patient after 2 years, are at the base of the lesion. D Mitotic figure among small and monotonous melanocytes.
with a follow-up of 5 months to 5 years.
Lohmann et al. {1444} studied 10 were thought to deviate from the normal While some of them are naevoid
patients with diagnostically controversial cells by only a single enzyme defect, and melanomas, many have the architectural
lesions who underwent sentinel node greatly resembled normal hepatocytes. patterns of ordinary superficial spread-
biopsy. The differential diagnosis was Initially the minimal-deviation melanomas ing melanomas, lentigo maligna
between Spitz naevus and melanoma. In were characterized as having small cells, melanomas, and acral-lentiginous
5 of the 10 patients, there were sentinel without much cytologic atypia, but they melanomas. In contrast, naevoid
node deposits of tumour in the parenchy- all had the architectural patterns of other melanomas closely resemble a benign
ma. All patients were alive and free of melanomas. As this concept evolved, compound or intradermal naevus in
disease on follow-up of 10 to 54 months. minimal deviation melanomas were divid- architecture. They are all included in the
ed into the following types: blue naevus original concept of minimal deviation
type, Spitz naevus type, halo naevus melanoma. Confusion in terminology
Variants and differential type, borderline melanoma, as well as arises between small cell melanoma and
diagnosis the ordinary minimal deviation what we define as naevoid melanoma.
melanomas. This created considerable This confusion is due to the use of the
Minimal deviation melanoma confusion, particularly since the name terms “small naevoid cell type” in small
In the writings of Dr Richard Reed et al. “minimal deviation” implies a better prog- cell melanomas, just on the basis of cell
{1911}, this category was analogous to nosis, which has not been a consistent size and without restrictions on the archi-
the minimal deviation hepatomas of finding {2255}. Naevoid melanoma as tecture of the lesion. As defined above, a
experimental liver carcinogenesis, which defined here was mixed into the various diagnosis of naevoid melanoma requires
types of minimal deviation melanoma both architectural and cytological mimic-
and was not recognized as a separate ry of a naevus.
category {1911}. The concept of minimal Recently a subtype of small-cell naevoid
deviation melanoma has become so melanoma has been described that
vague that the recommendation has develops predominantly in elderly indi-
been made to stop use of that term. viduals with sun-damaged skin {1313}.
However, there are attempts to clarify the This variant has an atypical lentiginous
definition of minimal deviation melanoma junctional melanocytic proliferation with a
as distinct from naevoid melanoma nested pattern that may be mistaken for
{568}. a junctional naevus. This variant has a
male predominance and the melanomas
Small cell melanoma occur predominantly on the trunk. The
Fig. 2.36 Naevoid melanoma. The lesion has a ver- Melanomas composed of small cells epidemiology suggests that these junc-
rucous profile, easily mistaken for papillomatous have been studied separately by tional lesions may be precursors of lenti-
naevus. Kossard and Wilkinson in 1997 {1317}. go maligna or superficial spreading

88 Melanocytic tumours
melanoma in situ. This type of lesion short-term follow-up. The cases with only they lack an epidermal component and
needs further studies as to whether it a single nodal metastasis have been are composed of small epithelioid cells.
represents a melanoma sui generis or a called metastasizing Spitz naevi. Some
lesion with a high propensity to develop of these lesions fit the restricted definition Early nodular melanoma
further mutations leading to melanoma. It of naevoid melanomas if they do not It is most likely that some naevoid
does not fit into the current restricted def- have a significant junctional component. melanomas are an early stage in the evo-
inition of naevoid melanoma since it has Anecdotal reports indicate that some lution of nodular melanomas.
a prominent junctional component and cases classified as metastasizing Spitz
does not involve the dermis in the early naevus by one institution go to another Desmoplastic/neurotropic melanoma
stages. institution years later with widespread Although some of these lesions could fit
metastases leading to death. The criteria into the definition of naevoid melanoma,
Deep penetrating naevus to distinguish between Spitzoid it is conventional to separate them as a
This type of naevus has a plexiform melanoma, melanoma arising in a Spitz distinct entity. Desmoplastic melanomas
growth pattern in the dermis, and despite naevus, Spitzoid variant of naevoid generally have spindle-shaped cells and
its name “deep penetrating” most of the melanoma, and metastasizing Spitz nae- naevoid melanomas, as defined here,
lesions are restricted to the upper and vus are controversial and require further generally have more epithelioid cells.
middle reticular dermis, giving rise to the investigation. Examination of sentinel Both tumours can present as predomi-
concept of the “superficial form of deep lymph nodes in controversial cases of nantly dermal lesions. Desmoplastic
penetrating naevus” {2127}. The naevus Spitzoid tumours has found a significant melanomas can resemble desmoplastic
cells form cords in the dermis composed number of nodal implants of tumour naevi, especially hypopigmented blue
of large spindled and epithelioid cells {1444}. naevi. Desmoplastic and neurotropic
resembling a combination of the cells in melanomas are best separated from
a blue naevus with cells in a Spitz nae- Proliferative nodules in a congenital naevoid melanomas since they can be
vus. Mitotic figures are very rare and are naevus recognized as a distinct group of
not atypical. They do not have much of Benign proliferative nodules may arise in tumours that has been characterized suf-
an epidermal component unless the the dermis in congenital naevi in some ficiently for diagnosis.
deep penetrating naevus component is very young patients and may be multiple.
part of a combined naevus. They must Distinction from naevoid melanoma may Metastatic melanoma
be distinguished from naevoid be difficult since mitotic figures are pres- The histologic features of naevoid
melanoma, large cell type, which has ent in the dermal nodules of naevus melanoma can be exactly reproduced in
mitoses in the dermis. However, some cells. Features of benign proliferative satellite metastatic papules and nodules
lesions given a diagnosis of deep pene- nodules that have been emphasized are of melanoma in the skin. The lack of an
trating naevus (with mitoses) have multiplicity of nodules of similar sizes and intraepidermal component, confluent
metastasized and may represent exam- appearances, and a gradual blending of growth patterns, sharp circumscription,
ples of naevoid melanomas. the cells of the nodule with the surround- symmetry, and dermal mitotic figures can
ing background congenital naevus cells all be found in metastatic melanoma. A
Spitzoid melanoma at the periphery of the nodules. Sharp diagnosis of naevoid melanoma should
This designation is used primarily for demarcation of the proliferative nodules be made with great caution in an individ-
melanomas that mimic a Spitz naevus. is more common in naevoid melanomas ual with a known history of melanoma.
The presence of a significant junctional arising in the dermal component of a Misdiagnosis of primary naevoid
component and prominent pagetoid congenital naevus {568}. melanoma as metastatic melanoma can
upward migration of large atypical lead to the clinical impression of a
melanocytes distinguish this tumour from Melanoma arising in the dermal metastatic melanoma for which a primary
a naevoid melanoma. If the Spitzoid component of a large or “giant” lesion is never found. On the other hand,
melanoma is almost entirely intradermal, congenital naevus individuals given a diagnosis of naevoid
it is a variant that would fit into the defini- In studies of melanomas arising in giant melanoma, who subsequently rapidly
tion of naevoid melanoma, large cell congenital naevi, many arose from the develop extensive metastases, may
type. dermal component {254,1912,1928}. A actually represent patients with a
significant proportion of such metastatic lesion that resembled a pri-
Metastasizing Spitz naevus melanomas are composed of small, mary naevoid melanoma. Multiplicity of
A small number of lesions given the initial hyperchromatic atypical cells and were lesions resembling naevoid melanomas
diagnosis of Spitz naevi have led to interpreted to be similar to melanoblasts, simultaneously in the same patient points
metastases and even the death of leading to diagnosis of melanoblastoma. toward metastatic disease. However mul-
patients. Some cases have had only a These lesions were highly malignant. tiple naevoid melanomas have been
single lymph node metastasis removed They are a variant that fits the current reported in an immunodeficient patient
without further evidence of disease on definition of naevoid melanoma since {1804}.

Naevoid melanoma 89
Persistent melanoma and local P.J. Heenan
J.C. Maize
metastasis of melanoma M.G. Cook
P.E. LeBoit

Definition Epidemiology head and neck, probably due to the

Persistent melanoma is defined as the The epidemiological characteristics are higher incidence of poorly defined vari-
persistent growth of residual, incom- those of the original primary melanoma. ants of melanoma in this site. These
pletely excised primary malignant include lentigo maligna, in particular the
melanoma, of either the epidermal or the Etiology amelanotic variant, and desmoplastic
invasive component, or both. It repre- The etiological factors are those of the melanoma which is particularly suscepti-
sents one form of “local recurrence” of primary melanoma. ble to incomplete excision because of its
melanoma, the other being local metas- poorly defined borders.
tasis {30,1001}. Localization
Persistent melanoma may follow removal Clinical features
Synonym of melanoma from any site of the body The most common clinical presentation
Local recurrence of melanoma. although it seems more common on the is the persistence or recurrence of a flat,

Table 2.08
Histological features of persistent melanoma and local metastases of melanoma.

Persistent melanoma Metastatic melanoma

Epidermal component Usually present, with or without a dermal component A. Absent in most cases.
. B. Epidermotropism uncommonly. The dermal component
usually extends beyond a zone of epidermotropism when
present. Sometimes the epidermotropic component is more
extensive, simulating primary melanoma {998}.

Dermal growth pattern The full range of patterns associated with A. Single or multiple symmetrical dermal and/or
primary melanoma. subcutaneous nodules.
B. Diffuse small groups and strands of neoplastic
melanocytes (this pattern occurs in the smallest and
presumably earliest metastases).

Inflammation Lymphocytic inflammation usually present. Absent or sparse.

Vascular invasion Sometimes present. Present in many cases.

Mitotic rate Variable High (usually > than 6/mm2)

Cell type The full range of cell types seen in primary melanoma, Usually monomorphic atypical melanocytic population of
frequently including a mixture of cell types. epithelioid, spindle or small (naevoid) cells.

Associated naevus Commonly present. Rare (coincidental).

Necrosis Uncommon Often present in the centres of the nodules.

Epidermal collarette Uncommon Usually present, when nodules of metastatic melanoma are in
the superficial dermis.

Fibrosis Frequently present in zones of regression and in Little or no reactive fibrosis in the stroma of the tumour.

Scarring Present in the dermis and often also in the subcutis. Present when the metastasis occurs at the primary
excision site.

NOTE: 1. In cases of persistent melanoma, histological review of the primary excision confirms the presence of in-situ or invasive melanoma (or both) at a margin of excision.
2. The microscopic features of metastatic melanoma involving the scar of the primary excision are the same as those of metastatic melanoma at a site distant from the
scar, with the additional feature of the scar at the site of the completely excised primary melanoma {2573}.

90 Melanocytic tumours
variably pigmented patch adjacent to or
surrounding the scar of the primary exci-
sion site. In some cases there may also
be nodule formation when there is per-
sistent dermal invasion, especially of
desmoplastic melanoma.

The lesion frequently is a variably pig-
mented, often pale macule with poorly
defined borders. In many cases of per-
sistent desmoplastic melanoma there is
no abnormal pigmentation in the epider-
mis overlying a firm nodule.

In the uncommon event of incomplete
excision of both the epidermal and inva-
sive components of one of the common
forms of cutaneous melanoma, the histo-
logic appearances are those of the origi-
nal tumour, frequently with pagetoid infil-
tration of the epidermis overlying inva-
sive atypical epithelioid melanocytes,
usually with little or no pigmentation,
forming an expansile growth pattern
adjacent to a zone of scarring. More
commonly, the persistent lesion consists
of in-situ melanoma with or without focal
dermal invasion. Persistence of incom-
pletely excised desmoplastic melanoma
may present only sparse, subtle infiltra-
tion of a sclerotic nodule in the dermis
and/or subcutis, containing atypical
spindle cells with hyperchromatic, vari-
ably pleomorphic nuclei and sometimes
only sparse mitoses, distributed singly
and in strands between the collagen
bundles. As in the primary tumour, a
patchy lymphocytic infiltrate may provide
a clue to perineural invasion. Desmo-
plastic melanoma may very closely simu- Fig. 2.39 Persistent melanoma. A Melanoma in-situ at the lateral margin of the excision of a primary
late a surgical scar in the primary lesion melanoma. B "Local recurrence", at the excision site two years later, showing invasive melanoma, exten-
and can be very poorly circumscribed sive adjacent melanoma in-situ and dermal scarring.
{1194}. However it can be distinguished
by its infiltrative pattern beyond the zone
usually expected to be involved with scarring following surgery. The features excision of melanoma may be due to the
of persistent desmoplastic/neurotropic coincidental growth of an entirely new
melanoma may be seen proximal or dis- and distinct tumour such as dermatofi-
tal to the scar at the primary excision site, broma or pigmented basal cell carcino-
along the line of nerves. ma. The most important differential diag-
In assessing locally recurrent melanoma nosis, however, lies between true persist-
it should always be remembered that ence of incompletely excised primary
melanoma metastases may be epider- melanoma and the other form of “local
motropic and simulate primary recurrence” due to metastatic mela-
melanoma {998}. noma. Metastatic melanoma in or adja-
Fig. 2.38 Local melanoma metastasis. So-called cent to the primary excision scar usually
"local recurrence" of melanoma in the scar at the Differential diagnosis presents as a rapidly growing papule or
excision site of a primary melanoma completely Rarely, pigmentation of the epidermis or nodule without pigmentation of the over-
excised with a margin of 25mm. growth of a nodule at the site of previous lying dermis, sometimes associated with

Persistent melanoma 91
multiple similar, rapidly growing lesions
separate from the primary excision site.
Histologically, metastases involving the
scar present exactly the same features
as cutaneous metastases at a distance
from the scar {2573}

Persistent melanoma occurs because a
primary melanoma was incompletely A B
excised. The histogenesis, therefore, is
essentially that of the original melanoma.

Somatic genetics
The genetic factors are those that apply
to the original melanoma.

Prognosis and predictive factors

The prognosis for persistent melanoma is
assessed in the same manner as for the
original tumour, tumour thickness still C D
being the most important single factor, Fig. 2.40 Metastatic melanoma. A In this epidermotropic metastatic melanoma, a papule has formed large-
unlike local recurrence due to metastasis ly due to the irregular epidermal hyperplasia. B On the left side of the lesion, one can see sharp circum-
which is a manifestation of systemic scription, contributing to resemblance to a Spitz naevus. C Metastatic melanoma simulating blue naevus.
metastasis and portends a poor progno- D Irregular nests of melanoma cells are visible at the base of the lesion in the subcutis.

92 Melanocytic tumours
Congenital melanocytic naevus H. Kerl
D. Massi
P.E. LeBoit
B.C. Bastian

Superficial type fuse infiltrates of small monomorphous Somatic genetics

melano-cytes are found in the upper part Like the majority of melanocytic naevi
Definition of the dermis and the mid-portion of the except Spitz and blue naevi, congenital
Congenital melanocytic naevi (CMN) of reticular dermis. The melanocytes are melanocytic naevi have frequent BRAF
the superficial type are melanocytic pro- frequently arranged in a band-like pat- mutations and show no chromosomal
liferations present at birth. The term con- tern and are disposed in single files aberrations {173,1850}.
genital has been also applied to lesions between collagen bundles (“splaying of
displaying clinical and histopathological melanocytes“). Prognosis and predictive factors
features of congenital melanocytic naevi An important criterion for diagnosis is the Recent studies revealed in a significant
which may not be apparent at birth. presence of melanocytes along epithelial number of malignant melanomas an
These lesions are designated as tardive structures of adnexa and their angiocen- association with melanocytic naevi with a
congenital melanocytic naevi. tric distribution. They may be found with- congenital histopathologic pattern
in sebaceous glands, vessels, nerves {159,1245}. However, the pathogenetic
ICD-O code 8761/0 and in smooth muscles {1168,1531}. In role of small congenital melanocytic
the compound type of a congenital nae- naevi as precursor lesions of melanoma
Synonyms vus – superficial type, nests of melano- is controversial {1508, 2323}. Clinical fol-
Congenital pattern-like naevus; tardive cytes are present in the epidermis, most- low-up of 3922 patients with small CMN
congenital naevus; congenital naevus- ly at the dermo-epidermal junction. found no significant risk of melanoma
like naevus. Melanomas are very rare in newborn and development {205}.
young infants (see chapter on childhood
Clinical features melanoma). Congenital melanocytic
Congenital melanocytic naevi - superfi- naevi, biopsied shortly after birth or in the Proliferative nodules in
cial type are frequently observed. They first years of life can display atypical congenital melanocytic naevi
can be found on any anatomic site and intraepidermal changes (pagetoid
belong to the group of small congenital melanocytes arranged as solitary units Definition
naevi with a diameter smaller than 1,5 and nests; single cells present in the Proliferative nodules in congenital
cm. upper layers of the epidermis) similar to melanocytic naevi are defined as atypi-
On gross examination they vary from those of melanoma in situ {1514}. This cal melanocytic proliferations which
macules and papules to plaques and finding is more commonly found in giant manifest predominantly in the neonatal
reveal different colours from light brown congenital naevi than in small ones. period within a pre-existing large (deep)
to black. The lesions are usually round or The clues for diagnosis of this unusual congenital melanocytic naevus.
oval with a smooth or papillated surface. change in a benign naevus are found in
They may be hairy or hairless. the dermis where the large, pale ICD-O code 8762/1
melanocytes merge with smaller ones
Histopathology that have the characteristic features of a Synonyms
In the superficial type of CMN, dense dif- congenital melanocytic naevus. Atypical proliferative nodules in giant

Fig. 2.41 Congenital melanocytic naevus, superficial type. A Papule with brown to black colors and a mamillated surface. B Band-like infiltrate of melanocytes in
the upper dermis. Adnexocentric arragement and "splaying" of melanocytes between bundles of collagen in the upper and mid-portion of the reticular dermis.
C Monomorphous melanocytes around and focally within an arrector pili muscle.

Congenital melanocytic naevi 93

Fig. 2.42 Proliferative nodule in a large congenital Fig. 2.43 Proliferative nodule in a congenital melanocytic naevus. The congenital melanocytic naevus, with
melanocytic naevus (garment type). A black plaque small naevoid cells can be recognized on the left side of the picture. Melanophages are distributed in a uni-
above the sacrum representing the proliferative form fashion in the upper dermis. The profilerative nodule reveals cellularity with relatively monomorphous
nodule is recognizable. large cells with prominent nucleoli.

congenital naevi; dermal variant of mini- entire dermis and often extending into seven out of nine cases showed chromo-
mal deviation melanoma in a giant con- the septa of the subcutaneous fat can be somal aberrations {175}. Six of the seven
genital naevus {1907}, dermal melano- observed. cases with aberrations (86%) showed
cytic tumour of uncertain potential in a The “proliferative“ nodule, which is usual- numerical aberrations of whole chromo-
giant congenital naevus. ly found in the upper and mid dermis somes exclusively. This pattern differs
consists of roundish epithelioid or spin- significantly from the findings in
Clinical features dled melanocytes. The cells are large melanomas arising in congenital naevi or
There is usually a dark brown to black and appear to blend with the surround- melanoma in general in which the major-
plaque or nodule above a giant congen- ing smaller melanocytes (naevus cells). ity (96%) have aberrations involving only
ital melanocytic naevus. The lesions may Atypical nuclei and mitotic figures can be partial chromosomes {173}. Loss of chro-
become lighter and show regression observed. mosome 7 was seen in three of the nine
after years. Occasionally a palpable proliferative nodules. Loss of chromo-
mass can be found deeply in the skin. Differential diagnosis some 7 was not observed in 132
These nodular proliferations in congenital Proliferative nodules in congenital melanomas that were not associated with
melanocytic naevi behave in a benign melanocytic naevi can be misinterpreted giant congenital naevi {173}. However,
fashion. as a melanoma that developed in the one melanoma arising in a congenital
intradermal component of a congenital naevus in an eight-year-old boy showed
Histopathology naevus (see Melanoma arising in giant a similar loss of chromosome 7.
The background congenital melanocytic congenital naevi) {1009}.
naevus reveals the characteristic fea-
tures of a congenital melanocytic naevus Somatic genetics
of the deep type. A dense diffuse infil- In a study of proliferative nodules using
trate of small melanocytes involving the comparative genomic hybridization

94 Melanocytic tumours
Blue naevi E. Calonje
K. Blessing
E. Glusac
G. Strutton

Common blue naevus Clinical features lesions often display prominent sclerotic
The most common presentation consists stroma making the diagnosis difficult.
Definition of a single asymptomatic, relatively well- Lesions with very poor pigmentation are
Common blue naevus (BN) is a benign, circumscribed, dome-shaped blue or rarely encountered {234,402}. Tumour
usually intradermal melanocytic lesion blue-black papule less than 1 cm in cells are bland and spindle-shaped or
characterized by pigmented dendritic diameter. The characteristic blue colour dendritic and usually contain abundant
spindle-shaped melanocytes and, more is produced by the Tyndall effect. cytoplasmic coarse melanin pigment.
rarely, epithelioid melanocytes. The Tumours may rarely present as a plaque Nuclei are small, and an inconspicuous
melanocytes are usually separated by {1025,2494}. Eruptive lesions have rarely basophilic nucleolus is sometimes pres-
thickened collagen bundles. been documented. Exceptional clinical ent. Numerous melanophages are a rela-
presentations include a speckled variant tively constant feature in the vicinity of
ICD-O code 8780/0 {1044}, hypopigmented lesions {278}, an tumour cells. Extension of tumour cells
example with satellite lesions {1195} and into nerves and, less frequently, blood
Epidemiology a case with widespread lesions. vessel walls, may be found. Mitotic fig-
BN is relatively frequent, has predilection Localized hypertrichosis has been ures are exceptional. Rarely, a blue nae-
for females and presents mainly in young described in a single case {57}. vus may coexist with a trichoepithelioma
adults between the second and fourth {48}.
decades. Although most tumours are Histopathology In some instances, metastatic melanoma
acquired, congenital examples have BN and cellular blue naevus show a wide may mimic common blue naevus {354}.
been documented {1872}. Familial cases histological spectrum, frequently over- Blue naevus may co-exists with other
may be seen and usually present with lapping with other melanocytic lesions types of naevus (see combined naevus).
multiple lesions {258,1292}. including deep penetrating naevus and
pigmented Spitz naevus {1637}. Immunoprofile
Localization BN is typically located in the reticular Tumour cells are usually diffusely positive
The anatomical distribution is wide but dermis and only exceptionally extends for melanocytic markers including S-100,
most lesions occur on the distal upper into the papillary dermis or subcutis. The HMB45, melan A and microphthalmia
limbs (particularly the dorsum of the epidermis appears unremarkable, transcription factor (MITF-1). Unlike the
hand), followed by the lower limbs, except in the rare so-called compound case in most other benign melanocytic
scalp, face and buttocks. Lesions have blue naevus, in which dendritic junction- naevi and in melanomas, HMB45 strong-
also been documented in the vagina al melanocytes are identified {733, ly stains the entire lesion in blue naevi.
{1002,2356}, cervix {2393}, prostate 1190}. Low power examination reveals a
{1414}, oral cavity (mainly the hard generally symmetric but often ill-defined Somatic genetics
palate) {327,328} and the capsule of tumour of variable cellularity. Concen- Mutations in the BRAF gene appear to be
lymph nodes without a primary cuta- tration around adnexa without adnexal rare in BN. Chromosomal aberrations are
neous lesion {695,858,1497}. destruction is typical. Poorly cellular uncommon {1490}.

Fig. 2.44 Common blue naevus. A Typical clinical appearance of a common blue naevus. B A more cellular example with hyalinization of dermal collagen.
C Melanocytes often extend into the perineurium of dermal nerves.

Blue naevi 95
Fig. 2.45 A Mongolian spot. Typical prominent macular blue/grey discolouration on lower back and buttocks. B Naevus of Ota with involvement of the periorbital
skin and conjunctiva. The blue cast is typical. C Naevus of Ota. Bipolar, deeply pigmented melanocytes in the reticular dermis.

Prognosis and predictive factors appear unremarkable. Low power exam- the nasal and oral mucosa, optic tract
BN is benign, and malignant transforma- ination reveals a mild increase in cellular- and the leptomeninges are involved.
tion is exceptional {883} (see chapter ity in the deep reticular dermis, consist- Lesions identical to naevus of Ito or nae-
Melanoma arising from blue naevus). ing of few variably pigmented dendritic vus of Ota may present rarely in other
Simple excision is curative and local melanocytes, which are usually, oriented anatomical sites. A limited form resem-
recurrence is very rare {973}. parallel to the epidermis. Melanophages bling naevus of Ota presenting in the
are occasionally seen. zygomatic area is called naevus of Sun.
Mongolian spot
Clinical features
Definition Naevus of Ito and Lesions are usually large, macular, ill
Mongolian spot (MS) is a form of dermal Naevus of Ota defined and have a blue or blue-grey
melanocytosis presenting on the lower colour. A speckled appearance is seen
back and characterized by scattered Definition rarely. There is no tendency for sponta-
pigmented dendritic melanocytes in the Naevus of Ito (NI) and naevus of Ota neous regression. Bilateral involvement
reticular dermis. (NO) are dermal melanocytoses with has been documented rarely {1026}. Co-
identical histological features, which dif- existence between NI and NO is a rare
Epidemiology fer in their characteristic clinical presen- occurrence {615,1026}. Glaucoma is a
MS presents at birth and has marked tation. NI typically presents in the shoul- rare complication of NO {1434}.
predilection for Black and Oriental der region, following the distribution of
patients with the same sex incidence the lateral brachial and posterior supra- Histopathology
{1260,1261}. The incidence in Caucasian clavicular nerves. NO involves the skin The histology of NI and NO is indistin-
children is approximately 9.5% {543}. and mucosal surfaces (including the guishable. The epidermis appears unre-
conjunctiva), following the distribution of markable but may show increased
Localization the ophthalmic and maxillary branches of melanin in basal cells and a mild
Most lesions occur on the lower posterior the trigeminal nerve. increase in the number of basal melano-
trunk with predilection for the sacro- cytes. In the superficial and mid-dermis
gluteal region. Lesions identical to MS Synonyms there are scattered dendritic or spindle-
and naevus of Ito or naevus of Ota may Naevus Ota: Oculodermal melanocyto- shaped, often bipolar deeply pigmented
present rarely in other anatomical sites. sis, Naevus fuscoceruleus ophthalmo- melanocytes. Melanophages are rare.
Clinical features Prognosis and predictive factors
MS is characterized by a macular area of Epidemiology Malignant transformation is exceptional
blue-green or blue-grey discolouration Both NI and NO are relatively rare, affect and more common in NO {1783,2194,
varying in size from a few to 10 or more mainly patients of Oriental or African ori- 2345,2414}. In the latter setting it may
cm. Lesions fade gradually, usually dis- gin and have some predilection for occur in the skin, eye or meninges.
appearing completely when patients females {1027,1307,1626,2243}. Presen-
reach adolescence. tation is mainly at birth (up to 50%) or
Association with cleft lip {1096} and the during childhood and adolescence. Cellular blue naevus
mucopolysaccharidoses, including Hur- Adult onset is very rare {447}.
ler and Hunter syndromes) {880, 2063} Definition
has been documented. Lesions with the Localization Cellular blue naevus (CBN) is an
clinical and histological features of MS NI typically involves the supraclavicular, acquired dermal/subcutaneous pigment-
may rarely present at other body sites. deltoid and less commonly, the scapular ed tumour with prominent cellularity and
area. NO usually involves the sclera, an expansile growth pattern.
Histopathology conjunctiva, and skin around the eye and
The epidermis and superficial dermis zygomatic and temporal areas. Rarely ICD-O code 8790/0

96 Melanocytic tumours
Epidemiology cellular areas may alternate with sclerot-
CBN tends to present between the sec- ic or hypocellular areas. In most cases
ond and fourth decades of life with there are focal areas representing or sim-
female predilection, and it is more com- ulating a common blue naevus. High
mon in Caucasians. Congenital cases power examination reveals bundles of
are exceptional {1095}. oval or spindle-shaped cells with pale
cytoplasm, alternating with bundles of
Localization deeply pigmented spindle-shaped cells.
The anatomical distribution is wide, but In addition, dendritic melanocytes and/or
CBN have predilection for the buttocks round, somewhat epithelioid melano-
and sacral region (50% of cases), fol- cytes may be seen. Cytoplasmic melanin
Fig. 2.46 Cellular blue naevi on the upper back.
lowed by the scalp, face, distal limbs and is coarse and granular, and nuclei are
other sites on the trunk {1957,2336}. regular and vesicular, with a single small
Lesions may also rarely occur on the usually present with multiple lesions inconspicuous basophilic nucleolus.
eyes, cervix, vagina, breast and sper- {396,399}. Sporadic lesions are usually Maturation with depth is not a feature. A
matic cord {266,1957,2336}. Aggregates solitary and may occur in genital skin frequent finding however, is the focal
of tumour cells have been reported in the {1117,1646,1736}. presence of elongated slender melano-
capsules of regional lymph nodes drain- cytes resembling Schwann cells, indica-
ing an area where an otherwise typical Macroscopy tive of neurotization as seen in ordinary
benign cellular blue naevus is present The cut surface of a CBN characteristi- naevi. Some tumours exhibit a focal alve-
{287,1957,2261,2336}. This phenome- cally shows a dark brown to black, well- olar growth pattern {1597} and desmo-
non is regarded as a benign occurrence defined dermal and subcutaneous plasia is occasionally prominent {1599}.
rather than an ominous finding. tumour. In some cases there are areas of Degenerative changes including haem-
haemorrhage and cystic degeneration. orrhage, cystic change and fibrosis, are
Clinical features seen in some cases. Focal mild or promi-
Tumours are usually large, varying from 1 Histopathology nent myxoid oedematous change may
to several centimetres, and the colour Low-power examination reveals a fairly also be a feature {1598}, and balloon cell
varies from light blue-brown to dark blue. characteristic picture with a dumbbell- change has been documented {1806}.
Lesions are asymptomatic and grow very shaped multinodular tumour occupying Occasional cases display a number of
slowly, presenting as a non-ulcerated the reticular dermis and often extending unusual features including mitotic figures
firm nodule {1957,2336}. Exceptional into subcutaneous tissue. A junctional (1/10 HPFs), focal necrosis, and/or
cases present as a large plaque {358}. component is not usually found. Areas of nuclear pleomorphism or hyperchroma-
Rare tumours arising in the scalp have pigmentation alternate with poorly pig- tism. Such cases show some overlap
been described with invasion of the mented areas and, in a minority of cases, with the malignant variant of CBN and
underlying bone {1596} and even the pigment is very scanty {2595}. Cellular have been described as atypical CBN
brain {854}. areas tend to be more prominent towards {118,2371}.
The epithelioid variant of blue naevus is the centre of the tumour, and the cellular- The epithelioid blue naevus is composed
very rare and has mainly been described ity may be most marked where the neo- of large round epithelioid and short spin-
in patients with Carney complex who plasm protrudes into the subcutis. The dle-shaped deeply pigmented melano-

Fig. 2.47 Cellular blue naevus. A Typical low-power appearance with a dumb-bell architecture. B Bundles of bland spindle-shaped melanocytes alternating with
focally pigmented cells. Scattered melanophages are also seen. C Typical small vesicular nuclei with a small basophilic nucleolus.

Blue naevi 97

Fig. 2.48 Hypopigmented cellular blue naevus. A In some cases, melanin is almost completely absent. Fig. 2.49 Cellular blue naevus. A This lesion has a
B Myxoid change may be prominent in some cases. C One of the melanocytes is much larger than the oth- central focus of cystic change. B The edge of the
ers. Some refer to such cases as ‘atypical cellular blue naevus’. D Large melanocytes are present, some cystic area.
are multinucleated.

cytes. Some examples of this variant of Deep penetrating naevus mented dermal and, very rarely, superfi-
BN probably represent combined naevi cial subcutaneous tumour. The base of
{903}. Definition the lesion parallels the epidermis. The
Deep penetrating naevus (DPN) is a dis- junctional component, which is usually
Immunoprofile tinctive deeply pigmented lesion show- present and may be subtle, consists of
Tumour cells in CBN are positive for S- ing overlapping features with blue nae- small round nests of ordinary naevus
100, melan-A and HMB45. In tumours vus and Spitz naevus. cells. In fact, in most cases, a superficial
with prominent desmoplasia, and in dermal component, representing an ordi-
those with neurotization, staining for Synonym nary naevus, may be found and therefore
melan-A and HMB45 tends to be patchy. Some cases have been described under these lesions may be regarded as com-
CD34 has been reported to be positive in the heading of plexiform spindle cell bined naevi {1953}. Much less common-
tumour cells in a group of congenital naevus {164}. ly, focal changes mimicking a Spitz nae-
CBN {2204}. vus or a blue naevus are found {1953,
Epidemiology 2127}. Tumour cells are arranged in
Genetics DPN is an acquired lesion presenting nests or bundles and have a short spin-
Similar to other naevi, cellular blue naevi mainly between the second and third dle-shaped or, less commonly, round
do not show chromosomal aberrations decades of life with no sex predilection morphology. The cytoplasm contains
when analysed by CGH. In a small series {1953,2127}.
of atypical cellular blue naevi, three out
of eight cases showed single chromoso- Localization
mal losses with chromosome 3p being DPN has a wide anatomical distribution
affected in two of these cases {1490}. with predilection for the face, upper trunk
and proximal limbs {164,537,1575,1953,
Prognosis and predictive factors 2127}.
Although limited case series have char-
acterized these lesions as benign, some Clinical features
cases with atypical features have result- The tumour presents as a solitary, well-
ed in recurrences or death from systemic circumscribed blue or dark brown/black
metastasis. They may therefore be dome-shaped papule or nodule usually
regarded as having uncertain malignant less than 1 cm in diameter.
potential and treated with complete exci-
sion if possible and perhaps long term Histopathology
follow-up. Malignant transformation in Low power examination typically reveals Fig. 2.50 Deep penetrating naevus with a typical
CBN is very rare {64,883}. a compound wedge-shaped deeply pig- wedge-shaped architecture.

98 Melanocytic tumours
abundant melanin and nuclei are vesicu-
lar with frequent intranuclear inclusions
and a single small basophilic nucleolus.
Hyperchromatism and variation in
nuclear size may be seen, but as a rule
mitotic activity is low or absent (usually
not more than 1 per section). The
melanocytes follow the path of adnexal
structures and blood vessels and there is
frequent perineural extension. Maturation
is not seen. Some tumours have the cyto-
morphology of DPN but are superficial
and lack the deep penetrating compo-
nent. Similar changes are seen in a com-
mon form of combined naevus.
Prognosis and predictive factors
Local recurrence is exceptional, and only
a single case has been reported spread-
ing to a regional lymph node {874}.

Fig. 2.51 Deep penetrating naevus. A A wedge shape and nests of cells around adnexal structures are char-
acteristic findings. B The large pale cells in a deep penetrating naevus are arranged as discrete nests.
C A thin rim of sustentacular cells is present around the edges of many nests. D Toward the base of the
lesion nests of pale large cells are present near adnexal structures.

Blue naevi 99
Combined naevus R.L. Barnhill

Definition cases, the head and neck in 23.6%, Table 2.09 The naevus components potentially
A combined naevus or “melanocytic nae- upper extremities in 22.0%, lower occurring in combined naevus
vus with phenotypic heterogeneity” is a extremities in 9.9%, and perineum and
melanocytic naevus either congenital or buttocks in 4.4% {2116}. Naevi with a sig- Common acquired naevi
– junctional
acquired, containing two or more distinct nificant blue naevus component com-
– compound
melanocytic naevus components. monly involve the face, back, and shoul-
– dermal
der {757}. Naevi with prominent compo- Congenital naevi
Synonyms and historical annotation nents of Spitz naevus often occur on the – junctional
Melanocytic naevus with phenotypic het- head and neck (face) or extremities as – compound
erogeneity; inverted type A naevus; nae- do conventional Spitz naevi {1961}. – dermal
vus with focal dermal epithelioid compo- Dysplastic naevi (naevi with architectural dis-
nent, and naevi with dermal nodules. Clinical features order and cytological atypia)
The term combined naevus was used ini- The gross morphological features of – junctional
tially to describe the combination of a combined naevi are probably related to – compound
Blue naevi
conventional naevus and blue naevus the types of and predominant cellular
– ordinary or common
{61,653,702,1402,2331}. However, the populations present, e.g., focal dermal
– hypercellular
spectrum of combined naevus has been pigmented components, blue naevus, – cellular
subsequently extended to include com- Spitz naevus, etc. Most of these naevi – plaque
ponents of any type of naevus (Table measure less than 5 to 6 mm in greatest – epithelioid
2.09){135,156,520,1610}. There may be diameter {156,757,1864,2116}, are rea- Spitz naevi
poor concordance in the interpretation of sonably symmetrical, are well-circum- – junctional
some cases, because of overlapping scribed papular or dome-shaped – compound
features and the difficulty of defining the lesions, and exhibit dark brown, blue to – dermal
morphological limits of blue naevi, Spitz black colouration. Thus many such naevi – desmoplastic
Deep penetrating naevi
naevi, deep penetrating naevi, plexiform are often diagnosed clinically as blue
Plexiform pigmented spindle cell naevi
pigmented spindle cell naevi, and naevi naevi or melanoma because of the pre-
Naevi with dermal epithelioid cell components
with dermal epithelioid cell components. dominant dark colour. Some of these (clonal naevus)
naevi may also demonstrate a small well- – inverted type A naevus
Epidemiology circumscribed blue or blue-black focus, – naevus with dermal nodules
There are no population-based data e.g., often 1–3 mm in diameter, within an Other
available as to the prevalence of com- otherwise ordinary flesh-coloured, tan, or
bined naevi. However they appear to brown naevus (melanocytic naevi with
constitute less than 1% of melanocytic focal dermal pigmented components) nents are intimately admixed in 82% of
naevi sampled for histopathological {135,156,520,757,2116}. Some naevi cases whereas they are adjacent in the
examination {2116}. These naevi occur in may show irregular borders and pigment remainder. The most common pattern of
all age groups (3 to 83 years in a recent patterns also raising concern for combined naevus is that of a common
study) with a mean age of 30 years melanoma. acquired or congential naevus in combi-
{2116}. A slight predominance of women Naevi with prominent Spitz components nation with discreet foci of pigmented
has been consistently reported in sever- are often diagnosed as an unusual nae- epithelioid and/or spindle cells (which
al studies {757,1864,1961,2116}. vus, Spitz naevus, dermatofibroma, or probably includes inverted type A nae-
The developmental biology of combined possibly melanoma. vus and melanocytic naevus with dermal
naevi has not been delineated. Their epithelioid cell components, dermal nod-
genesis may be related to more than one Histopathology ules, or a component of “deep penetrat-
pathway of melanocytic differentiation Combined naevi may potentially encom- ing” or plexiform pigmented spindle cell
occurring in a single naevus. It cannot be pass the entire phenotypic repertoire of naevus) {158,164,537,2126}. The latter
excluded that there is focal neoplastic melanocytic naevi. By definition two or cells are often enlarged, contain abun-
progression in some proportion of these more distinct naevus components are dant granular melanin, and are disposed
lesions. present. Any combination of naevus in nests or fascicles in the superficial,
components and percentage of the nae- superficial and deep, or deep portions of
Localization vus components may occur. However or beneath the ordinary naevus, some-
Scolyer et al. found a predilection for the 99% of combined naevi have only two times or commonly in plexiform arrange-
trunk (chest, back, abdomen) in 35.2% of components {2116}. The two compo- ments. The sizes of the nests or fascicles

100 Melanocytic tumours


Fig 2.52 Combined naevus. A Combined naevus (melanocytic naevus with phenotypic heterogeneity). The lesion is well-defined with central dark brown papule and
lighter brown annulus (Courtesy of Harold Rabinovitz, M.D.). B There is a conventional compound naevus with small fairly discrete aggregates of heavily pigment-
ed cells in the dermis. C This field shows small nests of pigmented polygonal melanocytes and melanophages admixed with the background conventional naevus.
D The pigmented polygonal melanocytes have abundant cytoplasms and contain nuclei that resemble those in the surrounding small naevus cells. The polygonal
cells show transition to the surrounding conventional cells.

may vary from being minuscule to large melanocytes, melanophages, and vari- combination of cell types is possible
lobular or digitate aggregates. The nuclei able fibrosis. Less commonly, the spindle {156,2116}. Thus, one may encounter
are usually comparable in size to the sur- cells typical of cellular blue naevus may naevi containing various admixtures of
rounding conventional naevus cells, or also be present with or without dendritic ordinary naevus cells, dendritic
may be slightly enlarged round, oval, or cells. The component of blue naevus melanocytes, Spitz naevus cells, and
elongate and uniform. On occasion the may extend deeply into the reticular der- perhaps other transitional cell types.
nuclei may show variable often slight to mis as nests or fascicles, often in a plex- Atypical features may also be observed
moderate atypia. Melanophages are also iform configuration. Despite the two or such as disordered patterns of melano-
frequently associated with these pig- more components, such naevi are usual- cytes and cytological atypia of both the
mented foci. This pattern of combined ly symmetric, well-circumscribed, order- intraepidermal and dermal components.
naevus is also probably morphologically ly, and display little or no cellular atypia.
identical to that of deep-penetrating nae- Spitz naevi uncommonly are observed in Somatic genetics
vus and plexiform pigmented spindle cell association with ordinary naevus ele- The conventional naevus component will
naevus {158,164,537,2126}. ments {1961}. The topographic relation- demonstrate frequent BRAF mutations in
Another common pattern is that of an ships of these two components include contrast to their absence in blue or Spitz
ordinary naevus and blue naevus. The the Spitz naevus component being adja- naevus components.
ordinary naevus component may be cent to, beneath, or admixed with the
compound or dermal, often overlies or is common naevus elements. Such naevi Differential diagnosis
adjacent to the blue naevus component, also may have a desmoplastic stroma as The differential diagnosis of combined
and commonly has a congenital pattern. in desmoplastic Spitz naevi. naevus is dependent on the particular
The blue naevus elements most often After the above relatively well-recognized cellular populations present. The histo-
consist of heavily-pigmented dendritic forms of combined naevus, almost any logical feature often of most concern is

Combined naevus 101

Table 2.10 ly is of ordinary type is generally unre-
Comparison of combined naevus and melanoma markable with reference to atypicality. An
Combined naevus Melanoma occasional mitosis may be observed in
such a focus without undue concern;
Symmetry Frequent Uncommon however, the presence of 2 or more
mitoses per high power field should
prompt careful inspection for melanoma
Size < 6mm often > 1cm often {156}.

Lateral border Sharply defined Poorly-defined Prognosis and predictive factors

Combined naevi are by definition benign.
Focus, foci of altered cells* Present, transition (maturation) Variable
However it must be acknowledged that
to surrounding ordinary naevus as with cellular blue naevi and Spitz
naevi, there are unusual variants often
characterized by a number of abnormal
Cytologic atypia Usually absent or low-grade High-grade features. Such atypical lesions rarely
may result in metastases and require fur-
Mitotic activity Absent or minimal (usually < Frequent ther study as to more definitive criteria for
2/mm2 malignancy. Thus such atypical variants
prospectively are best designated as
biologically indeterminate and require
Mononuclear cell infiltrates Uncommon Frequent
complete excision and close clinical
*Focus of epithelioid/spindle cells in ordinary naevus (as also observed in inverted type A and clonal naevi)

an aberrant focus of cytologically (maturation) to the surrounding naevus.

altered/atypical cells in an otherwise Although combined naevi are heteroge-
ordinary naevus. Such a finding is of con- nous, they are usually present in young
cern for early transformation to individuals (< 30 to 40 years), measure
melanoma or, even fully-evolved less than 5 or 6 mm, and exhibit an over-
melanoma. The latter histologic alteration all symmetry and regular appearance. A
is present most commonly in the dermis. focal aggregate of pigment-laden epithe-
However, the development of melanoma lioid/spindle cells is usually the feature of
in the dermal component of a naevus is concern. Although occasional aggre-
highly unusual. Therefore, such a diag- gates of epithelioid cells are large, many
nosis must be carefully considered and are small and well-circumscribed.
based on sufficient criteria of atypicality, Cytologic atypia is usually low-grade or
mitotic activity, nodular (confluent) prolif- insignificant compared to melanoma.
eration, and usually the lack of transition The surrounding naevus which common-

102 Melanocytic tumours

Melanotic macules, simple lentigo and H. Kerl
D. Massi
lentiginous melanocytic naevus

Melanotic macules ineum, the introitus, vagina and cervix. Reticulated melanotic macule
They may be difficult to distinguish from These lesions appear on sun-exposed
Definition melanoma {1400}. areas of the trunk or shoulders as a dark-
Melanotic macules are pigmented brown or black reticulated macule with
lesions that occur on skin, mucous mem- Penile melanotic macule irregular borders.
branes, and in nail units {2035}. The This lesion usually presents in adult life Although the lesion has been named
lesions are characterized by hyperpig- as a pigmented patch, uniform or varie- “reticulated black solar lentigo” {277}, it
mentation of the epidermal/epithelial gated in colour with irregular borders, on is different from the conventional solar
basal layer accompanied by a slight the glans penis or on the penile shaft. lentigo {1171}.
increase in number of melanocytes. Multiple macules can be observed.
There are several syndromes, which are PUVA-lentigines
associated with multiple melanotic mac- Labial melanotic macule PUVA-lentigines are pigmented macules,
ules/lentigines (Peutz-Jeghers, NAME, The lesion occurs in about 3% of per- which develop as a direct response to
LAMB, LEOPARD, Carney complex (See sons, mostly in women on the vermilion the effects of long-term therapy with
Chapter 7). border of the lower lip. The lesions can PUVA (psoralens + UVA).
be also present on the oral mucosa and
Synonyms on the tongue. A single or multiple (oral Histopathology
Genital: Genital melanosis/lentiginosis; melanosis), brownish-black or black Similar histopathologic changes can be
Vulvar melanotic macule; penile melanot- macules with irregular sharply demarcat- demonstrated in all types of melanotic
ic macule; penile lentigo. ed borders can be observed {925}. macules. There is usually no perceptible
Labial/oral: Labial/oral melanosis; labial or a slight increase in the number of
melanotic macule; labial lentigo. Variants melanocytes, which are situated at the
Volar: Volar melanosis. Volar melanotic macule dermo-epidermal junction in solitary
Nail apparatus: Melanosis of the nail bed Clinically a brown, tan, or grey macule units. The melanocytes exhibit small and
and matrix; ungual melanosis. (less than 5 mm in diameter) is located monomorphous nuclei and delicate den-
Skin: Reticulated black solar lentigo; “ink on palms and soles usually in Black drites. Using Fontana-Masson silver
spot” lentigo. patients. stain, the dendrites are better visible.
Atypia is not observed. The basal layer
Clinical features Ungual melanotic macule reveals prominent hyperpigmentation.
Melanotic macule of vulvar and other Pigmented bands (not thicker than 3 Occasionally hyperplasia of the epider-
female genital sites mm) are observed in the fingernails of mis can be seen. Melanophages and a
The condition occurs usually on the vulva young individuals (longitudinal melano- mild inflammatory infiltrate are often
as a flat asymmetric macule with a dia- nychia). The lesions are common in dark- present in the superficial dermis.
meter from less than 1–5 cm. Multiple skinned races and in the Japanese pop- Reticulated melanotic macules show
lesions are present in >50% of the cases. ulation. In Laugier-Hunziker syndrome, marked hyperpigmentation of the epider-
The tan-brown to blue-black macules longitudinal melanonychia is accompa- mis especially at the tips of the rete
mostly involve the labia minora. But they nied with labial/oral melanotic macules. ridges whereas the suprapapillary plates
can also occur on the labia majora, per- are spared and nearly devoid of melanin.
A slightly increased number of finely
dendritic melanocytes can be observed
in the lower layers of the epidermis. In
contrast, solar lentigo represents an
evolving seborrhoeic keratosis revealing
small buds or nubbins of hyperpigment-
ed keratinocytes.
PUVA-lentigines are characterized by an
increased number of melanocytes, which
are concentrated mostly in pigmented
rete ridges as solitary units. Some
A B melanocytes may show atypical nuclei.
Fig. 2.53 Melanotic macule on the lip. A Brown-black macule with irregular margins on the lower lip.
B Pigmentation of the epithelial basal layer and melanophages in the papillary dermis.

Melanotic macules, simple lentigo and lentiginous melanocytic naevus 103

layer; lentiginous junctional melanocytic
naevus shows in addition formation of
small junctional nests. In compound
lentiginous melanocytic naevi, small
round melanocytes are also present in
the papillary dermis.

Lentigo simplex, naevus incipiens.

B Clinical features
Small flat roundish uniform brown or
black sharply circumscribed macules
usually less than 6 mm in diameter, which
are most frequently found on the trunk
and extremities of children and adults,
are observed.

Simple lentigo consists of an increased
number of melanocytes disposed as soli-
tary units in the basal layer of variably
A C elongated and hyperpigmented rete
Fig. 2.54 Simple lentigo - Lentiginous melanocytic naevus. A Small uniform brown macules; (stars) simple ridges. The melanocytes have small
lentigo. (arrows) lentiginous melanocytic naevus. B Simple lentigo. Increase in the number of melanocytes round to oval and monomorphous nuclei.
in single units along the basal layer - especially around elongated hyperpigmented rete ridges. Distinct They are positioned equidistant from one
nests are absent. C Lentiginous melanocytic naevus. Features of lentigo simplex can be recognized. The another and are seen more pronounced
aggregation of melanocytes in tiny nests indicates the transformation of this lentigo simplex into a lentigi- at the tips of the rete ridges. Pigment is
nous melanocytic naevus.
abundant and found throughout the epi-
dermis including the stratum corneum.
Differential diagnosis tional sampling, over time if indicated. If Melanophages are usually present in the
Early stages of melanoma in situ must be the problem cannot be resolved com- papillary dermis. Giant melanosomes
differentiated from melanotic macules. plete excision may be appropriate. can be present.
Melanoma in situ (genital / labial areas) When one or more small nests of
can manifest as a sparsely cellular prolif- melanocytes (i.e. three or more melano-
eration of melanocytes. Sometimes in a Simple lentigo – lentiginous cytes per congregation) in such a lesion
partial biopsy the only clues are nuclear melanocytic naevus is observed, it is then called lentiginous
hyperchromasia or irregularly shaped naevus (evolving junctional naevus).
dendrites. In more fully developed Definition The histology of naevus spilus (congeni-
cases, melanocytes are more regularly Simple lentigo and lentiginous tal speckled lentiginous naevus) is indis-
distributed, can become confluent and melanocytic naevus are pigmented mac- tinguishable from simple lentigo-lentigi-
may also be situated above the junction. ules representing the early stages in the nous melanocytic junctional naevus.
Lesions with more than a slight increase development of a melanocytic naevus. In
in melanocytes, even without atypia simple lentigo, melanocytes are Prognosis and predictive factors
should be carefully evaluated, with addi- increased in number along the basal Melanotic macules have been incorrectly
interpreted as premalignant lesions and
possible precursors of melanoma
{1757A,2394A}. Current evidence sup-
ports the notion that melanotic macules,
irrespective of their location, should be
considered benign in their clinical
behaviour, since they tend to remain sta-
ble and unchanged when followed over a
long period of time.
Simple lentigo and lentiginous melanocy-
tic naevus are wholly benign melanocytic
A B proliferations which have no potential for
Fig. 2.55 Lentiginous junctional melanocytic naevus. A There are elongated rete ridges with increased malignant transformation.
numbers of single melanocytes at their sides and bases, with some tiny junctional nests. B In this exam-
ple, there are lymphocytic infiltrates and fibroplasia of the papillary dermis.

104 Melanocytic tumours

Dysplastic naevus C.J. Cockerell
J. Grant-Kels
J.C. Cather
P. LeBoit

Definition quently, the “B-K Mole Syndrome” was aggregated pigmented lesions (common
Solitary or multiple naevi, variable in renamed to ‘Dysplastic Naevus Syn- acquired naevi and dysplastic naevi)
colour, border, and size, with preferential drome’, with further sub-classification confined to the left upper quadrant of his
location on the upper trunk and extremi- into sporadic or familial types. body. Within this quadrant, two malignant
ties. Dysplastic naevi (DN) occur as spo- In 1992, a U.S. National Institutes of melanomas at different stages of pro-
radic lesions and in a familial setting. Health Consensus Conference recom- gression developed from dysplastic
They may progress to malignant mended “naevus with architectural disor- naevi {2266}. Hidden areas such as the
melanoma. der” in order to avoid the negative con- scalp and genitalia need thorough evalu-
notation associated with the word “dys- ation as dysplastic naevi may be seen in
ICD-O code 8727/0 plasia” {1}. However, this term has failed these areas {731,2029}. In Greene’s orig-
to gain wide acceptance {2153}. inal description, it was noted that unlike
Synonyms In a recent survey by the American ordinary moles, dysplastic naevi are
Atypical naevus {896} has been pro- Academy of Dermatology, 98% of often found on the scalp, buttocks and
posed as a synonym for clinically dys- respondents recognized the dysplastic female breast {897}. Lesions on the
plastic naevus. Other past designations naevus as a distinct entity {2373}. scalp, genitalia and upper back should
include naevus with architectural disor- be considered for excision due to the dif-
der {1}, and melanocytic naevus with Epidemiology ficulty with patient self-examination of
architectural disorder and cytologic atyp- The estimated total number of individuals these locations {749}, although careful
ia {1,2158}. The concept of Clark naevus affected by the familial form is approxi- follow-up is a reasonable alternative.
includes a large number of junctional mately 32 000 in the United States
and superficial compound naevi of which {1320}. Clinical features
the dysplastic naevus is a subset. Sporadic, histologically dysplastic naevi Patients may have one, several or up to
are seen in up to 50% of White adults, hundreds of lesions. In one study,
Historical annotation depending on how the lesion is defined. patients who had DN outside the familial
Originally, Wallace H. Clark and cowork- {535,571,1828}. The estimated preva- melanoma setting had an average of 10
ers described patients with multiple atyp- lences of dysplasia in a population per person {157}. The clinical features
ical naevi for which they proposed the based series of naevi ranged from 7-32% originally ascribed to DN included ill-
term “B-K mole syndrome”, using the first {1829}. The prevalence of clinically defined or irregular border, irregularly
initial of the surname of two probands defined dysplastic naevi also varies distributed pigmentation, background
{496}. The authors photographically doc- according to the criteria used, ranging erythema, and size greater than 5 mm
umented two lesions that progressed from 5–20%. {496,2029}. Lesions often differ from one
over time to malignant melanoma. another in the same individual and in
Therefore, the authors considered the “B- Etiology addition, they are often different between
K mole” a precursor of melanoma. Soon Ultraviolet radiation has been implicated individuals {778}. Some lesions may
thereafter, in 1980, Elder et al found in the genesis of dysplastic naevi and have a central papular component with a
lesions similar to those in “B-K mole” melanoma. Noz et al found higher in vitro macular flare that blends into surround-
patients with non-familial cutaneous sensitivity to DNA damage by ultraviolet ing tissue resulting in an ill-defined, fuzzy
malignant melanoma {673}. Subse- B radiation in melanocytic naevus cells periphery. The surface texture has been
compared to foreskin melanocytes described as “pebbly” {2476}. Other
{1732}. One recent study found an lesions are macular or plaque-like with-
increased relative risk for melanoma in a out a central papule or nodule. Irregula-
dysplastic naevus group with poor in rities in pigment range from tan to dark
vitro DNA repair capacity {1360}. brown to black. There are often areas of
pink and some lesions are amelanotic.
Localization Characteristically, lesions first appear
Dysplastic naevi can occur anywhere on around the time of puberty and if they are
the body but are most commonly found not apparent by age 20, it is unlikely that
on the trunk {496}. In females, there may an individual has the familial melanoma/
be a considerable number on the legs dysplastic naevi trait {897}.
{5559}. A “quadrant” form of dysplastic
Fig. 2.56 Dysplastic naevus. A solitary leasion on naevus distribution has been reported Diagnostic criteria
the abdomen. Note the variegated appearance. where a 59-year-old man had numerous The Dutch Working Group produced five

Dysplastic naevus 105

criteria for the clinical diagnosis of dys- Table 2.12
plastic naevi: 1) size greater than or Dermoscopy findings. From Steiner et al. {2259A}
equal to 5mm in diameter, 2) vague bor-
Dermoscopy finding Dysplastic naevi Melanoma
der, 3) asymmetric shape, 4) irregular
pigmentation , and 5) red hue {212}.
Pigment network Irregular discrete pigment Irregular, prominent (darkly
Additional diagnositic criteria have been network 55% pigmented) in 81%
advocated by Newton et al. and consist
of a scoring system. One point was Overall pigment Irregular 82% Irregular (85%)
awarded for the presence of one of five
parameters: 1) 100 or more naevi > Brown globules Irregularly arranged and of Irregular arrangement and size
2mm, 2) > two atypical naevi, 3) > one variable size (45%) (35%)
naevus on the scalp, 4) one naevus on
buttock or > 2 on dorsa of the feet, 5) > Margin of pigment network Irregular margin ends Abrupt ending of an irregular
gradually (68%) margin (63%)
one iris naevus. Individuals who have
three or more points are considered to
Black dots Present in 34% with irregular
have the dysplastic naevus syndrome arrangement at periphery in 26%
phenotype {1700}.
Radial streaming 1.7% 25%
Dermoscopy and imaging
Dermoscopy can be used to assist in dif- Pseudopods 1.7% 31%
ferentiating a DN from other benign or
malignant lesions. A lesion that does not Depigmentation Periphery (56%)
demonstrate features of the predominant
type of naevus seen in that individual
should be considered atypical and arise de novo. Histologic changes indis- recommend evaluating both cytology
receive special attention {1043}. This is tinguishable from those of dysplastic and architecture in the diagnosis of DN
analogous to the “ugly duckling” lesion naevi are often observed at the periph- {2158}. More recent descriptions of fea-
that refers to one that is distinct from oth- eries of primary melanomas not associat- tures common in DN histology included a
ers in a given patient. It has been recom- ed with naevi and such findings have central dermal naevocytic component
mended that such lesions be biopsied as been interpreted as representing “pre- with a peripheral extension of a junction-
they are more likely to be the ones that cursor” dysplastic naevi {672}. al component, elongated epidermal rete
demonstrate features suggestive of Dysplastic naevi may have chromosomal ridges, bridging of nests of melanocytes
melanoma {900}. instability and poor repair mechanisms at the dermo-epidermal junction, nests of
Several studies have demonstrated the after sunlight induced injury {1067,2128}. melanocytes at the sides of rete ridges
usefulness of regular whole body photo- Landi et al demonstrated an increased as well as at their bases, and concentric
graphs {1474} and computerized imag- relative risk for melanoma in a dysplastic eosinophilic papillary dermal lamellar
ing for melanoma surveillance {387, naevus group with poor in vitro DNA fibrosis {1943}. Ackerman and others
1286,2440}. repair capacity {1360}. Elder classified 6 have placed emphasis on the “shoulder
stages of tumour progression via mono- phenomenon” which describes peripher-
Progression to malignant melanoma clonal antibodies to melanoma cells or al extension of the junctional component
Although melanomas in patients with their extracts on frozen tissue sections beyond the dermal component in dys-
dysplastic naevi may arise within preex- {675A}. plastic naevi {18,1828}.
isting dysplastic naevi, the vast majority In general, histologic criteria involving
Histopathology architecture used to describe dysplastic
Definition and description naevi include: circumscription, symme-
Table 2.11. The major histopathologic criteria try, cohesion, suprabasalar melanocytes,
Clinical characteristics of dysplastic naevi include architectural and cytologic fea- confluence and single cell proliferation.
tures: size ≥4 mm, junctional component Cytologic features include: nuclear
>Variable size (<5mm-over 1 cm): great often adjacent to a compound naevic shape and staining, nuclear size, nucleo-
intralesional variation with respect to size
component, nested and single melano- lar prominence, and cell size {2158}.
>Irregular colour: irregular browns, red papule
cytes mainly near the tips and sides of One of the problems in the definition of
with brown halos, speckled elongated rete ridges, stromal reactions these lesions is that the histologic
and mild to moderate cytologic atypia. changes are non-specific and may be
>Irregular contour: macular or macular with There is lack of consensus regarding the seen in a number of other naevi without
central papular component histologic classification of dysplastic clinical features of “dysplastic” naevi
naevi. Historically, some groups advo- such as growing naevi in children and
>Ill-defined border, often “fuzzy” cate that atypical architecture is all that is naevi located on certain anatomic sites
required to establish the diagnosis such as the scalp and flexural areas.
>Preferential location on the trunk {1943,1980}, while others require cyto- Furthermore, the definitions used to
logical abnormalities {1925}. Shea et al describe cytologic atypia are subjective

106 Melanocytic tumours

Fig. 2.57 Dysplastic naevus. A The naevus cell nests are confined predominantly to the tips of the rete pegs. B Note the cytological atypia with nuclear hyper-

as in no case are the atypical cytologic Growth fraction / MIB-1 index Electron microscopy
features as frankly atypical as seen in Some authors assert that the presence of The melanosomes in epidermal
fully developed melanoma. the proliferation marker Ki-67 in dysplas- melanocytes in dyslastic naevi are
tic naevi indicates that these lesions are abnormal, with incompletely developed
Immunoprofile precursors to melanoma {760}. The per- lamellae and uneven melanization
Mild to moderate staining of dysplastic centage of cells that expressed Ki-67 {2476}. Abnormal spherical and partially
naevi is observed using antibody to was an independent prognostic factor melanized melanosomes similar to those
HMB45 antigen. This antibody also often {1308}. Kanter et al found that percent- observed in superficial spreading
stains intradermal melanocytes within ages of MIB-1 immunoreactivity in the melanoma have been observed by elec-
melanomas but not as strongly in com- intradermal portion of the lesions was tron microscopy {672,1363}. Based on
mon melanocytic naevi {2214}. S-100 is a negligible for benign congenital and these transmission electron microscopy
protein found in the central nervous sys- acquired naevi, as well as in dysplastic findings, one group suggested that dys-
tem that is also present in melanocytes, naevi compared to melanomas which plastic naevi lie on a continuum between
including melanoma. S-100 protein is exhibited a markedly increased prolifera- naevi and superficial spreading
found at the dermo-epidermal junction tive activity, especially vertical phase melanoma. No correlation has been
and at all levels of the dermis in dysplas- melanomas {1201}. At the current time, it shown prospectively between ultrastruc-
tic naevi {1792}. However, S-100 staining is not recommended that proliferation tural findings and progression or
is non-specific as it is seen in common markers be used as a reliable method for predilection to the development of MM.
naevi, dysplastic naevi as well as malig- distinguishing between naevi and
nant melanoma. melanoma.

Fig. 2.58 Dysplastic naevus. A The junctional component shows both architectural and cytological atypia. There is a mild, superficial perivascular lymphocytic infil-
trate. B Mild atypia of the junctional nests and dermal papillary fibroplasia.These is some melanin incontinence.

Dysplastic naevus 107

Fig. 2.59 Dysplastic naevus. A Some naevus cell nests extend above the the tips of the rete pegs. B Mild cytological atypia of the junctional nests.

Variants ria for grading dysplastic naevi {1925}. In compared with pooled controls {377}.
Toussaint and Kamino observed 1993, Duncan et al advocated grading However, the criteria used to define
histopathologic changes of “dysplastic” dysplatic naevi into groups based on lesions as “dysplastic” naevi were sub-
naevi in other types of naevi. They also cytology. Dysplastic naevi with slight, jective from the outset so the validity of
noted that some dysplastic naevi demon- moderate and severe cytologic atypia such studies remains in question.
strated features of other varieties of were differentiated. However, concor- Park and Vortmeyer examined the fre-
naevi. 2,164 cases of compound dance between experienced der- quency of p16 and p53 deletion in nine
melanocytic naevi that fulfilled the matopathologists ranged from 35% to dysplastic naevi and 13 benign intrader-
histopathologic criteria for the diagnosis 58%. Because of lack of reproducibility, mal naevi with five microsatellite mark-
of compound dysplastic naevus were DeWit et al. did not recommend grading ers. Hemizygous deletion was detected
reviewed. 87.6% had the histopathologic atypia in dysplastic naevi {612}. An in seven of nine dysplastic naevi at one
characteristics of dysplastic naevus, analysis of 12 histologic parameters in or more loci for p16. No loss of heterozy-
8.3% showed a dermal component with 123 dysplastic naevi failed to identify gosity was detected in any of the benign
a congenital pattern, 3.1% demonstrated parameters useful in differentiating mild intradermal naevi {1775}.
epidermal and dermal characteristics of from moderate dysplasia {1854}. Despite
Spitz naevus, 0.3% had features of a these considerations, melanoma risk has Molecular genetic alterations
combined blue naevus, 0.6% had a halo been associated with the degree of atyp- Greene performed an extensive review of
phenomenon and 0.1% showed intrader- ia in dysplastic nevi {102}. the genetics of malignant melanoma and
mal naevus. The authors advocate dysplastic naevi in 1998. Many studies
describing dysplastic melanocytic naevi Somatic genetics demonstrate an autosomal dominant
by categorizing them into six groups: 1) Cytogenetics and CGH mode of inheritance and speculate
dysplastic naevus; 2) dysplastic naevus Jaspers et al performed cytogenetic pleiotropic manifestations of a proposed
with a congenital pattern; 3) dysplastic investigations on lymphocytes and melanoma gene on chromosome 1
Spitz naevus; 4) dysplastic combined fibroblasts from 25 individuals with dys- (1p36). CDKN2A, a tumour suppressor
blue naevus; 5) dysplastic halo naevus; plastic naevus syndrome and compared gene localized on chromosome 9, is also
and 6) dysplastic neuronaevus {2370}. the results with a a control population of reported to be a melanoma gene. The
clinically normal relatives and unrelated relationship of melanoma to mutation of
Differential diagnosis individuals. In five DNS patients, CDKN2A has been confirmed {895}.
The clinical differential diagnosis of dys- increased frequencies of cells with ran- Hussein evaluated skin tissue samples of
plastic naevi includes congenital dom chromosomal rearrangements melanoma, dysplastic naevi and benign
melanocytic naevi, pigmented basal cell including translocations and inversions melanocytic naevi for microsatellite insta-
carcinoma, Spitz naevus, common were observed. These abnormalities bility. Microsatellites are short single
acquired melanocytic naevi, melanoma were absent in the control population sequence motifs repetitively scattered
in situ, and superficial spreading malig- {1134}. throughout the human genome. The vari-
nant melanoma. The histologic differen- Caporaso analyzed the karyotypes of ation in microsatellite pattern length
tial diagnosis includes melanoma, recur- 163 family members from 13 melanoma- between tumourous and matching non-
rent naevus, halo naevus, congenital prone families to investigate whether tumourous tissues is referred to as
naevus, a growing naevus in a child and chromosomal instability contributes to microsatellite instability. Microsatellite
Spitz naevus. familial melanoma. Cutaneous malignant instability has been associated with other
melanoma and dysplastic naevi syn- familial and sporadic tumours. Hussein’s
Grading drome patients each had increased results demonstrated MSI at 1p and 9p
Some authors emphasize cytologic crite- structural and numerical abnormalities chromosomal regions in dysplastic naevi

108 Melanocytic tumours

and malignant melanoma but not in ered as high risk precursors of may have multiple primary melanomas
benign naevi lending further support to melanoma, but rather as markers that {1320}.
others that have speculated on the pres- allow identification of individuals at
ence of “melanoma genes” involving the increased risk for melanoma. Histopathological criteria
short arm of chromosomes 1 (1p36) and There is evidence that histological atypia
9 (9p21) {1087}. In 2002, Tucker provid- Number of dysplastic naevi and family does correlate with melanoma risk. A
ed 25-year prospective data regarding history recent study of more than 20,000 naevi
33 families with familial melanoma and Patients with greater numbers of naevi, divided them microscopically into mild,
dysplastic naevi. Seventeen members dysplastic or otherwise, are at greater moderate, or severe categories of dys-
were found to have mutations in risk for melanoma {2386}. Dermatologists plasia. A personal history of melanoma
CDKN2A. Tucker found that the majority acknowledge patients with multiple dys- was present in 5.7 of the patients with
of clinically diagnosed dysplastic naevi plastic naevi, especially if there is a per- mild, 8.1 with moderate and 19.7 with
remained stable or regressed over time. sonal or family history, are at greater risk severe atypia. It was concluded that the
The majority of melanomas detected for developing melanoma {2373}. If risk of melanoma was greater for persons
over the course of the study arose from patients are from “melanoma-prone fam- who tend to make naevi with high-grade
naevi although some arose de novo ilies” and have clinically dysplastic naevi, histological atypia {102}.
{2384}. as defined by criteria that include lesion-
al diameter, their individual risk for devel- Genetic predictive factors
Genetic susceptibility oping a melanoma is several hundred Currently, there are no commercially
As discussed above, Clark originally times that of the general population, with available genetic tests that would be pre-
described dysplastic naevi in relation to a risk for lifetime incidence of melanoma dictive of dysplastic naevi progression to
a familial syndrome called the B-K mole approaching 100% {744,846}. The signif- melanoma.
syndome {496}. Most dermatologists icance of a single histologically dysplas-
agree that family members of patients tic naevus in this context has not been
with dysplastic naevi need evaluation determined. One study evaluated
{2373}. Familial dysplastic naevi and patients with an established diagnosis of
melanomas have rarely been reported melanoma (n=716) compared with nor-
with other systemic malignancies involv- mal controls (n=1014) and found that
ing the central nervous and digestive one clinically dysplastic naevus was
system {129,213}. associated with a 2-fold risk, while 10 or
more conferred a 12-fold risk of
Prognosis and predictive factors melanoma {2386}. In the same study,
The incidence of melanoma developing patients who bore 100 or more clinically
in a given dysplastic naevus has been non-dysplastic naevi had a relative risk of
estimated at 1:3000 per year. Therefore, 3.4. Approximately 50% of dysplastic
dysplastic naevi should not be consid- naevi patients with a family history of MM

Dysplastic naevus 109

Site specific and Meyerson naevi H. Kamino
D. Weedon

In some anatomic sites, naevi may have difficult to clinically distinguish from have been found the most reliable fea-
atypical histological features. This chap- melanoma {289,1511,2013,2017,2018}. tures indicative of melanoma {493,707}.
ter discusses three clinicopathologic On epiluminesence microscopy (ELM)
entities: acral, genital and Meyerson dermatoscopy), the pigmentation of AN
naevi, but other site specific features is accentuated in dermal glyphic furrows Genital naevus
have been described, including naevi and occasionally around eccrine ostia,
occuring in flexures, umbilicus, ear and thereby creating reproducible patterns Definition
scalp. {45,1232,2014,2015}. In acral melano- Melanocytic naevi on the perineum and
mas the pigment is distributed along the genitalia, hereafter “genital naevi (GN)”,
dermatoglyphic ridges {45}. include different naevic types distin-
Acral naevus guished and united by unusual, variably
Etiology present junctional features.
Definition The origin of AN is hypothesized to
Acral naevi (AN) are benign melanocytic involve repeated trauma {701,2181, Synonyms
proliferations from the palms and soles. 2182}, foci of “unstable” melanocytes A subgroup of GN with "unusual histolog-
{1416} and racially-correlated variations ic features" {480,782} or "atypism" {1608}
Synonyms in melanosome aggregation {1612}. have been dubbed "atypical melanocytic
AN or “naevi on volar skin” include histo- naevus of the genital type (AMNGT)
logic subtypes termed “Melanocytic Histopathology {495}".
Acral Naevus with Intraepidermal Ascent Distinction of acral naevi from melanoma
of Cells (MANIAC)” {1545} and “atypical can be difficult because both may be Epidemiology
or acral lentiginous naevus” {501,1511}. asymmetric, poorly circumscribed and About 10% of men and women have pig-
have intraepidermal ascent of cells {292, mented genital lesions {574,784,1955},
Epidemiology 701,984,1545,2181,2182}. Suprabasal but many are lentigines {784,1955}.
Clinical studies which are unable to dis- melanocytes in AN are relatively more Histologically confirmed GN occur in 2%
tinguish lentigines from true naevi, record columnar, circumscript and less volumi- of women {267,480,1955}.
discrete pigmented volar lesions in less nous than in melanomas {1246}. AMNGT comprise a minority of all GN
than 1{1763} to 92% {1416} of subjects, Signoretti et-al. have shown that symme- {267,480,1955}. They typically present
with most studies suggesting a range of try, circumscription, the columnar organ- by the twenties {1608} and, in contrast to
3 – 41% of the population {63,519,574, ization of ascending melanocytes and vulvar melanoma, are seen exclusively in
1338,2223,2418}. In a histologically con- organization of the junctional component premenopausal women {1608,2015}.
firmed study, 3.9% of Caucasians had are all influenced by the histologic plane Dysplastic naevi may also occur on the
AN {1473}. Darker patients tend to have of section; to wit, naevi sectioned per- genitalia but they are usually observed in
a greater percentage {519,1763} and pendicular to dermal glyphics are more people with dysplastic naevi elsewhere
higher total of naevi on acral surfaces likely to have benign attributes {2017, on their bodies {267,1608}. Vulvar naevi
{63,519,1553,2418}, though this is not 2018}. Subsequently, severe melanocytic were said to have increased premalig-
always found {574,1416}. Pigmented atypia and a dense lymphocytic infiltrate nant potential {1763}, though recent data
acral lesions are generally more common
in the second and third decades

Plantar naevi are probably more common
than palmar naevi {63,574,1473,2418}.
AN may occur on both pressure-bearing
and pressure-spared surfaces {45,63,

Clinical features A B
AN are usually less than 8 mm with a light Fig. 2.60 Acral naevus. A Epiluminesence microscopy of an acral naevus demonstrating linear hyperpig-
to dark brown striated macular compo- mentation within the furrows of dermal glyphics. B Intraepidermal melanocytes with short dendrites are
nent. Congenital AN can be particularly seen along and above the basal layer.

110 Melanocytic tumours

melanoma by circumscription, matura-
tion, and symmetry {17,24,391,782}.

Meyerson naevus

Meyerson naevus is a benign naevus of
junctional, compound or intradermal type
surrounded by an eczematous halo

Synonyms and historical annotation

"Spongiotic change in melanocytic naevi"
Fig. 2.61 Genital naevus. This example contains features of a dysplastic naevus. Junctional melanocytes {2478}, halo dermatitis {352,2330}, halo
are arranged as both nests and single units. There is bridging of rete ridges and lamellar fibroplasia. Dermal
eczema {1329} and perinaevic eczema
melanocytes mature and melanocytes do not ascend above the basal layer.
The eponym "Meyerson naevus" (MN)
refutes this {1954}. Histological studies shaped” with a base composed of matur- was suggested {1706} to honour the
suggest that from 1% {391} to 12% {495} ing melanocytes similar to a common 1971 description of a spongiotic dermati-
of vulvar melanomas are associated with naevus. Melanocytes at the dermal-epi- tis involving melanocytic naevi {1595}.
a naevus. dermal junction are arranged in one of
three patterns: nests; dyshesive nests; Epidemiology
Localization and crowded, ill-defined nests and sin- MN typically occur in young adults
AMNGT are more commonly seen on the gle melanocytes. In about half of AMNGT {1706} and children {2167}. Affected men
labia minora and clitoris {495}. Although there are “skip areas” at the dermo-epi- have been reported about three times
infrequent, AMNGT may occur on male dermal junction which lack melanocytes. more frequently than women {1706}.
genitalia {495}. Naevi with histologic fea- Thus, it is the junctional component in
tures similar to AMNGT may be observed AMNGT which is worrisome for Localization
on flexural sites and along the vestigal melanoma. Unlike dysplastic naevi, Eczema may involve one or several naevi
“milk-line” from the axilla to the upper AMNGT usually lack a lymphocytic infil- {1329,1706} and may spread beyond
thighs {1964}. Dysplastic naevi more trate. The “ill-defined” stroma of AMNGT naevi to previously normal skin {306,
commonly occur on the labia majora and is different from that typically seen in 729}. There are no clinical features to
perineum {495} melanomas or dysplastic naevi {495}. suggest which naevi become dermatitic
The histopathologic features of dysplas- {1329,1706}.
Clinical features tic GN are similar to dysplastic naevi
Common type GN are dome shaped, elsewhere {267,495,1955}. Rarely, geni- Clinical features
evenly pigmented, tan to dark brown tal naevi may be distorted by coexistent The change may involve one or more
papules less than 1 cm {1955}. Both lichen sclerosus et atrophicus, produc- naevi simultaneously. The naevus does
AMNGT and dysplastic GN can be poly- ing histologic changes similar to those not usually undergo regression as a
poid or flat {495}. They are usually tan- seen in recurrent naevi {17,352,390}. result of this change although the trans-
brown, often with some black areas Unlike melanomas, vulvar naevi are said formation of a Meyerson naevus into a
{495}. Clark et-al report a size range from to lack intraepidermal ascent of halo naevus has been recorded once
2 to 24 mm {495}. Despite a long history melanocytes {17,24,391,782}, though {1884}. MN are characterized by a prurit-
of advice to the contrary, prophylactic this has been disputed {984,1608}. ic, raised erythematous, scaling and
removal of all genital naevi is not recom- Regardless of subtype, GN differ from crusted plaque which extends symmetri-
mended {480,784,1955}. AMNGT obser- cally 1–2 cm from the central naevus
ved from 1 to 16 years have not recurred {306, 1329,1595}. Upon resolution the
or metastasized; yet, their conservative naevus persists unchanged {1595,2330},
reexicision has been advised {495}. though post-inflammatory hypopigmen-
tation may occur {1595,2330}.
The genesis of GN is poorly understood. Etiology
Possible influences include repeated The inflammation of MN has been likened
superficial trauma, sex hormones, genet- to pityriasis rosea {564,1595} and aller-
ic determination and stroma type {391, gic contact dermatitis {2478}. One case
495,1964}. was triggered by interferon alpha {1328}.

Histopathology Fig. 2.62 Meyerson naevus. Note the eczemetous Histopathology

AMNGT are typically “mushroom halo around a pigmented naevus. MN are characterized by spongiosis,

Site specific and Meyerson naevi 111

microvesiculation, irregular acanthosis,
parakeratosis, focal crust and a superfi-
cial perivascular infiltrate of lymphocytes
and eosinophils {306,676,1595,2478}.
There is no histologic regression nor
depigmentation {2478}.
There is a naevocellular naevus of junc-
tional, compound or intradermal type
with an associated subacute spongiotic
dermatitis {1706}. There is variable epi-
dermal acanthosis and a mild to moder-
ate superficial perivascular and intersti-
tial infiltrate of lymphocytes. Usually
there are a few eosinophils. There is
often mild exocytosis of lymphocytes into
the epidermis. There is no regression,
although one exception has been
recorded (see above). Rarely, dysplastic
naevi have been involved {676,1328}.

Lymphocytes in MN are predominately Fig. 2.63 Meyerson naevus. Spongiosis, parakeratosis and irregular acanthosis characterize the epidermis.
CD4 positive {729,1816}. ICAM-1 has
been reported to be increased on ker-
atinocytes and endothelium within MN

112 Melanocytic tumours

Persistent (recurrent) melanocytic H. Kerl


Definition Histopathology Differential diagnosis

Persistent melanocytic naevi are benign Scanning magnification shows common- The features within the epidermis and in
compound or intradermal melanocytic ly above a dermal melanocytic naevus a epithelial structures of adnexa may simu-
naevi that persist (recur) after incomplete scar with fibrosis. The intraepidermal late a melanoma in situ.
excision. changes are characterized by sharp cir- However, the sharp circumscription of
cumscription and confluent nests of the intraepidermal component, the pres-
Synonym melanocytes, that are not equidistant ence of melanocytes in nests and as sin-
Pseudomelanoma {1310} and vary in sizes and shapes. The nests gle units mostly at the junction and the
are mostly situated at the dermo-epider- typical naevoid cells of the preexisting
Clinical features mal junction. Melanocytes are also dermal melanocytic naevus beneath a
Persistent melanocytic naevi are the arranged as solitary units at the dermo- scar are helpful clues to the diagnosis of
result of incomplete removal after super- epidermal junction and sometimes persistence (recurrence). Furthermore in
ficial shave technics, dermabrasion or above it in upper layers of the epidermis persistent melanocytic naevi the melano-
laser treatment {271}. The lesions ‘recur’ {1037}. cytic proliferation within the epidermis is
usually after weeks or months after ther- Assessment of the original specimen is confined to the area above the scar.
apy. They are characterized by variably very important for an accurate diagnosis
pigmented macules, papules or plaques to ensure that the lesion is really a per-
with irregular borders. A scar from previ- sistent melanocytic naevus and not a
ous surgery can be usually recognized. persistent melanoma.

Fig. 2.64 Persistent (recurrent) melanocytic naevus. A Small irregular black macule. A scar surrounds the
lesion. B Persistent (recurrent) melanocytic naevus. Melanocytes are arranged as solitary units along the
dermo-epidermal junction and also above it. Atypical nuclei can be observed. Note involvement of the fol-

Fig. 2.65 Persistent (recurrent) melanocytic naevus. Trizonal arrangement: 1) Dermal melanocytic naevus.
2) Above the melanocytic naevus a scar revealing fibrosis. 3) Intraepidermal changes with nests of
melanocytes with irregular shapes and a tendency to confluence at the dermo-epidermal junction.

Persistent (recurrent) melanocytic naevus 113

Spitz naevus P.E. LeBoit
B.C. Bastian
W.J. Mooi

Definition Localization Spitz naevi, except in children who trau-

Spitz naevus is a benign proliferation of Spitz naevi can occur on any areas of the matize them in play or excoriate them.
large spindled, oval or large round body, although the face of children and The presence of an ulcer outside of these
(epithelioid) melanocytes that begins in thighs of young women are stereotypical settings merits reconsideration as
the epidermis, and evolves into com- associations. melanoma.
pound or intradermal stages. This distin- Most Spitz naevi are single lesions.
guishes it from some forms of blue nae- Clinical findings However, groups of Spitz naevi can
vus, in which the lesion is wholly intra- The earliest recognizable Spitz naevi are occur in a single area in agminated Spitz
dermal from the outset. about a mm. or so in diameter, and the naevus {44,2002}. In such cases, the epi-
largest recorded are over 2 cm. While the dermis in between the papules of Spitz
ICD code 8770/0 criterion of size has been popularized in naevus can be normal in appearance, or
the differential diagnosis between Spitz more commonly is lightly pigmented,
Synonyms naevus and melanoma, many Spitz naevi resembling a café au lait spot (when it
Spindle and epithelioid cell naevus, nae- are over 1 cm. in diameter. There occurs in Caucasian patients). In erup-
vus of spindled and/or epithelioid cells, appears to be an initial period of rapid tive Spitz naevus, a patient may have
benign juvenile melanoma {2239}. growth, followed by stabilization. This is many papules of Spitz naevus appear on
Pigmented spindle cell naevus (Reed) is in contrast to melanoma, in which the a limb or even over the entire integument
probably a distinctive variant of Spitz diameter of the lesion is seldom stable. within a few weeks or months. This obvi-
naevus {158,162,2005}. Most Spitz naevi are lightly pigmented. ously distressing situation can be con-
The classic lesion is a pink to red papule, fused with metastasis of melanoma.
Epidemiology with an even round border and a domed
Spitz naevus is most common in the first shape. There is slight scale. The degree Etiology
two decades of life {1015,2155}. of erythema is often such that the clini- The cause of Spitz naevus is unknown.
Accurate population based studies on its cian considers the diagnosis of haeman- Sunburn and biopsy of a single Spitz
prevalence are not available, and are gioma. However, if one looks at the initial naevus have been linked to eruptive
coloured by the caution shown by pathol- description by Spitz, it is clear that there lesions {597}.
ogists in making an outright diagnosis of is considerable heterogeneity, with tan
Spitz naevus in middle aged or older and medium or even dark brown lesions, Histopathology
adults, and in making a diagnosis of and verrucous ones also possible Because the findings of Spitz naevus dif-
Spitz naevus in young adults if there are {2239}. In dark skinned people, Spitz fer significantly at various stages, we will
any unusual microscopic features. naevi are usually darker than their normal describe those in detail. Spitz naevus
Spitz naevi are mostly recorded in skin colour. There is usually a uniformity begins as a proliferation of large oval
Caucasian patients. However, they occur of pigmentation, with the notable excep- melanocytes at the dermal-epidermal
in all racial groups, and their occurrence tions of combined Spitz naevi and Spitz junction. This can occur along a front of
in Asians and Africans may be underes- naevi with a halo reaction. only a few mm., and is first recognizable
timated. Ulceration is practically never present in by single, large melanocytes with abun-
dant eosinophilic cytoplasm and large
vesicular nuclei. There are often a large
number of cells with several nuclei, even
in small lesions. Cytoplasm is abundant,
and even though the nuclei may be
large, they are usually monomorphous.
Clefts demarcate the melanocytes from
adjacent keratinocytes. Even if single
cells are present in number above the
junction, they are evenly distributed
{355}. As these lesions enlarge, the epi-
dermis above the proliferation thickens,
and nests begin to form. The epidermal
A B thickening is largely via hyperplasia of
Fig. 2.66 Spitz naevus. A A sharply circumscribed, dome-shaped lesion, which may be mistaken for hae- the spinous layer, with squamatization of
mangioma. B Small brown papules form an agminated lesion. This configuration is often alarming. the basal layer and pointed rete ridges.

114 Melanocytic tumours

There is corresponding hypergranulosis
and compact hyperkeratosis.
Within the junctional nests of a Spitz nae-
vus are clefts, separating the melano-
cytes from one another, and from the epi-
dermis. The clefts tend to be prominent
over the apices of junctional nests. The
nests may appear to be embedded in the
epidermis, rather than lying at the bases
of rete ridges. The epidermal hyperplasia
of a well developed junctional Spitz nae-
vus, and the nests of the naevus itself are
both well circumscribed {19,1636,
1638,1769,2479}. By the time that nests
are of substantial size, one may
encounter Kamino bodies in the epider-
mis. Kamino bodies are dull pink staining
globules, up to the size of several ker-
atinocytes, often with a scalloped border
and a periphery in which there are cres-
cent shaped, compressed appearing
keratinocytes {1186}. Unlike dyskeratotic Fig. 2.67 Spitz naevus, junctional type, Clefts separate melanocytes from one another. Several large Kamino
cells, which are more brightly eosino- bodies are present.
philic, their major ingredient is basement
membrane material. They stain with PAS-
D and with immunoperoxidase stains for The nests of melanocytes are often pres- Another difficult variant is persistent Spitz
basement membrane components, such ent between thickened collagen bundles naevus. The great majority of Spitz naevi
as laminin and type IV collagen {2499}. in the lower part of the lesion. When this do not recur at the biopsy site if the
Compound Spitz naevus forms when is prominent, some apply the term lesion seems to be removed clinically,
junctional nests become incorporated desmoplastic Spitz naevus. Unlike the but goes to a margin. Those that do can
into the dermis. In early compound case in desmoplastic melanoma, there show suprabasal scatter of melanocytes
lesions, one may see a dense lympho- are no markedly elongated fascicles of (as in other recurrent naevi), a com-
cytic infiltrate, rather than the sparse cells. If the proliferation abuts the sub- pound Spitz naevus over a scar, a nodule
perivascular one that most authors cutis, one may see lymphoid nodules. next to a scar, or a picture resembling
describe. The dermal nests tend to be For both compound and intradermal desmoplastic Spitz naevus {969}.
smaller than the junctional ones, and as lesions, an important finding is that the Lastly, there is a “grey zone” of lesions in
melanocytes descend into the reticular nests at each level of the lesion should which there are many findings of Spitz
dermis, one can discern a gradient from be similar in size, with the cells similar in naevus, but the diagnosis is less certain.
large nests to smaller ones, and single overall and nuclear size and in pigmen- For lesions in which the diagnosis is Spitz
cells may predominate at the base. tation. naevus, but there are a few findings that
Mitotic figures can be present in the There are many important variants of are unusual, many use the term “atypical
upper part of a compound Spitz naevus, Spitz naevus. On acral skin, one may see Spitz naevus”, although this may be
but tend to decrease in number toward many single melanocytes scattered attacked on semantic and functional
the base of the lesion. Maturation of above the junction. A halo reaction may grounds. If one is not sure of the diagno-
melanocytes is also a correlate, with be present, sometimes accompanied by sis, a descriptive term, such as “prolifer-
smaller cells that have less cytoplasm, a clinical halo. The lymphocytes are ation of large melanocytes involving the
smaller nuclei, and smaller and less evenly dispersed throughout the lesion, epidermis and dermis” is preferable. This
eosinophilic nucleoli all findings that and some may be apposed to pyknotic should be accompanied by a note or
reassure the pathologist. If a Spitz nae- melanocytes . The stroma may be scle- comment explaining the difficulties, dif-
vus is pigmented, the pigmentation rotic (hyalinizing Spitz naevus) or highly ferential diagnosis, including if appropri-
lessens in the lower half of the lesion. vascular {2293} . Some nests may have ate, microstaging parameters that would
Fully formed compound lesions often an empty appearing centre (tubular Spitz be appropriate if the lesion were regard-
have a domed surface and a wedge naevus) {2228}. In combined Spitz nae- ed as melanoma, and advising reason-
shape. Unlike the case in early com- vus, other populations of melanocytes able management. The role, if any for
pound, or even junctional lesions, lym- (e.g. small round, bipolar-dendritic, bal- sentinel lymph node biopsy in difficult
phocytic infiltrates are usually sparse loon, etc.) may be present {1961}. This is cases is currently considered controver-
and perivascular. one of the most difficult variants to deal sial {1444,2286}.
Intradermal Spitz naevi preserve the with, as the large cells may not mature Among these “grey-zone” lesions is an
domed/wedge shape noted above. The and dense lymphocytic infiltrates (up to a emerging, relatively homogeneous group
epidermis is often slightly hyperplastic. halo reaction) may be present {972}. of lesions with a distinctive pattern, often

Spitz naevus 115

Fig. 2.68 Spitz naevus, compound type. A Junctional portion of Spitz naevus with epidermal hyperplasia. B The upper part of the lesion is highly cellular. C Toward
the base single large oval melanocytes are interspersed between thick collagen bundles.

found from early childhood to young data has been presented to the effect show chromosomal aberrations, whereas
adulthood in which there are some fea- that systemic metastasis may not occur, 25% showed an isolated gain of chromo-
tures of Spitz naevus and others of or may be much less frequent than in some 11p {174}. Preliminary studies indi-
melanoma. Common denominators adults with conventional melanomas cate that the increased copy number of
include a vertical orientation, extension matched for thickness. Clearly, further chromosome 11p is due to the formation
into the subcutis with no diminution in studies are needed to determine if these of an isochromosome 11p {1494}. About
cellularity and a blunt, multinodular inter- lesions are fundamentally Spitz naevus, 70% of the Spitz naevi with increased
face, ulceration, a plasmacytic infiltrate melanoma, or neither. copies of chromosome 11p have muta-
and deep mitotic figures. Such cases tions in the HRAS gene which maps to
have been described as “malignant Spitz Somatic genetics this location {172}. HRAS mutations have
naevus” and also simply regarded as While most cells in most Spitz naevi been found only in a minority of cases (<
melanomas {2205}. In the initial study of seem to be diploid, there are a propor- 10%) with normal copy number of chro-
“malignant Spitz naevus” there were 3/32 tion of polyploid cells, at least in the mosome 11p. Preliminary studies indi-
lesions in which palpable lymph node upper part of lesions as judged by image cate that mutations in BRAF occur infre-
enlargement had occurred, and another analysis cytometry {1386}. True aneu- quently in Spitz naevi.
3 in which lymph node involvement was ploidy may be uncommon, as evaluated
detected on elective dissection. Very by flow cytometry {2439}. In an analysis
similar lesions have been described as using comparative genomic hybridiza-
melanomas in children {1632}. Follow up tion the majority of Spitz naevi did not

Fig. 2.69 Spitz naevus, desmoplastic type. A Rete ridges are uniformly elongated but jagged above the upper part of the lesion. B Thin spindle cells are present
between collagen bundles.

116 Melanocytic tumours

Pigmented spindle cell naevus (Reed) L. Cerroni

Definition scription. Spindled, pigmented melano- melanophages is found within the papil-
Pigmented spindle cell naevus (Reed) is cytes arranged in vertical nests at the lary dermis. A subset of cases shows a
a benign melanocytic naevus showing dermo-epidermal junction predominate considerable overlap with Spitz naevi.
dark pigmentation clinically, and a prolif- {158,2005,2068}. A few, and in some Cases with some cytological atypia have
eration of spindled melanocytes histo- instances many, melanocytes may be been termed “atypical pigmented spin-
pathologically. seen above the dermal/epidermal junc- dle cell naevus - pigmented spindle cell
tion, as well as confluence of the nests. naevus with architectural and/or cytolog-
ICD-O code 8770/0 The proliferation of melanocytes may be ic atypia”, and may represent a source of
confined to the epidermis, or may extend problem in differential diagnosis from
Synonyms and annotation into the papillary dermis. Occasional malignant melanoma {158}. A variant
This melanocytic naevus has been mitoses may be found. Cytomor- described as “plexiform pigmented spin-
named eponymously after Richard Reed, phologically there is a uniform prolifera- dle cell naevus” probably represents a
who described it in 1975 {1909}. It has tion of elongated, fusiform melanocytes, pigmnented spindle cells naevus invol-
also been referred to as Reed naevus or usually without atypical features. The ving the reticular dermis {158}.
Reed tumour. While some authors regard nuclei are relatively small, with uniform,
it as a subtype of the Spitz naevus, pig- delicate chromatin. Epithelioid melano- Prognosis and predictive factors
mented spindle cell naevus (Reed) pres- cytes are admixed in a minority of cases. Pigmented spindle cell naevus (Reed) is
ents with peculiar clinical and Commonly, the epidermis is slightly a benign melanocytic proliferation with
histopathologic features, allowing a hyperplastic and shows marked hyper- no potential for distant metastases. Local
reproducible diagnosis and classification pigmentation of the basal keratinocytes. recurrences may be observed in tumours
to be made. Intraepidermal eosinophilic globules (so- that were incompletely excised.
called “Kamino bodies”) can be
Epidemiology observed in about half of the cases. An
Pigmented spindle cell naevus (Reed) is inflammatory infiltrate composed of lym-
a melanocytic tumour found in children, phocytes and histiocytes with many
adults, and, rarely, older patients, with a
peak in the third decade. There is a pre-
dominance for females.

Clinical features
The patients present with a darkly,
homogenously pigmented, flat or slightly
dome-shaped, sharply circumscribed
papule or plaque located usually on the
limbs, especially the thigh {158,2005,
2068}. Less common locations are the
trunk and the head and neck region. The A B
lesions are usually of recent onset and
smaller than 1 cm. Surface skin micro-
scopy (dermatoscopy, dermoscopy)
reveals typically a “starburst” pattern
(characterized by the presence of pig-
mented streaks disposed in a radial
arrangement at the edge of the lesion).
A clinical misdiagnosis of malignant
melanoma is not infrequent, due to the
dark pigmentation and recent onset of C D
the lesions. Fig. 2.70 Pigmented spindle cell naevus (Reed). A Small, flat, dark papule. B Dermoscopy shows the char-
acteristic "starburst" pattern. C Elongated nests at the dermoepidermal junction and in the papillary dermis;
Histopathology note pigmentation of the basal keratinocytes and melanocytes, and the presence of numerous
Histologically, the tumours are symmetri- melanophages in the papillary dermis. D Fusiform melanocytes predominate. Note the mitosis in the upper
cal and show a sharp lateral circum- left corner.

Pigmented spindle cell naevus (Reed) 117

Halo naevus D. E Elder
X. Xu

Definition halo around a compound naevus, fol- tend to become smaller (i.e., more
A halo naevus presents as a small cir- lowed by fading and disappearance of “mature”) from the top to the bottom of
cumscribed symmetrical, usually papular the naevus. The halo then gradually re- the lesion. The epidermis may be hyper-
pigmented lesion with the appearance of pigments over a year or two, returning to keratotic with follicular plugging {2469}.
a common benign compound naevus, the appearance of normal skin. During The feature that distinguishes a halo nae-
surrounded by a symmetrical area of this period, especially in teenagers, other vus from a banal naevus is the presence
depigmentation, representing the “halo” similar lesions may develop. of a striking dense lymphocytic infiltrate,
{2469}. The lesion is defined histological- Studies in patients with halo naevi have an appearance that may arouse a suspi-
ly by the presence of a brisk lymphocyt- demonstrated circulating antibodies that cion of melanoma in some cases. The
ic infiltrate among dermal naevus cells, are reactive with neoplastic melanocytes lymphocytes extend among the lesional
and by loss of pigment in the epidermis including melanoma cells, and the infil- naevus cells, tending to obscure their
adjacent to the naevus. Some naevi with trating cells have been shown to be underlying nested pattern in some
a lymphocytic response of the type seen mainly T lymphocytes {2090}. Antigen- cases. Melanin-laden histiocytes and
in halo naevi do not have an obvious clin- presenting cells and CD8+ T cells have mast cells can be present as well as lym-
ical or histologic depigmented halo been identified in the inflammatory infil- phocytes {2090}. Occasional halo naevi
{948}. trates of halo naevi, implicating cytotoxic contain a few giant cells or there may be
mechanisms in destruction of naevus a frankly granulomatous response. Over
ICD-O code 8723/0 cells {2581}. Affected individuals also the ensuing weeks or months, the dermal
show activated lymphocytes in their naevus cells disappear and then the his-
Synonyms peripheral blood {148} as well as T cell tologic differential diagnosis may include
Sutton naevus; leukoderma acquisitum clonal expansion {1670} and anti-naevic lichenoid inflammatory dermatoses. Over
centrifugum {2297}. IgM antibody production {2359}. These a period of a year or two, the inflammato-
findings are consistent with the idea that ry cells disappear and histologic exami-
Clinical features halo naevi represent immunologically - nation of the site of a completely resolved
Halo naevi often present during the sum- mediated rejection of a naevus. The halo halo naevus may disclose essentially
mer, perhaps because the halo contrasts develops outside the naevus proper, normal skin, with little or no evidence of
better with tanned skin. They are most suggesting that there may be a cross- scarring or residual pigment {2469}. In
common in teenagers and young adults. reaction with a “field” of melanocytes that most halo naevi, there is little or no read-
In these cases, they are sometimes asso- surrounded the naevus prior to the onset ily observable melanocytic abnormality
ciated with dysplastic naevi, and are of the intense inflammation in the dermal in the epidermis at the “shoulder” of the
sometimes multiple. Less often, a solitary component. lesion beyond the lateral border of the
halo lesion develops in an older adult, dermal component, even though it is in
and in this circumstance the possibility of Histopathology this region that the striking clinical halo is
melanoma should be ruled out histologi- An early halo naevus presents as a small located. However, DOPA stains for tyrosi-
cally, especially if the central pigmented circumscribed lesion, less then 4 mm in nase and immunohistochemical (e.g.
lesion is clinically atypical or if the halo is diameter as a rule, composed of naevus Melan-A) or argentaffin stains for
eccentric or asymmetrical in contour. cells located in the papillary dermis and melanocytes reveal greatly reduced
Serial follow-up of halo naevi demon- usually also in the epidermis. The lesion numbers of them in the area of the halo
strates a characteristic time sequence, is symmetrical, and is composed of cells compared to the surrounding skin
beginning with the appearance of the that are uniform from side to side and {2469}.

Fig. 2.71 Halo naevus. There are two small naevi Fig. 2.72 Halo naevus. There is an apparently well circumscribed lesion which at first glance may be mis-
surrounded by rims of depigmentation. taken for a lymphocytic infiltrate.

118 Melanocytic tumours

Fig. 2.73 Halo naevus. A Infiltrating lymphocytes are intimately admixed with naevus cells, which will lead to apoptosis and ultimate disappearance of the naevus
cells. In later examples, naevus cells are more inconspicuous than they are in this field. B Extending 1 to 2 mm beyond the lateral border of the dermal naevus com-
ponent, the papillary dermis is widened with slight fibroplasia, there is a patchy lymphocytic infiltrate, and there is absence of pigment and of melanocytes in the
overlying epidermis. This region constitutes the clinical halo. C Normal skin adjacent to the halo shows a normal papillary dermis, normal melanin pigment in basal
keratinocytes, and the presence of melanocytes, which can be demonstrated if desired with a Melan-A stain.

The lesional cells in most halo naevi are an absence of identifiable melanocytes. naevus cells, and there is little or no ten-
unremarkable dermal naevus cells of the In comparison with adjacent normal epi- dency to single-cell upward (“pagetoid”)
large pigmented (type A) or small non- dermis, pigment may be visibly reduced, intraepidermal spread of the junctional
pigmented (type B) cytology. Pigment is and this contrast can be enhanced with a cells.
located in naevus cells and in melano- melanin stain. In most lesions, there is no Some halo naevi may be difficult to dis-
phages superficially, and is usually intra-epidermal melanocytic proliferation tinguish from dysplastic naevi that have
coarse in texture. In some lesions, the adjacent to the dermal component, but in an unusually brisk lymphocytic infiltrate.
dermal cells have nuclei that are larger a few lesions an adjacent component of Indeed, not only do halo naevi appear to
than is usual in common naevi, and melanocytic dysplasia may be observed. be common in patients with dysplastic
sometimes there is hyperchromatism and If an in situ or microinvasive (“ radial naevi but also a halo response may be
a degree of pleomorphism, with or with- growth phase”) component diagnostic of seen, clinically and histologically, in dys-
out nucleoli, representing cytologic atyp- melanoma is present adjacent to a der- plastic naevi themselves. If the charac-
ia which is present in about 50% of halo mal lesion simulating halo naevus, the teristic patterns of dysplasia are seen at
naevi and is usually mild or at worst mod- entire lesion is most likely to represent the “shoulder” of the compound portion
erate in degree {1640}. This cytologic melanoma. of a lesion whose other features are con-
atypia may represent a form of “inflam- sistent with a halo naevus, the diagnosis
matory” or reactive atypia. Mitotic figures Differential diagnosis of dysplastic naevus with halo reaction
are completely absent in most lesions. The distinction from common acquired or can be made. Especially if there is a his-
However, a few lesions judged to be most other types of naevi is usually easy tory of other atypical naevi and/or a per-
benign halo naevi have shown one or two because of the dense lymphocytic infil- sonal or family history of melanoma, sur-
mitotic figures {1909}. Such a finding trate. The most important differential veillance may be warranted for such indi-
should provoke careful examination of diagnosis is with melanoma. Compared viduals.
the lesion to rule out melanoma, with to nodular melanoma or to the tumouri- When naevus cells are inconspicuous
deeper sections and embedding of any genic (vertical growth phase) component among a dense infiltrate of lymphocytes,
residual gross tissue. Findings sugges- of superficial spreading melanoma, a inflammatory dermatoses such as
tive of melanoma in a lesion simulating a halo naevus is usually smaller (the cen- lichenoid keratoses may be simulated
halo naevus include the presence of a tral naevus is usually less than 4 mm in {844}. In these circumstances, an S-100,
separate population of cells with an diameter, while most melanomas are Melan-A or HMB45 stain may reveal the
expansile pattern of growth, severe uni- larger than 6 mm, though these values hidden naevus cells. Care must be taken
form cytologic atypia, and/or the pres- are by no means absolute). However, we in interpretation, since histiocytes may
ence of frequent mitoses, ulceration or have rarely observed small melanomas weakly express S-100, whereas activat-
necrosis. The halo phenomenon may with naevoid characteristics but with dif- ed melanocytes and melanoma cells
occasionally involve other types of naevi, fuse cellular atypia combined with mitot- may express HMB45. Finally, there are
including dysplastic naevi {2370}, Spitz ic activity in which diffuse lymphoid infil- lesions that have an infiltrative lympho-
naevi {972} and congenital naevi {2359}, tration was a prominent pattern. When cytic response similar to that of a halo
as well as melanomas {2090}, and there- pigment is present in a halo naevus, it is naevus but there is no clinical halo.
fore careful inspection of the underlying usually in the form of coarsely divided These lesions may be signed out
lesional architecture and cytology in mul- granules as is the case in most benign descriptively as “compound (or dermal)
tiple sections may be required for defini- naevi, and if there is a junctional compo- naevi with halo reaction” {1909}.
tive classification. nent, its character is that of a naevus Conversely, some naevi with a clinical
The halo region at the periphery of the rather than a melanoma. Thus, there is halo may lack a lymphocytic infiltrate of
dermal component of the lesion may usually a discontinuous rather than con- the type seen in halo naevi {812}. These
contain a few lymphocytes at the dermal- tinuous proliferation of predominantly may be termed “non-inflammatory halo
epidermal interface, with a reduction or nested rather than predominantly single naevi”.

Halo naevus 119


Appendageal Tumours

Appendageal tumours are neoplasms whose differentiation is

toward one or more of the adnexal structures of the skin. While
mesenchymal tumours of various kinds are technically in this
category, conventionally, the term refers to those with origin
from, or differentiation toward epithelial adnexal neoplasms.
Depending on their presumed origin, adnexal tumours are
categorized into those with apocrine and eccrine, foliicular and
sebaceous differentiation. For most of these tumour types there
are benign and malignant counterparts. The histopathological-
criteria for prognosis of biological behaviour are well estab-
The WHO Working Group was aware of recent evidence indi-
cating that basal cell carcinoma (BCC) should be included
under the adnexal neoplasms under the term trichoblastic car-
cinoma. The inclusion of BCC in the chapter on keratinocytic
tumours reflects the traditional categorization but does not indi-
cate that the Working Group denies their adnexal origin.
WHO histological classification of appendageal tumours
Tumours with apocrine and eccrine differentiation Tubular adenoma 8211/0
Malignant tumours Tubular papillary adenoma 8263/0
Tubular carcinoma 8211/3 Syringocystadenoma papilliferum 8406/0
Microcystic adnexal carcinoma 8407/3 Hidradenoma papilliferum 8405/0
Porocarcinoma 8409/3 Mixed tumour (chondroid syringoma) 8940/0
Spiradenocarcinoma 8403/3
Malignant mixed tumour 8940/3 Tumours with follicular differentiation
Hidradenocarcinoma 8400/3 Malignant tumours
Mucinous carcinoma 8480/3 Pilomatrical carcinoma 8110/3
Digital papillary carcinoma 8408/3 Proliferating tricholemmal tumour 8103/1
Adenoid cystic carcinoma 8200/3 Benign tumours
Apocrine carcinoma 8401/3 Trichoblastoma 8100/0
Paget disease of breast 8540/3 Pilomatricoma 8110/0
Extramammary Paget disease 8542/3 Tricholemmoma 8102/0
Multiple tricholemmomas 8102/0
Benign tumours Trichofolliculoma 8101/0
Hidrocystoma 8404/0 Fibrofolliculoma / trichodiscoma 8391/0
Syringoma 8407/0
Poroma 8409/0 Tumours with sebaceous differentiation
Syringofibroadenoma 8392/0 Sebaceous carcinoma 8410/3
Hidradenoma 8402/0 Sebaceous adenoma 8410/0
Spiradenoma 8403/0 Sebaceoma 8410/0
Cylindroma 8200/0 Cystic sebaceous tumour 8410/0

Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.

TNM classification of skin appendageal carcinomas

TNM classification 1,2 M – Distant metastasis
MX Distant metastasis cannot be assessed
T – Primary tumour M0 No distant metastasis
TX Primary tumour cannot be assessed M1 Distant metastasis
T0 No evidence of primary tumour
Tis Carcinoma in situ
Stage grouping
T1 Tumour 2 cm or less in greatest dimension Stage 0 Tis N0 M0
T2 Tumour more than 2 cm but no more than 5 cm in greatest Stage I T1 N0 M0
dimension Stage II T2, T3 N0 M0
T3 Tumour more than 5 cm in greatest dimension Stage III T4 N0 M0
T4 Tumour invades deep extradermal structures, i.e., cartilage, Any T N1 M0
skeletal muscle, or bone Stage IV Any T Any N M1
Note: In the case of multiple simultaneous tumours, the tumour with the
highest T category is classified and the number of separate tumours is
indicated in parentheses, e.g., T2(5).

N – Regional lymph nodes

NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis

A help desk for specific questions about the TNM classification is available at www.uicc.org/index.php?id=508 .

122 Appendageal tumours

Appendageal skin tumours: P.E. LeBoit


Epidemiology Pathology A complex array of keratins are

Most studies on adnexal neoplasms Diagnostic criteria of adnexal expressed in adnexal neoplasms. Those
have taken place in western countries carcinomas with follicular germinative differentiation
with Caucasian populations. Benign > Irregular borders, asymmetry at scan- express cytokeratins seen in follicular
adnexal neoplasms tend to occur in ning magnification germs in embryonic and neonatal life.
younger patients than carcinomas do. > Horizontal orientation Those with ductular differentiation have
Adnexal carcinomas vary from those in > Markedly irrregular aggregates of lumens that stain for carcinoembryonic
which actinic damage is the norm, such epithelial cells antigen (CEA), and express simple
as the common basal cell carcinoma > Necrosis en masse epithelial keratins. Sebaceous differenti-
(which differentiates toward follicular > Infiltration of the dermis or subcutis ation is characterized by expression of
germ) to those that seem to have little without the interposition of densely epithelial membrane antigen in a
relationship to sun exposure (such as fibrotic stroma microvacuolar pattern.
spiradenocarcinoma). > Mitoses frequent, can be atypical
> Stroma irregular, often scant, Precursor lesions
Etiology sometimes myxoid Benign adnexal neoplasms of various
No known triggering event is evident in > Nuclei pleomorphic. Some neoplasms sorts can arise in naevus sebaceous, a
the vast majority of adnexal neoplasms. with monomorphous nuclei, e.g. malformation involving the epidermis,
There are some cases in which the cause microcystic adnexal carcinoma, are dermis and adnexae. Otherwise, most
is an autosomal dominant mutation in a exceptions. benign adnexal neoplasms arise de
tumour suppressor gene. novo. This is also the case for malignant
Diagnostic criteria of benign epithelial adnexal neoplasms. Rare apocrine carci-
Clinical signs and symptoms adnexal neoplasms {28}: nomas arise in naevus sebaceous.
Most benign adnexal neoplasms are > Symmetric and smooth bordered at Rarely, porocarcinoma, spiradenocarci-
smooth surfaced, symmetrical papules scanning magnification noma or hidradenocarcinoma may arise
or nodules the same colour as the > Vertically oriented with respect to the in a pre-existent poroma, spiradenoma,
patient’s skin or darker. Some, such as surface of the skin or hidradenoma, respectively. The vast
sebaceous adenoma and syringocys- > Aggregates of epithelial cells uniform majority of basal cell carcinomas arises
tadenoma papilliferum, have eroded sur- > No necrosis en masse (with the exce- de novo. Rarely, basal cell carcinomas
faces, but in general, ulceration is a sign tion of poroma) occur in pre-existent trichoblastomas.
of malignancy. Most adnexal carcinomas > Mitoses variable, but typical
are irregularly shaped plaques, some- > Densely fibrotic stroma, rich in fibro- Histogenesis
times ulcerated. cytes in the case of trichogenic The origin of most adnexal neoplasms is
> Neoplasms forming a blunt, rounded unknown. It is better to speak of their dif-
Tumour spread and staging interface with the native dermis. An ferentiation. The most clear-cut evidence
In general, low-grade carcinomas sel- exception is poroma, which has of differentiation is in follicular neo-
dom metastasize; for some, e.g. micro- vascular, myxoid stroma. plasms, where such signs as follicular
cystic adnexal carcinoma, metastasis > Nuclei monomorphous; rare excep- papillae and germs (as in the trichoblas-
has not yet been recorded. tions include atypical squamous tomas) or trichohyaline granules (as are
A haematogenous pattern seems the rule nuclei in poromas. focally found in pilomatricoma and in
for a few carcinomas, such as adenoid matrical carcinomas) can occur. Clear-
cystic carcinoma, but most can spread Immunoprofile cut apocrine differentiation, in which
via either lymphatic or haematogenous Most adnexal neoplasms are accompa- decapitation secretion of columnar cells
dissemination. Carcino-mas with eccrine nied by variably dense infiltrates of T- that have brightly eosinophilic cytoplas-
differentiation have a propensity to cells. These are intimately admixed with mic granules is also specific. However,
metastasize to the skin. the neoplasm (spiradenoma, cutaneous there is a marked similarity between
lymphadenoma, adamantinoid tricho- eccrine and apocrine ducts. Also, the
Sentinel node biopsy blastoma) and lymphoepithelioma-like columnar cells of eccrine secretory coils
While a few sentinel node biopsies have carcinoma among malignancies are can resemble poorly differentiated apoc-
been performed for adnexal carcinomas, examples. Syringocystadenoma papil- rine secretory cells. Hence, neoplasms
not enough data have been collected to liferum has a complement of plasma with ductular differentiation often have
validate this procedure {274}. cells, many of which secrete IgA. debatable histogenesis {1543}. To some

Introduction 123
extent, the differentiation of neoplasms syndrome). Trichilemmomas have muta-
probably reflects their distribution {1544}. tions in PTEN, the same gene as involved
in Cowden syndrome. Mutations in DNA
Genetics repair genes occur in the sebaceous
Approximately one third of sweat gland neoplasms of the Muir-Torre syndrome
carcinomas contain TP53 mutations and, to a lesser degree, in sporadic
{239A}. Otherwise, little is known about sebaceous neoplasms.
the genetics of most epithelial neo-
plasms, with the exception of those that Prognosis and predictive factors
occur in multiplicity as part of autosomal In general, adnexal carcinomas of low
dominant syndromes (see Chapter 7). cytologic grade have a good prognosis,
The mutations found in the germlines of especially if the lesion is relatively small
patients with syndromes and multiple and completely excised. Those of high
tumour suppressor genes tend to be the cytologic grade may metastasize widely.
same as occur as somatic mutations in For many adnexal carcinomas, there are
sporadic adnexal neoplasms. Some simply insufficient numbers of reported
trichoblastomas have mutations in the cases to develop much of an idea
PTCH gene, as found in naevoid basal regarding their prognosis.
cell carcinoma syndrome (Gorlin-Goltz

124 Appendageal tumours

Malignant tumours with apocrine and L. Requena
H. Kutzner
Y. M. Mengesha
S. Kohler
eccrine differentiation M. A. Hurt
D. J. Santa Cruz
Z B. Argenyi
J. McNiff
A.H. Mehregan P. Rudolph
O. P. Sangüeza

Tubular carcinoma Histopathology carcinoma of the skin is established, the

At scanning magnification, the neoplasm possibility of cutaneous metastasis from
Definition is asymmetric, poorly circumscribed, a visceral tubular carcinoma should be
Tubular carcinoma is the malignant coun- and infiltrative with prominent and crowd- ruled out.
terpart of tubular adenoma, featuring ed tubular and ductal structures. The
apocrine differentiation with prominent lesion often involves the full-thickness of Immunoprofile
tubular structures. the dermis and it may extend to the sub- Tubular carcinoma shows immunoreac-
cutaneous tissue. Neoplastic structures tivity with low molecular weight cytoker-
ICD-O code 8211/3 show marked variation in size and shape, atins and the luminal cells express EMA
but, in general, the size of the tubules and GCDFP-15. Expression of CEA is
Historical annotation tends to decrease from superficial to variable {1785,2569}.
Probably the first reported examples of deeper areas. The more superficial larg-
tubular carcinoma were included in the er tubules may show luminal papillations. Histogenesis
series of carcinomas of sweat glands At higher magnification, epithelial cells The presence of decapitation secretion
published by Stout and Cooley in 1951 lining the tubules show abundant and continuity between neoplastic
{2274}. eosinophilic or granular cytoplasm and tubules and follicular infundibula are
pleomorphic nuclei, some of them in signs of apocrine differentiation. This is
Epidemiology mitosis. Often the cytoplasm of these further supported by enzyme histochem-
Tubular carcinoma seems to be slightly cells exhibits signs of decapitation istry.
more frequent in women. Most patients secretion. Lumina are often filled with
are middle-aged adults. homogenous eosinophilic material, Prognosis and predictive factors
foamy histiocytes and necrotic debris. Tubular carcinoma of the skin behaves in
Localization Examples of tubular carcinoma may also a highly malignant fashion. Of the 44
The axilla is the most common location, exhibit focally solid areas with a combi- examples reported in the literature, neo-
with rare bilateral involvement. Other nation of cribriform or adenoid cystic pat- plasms from 21 patients metastasized
sites rich in apocrine glands may also be terns as additional morphologic expres- and at least 9 patients died as a result of
involved {114,127,1705,1785,2274,2397, sions. Areas of necrosis en masse are widespread metastatic disease {1705,
2460,2569}. also frequent, but in contrast with ade- 1785,2397,2569}.
noid cystic carcinoma, tubular carcino-
Clinical features ma shows no deposits of basement
Tubular carcinoma usually presents as a membrane material within the aggrega- Microcystic adnexal carcinoma
firm erythematous nodule, which may be tions of neoplastic cells and perineural
ulcerated or adherent to deeper tissues. involvement is usually absent. The stro- Definition
Tubular carcinomas may arise in naevus ma is sparse. Microcystic adnexal carcinoma {861} is a
sebaceous {644}. Before a diagnosis of primary tubular locally infiltrative and destructive low-

Fig. 3.01 Tubular carcinoma on the retroauricular Fig. 3.02 Tubular carcinoma. A The neoplasm involves the full-thickness of the dermis and extends into sub-
left region. cutaneous tissue. The stroma is sparse and the epithelium predominates over the stroma. B Some neo-
plastic aggregations of this tubular carcinoma exhibit focally an adenoid cystic pattern.

Malignant tumours with apocrine and eccrine differentiation 125

grade adenocarcinoma differentiated
toward ducts. It has little capacity to

ICD-O code 8407/3

Sclerosing sweat duct carcinoma {541},
eccrine epithelioma, syringomatous car-

Clinical features
The carcinoma occurs on the face of
adults, more commonly in women. It
affects commonly the face {469} and lip,
Fig. 3.03 Microcystic adnexal carcinoma. Scanning magnification of microcystic adnexal carcinoma illus-
uncommonly other locations, and grows trates the zonal effect with solid nests and cysts superficially with complex glands deep.
slowly over a period of months to years.
It is similar usually to a depressed scar
and rarely causes ulceration. cysts) to deep (epithelial cords and scle- ogy. Cytologically, the lesions are well
rosis). differentiated, lacking nuclear pleomor-
Histopathology Unusual examples contain sebocytic phism or mitotic figures. In fact, the find-
The classical pattern is that of small, zones {1862}, and others contain areas ing of nuclear pleomorphism should
superficial, solid to cystic structures that similar to follicular sheath, thus suggest- cause one to reconsider whether the
are similar to small infundibular cysts and ing differentiation toward the folliculo- diagnosis of microcystic adnexal carci-
ducts. In the middle depth, the lesion is sebaceous-apocrine unit. In other cases, noma is correct.
composed completely of small ducts, the lesions are exclusively ductal, caus-
often in very subtle patterns, frequently ing some authors to designate them as Immunoprofile
with involvement of nerves and perineur- “syringomatous carcinoma” or “scleros- There is cytoplasmic staining with
al spaces. In the deepest areas, “Indian” ing sweat duct carcinoma” and suggest- AE1/AE3, CK7, and bcl-2. EMA and Ber-
filing and sclerosis are common findings. ing that these examples could be EP4 stain in a membranous pattern
Thus, there is a sense that the lesion is derived from eccrine ducts. Some MACs around ductal cells near the lumen.
stratified from superficial (tubules and have solid poromatous or clear cell cytol- Alpha SMA and S100 protein stain the


Fig. 3.04 Microcystic adnexal carcinoma. A There are a few cysts and solid nests, but no nuclear pleomorphism. The pattern of the lesion helps to recognize it as
carcinoma. B Not only are there ducts; there are also strands and small nests of neoplastic cells. C This example of microcystic adnexal carcinoma again illus-
trates the zonation pattern, in this case with a few cysts superficially. Note the deep nests that are present in and around the sucutis; not every case will contain
compressed ducts exclusively in the deep zones. D This example is similar to some poromas. There are solid nests of monomorphous cells as wells as nests of
cells with clear cytoplasm. Some authors have designated these lesions "syringomatous" carcinoma. E Despite the striking structural patterns of these lesions,
most do not contain nuclear pleomorphism. F Peripheral nerve, completely encircled by the neoplasm. Note the ductal space.

126 Appendageal tumours

tubules peripherally. P53 is positive in
less than 25% of the neoplastic cells.
There is a low proliferative index, as Ki-
67 is positive in less than 5% of the neo-
plastic cells. CK20, c-erb-2, and CD34
are negative {2207}.

Differential diagnosis
The principal differential diagnoses are
with superficial biopsies of columnar tri-
choblastoma (desmoplastic trichoepithe-
lioma) or morpheiform basal cell carcino-
ma (trichoblastic carcinoma), all of which
are CK7 negative. Syringoma is a possi-
ble consideration in some cases. Rare
examples of metastatic carcinoma to the
skin can also mimic it.

There is a single report of a 6q deletion
{2538}. There is also a report of 2 micro- Fig. 3.05 Malignant mixed tumour. Lobulated biphasic tumour consisting of epithelial and mucinous-mes-
cystic adnexal carcinomas, one of which enchymal components. The former predominate at the periphery, while the latter predominate at the cen-
was diploid, and the other, aneuploid, ter.
when examined with DNA image cytom-
etry {2437}.

Treatment is surgical, with microscopic
control of margins if possible {9}.
Radiotherapy has proven successful
rarely, but some reported cases have
taken on an even more virulent biology
after such treatment.
Malignant mixed tumour

Malignant mixed tumour (MMT) is an
exceedingly rare cutaneous adnexal car-
cinoma with a significant risk for aggres-
sive behaviour and a propensity for
metastasis. MMT is regarded as the
malignant counterpart of benign mixed
tumour {1919} albeit histological diagno- C D
sis is foremost based on the biphasic
nature of the neoplasm rather than an
admixture of benign mixed tumour rem-
nants with carcinomatous tissue {2515}.

ICD-O code 8940/3

Malignant apocrine mixed tumour.
Malignant chondroid syringoma. E F
Fig. 3.06 Malignant mixed tumour. A Hyperchromatic tumour cells with mitoses. B Note variations of cyto-
Epidemiology logical differentiation and pleomorphism. C Focal zone of tubule formation. D Highly pleomorphic tumour
MMT represents an exceedingly rare lobules with mitoses at the periphery of the tumour. E Note the pseudo-sarcomatous pattern with hyper-
cutaneous adnexal neoplasm which chromatic spindle cells and many mitoses. F Nests of plasmacytoid tumour cells amidst a myxoid stroma.
occurs in a wide age range (15 months Plasmacytoid epithelial differentiation is a hallmark of myoepithelial differentiation.

Malignant tumours with apocrine and eccrine differentiation 127

to 89 years; average 50 years) and is Tubular structures may be either of the consists of non-cohesive elongated
twice more common in women than in elongated apocrine type lined by at least tumour nests without ductal or tubular
men {177,1919}. two layers of epithelial cells, with luminal structures. Tumour cells are cytokeratin
cells exhibiting signs of apocrine secre- negative. Mucinous carcinoma and myx-
Localization tion and abluminal cells showing plasma- opapillary ependymoma show distinct
In marked contrast to its benign counter- cytoid / myoepithelial differentiation, or – PAS positivity of the extracellular myxoid
part MMT shows a predilection for the more rarely – of the eccrine type showing stroma. Cutaneous myoepithelial carci-
trunk and the extremities, foremost the small round structures lined by a single noma favours monophasic differentiation
hands and feet {177,961,1593,1903, layer of atypical epithelial cells {961, with a very discrete myxoid stroma
1919,2177,2377}. 1919}. Often, however, MMT consists {1585}. MMT and cutaneous myoepithe-
only of solid aggregations devoid of lial carcinoma may fall along a spectrum
Clinical features tubules {928, 1919, 2471}. Epithelial of tumours with overlapping histologic
MMT shares most clinical characteristics tumour cells may either have a decep- appearances {1585}.
with its benign counterpart, albeit tively bland appearance {1112,2100} or
tumours of the former are much larger at show distinctive atypia and pleomor- Histogenesis
the time of presentation (2-15 cm in phism of nuclei with a high nuclear-cyto- MMT probably does not originate in
diameter). Rarely, rapid growth, ulcera- plasmic ratio and numerous mitotic fig- association with its benign counterpart,
tion, or pain in a previously indolent skin ures {1919}. Zones of necrosis are com- but develops de novo {1919}. A myoep-
tumour indicate carcinomatous growth. mon. Characteristic epithelial tumour ithelial origin of MMT appears to be most
Most MMT, however, present in a rather cells are cuboidal with distinctive polyg- plausible {177,1585,2100}, and MMT
bland way with a long history prior to onal or plasmacytoid features {961, may be included in the spectrum of cuta-
excision. These tumours are well circum- 1919}. The latter is considered an indica- neous myoepithelial neoplasms {1585}.
scribed and may appear cystic. They are tor of the myoepithelial/apocrine origin of
not painful, not ulcerated, and show no the neoplasm and may be seen as a clue Prognosis and predictive factors
distinctive clinical appearance. to the diagnosis of MMT {1919}. MMT proliferates in an invasive and
destructive fashion, with a high rate of
Macroscopy Immunoprofile local recurrences and metastases
Grossly, most MMT are firm, circum- Tumour cells may show a myoepithelial (>50%) into regional lymph nodes, lung,
scribed, asymmetrical cutaneous or sub- immunophenotype with coexpression of and bone {177,1593}. Death ensues in
cutaneous tumours with a diameter of up S100 and cytokeratin {177,976,1839, >25% {177}. However, in >30% MMT nei-
to 15 cm. The tumour cut surface may 2471} and actin expression in a minority ther recurred nor metastasized (“atypical
reveal gelatinous material in variable of cells {1488}. Spindle cells within the mixed tumour of the skin”) {177}. In gen-
amount {1919}. Because of the infiltrative myxoid stroma are vimentin-positive eral, MMT is characterized by its pro-
tumour growth enucleation is not possi- {2117}. longed course {2467}. It is remarkable
ble. that non-metastasizing MMTs showed
Electron microscopy the same histological spectrum as those
Histopathology Tumour cells exhibit ultrastructural fea- of proven malignancy {1919}, ranging
MMT originates within the dermis or tures of myoepithelia with desmosomes from bland cytological appearance {961}
superficial subcutis, and presents as a and abundant intracytoplasmic filaments to marked nuclear pleomorphism and a
large, asymmetrical, poorly circum- {177,1839,2471}. However, ultrastructur- high mitotic count {2377}. Complete exci-
scribed, lobulated biphasic tumour with al studies so far have not presented con- sion before metastasis results in tumour
infiltrative tumour margins and adjacent vincing evidence of either apocrine or free survival {1919}.
satellite tumour nodules. Juxtaposed eccrine differentiation of MMT {1919}.
areas of benign and malignant mixed
tumour may rarely occur, but are not a Variants Porocarcinoma
prerequisite for the diagnosis of MMT. MMT may exhibit deceptively bland cyto-
MMT is composed of both epithelial and logical features {1112,2100} albeit asso- Definition
mesenchymal components, with epithe- ciated with distinctive architectural crite- Eccrine porocarcinoma is a malignant
lial components predominating at the ria of malignancy, e.g. asymmetry, poor tumour related to the sweat gland duct,
periphery and mesenchymal chondro- circumscription, infiltrative tumour mar- showing both intraepidermal and dermal
myxoid elements being more abundant gins, and satellite nodules. components.
toward the centre {2100}. The chondro- The recently described malignant mixed
myxoid tumour stroma is PAS-negative tumour of soft tissue {1062} shows over- ICD-O code 8409/3
and consists of hyaluronic acid and sul- lapping histologic criteria with MMT of
phated acid mucopolysaccharides the skin. The former is considered to be Synonyms and historical annotation
{1112}. Stroma ossification is rare {961, part of the morphological spectrum of Epidermotropic eccrine carcinoma,
2177}. Epithelial tumour aggregations myoepithelial tumours of soft tissue. malignant eccrine poroma, malignant
present as confluent cords and nests of hidroacanthoma simplex, malignant
variable size and shape, with inter- Differential diagnosis intraepidermal eccrine poroma, poroep-
spersed zones of tubule formation. Extraskeletal myxoid chondrosarcoma ithelioma. The tumour was first described

128 Appendageal tumours


Fig. 3.07 Porocarcinoma. A Multinodular ulcerated Fig. 3.08 Porocarcinoma. There is a dermal component, partly in apposition with the epidermis, and a large
plaque. B Closely arranged polygonal cells with tumour nodule extending into the deep subcutaneous tissues. The lesion is remarkably well demarkated.

by Pinkus and Mehregan in 1963 as epi- fibroma, basal cell carcinoma, squamous tiated from Paget disease by its relative-
dermotropic eccrine carcinoma {1837}. cell carcinoma, or pyogenic granuloma. ly sparse epidermal involvement and
Diagnosis is made by skin biopsy. greater dermal invasion, and the pres-
Epidemiology ence of glycogen rather than mucin in
Eccrine porocarcinoma is a rare tumour, Histopathology tumour cells {913}. In the absence of
predominantly observed in elderly Eccrine porocarcinoma forms intraepi- residual eccrine poroma, it is very diffi-
patients with an average age of 67 years dermal and dermal nests and cords of cult to differentiate eccrine porocarcino-
{1072}. Women and men are equally epithelial cells with pale cytoplasm. The ma from squamous cell carcinoma
affected. The incidence in one large tumour masses form clearly demarcated {1571}.
series was 18 per 450,000 cases and frequently rounded nests of polygo-
(0.004%) {1571}. nal cells with pleomorphic and irregular- Immunoprofile
ly-shaped nuclei, prominent nucleoli, and The tumour nodules stain with antibodies
Etiology numerous mitotic figures. There is sharp to pan-cytokeratin; tumour cells may
Eccrine porocarcinomas may arise de demarcation of the epithelial nests of stain paler than adjacent epidermal ker-
novo or as a malignant transformation in cells from the adjacent epidermal ker- atinocytes {499,1072}. Ductal structures
a pre-existing poroma, hidroacanthoma atinocytes {1837}. The overlying epider- within the tumour stain strongly positive
simplex, or in association with naevus mis may be acanthotic. Both single with CEA and EMA {1359,2216}.
sebaceous {1571,2216,2604}. 18 to 50% tumour cells and nests of cells may
of eccrine porocarcinomas are associat- involve the epidermis in a pagetoid fash- Genetics
ed with pre-existing eccrine poromas. ion {1359}. Keratinization is usually Mutation of the p53 gene with loss of its
absent. Intercellular bridging between suppressor function has been widely
Localization the tumour cells is inconspicuous. The noted with malignant transformation. P53
Forty-four to 50% of eccrine porocarcino- tumour cells may contain glycogen protein expression has been observed in
mas arise on the legs, buttocks, or feet {2000}. Connection to the intradermal both eccrine poromas and eccrine poro-
{2216}. The trunk accounts for 24% of the eccrine ducts may be observed. Deep carcinoma {43,2327}. P16 staining is uni-
lesions and the head 18% of the lesions dermal intralymphatic invasion may be formly negative {914}.
with less frequent lesions located on the observed in up to 15% of the lesions
upper extremities {1072}. {1952}. Prognosis and predictive factors
The differential diagnosis includes Approximately 20% of eccrine porocarci-
Clinical features eccrine poroma, hidroacanthoma sim- nomas recur after excision {2216}.
Eccrine porocarcinoma presents as a plex, and Paget disease {913}. Eccrine Regional lymph node metastasis occurs
verrucous nodulo-ulcerative plaque. poroma and hidroacanthoma simplex in 20% of patients, while 12% develop
Clinically the lesions may resemble an may show focal atypia, but the lesions distant metastases {2216}. Patients with
eccrine poroma, verruca vulgaris, sebor- are symmetrical and well circumscribed. metastatic disease have a high mortality
rhoeic keratosis, melanocytic naevus, Eccrine porocarcinoma may be differen- rate {170}. Increased number of mitoses,

Malignant tumours with apocrine and eccrine differentiation 129

In all cases there are recognizable areas
of a benign spiradenoma with the usual
well-defined dermal nodules composed
of two cell types. Spiradenocarcinoma
arising from benign spiradenoma pres-
ents two major histologic patterns {89,
725,884}. In one type, there are areas
showing gradual transition from benign
to a malignant neoplasm. In these lesions
B the dual cell population of the benign
neoplasm imperceptibly merges with the
monomorphous cell population of the
carcinoma. The usual structural pattern
of spiradenoma disappears and is
replaced by poorly defined cell nests
and cords. Glandular and duct-like struc-
tures, as well as hyaline globules, are
diminished or may be missing. These
changes can be very focal in early
lesions and can easily be missed without
adequate tissue sampling. In the second
A C type, the malignant changes are adja-
Fig. 3.09 Spiradenocarcinoma. A Transitional changes from benign to malignant. Note transitional area with cent to the spiradenoma without structur-
hypercellularity, hyperchromasia and diminished preservation of the usual histologic pattern of a spirade- al or cytological transition. These neo-
noma. B Spiradenocarcinoma with transitional changes from benign to malignant. Malignant area with plasms can present a wide spectrum of
occasional residual duct-like structures with clear cell changes and prominent cytologic atypia. histologic features including squamous,
C Spiradenocarcinoma with unusual cytodifferentiation, squamous "bowenoid" dysplasia. bowenoid, adenomatous, ductal carcino-
ma-like, and even histiocyte-like and car-
lymphovascular invasion and tumour Synonym cinosarcomatous changes with rhab-
depth greater than 7 mm have all been Malignant spiradenoma domyoblastic or osteosarcomatous dif-
associated with a relatively poor progno- ferentiation {1391,1548,1958}. In advan-
sis {1952}. Epidemiology ced stages of both subtypes, necrosis,
Spiradenocarcinoma is an extremely rare haemorrhage, and infiltrative growth can
tumour. Approximately 50 well-docu- be observed.
Spiradenocarcinoma mented cases have been reported. The
tumour mainly affects middle age per- Immunoprofile
Definition sons (mean age is 55 yr), and its inci- Spiradenocarcinoma is positive for the
Spiradenocarcinoma is a malignant dence is similar in both sexes. majority of cytokeratins, CEA, EMA, and
adnexal neoplasm resulting from malig- shows a spotty reaction for S-100 pro-
nant transformation of a benign spirade- Localization tein. Over-expression of P53 has also
noma. Spiradenocarcinoma can affect any been reported {89,726,1555,2516}.
body site, but the most common loca-
ICD-O code 8403/3 tions are the upper extremities, followed
by the lower extremities, trunk, and the
head and neck areas {725,884}.

Clinical features
Typically there is a history of a long-
standing lesion that suddenly became
enlarged, ulcerated, tender, or changed
its colour. The size of the tumour ranges
from 0.8-10 cm. The mean duration of a
pre-existent lesion is about 20 years
before the diagnosis is made {725}. The
patient may also have multiple long-
standing spiradenomas, which often
Fig. 3.10 Spiradenocarcinoma. Well-defined, coexist with cylindromas {89}. Fig. 3.11 Hidradenocarcinoma involving the left
encapsulated mass with areas of solid and cystic preauricular skin of an elderly male. Note the pres-
changes and haemorrhage. ence of a retroauricular lymphadenopathy.

130 Appendageal tumours

Fig. 3.12 Hidradenocarcinoma. A At scanning power the neoplasm appears as a well-circumscribed round nodule involving the full thickness of the dermis.
B Although the neoplasm is mostly a solid tumour, in some areas there is evidence of ductal differentiation in the form of cytoplasmic vacuoles and small round

Histogenesis moid hidradenocarcinoma {637}, and Immunoprofile

Theoretically, spiradenocarcinoma can malignant nodular clear-cell hidradeno- Neoplastic cells express low molecular
develop de novo. However, the tumour ma {204}. weight cytokeratin CAM 5.2 and cytoker-
lacks distinctive microscopic features, atin 19. CEA and EMA decorate the lumi-
therefore its histopathologic diagnosis Epidemiology nal border of ductal structures.
requires recognition of a spiradenoma in Hidradenocarcinoma seems to be slight-
association with the malignant changes. ly more frequent in women than in men, Histogenesis
with the mean age of 50 years, but cases Most neoplasms have apocrine differen-
Somatic genetics have been also recorded in children tiation, but some show eccrine features.
TP53 mutations have been identified in {237,477}.
carcinomatous portion of spiradenocar- Prognosis and predictive factors
cinoma, whereas the spiradenoma part Etiology This carcinoma may metastasize widely
lacked mutations {239A}. Most cases of this carcinoma arise de and cause death. Of the 76 patients with
novo, but some cases are associated this carcinoma described in the litera-
Prognosis and predictive factors with a hidradenoma {237,1013,1237, ture, 22 developed metastases {204,485,
Spiradenocarcinoma is an aggressive 1249,1427}. 992,1013,1162, 2468}.
neoplasm with multiple local recurrences
and eventual widespread metastases, Localization
resulting in death. The metastases most This carcinoma may appear in any area.
often involve lymph nodes, bones, and
lungs. Management is primarily surgical; Clinical features
the role of radiation and chemotherapy is The neoplasm does not have any distinc-
still to be defined {1110,1594}. tive clinical features and usually presents
as a slow growing solitary dermal or sub-
cutaneous nodule.
Definition Hidradenocarcinoma is composed of
Hidradenocarcinoma is the malignant one or several tumour nodules, which
counterpart of hidradenoma. vary in size and shape. Focal tubular and
ductal structures may be present. Areas
ICD-O code 8400/3 of necrosis en masse are common.
Usually there is no connection between
Synonyms the epidermis and the tumour, but the
Clear-cell papillary carcinoma {1436}, surface epithelium may be ulcerated.
clear-cell hidradenocarcinoma {1249, The same cell types as seen in hidrade-
1470}, malignant clear-cell hidradenoma noma are found in hidradenocarcinoma.
{578,1237}, malignant clear-cell acro- Atypical cells with pleomorphic nuclei
spiroma {992}, malignant eccrine acro- and mitotic figures may be focally promi-
spiroma {1741}, primary mucoepider- nent, but some tumours lack nuclear
moid carcinoma of the skin {803, 2497}, atypia. Therefore, the diagnosis can be Fig. 3.13 Mucinous carcinoma. Note typical "honey-
nodular hidradenocarcinoma, clear-cell established only on the basis of architec- comb pattern" with small epithelial strands floating
eccrine carcinoma {2300}, mucoepider- tural characteristics. in lakes of mucin.

Malignant tumours with apocrine and eccrine differentiation 131

Fig. 3.14 Mucinous carcinoma. A Large mucin deposits clearly predominate over epithelial tumour components - in sharp contrast to cutaneous metastasis of muci-
nous breast carcinoma where epithelial tumour cells predominate and delicate fibrous septa are scarce. B Thin strands of epithelial tumour cells with little atypia
and very scarce mitoses. Note delicate fibrous septa and incipient tubule formation.

Mucinous carcinoma ing, painless nodular neoplasm. The that may be vacuolated. Nuclei are small
tumour has a tan, grey, or reddish colour, with very little atypia. Mitoses are rare.
Definition a smooth surface, and a consistency The epithelial mucin is PAS-positive,
Primary cutaneous mucinous carcinoma ranging from soft to firm. Positive trans- hyaluronidase and sialinase labile, and
(MC) is a rare epithelial neoplasm occur- illumination may be a helpful diagnostic consists of non-sulphated acid
ring mostly, but not exclusively, in mid- tool. mucopolysaccharides with sialic acid.
dle-aged and older patients. Although
MC is characterized by destructive local Macroscopy Immunoprofile
growth and the potential of metastasizing Grossly, most MC are well-circum- Neoplastic cells express low molecular
to regional lymph nodes and even be- scribed, un-encapsulated tumours in the weight cytokeratins, CEA, EMA, GCDFP-
yond them, it generally follows an indo- dermis and the subcutaneous fat. 15, alpha-lactalbumin, salivary amylase,
lent course with frequent local recurren- Tumour diameters range between 1 and beta-2-microglobulin. S100 expression is
ces. Mucinous carcinoma metastatic to 8 centimetres, albeit larger variants have inconstant {199,404,664}. Nuclear
skin from another organ, particularly the been reported {1231}. On excision, the expression of oestrogen receptors may
breast and gastrointestinal tract, may be tumour appears fixed to the adjacent be strong, but the pattern of progesteron
histologically indistinguishable from MC. dermis and does not “shell out” {1919}. receptors is more variable {945}.
The cut surface of excised specimens is Cytokeratin 20 expression allows differ-
ICD-O code 8480/3 gelatinous. entiation of mucinous gastrointestinal
carcinoma metastatic to the skin from
Synonyms Histopathology primary cytokeratin 20-negative cuta-
Primary cutaneous mucinous carcinoma. MC presents as an un-encapsulated neous MC {664}.
Colloid, gelatinous and adenocystic car- asymmetric dermal tumour that may
cinoma. extend into the subcutis and even deep- Variants
er tissue planes {1919}. Tumour satellites MC very rarely presents with focal neu-
Epidemiology may occur at some distance from the roendocrine differentiation {1876}, or with
MC is very rare and occurs mostly main tumour. MC is characterized by a growth pattern imitating infiltrating car-
between the fifth and seventh decades of large pools of basophilic mucin, which cinoma of the breast {2557}.
life, with an age range between 8 and 84 are compartmentalized by delicate Epidermotropism of neoplastic cells is
years. MC is slightly more common in fibrous septa, thereby creating a honey- unusual.
men than in women {1919}. comb pattern. Within the lakes of mucin
are small “floating” islands and bizarre Electron microscopy
Localization clusters of neoplastic epithelial cells, There are less well-differentiated inner
Most MC arise on the head, favouring sometimes exhibiting a cribriform pale cells and mucin-containing periph-
scalp and face with preference of the arrangement. The epithelial component eral dark cells {990}.
eyelids {199,305,1212,2217,2319}. Rare is denser at the periphery of the tumour.
sites are axillae, trunk, lower extremities, Small glandular or tubular structures Differential diagnosis
perianal area and vulva {1919}. containing mucin or showing signs of Before a diagnosis of MC is established,
apocrine secretion occur only rarely. The a primary carcinoma in a breast or anoth-
Clinical features small neoplastic cells are cuboidal, er organ (salivary and lacrimal glands,
MC presents as a solitary, slowly grow- round, or oval with abundant cytoplasm gastrointestinal tract, nose and

132 Appendageal tumours

paranasal sinuses, bronchi, ovary and
renal pelvis) should be specifically
sought and excluded as most cases of
mucinous carcinoma in the skin are
metastatic to it. Histological differentia-
tion between primary cutaneous MC and
metastatic mucinous carcinoma to the
skin may be impossible, albeit the latter
exhibits subtle histological variations
{1919}: e.g. larger clusters of cohesive
neoplastic cells, less quantities of mucin,
a striking predominance of epithelium
over mucin, and the absence of delicate
fibrous septa that intersect the lakes of
Malignant mixed tumour of the skin
exhibits tubular structures embedded in
a myxoid, chondroid, or osteoid stroma,
and distinctive polygonal and plasmacy-
toid neoplastic epithelia. The character-
istic honeycomb pattern of MC is not Fig. 3.15 Digital papillary carcinoma. Within the tumour nodules, papillae are formed by heaped up epitheli-
present {1919}. um without stromal cores.

Histogenesis cases originally classified histologically pattern of glands often fills the solid
Histogenesis of MC has not yet been elu- as adenoma developed metastases, areas of tumour, while papillary epithelial
cidated, but there is strong morphologi- demonstrating that histologic parameters projections are common within cystic
cal evidence that MC may be apocrine in do not accurately predict behaviour or spaces. The papillary projections are
nature {1919}. allow distinction between adenoma and associated with fibrovascular cores in
adenocarcinoma {655}. Therefore, the some areas, while in other areas papillae
Prognosis and predictive factors term aggressive digital papillary adeno- are formed by heaped up epithelium
In contrast to most other sweat gland ma has been abandoned in favour of without stromal support. The epithelium
carcinomas, MC is a low-grade malig- classification of all such lesions as digital is composed of low columnar or cuboidal
nant neoplasm with a tendency to persist papillary carcinoma. cells. Cytologic atypia is usually not
at the original site but with a low metasta- marked. Mitoses and necrosis are fre-
tic potential. 10% of the MC so far report- Epidemiology quent findings. Cysts contain either
ed metastasized to regional lymph Digital papillary carcinomas present necrotic debris or eosinophilic secretory
nodes, but only 3% metastasized in a almost exclusively on the fingers, toes, material. Some tumours are well-circum-
more widespread fashion {1830}. While palms, and soles. Hands are involved scribed, while others have an infiltrative
multiple recurrences, due to the exis- more frequently than feet. There is a male growth pattern.
tence of tumour satellites, are not unusu- predilection, and most affected individu-
al, death from MC is exceptional {1919}. als are adults in the fifth and sixth Differential diagnosis
decades of life. The differential diagnosis includes papil-
lary eccrine adenoma, which is usually
Digital papillary carcinoma Clinical features well-circumscribed, and composed of
Most cases present as a slowly growing dilated ducts with a distinct two cell layer
Definition deeply seated nodule on a digit. Lesions and delicate papillae. Malignant adnexal
Digital papillary carcinoma is regarded may be several centimetres in diameter. neoplasms such as malignant acrospiro-
as an uncommon malignant adnexal Pain is occasionally a presenting com- ma and malignant spiradenoma are also
neoplasm with potential for both recur- plaint, and may be related to tumour in the differential, but typically lack the
rence and metastasis. extension into underlying bone, joint, or pattern of papillary growth and/or back-
nerve. Rarely, metastasis is the first man- to-back glands that characterize digital
ICD-O code 8408/3 ifestation of disease. Unless underlying papillary carcinoma. In addition, malig-
bone has been invaded, routine nant spiradenoma usually retains its
Synonyms roentgenographic examination may be characteristic two cell population (small
Aggressive digital papillary adenoma, essentially unremarkable. basaloid cells and large pale peripheral
digital papillary adenocarcinoma cells) in at least some foci.
Historically, this group of lesions was Histopathology
divided histologically into aggressive Typically, tumours are composed of Histogenesis
digital papillary adenomas and digital multi-nodular epithelial aggregates with The occurrence of digital papillary carci-
adenocarcinomas {1205}. However, cystic spaces in the dermis. A cribriform noma on acral sites where eccrine

Malignant tumours with apocrine and eccrine differentiation 133

glands are abundant suggests an
eccrine origin of this tumour. Although
some cases show decapitation secre-
tion, as is common in apocrine lesions,
this phenomenon has also been
observed in eccrine tumours. In addition,
immunoreactivity for ferritin had led
investigators to favour that digital papil-
lary carcinomas derive from eccrine
glands {417}.

Prognosis and predictive factors

Complete surgical excision with negative
margins is indicated, and sometimes
requires amputation. Tumour recurrence
is seen in up to 50% of patients, espe-
cially in cases without adequate primary
excision {1205}. Metastatic disease has
been observed in 14% of cases {655}. A
Metastases may accompany recurrent
disease or occur without evidence of
local recurrence. Lungs seem a favoured
site for metastases, suggesting the prob-
ability of haematogenous spread of
tumour. Tumour recurrence and metasta-
sis does not seem to correlate with
patient age, tumour size, or duration of
tumour. Similarly, histologic features such
as tumour differentiation, circumscrip-
tion, or nuclear grade are not predictive
Fig. 3.16 Adenoid cystic carcinoma. A Low power view of an adenoid cystic carcinoma demonstrating a
of behaviour {655}.
poorly circumscribed neoplasm which is composed of collections of basophilic cells arranged in a sieve-
like pattern. B This photograph highlights the sieve-like pattern with prominent mucin within the glandular
spaces. Note also the irregularity of the size and shape of the cellular collections. C Mild degree of pleo-
Adenoid cystic carcinoma morphism is seen within the neoplastic cells.

Primary cutaneous adenoid cystic carci- ly 9.8 years {1219}. The size of the due to nuclear hyperchromatism and
noma is a neoplasm of disputed histoge- tumour ranges from 0.5-8 cm, with an crowding. Nuclear palisading is absent.
nesis characterized by a cribriform pat- average size of 3.2 cm. Patients typically The tumour nests are surrounded by a
tern and frequent perineural involvement. present with slowly expanding, firm, skin prominent eosinophilic hyaline basement
coloured nodules. Tenderness, ulcera- membrane-like material which is periodic
ICD-O code 8200/3 tion and bleeding are variable and acid-Schiff-positive, and diastase-resist-
depend on the site of involvement. In the ant. The cystic spaces often contain
Epidemiology scalp region, alopecia may be an associ- abundant mucin {1812}. The mucin is
Over 40 cases have been reported in the ated finding. characteristically alcian blue (pH 2.5)
literature. Adenoid cystic carcinoma positive. The epithelium consists of fairly
(ACC) affects middle-aged and older Histopathology uniform cells with darkly staining nuclei,
individuals (mean age: 58.1) and has a Primary cutaneous ACC is usually poorly which sometimes contain conspicuous,
predilection for women {1219}. circumscribed and is composed of small, solitary nucleoli. Individual tumour
islands, cords and strands of basaloid cells have a scant amphophilic cyto-
Localization cells with a glandular, cystic, cribriform plasm and an increased nuclear-cyto-
This neoplasm is most common on the and tubular arrangement embedded in a plasmic ratio. Mitotic activity is usually
scalp (35%) and chest and abdomen loose fibrous and sometimes mucinous sparse with 1-2 division figures per high
(24%) {446,1219}. stroma. It typically occupies the mid and power field (x40) {2514}. Perineural
deep dermis and may extend into the extension, a characteristic feature of sali-
Clinical features subcutaneous fat {793}. The epithelial vary gland adenoid cystic carcinoma
Primary cutaneous adenoid cystic carci- cords have an infiltrative pattern and are may be seen, however, not with the fre-
noma has an indolent and progressive not connected to the overlying epider- quency seen in other organs.
course. The average duration of the mis. The tumour has a characteristic Before the diagnosis of a primary cuta-
tumour prior to diagnosis is approximate- basophilic appearance on low power neous ACC is made, the possibility of a

134 Appendageal tumours

metastasis from other organs needs to Apocrine carcinoma gland carcinoma) and the eyelid (Moll
be ruled out on clinico-pathological gland carcinoma) {2139,2172}.
grounds. The adenoid cystic type of Definition
basal cell carcinoma is differentiated by Apocrine carcinoma (AC) is a malignant Clinical features
the presence of palisading of the nuclei sweat gland neoplasm with apocrine dif- Because reports are sporadic and may
and stromal retraction. ferentiation. Although an apocrine origin have included a proportion of benign
has also been postulated for adenoid lesions it is difficult to establish a precise
Immunoprofile cystic carcinoma, hidradenocarcinoma, clinical profile for AC. Apparently, there
Primary cutaneous adenoid cystic carci- spiradenocarcinoma, malignant cylindro- are no distinctive features that might
noma stain positively for epithelial mem- ma, and microcystic adnexal carcinoma, enable a confident clinical diagnosis of
brane antigen (EMA), carcinoembryonic this remains unproven. These entities AC. Most tumours are solitary, but a
antigen (CEA), broad-spectrum keratins, shall, therefore, be presented separately. patient with bilatelal axillary AC has been
and low-molecular-weight keratins (CAM reported. AC presents as single or multi-
5.2). Focal staining with S-100 and ICD-O code 8401/3 ple, firm or cystic nodules with a reddish
vimentin may be seen {210}. Epithelial or purplish hue of the ovelying skin, siz-
cells at the periphery of the tumour Synonyms ing between 1.5 and 8 cm {2460}.
islands may express actin. Apocrine adenocarcinoma, apocrine Ulceration and haemorrhage may be
gland carcinoma present. The patients’ age at presenta-
Histogenesis tion ranges from 25 to 91 years, with an
The eccrine or apocrine origin of this Epidemiology average age of 57.9 years {2460}. In
tumour remains disputed. In the past, it AC is a rare tumour. Both genders are many cases, the lesions had been stand-
has been regarded as an eccrine tumour, almost equally affected, and there ing for more than 10 years, and even up
although some have been shown to arise appears to be no racial predilection. to 30 years before diagnosis {1650}.
from modified apocrine glands {2407}. {1785,2460} Some tumours have arisen within a nae-
vus sebaceous {644}.
Prognosis and predictive factors Etiology
An indolent but progressive course is the The etiology of AC is unknown. The fact Histopathology
major characteristic of this tumour. The that all patients were over 25 years {824} AC is typically centred on the deeper
recurrence rate is high, ranging from 57- suggests that full maturity of the apocrine dermis and tends to spread into the sub-
70% and therefore wide surgical excision glands is a prerequisite. cutaneous fatty tissue {1785,2460}.
extending well beyond the clinical con- Extension into the epidermis also occurs,
fines of the tumour is recommended. Localization occasionally in the form of extramamma-
Recurrences have been reported even Most AC arise in the axilla and, to a less- ry Paget disease {1647}. The tumours are
with 2 cm margins and may occur many er extent, in the anogenital region. Rare usually poorly circumscribed with infil-
years after excision. For this reason locations include the scalp, face, chest, trating borders. Neighbouring apocrine
some people favour Mohs micrographic and distal upper extremities. {536,988, glands occasionally show in situ carcino-
surgery {462}. Only 4 cases have metas- 1785,2055,2460} Peculiar variants have ma. {988,2460}. The growth patterns of
tasized to the lymph nodes and lungs. been described on the ear (ceruminous AC are highly variable, including tubular,

Fig. 3.17 Apocrine carcinoma. A Well differentiated cutaneous apocrine carcinoma. Glandular structures with tubulopapillary growth pattern and apical decapita-
tion secretion. B Poorly differentiated cutaneous apocrine carcinoma. Micronodular and trabecular growth pattern with hardly any gland formation, hyaline stro-
ma. The cells have scanty amphophilic cytoplasm and contain vesicular nuclei with prominent nucleoli and occasional mitotic figures.

Malignant tumours with apocrine and eccrine differentiation 135

papillary, cystic, cribriform, micronodular,
and solid formations {1785,2460}. The
cells have abundant eosinophilic cyto-
plasm and large, round to oval, mostly
vesicular nuclei that often contain a sin-
gle prominent eosinophilic nucleolus
{1785}. Intacytoplasmic PAS-positive dia-
stase-resistant granules are characteris-
tic, and intracytoplasmic iron is some-
times demonstrable {988,1785,2139}. A
key diagnostic criterion, decapitation
Fig. 3.18 Mammary Paget disease (MPD). Sharply Fig. 3.19 MPD. Cytoplasmic melanin can accumu-
secretion in the form of apical snouts circumscribed erythematous and scaly plaque late in Paget cells and does not indicate
{2460} is usually recognizable but may affecting the nipple and areola. melanocytic differentiation.
be lacking in poorly differentiated
tumours. There is variable mitotic activity,
ranging from single mitotic figures in well ic to the skin or apocrine carcinomas underlying in situ or invasive ductal car-
differentiated tumours and up to 4 mitot- arising in ectopic breast tissue in the axil- cinoma of the breast.
ic figures per high power field in poorly la. Therefore, the diagnosis of primary Extramammary Paget disease (EMP) is a
differentiated carcinomas {2460}. Long cutaneous AC rests on a meticulous clin- scaly erythematous eruption affecting
standing tumours tend to show increas- ico-pathologic correlation. apocrine gland bearing areas of the skin,
ing anaplasia. The tumour stroma is usu- mainly the female and male genital
ally densely fibroblastic or hyaline and Histogenesis areas. The majority of cases represent an
may contain prominent lymphoplasma- AC is thought to arise from preexisting apocrine adenocarcinoma in situ that
cytic infiltrates. apocrine (sweat) glands {988,1785,2139, has a high recurrence rate and may
AC may exhibit focal mucinous carcino- 2459}. An interesting alternative origin invade the dermis and then possesses
ma-like features {2556} or may be com- are the newly described mammary-like metastatic potential. In a subset of cases
posed of signet ring cells {1126}. The lat- sweat glands of the anogenital region, EMP is the skin manifestation of an
ter tumours are mostly located on the which may also give rise to eccrine underlying internal malignancy. The skin
eyelid but may occur in the axilla {1343}. tumours {2408}. manifestations of these cases are clini-
Signet ring cell AC show a striking predo- cally and histologically indistinguishable
minance (10:1) in elderly males {1343}. Prognosis and predictive factors from cases not associated with internal
The majority of AC are slow growing malignancy.
Immunoprofile tumours with a tendency toward a pro-
The cells of AC express low molecular longed course. The overall mortality is ICD-O codes
weight cytokeratin (CAM5.2), epithelial low, despite frequent recurrences (30%) Paget disease of breast
membrane antigen, carcinoembryonic and metastases to regional lymph nodes 8540/3
antigen, cytokeratin15, gross cystic dis- (50%) {536,1785,2460}. Wide dissemina- Extramammary Paget disease
ease fluid protein (GCDFP)-15 {1785} tion and tumour-related deaths have nev- 8542/3
and occasionally S-100 protein {1343, ertheless been described {437,1785,
1785}. Myoepithelial cells, detectable by 2172,2460}. As distant metastases may Historical annotation
SMA or CK 5/6 immunostaining, are typi- be a late event in the course of AC a pro- In 1874 Sir James Paget first described
cally absent {988,2460}. longed follow-up is advisable. Reliable “about fifteen cases” of a chronic
predictive factors have not been estab- eczematous eruption of the nipple and
Differential diagnosis lished. areola and noted that mammary cancer
The main differential diagnosis is with developed in all patients within two years
(tubular) apocrine adenoma, and the his- {1766}. George Thin described the
tologic features that distiguish these two Paget disease and histopathologic features of this condition
conditions are often subtle. Whilst vascu- extramammary Paget disease in 1881. The term Paget disease was
lar and neural invasion are diagnostic of coined in 1889 by Radcliffe Crocker
carcinoma, stromal invasion is less so Definition when he described a morphologically
and may be difficult to ascertain. Tumour Paget disease of the breast and extra- and histologically similar eruption affect-
silhouette, cellular pleomorphism and mammary Paget disease are intraepider- ing the penis and scrotum {561}.
mitotic activity may provide clues to mal adenocarcinomas characterized by
malignancy. As focal squamous differen- large atypical and pale staining cells Epidemiology
tiation may occur in AC {1785} acan- scattered throughout the epidermis MPD occurs almost exclusively in
tholytic squamous cell carcinoma may either as single cells or in small clusters. women. Exceptional cases of men with
have to be considered in the diagnostic Mammary Paget disease (MPD) resem- MPD have been reported {927}. One to
differential. bles an eczematous eruption of the nip- two percent of female patients with
AC is otherwise indistinguishable from ple and areola, and in almost all cases breast carcinoma develop Paget disease
apocrine mammary carcinoma metastat- constitutes skin involvement by an {1971}. Ten to 28% of cases of Paget dis-

136 Appendageal tumours

Fig. 3.20 Mammary Paget disease (MPD). Paget cells with large nuclei, prominent nucleoli and abundant Fig. 3.21 Extramammary Paget disease (EMP).
pale cytoplasm permeate the entire epidermal thickness. Paget cells often have a propensity for tracking
along skin appendages.

ease are detected only on histologic develop erythema of the nipple and are- Tumour spread and staging
examination of the nipple in a mastecto- ola. The lesion then progresses to scaly, MPD without invasive carcinoma on his-
my specimen, without a clinically appar- crusted thick plaques and ultimately to tologic examination is classified as carci-
ent lesion {1971}. areas of erosion and ulceration. Patches noma in situ (Tis). MPD with a contiguous
No accurate epidemiologic data is avail- and plaques are almost always unilateral or non-contiguous invasive component
able for EMP. It is a rare condition that and sharply circumscribed, and some- on histology is staged according to the
comprises less than 2% of primary neo- times pruritic or painful. In approximately invasive component using the guidelines
plasms of the vulva. EMP occurring in half of the cases a breast mass is palpa- for staging of breast carcinoma.
sites other than the vulva is even less ble. Nipple retraction and serosan- Primary EMP is staged either according
common. In genital EMP, women are guinous discharge may be features of to the FIGO (Fédération Internationale de
more commonly affected than men. Most advanced cases with a large underlying Gynécologie et d’Obstétrique) or the
patients are above the age of 60. carcinoma. Not all patients with MPD TNM system of the AJCC (American Joint
have clinical symptoms; 10-28% of Committee on Cancer) for vulvar
Etiology cases are detected only on histologic tumours. After a long period of in situ
MPD is almost always associated with an examination in a mastectomy specimen growth EMP can eventually invade the
underlying carcinoma of the breast, and {1971}. The differential diagnosis dermis and acquire metastatic potential.
the etiology is the same as for breast car- includes squamous cell carcinoma in situ Typically, invasive carcinoma associated
cinoma. The inciting factors for primary and eczema. Once a diagnosis of MPD is with EMP first spreads to locoregional
EMP are unknown. Secondary EMP is an established the patient needs to be eval- lymph nodes and ultimately may develop
expression of an underlying internal uated with imaging studies and other distant metastases. Secondary EMP is
malignancy and the etiology parallels procedures for breast carcinoma. If MPD staged according to the criteria for the
that of the underlying tumour. is associated with a palpable tumour associated internal malignancy.
mass, the underlying carcinoma will be
Localization invasive in more than 90% of cases. If no Histopathology
MPD involves the nipple and areola and tumour mass can be detected clinically, On histologic examination MPD and EMP
in advanced cases may extend to the less than 40% of women will have inva- are characterized by neoplastic cells
adjacent skin. sive carcinoma. with large nuclei, prominent nucleoli and
EMP involves apocrine gland bearing Patients with EMP most commonly pres- abundant pale to amphophilic cytoplasm
areas and is most common in the genital ent with pruritus or burning. The skin that are scattered throughout the entire
area, groin, perineum or perianal region. shows well-demarcated erythematous epidermal thickness. These cells occur
Axillae, eyelids and external auditory scaly patches and plaques, which may singly and in clusters and often are more
canals rarely may be involved. be ulcerated. Following a diagnosis of numerous in the basal layers of the epi-
EMP the patient needs to undergo thor- dermis. Acinus formation may be pres-
Clinical features ough examination to rule out an associat- ent. Paget cells can contain cytoplasmic
Patients who present with MPD initially ed internal malignancy. melanin pigment, a feature that should

Malignant tumours with apocrine and eccrine differentia 137

not imply melanocytic differentiation. The The tumour cells in primary and second- intraepidermal cells of apocrine gland
epidermis is often hyperkeratotic and ary EMP are positive for simple cytoker- ducts. These cells, analogous to Toker
acanthotic, especially if the disease has atins (CAM5.2, AE1/AE3), EMA and CEA cells of the nipple, have been recently
been chronic. Particularly in EMP, the {1004,1539,1757,2548}. Immunohisto- demonstrated in the epidermis of vulvec-
tumour cells have a propensity to track chemistry can also suggest the presence tomy specimens in association with
along skin appendages. A dermal of an associated internal malignancy, mammary-like glands {2531}. In second-
perivascular lymphohistiocytic infiltrate because primary EMP has the staining ary EMP the disease represents migra-
accompanies the epidermal changes. characteristics of an apocrine carcinoma tion of an underlying internal malignancy
Paget cells are positive with convention- and is almost always CK7 positive and to the epidermis. Tumours associated
al mucin histochemistry in 40-70% of gross-cystic disease fluid protein with EMP include rectal adenocarcino-
cases {1297}. In MPD the associated in (GCDFP) positive, while CK20 is com- ma, transitional cell carcinoma of the ure-
situ or invasive breast carcinoma is of monly negative whereas the opposite is thra and bladder, carcinoma of the
ductal differentiation in the majority of true for EMP with associated internal Bartholins glands, prostate carcinoma,
cases. Lobular carcinoma only rarely malignancy. The cells in these latter cutaneous adnexal carcinoma and carci-
gives rise to MPD. Histologically, EMP cases are also mostly CK7 positive, but noma of the vagina and cervix.
without an internal malignancy cannot be more often express CK20 and do not
differentiated from those cases with stain for GCDFP {851,852,1298,1461}. In Prognosis and predictive factors
associated neoplasm. EMP positive staining with CK20 and lack The prognosis of MPD depends on the
The histopathologic differential diagnosis of staining with GCDFP should prompt an size and characteristics of the underlying
includes pagetoid squamous cell carci- even more thorough evaluation for under- breast carcinoma. Patients with MPD but
noma in situ, superficial spreading malig- lying malignancy. without a clinically detectable breast
nant melanoma, pagetoid Spitz naevus, The most useful keratin markers for MPD mass have a much better prognosis. In a
clear cells of Toker, pagetoid dyskerato- and EMP are CAM5.2 and CK7 because recent study, 61 patients with MPD and
sis, clear cell papulosis, sebaceous car- they stain >90% of Paget cells but do not without palpable mass were treated with
cinoma, intraepidermal Merkel cell carci- react with epidermal or mucosal ker- a cone excision of the nipple-areola com-
noma, eccrine porocarcinoma, cuta- atinocytes, a characteristic that makes plex and radiation therapy. Histologic
neous T-cell lymphoma, Langerhans cell both antibodies very useful in the evalua- examination revealed underlying DCIS in
histiocytosis and epidermotropic metas- tion of surgical margins and invasion. 93.3% of patients and Paget disease,
tasis. only, in 7%. The recurrence rate at a
Histogenesis median follow up of 6.4 years was 5.2%
Immunoprofile MPD is almost always associated with an (1 patient with DCIS and 3 patients with
The immunophenotype of MPD closely underlying carcinoma of the breast either invasive carcinoma) {242}.
matches that of the underlying breast in situ or invasive. MPD represents the The majority of cases of EMP are not
carcinoma {511}. Paget cells are practi- retrograde extension of an underlying associated with another neoplasm and
cally always positive for low molecular carcinoma into the epidermis, either in a show a recurrence rate of approximately
weight cytokeratins (detectable by spe- contiguous fashion, through spread 30% after surgery, but do not metasta-
cific or broad spectrum cytokeratins along the lactiferous ducts or through size. Around 10% of patients will develop
such as CK7, CAM5.2 and AE1/AE3) and intraepidermal metastasis. Cases without invasive adenocarcinoma that may
epithelial membrane antigen (EMA), vari- underlying carcinoma exist but are progress to metastatic disease {710}.
ably positive for polyclonal carcinoem- exceptional {1159}. The etiology of these The rate of an associated internal malig-
bryonic antigen (pCEA) and lack lym- cases is speculative, but probably they nancy varies from 15% to 33% and is
phoid markers such as leukocyte com- are analogous to primary EMP, repre- more common in perianal EMP than vul-
mon antigen (LCA) and CD3 senting apocrine adenocarcinomas in var EMP {1024}. In these cases the asso-
{1036,1461}. Gross cystic disease fluid situ, derived from Toker cells. Toker cells ciated tumour drives the clinical behav-
protein-15 (GCDFP-15) has been report- are cells with bland cytologic features iour, treatment and prognosis.
ed in approximately 50% of cases, simi- and clear cytoplasm that have been
lar to that of breast carcinoma in general identified by standard light microscopic
{511}. As in breast carcinoma, reports of means in ~10% of normal nipples {1461}.
S100 reactivity are quite variable, rang- They are derived from lactiferous duct
ing from 0-26% {1757,2548}. Approxi- lining cells and preferentially cluster in
mately 5% of Paget cases are oestrogen the epidermis near lactiferous duct ostia.
receptor (ER) and/or progesterone Primary EMP is an apocrine adenocarci-
receptor (PR) positive {511}. noma in situ that most likely arises from

138 Appendageal tumours

Benign tumours with apocrine and J. McNiff
T.H. McCalmont
C. Vassallo
R. Rosso
eccrine differentiation L. Requena
O. P. Sangüeza
G. Borroni
E.J. Glusac
R.O. Pichardo

Hidrocystoma but in some cases they may be present

in the subcutaneous fat. The cut surface
Definition reveals a well-circumscribed, unilocular
Hidrocystomas are cystic proliferations or multilocular cyst.
of the sweat glands. They have either
apocrine or eccrine differentiation, with Histopathology
the majority being of apocrine nature. Hidrocystomas can be uni or multilocular
Apocrine hidrocystomas are cystic ade- and are usually lined by a double layer of
nomas that arise from the apocrine epithelium. The inner layer contains large
secretory coil, while eccrine hidrocys- columnar cells with eosinophilic cyto-
tomas represent retention cysts of the Fig. 3.22 Hidrocystoma presenting as small, dome- plasm which has luminal decapitation
shaped lesion on the right side of the face, con-
eccrine cyst duct {607,1919,2047,2188}. secretion, while the outer layer is flat and
taining a clear fluid.
composed of myoepithelial cells. The
ICD-O code 8404/0 term “papillary apocrine gland cyst” has
to completely disappear with cold weath- been applied for hidrocystomas with
Synonyms er and atropine therapy {2236}. There is papillary projections of epithelium into
Several and sometimes confusing terms an increased incidence of hidrocystomas the lumen {1919}. Occasionally, hidro-
have been used to designate hidrocys- in hyperthyroid patients, perhaps related cystomas may show a single cystic cavi-
tomas, to wit: apocrine gland cyst, papil- to hyperhidrosis {1270,1673}. ty lined by one or two layers of flattened
lary apocrine gland cyst {1919}, apocrine epithelium as a consequence of the
cystadenoma {1568}. Macroscopy pressure exerted by the contents of the
The lesions are of variable size ranging cyst. In this circumstance, distinction
Epidemiology from 0.5-1.0 cm, although lesions of up to from eccrine hidrocystomas, which have
Hidrocystomas are relatively rare and 7.0 cm have been reported. Hidrocys- a similar lining, becomes impossible
account for approximately one per thou- tomas are usually located in the dermis, {671}.
sand of submitted cutaneous biopsies
{607}. They normally present as solitary
lesions, however patients with multiple
lesions have been observed. Hidro-
cystomas usually affect middle-aged or
older individuals although rare examples
have been described in children and
adolescents; both sexes are equally

Localization A B
Hidrocystomas have a predilection for
the face and neck, mainly the periorbital
area, but may also affect other parts of
the body such as the perineum.

Clinical features
Hidrocystomas present as dome-
shaped, cystic firm papules or nodules,
with a slightly blue colouration. In some
cases the content of the cyst is brown or C D
Fig. 3.23 Hidrocystoma, papillary cystadenoma. A Example of the so-called "papillary apocrine gland cyst".
These lesions are characterized by the presence of papillary projections of epithelium into the lumen.
Etiology B The papillary projections contain a core of connective tissue and are lined by cuboidal epithelium. C This
The exact cause of hidrocystomas is not picture depicts a typical example of an apocrine hidrocystoma. The lesion is cystic and lined by a cuboidal
known. They have been reported to be epithelium. D At higher magnification the cyst is lined by a double layer of cuboidal cells with evidence of
exacerbated with high temperatures and decapitation and secretion.

Benign tumours with aprocine and eccrine differentiation 139

Fig. 3.24 Syringoma. A Well circumscribed nodule within the upper dermis. B Tubules and cords of uniform epithelial cells in sclerotic stroma.

Immunoprofile Epidemiology epithelial cells of syringoma show small

Hidrocystomas express epithelial mem- Syringomas are common lesions, found nuclei, inconspicuous nucleoli and
brane antigen (EMA) and lysozyme in the more often in women than men. They absent mitotic figures. Cytoplasm ranges
cells of the cyst wall; carcinoembryonic appear more commonly in Asians than in from eosinophilic to clear.
antigen (CEA) decorates the luminal other races. Syringomas usually arise in The epithelial cells within tubular struc-
cells {1217}. The pattern of cytokeratin adolescence or early adulthood, but are tures show an inner layer of luminal cells
expression is variable {607,17444}; there most often biopsied in the 4th decade. and one or two rows of more peripheral
is expression of cytokeratins 7,8,18,19 in Most are sporadic, though some eruptive cells. Tubular lumina may be distended,
the luminal cell layer and cytokeratins and disseminated forms may be familial. causing flattening of the inner most lining
1,5,10,14 in the basal and luminal cell Syringomas appear to be more common cells. Larger aggregates of cords and
layers. in Down syndrome. A clear cell variant nests of cells may exhibit a “comma-like”
Smooth muscle actin (SMA) is present in has been associated with diabetes melli- or “tadpole-like” configuration. The
the basal layer {607}. Human milk fat tus in many instances {800,2474}. cords, nests and tubules of syringomas
globulin 1 (HMFG) is expressed by the branch and anastomose. Milia may be
apocrine sweat gland only {607}. S-100 Localization present, and these may rupture produc-
protein is positive in the secretory portion By far, the most common sites of involve- ing granulomatous inflammation and
of normal eccrine glands and in the ment are the lower eyelids. Involvement subsequent calcification. Syringomas
myoepithelial cells of apocrine glands of the upper cheeks is not uncommon. may become confluent. Eruptive syringo-
{1678,2358}. Unusual sites of involvement include the mas are similar to standard syringomas;
neck, chest, axillae, pubic area, perium- however, the stromal component is
Prognosis and predictive factors bilical region, penis, vulva, hands and sometimes less prominent.
Complete excision is usually curative. forehead. Unilateral linear lesions have In most conventional syringomas some
Topical atropine or scopolamine has also been described {552}. Eruptive syringo- epithelial cells have pale cytoplasm. In
been used {56,503,2236}. Avoidance of mas are typically numerous, widespread some lesions, these cells predominate,
a hot environment or other factors that and may appear in crops {1388}. and this pattern has been termed “clear-
increase perspiration lessens the severi- cell syringoma”; it has frequently been
ty of these lesions {1668}. Clinical features associated with diabetes mellitus, but it
The lesions are numerous, firm, smooth, may be seen sporadically.
dome-shaped, skin coloured or slightly
Syringoma yellowish papules, 1-3 mm in diameter, Differential diagnosis
usually situated in skin of the lower eye- Desmoplastic trichoepitheliomas differ
Definition lids. Syringomas are rarely solitary. from syringomas by being larger, deeper,
Syringomas are small benign adnexal and composed of epithelial elements that
neoplasms that are almost always multi- Histopathology show follicular differentiation. Superficial
ple. They are composed of sweat gland Syringomas are small lesions, restricted biopsies of microcystic adnexal carcino-
epithelium (presumably eccrine) within to the upper reticular dermis. They are ma may greatly resemble syringoma.
densely sclerotic stroma. composed of numerous small solid Microcystic adnexal carcinomas are
nests, cords and tubules of epithelial larger, asymmetric and less circum-
ICD-O code 8407/0 cells within a dense stroma of compactly scribed than syringoma. Virtually all
arranged bundles of collagen, accompa- microcystic adnexal carcinomas extend
Synonyms nied by relatively few fibrocytes. The into subcutaneous fat or skeletal muscle,
Eccrine syringoma, lymphangioma epithelial aggregates are usually evenly whereas syringomas are restricted to the
tuberosum multiplex. distributed throughout the lesion. The upper two thirds of the reticular dermis.

140 Appendageal tumours

Syringomas are benign. Association with
or progression towards carcinoma has
not been described.


Poromas are benign adnexal neoplasms
with terminal ductal differentiation.
Although historically considered a neo-
plasm of eccrine differentiation, poromas
can show either eccrine or apocrine line-

ICD-O code 8409/0

Eccrine poroma, hidroacanthoma sim-
plex, dermal duct tumour, syringoacan- B C
thoma Fig. 3.25 Poroma. A Broad tongues of uniform epithelium extend into the dermis from the undersurface of
the epidermis. B Pigmented poroma illustrating ductal structures and fibrovascular stroma. C Clear cell
Epidemiology change may be prominent in some poromas.
Poromas usually present as solitary
tumours on acral sites, although they can
be seen in virtually any cutaneous loca- rence in areas of chronic radiation der- of poroma within an acanthotic epidermis
tion. Most poromas arise in middle age matitis has been reported {1802}. with prominent surface keratinization.
with no sex predilection. Uncommonly, Occurrence of poroma within a naevus
multiple poromas are seen, either limited sebaceous has been documented Differential diagnosis
to palms and soles or in a widespread {1133}. Histologically the differential diagnosis
distribution, for which the term poromato- includes seborrheic keratosis, which typ-
sis has been applied. Histopathology ically shows keratinization with horn
Poromas are well-circumscribed tumours cysts, a more sharply demarcated lower
Clinical features composed of a proliferation of uniform border, and absence of ductal struc-
Poromas typically manifest as dome- basaloid, cuboidal cells punctuated by tures. Basal cell carcinoma may some-
shaped cutaneous papules, nodules or focal ducts and occasional cysts. The times be considered histologically, but
plaques, generally measuring less than 1 epithelial cells of poromas typically shows more obvious peripheral palisad-
cm in diameter. Some lesions are highly extend from the lower epidermis into the ing, nuclear variability, and little or no
vascular and may show a tendency to dermis in broad columns. The epithelium glycogen.
bleed, particularly on acral sites. of poromas is sharply demarcated from
Uncommonly, poromas are pigmented. adjacent keratinocytes. Nuclei are small Histogenesis
Rapid growth has been reported during and regular, and cytoplasm is modest in Poromas may show evidence of either
pregnancy {920}. Multiple poromas have amount. The cytoplasm often contains eccrine or apocrine differentiation {970}.
developed after electron beam therapy glycogen. Most poromas contain ductal Immunohistochemical studies reveal that
for mycosis fungoides {1348} and occur- structures lined by PAS positive diastase- poroma cells express a cytokeratin phe-
resistant cuticles. Small areas of necrosis notype similar to basal cells of the
as well as mitoses are seen in otherwise eccrine ducts in some cases {2466}. The
banal poromas, and are of no prognostic absence of myoepithelial cells also sug-
significance. Foci of sebaceous differen- gests differentiation toward the excretory
tiation may be observed. The stroma sur- (ductal) component of sweat glands.
rounding poromas is often richly vascu- Occurrence of poromas within follicu-
lar, and may contain granulation tissue. losebaceous lesions such as naevus
Architecturally, poromas show a spec- sebaceous, and presence of sebocytes
trum of change from predominately within poroma, implicates origin from
intraepidermal lesions (hidroacanthoma apocrine glands in some cases {662,
Fig. 3.26 Intraepidermal variant of poroma. There simplex) to primarily dermal-based neo- 970}.
are discrete nests of bland basaloid and cuboidal plasms (dermal duct tumour). Another
cells within the epidermis, associated with acrosy- rare variant has been termed syringoa- Genetics
ringium. canthoma, representing a clonal pattern Some cases of poromatosis have been

Benign tumours with aprocine and eccrine differentiation 141

Fig. 3.27 Syringofibroadenoma. A Clinical features of the verrucous, solitary type of syringofibroadenoma; a nodule localized on left sole of a 75-years old female,
lasting for three years. B Eccrine syringofibroadenoma (Mascaro). Presents in many cases as a verrucous plaque. C Eccrine syringofibroadenoma (Mascaro).
There are branching cords of small keratinocytes attached in multiple foci to the undersurface of the epidermis

associated with hidrotic ectodermal dys- Localization eyelid hidrocystomas, whose genetic
plasia {2519}. Rare cases of poroma Most of syringofibroadenomas arise on aberration has been localized to chromo-
have occurred in the setting of naevoid acral areas {498,685,769,2248,2313, some 13q {1259}.
basal cell carcinoma syndrome {904}. 2344,2399}.
Studies of p53 protein have shown high Histopathology
expression in some poromas as well as Clinical features Syringofibroadenoma is characterized
in some porocarcinomas, but staining is The most common clinical presentation by multiple anastomosing cords and
not correlated with duration of tumours is solitary, often verrucous papules or strands of monomorphous cuboidal cells
{43}. Therefore, while p53 mutation may nodules {1529,2248,2313}. Unusual pre- {26,1529}. The epithelial cords extend
be involved in progression of some poro- sentations include large plaques, linear usually into the mid-dermis, and are
mas to porocarcinoma, other oncogenes lesions, and disseminated tumours embedded in a loose fibrovascular stro-
or factors are also likely play a role in {1259,2189,2248}. ma. Rarely, a clear cell variant has been
malignant transformation of poromas. observed {781,2415}.
Prognosis Occasionally, syringofibroadenoma can Immunoprofile
Poromas are benign and simple excision be associated with other entities, both Light microscopy usually leads to a spe-
is curative. inflammatory and neoplastic, including cific diagnosis. The tumour cells are usu-
bullous pemphigoid {1720,1721}, lichen ally positive for both keratin 6 and 19 as
planus {780}, ulcers {1092,2399}, squa- well as filaggrin {1108,1304,1742,1745,
Syringofibroadenoma mous cell carcinoma {1399}, sebaceous 2314}.
naevus {1719}, and chronic lymphoede-
Definition ma {806}. Based on the latter association Prognosis and predictive factors
Syringofibroadenoma is a rare benign and the presence of fibrous stroma, Syringofibroadenoma is a benign condi-
eccrine tumour with anastomosing some authors consider syringofibroade- tion, and solitary lesions are cured by
strands and fibrovascular stroma, first noma as a hyperplasia rather than a neo- complete excision, while the treatment of
described by Mascaro {1529}. Multiple plasia {779,780,806,1092,1399,1719, multiple lesions is dependent on the size
lesions of syringofibroadenoma are 1720}. It may be associated with Schöpf- and location. Cases of syringofibroade-
referred to as eccrine syringofibroadeno- Schultz-Passarge syndrome {2189}, an noma with foci of atypical squamous
matosis {456,2189}. autosomal dominant syndrome with pal- cells have also been described {255,
moplantar keratoderma, hypodontia, and 1215}.
ICD-O code 8392/0

Eccrine syringofibroadenoma {663},
eccrine syringofibroadenomatous hyper-
plasia {1721}, eccrine syringofibroade-
nomatosis {456,2189}, acrosyringeal
adenomatosis {950}.

Syringofibroadenoma is rare, with about
75 reported cases. It occurs primarily in
older adults. A B
Fig. 3.28 Hidradenoma. A There is a multinodular solid and cystic proliferation of monomourphous adnexal
keratinocytes. B Areas with cytoplasmic pallor are common (‘clear cell hidradenoma’).

142 Appendageal tumours

Fig. 3.29 Spiradenoma. A A pigmented and painful nodule on the posterior aspect of the arm. B These aggregations of neoplastic cells show round shape and
smooth borders. C At higher magnification, numerous lymphocytes are seen scattered within the nodules of neoplastic epithelial cells. There are two distinct pop-
ulations of neoplastic epithelial cells, dark and pale. Dark cells are small, basaloid cells with hyperchromatic nuclei and pale cells are larger with vesicular nuclei
and ample pale cytoplasm.

Hidradenoma Clinical features sheets, punctuated by ducts and glan-

Hidradenomas lack any distinctive clini- dular areas which may show apocrine
Definition cal features, presenting as skin-coloured differentiation. Hybrid lesions including
Hidradenoma is a benign adnexal neo- to red-brown nodules. compact poroid cells with prominent
plasm, closely related to poroma, that ductal differentiation have been referred
displays a limited degree of ductal differ- Histopathology to as poroid hidradenomas.
entiation. While historically considered Hidradenoma is a mostly dermal neo-
eccrine, recent evidence suggests that plasm with a nodular, circumscribed pat- Prognosis
hidradenoma can be either apocrine or tern at scanning magnification. Some- Complete excision is curative.
eccrine {825,1543}. times an epidermal attachment can be
identified. The intervening stroma is often
ICD-O code 8402/0 sclerotic and may be highly vascular- Spiradenoma
ized, with ectatic vascular channels.
Synonyms Hidradenoma is composed of several Definition
Clear cell hidradenoma, nodular types of cells: Spiradenoma is a benign dermal neo-
hidradenoma, poroid hidradenoma, Clear or pale cells, which contain abun- plasm that can show either eccrine or
acrospiroma, solid-cystic hidradenoma dant glycogen, and show distinct cell apocrine differentiation, and significant
{825,980,1374}. membranes {578}. The number of clear morphologic overlap with cylindroma.
cells varies from lesion to lesion. When
Epidemiology these cells predominate, the name clear- Historical annotation
Hidradenomas are sporadic with no sex cell hidradenoma is appropriate {2544}. Chandeluz, in 1882, probably first
predilection. Most develop in adults, but Squamoid cells are polygonal with a cen- described this tumour {765}. Unna first
childhood onset has been documented tral vesicular nucleus and eosinophilic coined the term spiradenoma. In 1956
{715,1652}. Hidradenoma can also arise cytoplasm, and often are arranged in Kersting and Helwig published the clas-
as a secondary neoplasm with naevus whorls {1774}. sic paper on spiradenoma in 136
sebaceous. Mucinous cells are the least common patients {1250}. Additional series of spi-
component. They are large cells with fine radenoma have since been published
Localization basophilic granular cytoplasm. Cuboidal {12,1496}.
Hidradenomas commonly develop on or columnar cells line the tubules and
the scalp, trunk, and proximal extremi- show evidence of apocrine differentiation ICD-O code 8403/0
ties, and rarely on the hands and feet. {1427}.
Eyelid lesions have also been noted Transition between different types of cells Localization
{911}. is frequent. The cells are arranged in Most spiradenomas appear on the face

Benign tumours with apocrine and eccrine differentiation 143

Fig. 3.30 Cylindroma. A There is a puzzle-like array of basaloid cells with relatively sharp circumscription of individual nodules. The larger nodules on the left show
trabecular internal structure, suggesting overlap with spiradenoma. B The nests are outlined by a thick rim of PAS-positive and diastase-resistant basement mem-
brane material.

and upper trunk, but they can also affect basaloid cells with hyperchromatic nuclei Histogenesis
other sites. located at the periphery, whereas pale The histochemical and immunohisto-
cells, which are larger with vesicular chemical studies have not clarified the
Clinical features nuclei and ample pale cytoplasm, tend to histogenesis of spiradenoma. The fre-
Usually, spiradenoma appears as a soli- be near the centre of the clusters. quent association of spiradenoma and
tary, well-circumscribed, firm nodule, Tubules lined by two rows of epithelial cylindroma, a likely apocrine neoplasm,
measuring usually less than 1 cm, but cells may be found within the tumour and the sporadic association of spirade-
giant variants {546} and multiple lesions nodules. A characteristic feature is the noma with neoplasms with follicular dif-
have also been described {1725}. presence of eosinophilic PAS positive ferentiation such as trichoepithelioma
Unusual cases show multiple spiradeno- globules throughout the entire neoplasm, {2500}, support an apocrine line of differ-
mas arranged in a zosteriform linear pat- sometimes surrounded by neoplastic entiation for spiradenoma on the basis of
tern {926,2162}. Spiradenoma appears cells in pseudorosette fashion. These the common embryologic origin for the
in adult life, although there are also globules are composed of basement three elements of the folliculo-seba-
reports of congenital cases {2091}, and membrane material. Sometimes the stro- ceous-apocrine unit. This is furthermore
in one patient spiradenoma developed ma shows striking oedema. supported by some examples of spirade-
within a naevus sebaceous of Jadassohn Spiradenoma in children may show a dif- noma that show decapitation secretion in
{2154}. Pain is one of the main clinical ferent histopathologic pattern. The neo- the cells lining the luminal border of the
characteristics of spiradenoma {926, plastic cells appear more immature, tubular structures. Therefore, the qualify-
2091,2154}. The mechanism of pain or making the distinction between clear and ing term of “eccrine” that almost invari-
tenderness in spiradenoma is not clear. dark neoplastic epithelial cells difficult, ably is applied to spiradenoma is inac-
and the neoplasm may be misinterpreted curate.
Histopathology as a mesenchymal neoplasm {1206}.
At low power magnification, spiradeno- Spiradenoma and cylindroma show sig- Prognosis and predictive factors
ma appears as a solid neoplasm com- nificant morphological overlap. In some Spiradenoma is a benign neoplasm.
posed of a single or few nodules of basa- patients with multiple lesions, some Because of the sharp demarcation of the
loid cells. These aggregations are round tumours show features of spiradenoma, tumour from the surrounding stroma,
with smooth borders and involve the full and others features of cylindroma. This excision is easily accomplished. Several
thickness of the dermis, sometimes supports the notion that spiradenoma examples of carcinomas arising in long-
extending into the subcutaneous fat. and cylindroma are closely related, prob- standing spiradenomas have been
Often, the intervening stroma is oedema- ably representing two morphologic described. In those instances, enlarge-
tous with ectatic vessels {546}. Dilated expressions of the same basic neoplas- ment of a nodule that had been stable for
vessels rimmed by sclerosis have been tic process {846,2280}. many years seems to be the sign of
interpreted as “ancient” changes due to malignant transformation {89,240,539,
long-standing lesions {2229}. Immunoprofile 699,884,2602}. It appears to be accom-
Another characteristic finding is the pres- The tumour cells express cytokeratins, panied by increased expression of p53
ence of abundant lymphocytes scattered and the tubular structures are CEA posi- protein {239}.
within the tumour nodules. At higher tive {1801,2465}. Inflammatory cells scat-
magnification, two distinct populations of tered within the neoplastic aggregations
neoplastic epithelial cells can be seen, have been identified as abundant T lym-
dark and pale. Dark cells are small, phocytes and Langerhans cells.

144 Appendageal tumours

Fig. 3.31 Tubular adenoma. A A skin-coloured smooth surfaced nodule on the left parietal scalp. B Multiple irregularly shaped tubular glandular structures within
a partly sclerosed stroma. C Banal appearing tubular glandular elements lined by a double layer of epithelial cells within a sclerosed stroma. The peripheral layer
is cuboidal in appearance and the luminal layer demonstrates decapitation secretion. The lumina are filled with cellular debris and granular eosinophilic material.

Cylindroma Cylindroma can rarely be found as a sec- ICD-O code

ondary neoplasm within naevus seba- Tubular adenoma 8211/0
Definition ceous. Tubular papillary adenoma
Cylindroma is a relatively undifferentiated 8263/0
benign adnexal neoplasm with a mosaic Histopathology
microscopical pattern. Cylindroma com- Cylindroma is a mostly dermal and Synonyms
monly occurs as a hybrid with spirade- sometimes subcutaneous neoplasm with Apocrine adenoma, tubular adenoma,
noma, an event that has been referred to a multinodular, circumscribed pattern at tubulopapillary hidradenoma, papillary
as cylindrospiradenoma or spiradeno- scanning magnification. Individual nod- tubular adenoma
cylindroma {301,846,1543,1600}. ules are composed of mosaic nests of
undifferentiated basaloid cells with small Epidemiology
ICD-O code 8200/0 darkly-staining nuclei and scant cyto- Tubular apocrine adenomas occur spo-
plasm; individual nests fit tightly and radically with a female predilection
Synonyms neatly within larger nodules in a pattern {1361}. A broad age group may be
Cylindrospiradenoma {301}, spiradeno- that has been likened to that of a jigsaw affected {1361}. Some neoplasms may
cylindroma {1600} puzzle. The nests of cylindroma are com- occur in association with a syringocys-
monly surrounded by a rim of densely tadenoma papilliferum {76,489,1111,
Epidemiology eosinophilic PAS-positive basement 2364} and can also arise within an
Cylindromas may be solitary or multiple, membrane material, and the nests are organoid naevus {1111,1361,2394}.
arising on a sporadic basis or as part of also punctuated by small round
Brooke-Spiegler syndrome. There is no “droplets” with similar staining qualities. Localization
sex predilection. Hybrid lesions with areas of cylindroma Tubular apocrine adenomas commonly
and spiradenoma in juxtaposition are not occur on the scalp and less often at other
Etiology uncommon {301,846,1543,1600}. sites including the leg, trunk, axillary and
The etiology is unknown. A link to chro- anogenital areas {1361}.
mosome 9 seems likely for multiple spi- Immunoprofile and histogenesis
radenomas and cylindromas in the con- Refer to the previous chapter on spirade- Clinical features
text of the Brooke-Spiegler syndrome, as noma. Tubular apocrine adenomas present as
the gene has been mapped to 9p21 asymptomatic solitary nodules that are
{951,1538}. Prognosis and predictive factors skin-coloured to pink-red in appearance
Simple excision is usually curative. with either a smooth or irregular appear-
Localization Malignant transformation is extremely ance {1361}. Most tumours range in over-
The vast majority of cylindromas occur uncommon. all dimension between 1 to 2 cm but
on the scalp or face, especially in the rarely may be as large as 7 cm {1361}.
vicinity of the ear. Uncommonly, cylindro-
mas develop on the trunk or proximal Tubular and tubular papillary Histopathology
extremity. adenoma Tubular apocrine adenomas are well-cir-
cumscribed dermal neoplasms that may
Clinical features Definition extend into the subcutis. They have an
Cylindromas are typically smooth, dome- Tubular apocrine adenoma is a benign overall lobular architecture and are typi-
shaped hairless red-brown papules and dermal adnexal neoplasm demonstrating cally encased by a fibrous stroma. The
nodules. Extensive scalp involvement apocrine differentiation that typically lobules consist of multiple irregularly
can create clinical morphology resem- occurs in a broad age group of women shaped tubular structures that have a
bling a headpiece (“turban tumour”). on the scalp region. double to several layered epithelial lin-

Benign tumours with apocrine and eccrine differentiation 145

favoured sites; those on the scalp are
typically alopecic. Syringocystadenomas
may develop during puberty in a pre-
existing naevus sebaceous, and at least
one-third are associated with an underly-
ing organoid naevus.

Histologically, endophytic invaginations
of epithelium extend from the epithelial
surface into the dermis. Typically squa-
A B mous epithelium is present at the surface
of the invaginations, and is contiguous
Fig. 3.32 Syringocystadenoma papilliferum. A Keratinizing squamous epithelium at the surface merges with
columnar epithelium in the deeper portions of the tumour. B Papillary projections are lined by pseudos-
with a double layer of cuboidal and
tratified columnar epithelium, and plasma cells are typically noted in the stroma. columnar epithelium in the deeper por-
tions of the lesion. Within the dermis,
broad villous projections protrude into
ing. The peripheral epithelial layer con- Histogenesis cystic spaces. Columnar epithelium is
sists of cuboidal to flattened cells Enzyme histochemistry {1361} and ultra- present toward the lumen of the spaces,
(myoepithelial) and the luminal layer of structural analysis {1361,2394} have and simple cuboidal epithelium can be
columnar cells that demonstrate decapi- demonstrated tubular apocrine adeno- seen at the periphery. Decapitation
tation secretion. In some tubules papil- mas to be of apocrine differentiation. secretion of luminal cells is a frequent
lary cellular extensions that are devoid of finding. Plasma cells are consistently
stroma project into the lumina. Addi- Prognosis numerous within the stroma, and are a
tionally, cellular debris and eosinophilic Tubular apocrine adenomas are benign highly reproducible finding in the stroma
granular material are identified within slow-growing neoplasms. Simple exci- of syringocystadenomas.
some lumina {1361}. The neoplasm lacks sion is curative. The differential diagnosis includes
cytologic atypia and mitotic activity. hidradenoma papilliferum, which differs
Overlying epidermal hyperplasia may be clinically by location in the perineal
present. In those neoplasms that occur in Syringocystadenoma region, and histologically by dermal nod-
conjunction with syringocystadenoma papilliferum ules showing a more complex papillary
papilliferum {76,489,2364}, the tubular growth pattern, and absence of plasma
adenoma component is typically present Definition cells in the stroma. The epithelial lining of
underlying the syringocystadenoma Syringocystadenoma papilliferum is a the two lesions shows histologic overlap,
component. The differential diagnosis benign adnexal neoplasm that occurs in however.
includes apocrine adenocarcinoma and association with an organoid naevus
papillary eccrine adenoma. In contrast to such as naevus sebaceous in at least Precursor lesions
apocrine adenocarcinoma tubular apoc- one-third of cases. Approximately one-third of cases arise in
rine adenomas lack cytologic atypia, are organoid naevi.
well circumscribed and possess a ICD-O code 8406/0
peripheral myoepithelial layer {1751}. Histogenesis
Tubular apocrine adenomas resemble Synonmys Syringocystadenomas show differentia-
papillary eccrine adenomas in many Syringoadenoma tion that is predominantly apocrine in
respects and previously these were pattern, but eccrine origin has been sug-
believed to be related neoplasms {489}. Epidemiology gested in some cases, as exemplified by
However on the basis of morphologic cri- Syringocystadenoma papilliferum occurs immunohistochemical labelling with
teria (papillary eccrine adenomas lack with equal frequency in both sexes. It is a eccrine marker IKH-4 {1109}. An intrigu-
decapitation secretion) and enzyme his- tumour of childhood or adolescence, ing finding is the presence of IgA and
tochemistry and ultrastructural analysis with many examples noted at birth. secretory component within the epithelial
demonstrating differences in differentia- These lesions tend to increase in size at cells in syringocystadenomas, and IgA
tion (apocrine versus eccrine) they are puberty, and sometimes multiply in num- and well as IgG within the plasma cells
now believed to represent distinct neo- ber as well as becoming more papillo- {2420}. This observation suggests that
plasms. In some instances both eccrine matous over time. plasma cells are attracted to tumour
and apocrine differentiation may be epithelium via a mechanism similar to
observed making a distinction between Clinical features that used by glands of the normal secre-
these neoplasms impossible {771}. The The majority of syringocystadenomas tory immune system.
terms tubulopapillary hidradenoma {705} affect the head and neck area, typically
and papillary tubular adenoma {2335} as one or more warty papules, some- Somatic genetics
have been suggested for cases with times in a linear array, or as a solitary Allelic deletions of the patched gene
apocrine and eccrine differentiation. grey or red plaque. Scalp and neck are 9q22 and loss of heterozygosity at 9p21

146 Appendageal tumours

Fig. 3.33 Hidradenoma papilliferum. A Hidradenoma papilliferum of the vulva. A polypoid exophytic lesion involving the left labius majus of an elderly woman. B The
neoplasm shows a prominent papillary pattern. C Columnar cells shows evidence of decapitation secretion in their luminal border.

(p16) have been reported in syringocys- Histopathology tive {2257}. Neoplastic epithelial cells lin-
tadenoma papilliferum {281}. At scanning magnification, hidradenoma ing tubules and papillations also express
papilliferum consists of a cystic neo- strong immunoreactivity for androgen
Prognosis and predictive factors plasm composed of elongated tubules and oestrogen receptors {1739}.
Syringocystadenonas are benign and and large papillary structures with a
simple excision is curative. frond-like pattern. The papillae are com- Histogenesis
posed of a central axis of connective tis- Both the histopathologic and ultrastruc-
Hidradenoma papilliferum sue lined by two layers of epithelial cells. tural characteristics of hidradenoma
The basal layer is composed of pale- papilliferum support an apocrine line of
Definition staining cuboidal myoepithelial cells and differentiation, although some authors
Hidradenoma papilliferum is a benign the luminal layer is made up by columnar have postulated the possibility of origin
cystic and papillary neoplasm that cells with decapitation secretion. The from Wolffian ducts or accessory mam-
almost always develops in the vulval and cystic cavity and the lumina of the tubu- mary glands {576,1633}.
perianal regions of middle-aged women. lar structures contain apocrine secre-
tions in the form of eosinophilic homoge- Prognosis and predictive features
ICD-O code 8405/0 neous material. Hidradenoma papilliferum is a benign
The epithelial cells at the periphery are neoplasm cured by simple excision.
Epidemiology flattened, and decapitation secretion is Malignant transformation is a very
Most cases appear in women, although less evident, as a consequence of the uncommon event {588,1730,2274,2460}.
there are also reports in males {588, pressure exerted by the cyst contents. A case of adenosquamous carcinoma of
1441,1697,2421}. The neoplasm is rare The stroma surrounding the cystic cavity the vulva developing from a pre-existing
in Black patients. The age of presenta- is composed of compressed fibrous tis- hidradenoma papilliferum has also been
tion ranges from 20-90 years {2428, sue that is separated from the normal reported {142}.
2435}. adjacent dermis by clefts. These clefts
are responsible for the tendency of the Mixed tumour
Localization neoplasm to shell out easily after incision (chondroid syringoma)
The skin of the vulva and perianal of the epidermis.
regions are the most frequently involved In contrast with syringocystadenoma Definition
areas {588,1106,1441,1565,1568,1697, papilliferum, hidradenoma papilliferum is Cutaneous mixed tumours are benign
2324,2421}, although rare examples of not connected with follicular infundibula adnexal tumours of skin composed of
extra-genital or ectopic hidradenoma and there are not plasma cells in the axis epithelial and stromal elements with a
papilliferum have been reported on of connective tissue of the papillations. wide spectrum of patterns. These
postauricular skin {247}, eyelids {1106, Sometimes, neutrophils are scattered tumours are histologically analogous to
1697,2056,2421}, external auditory canal within the connective tissue framework. mixed tumours of the salivary gland, but
{1718}, face {1106,1697} scalp {845}, lack the tendency for local recurrence
axilla {1106,2421}, upper limb {2421}, Immunoprofile seen in the latter lesions.
back {727,1106} and thigh {2421}. Immunohistochemical studies demon-
strated that epithelial cells lining the ICD-O code 8940/0
Clinical features papillations express low-molecular
The lesion appears as a slow-growing weight cytokeratins. The luminal border Synonyms
cystic dermal nodule, usually asympto- of the cells lining tubular structures is Chondroid syringoma, mixed tumour of
matic, although it sometimes ulcerates also decorated by carcinoembryonic skin.
and bleeds. The neoplasm is a unilateral antigen, epithelial membrane antigen
skin-coloured nodule, papule or polypoid and gross cystic disease fluid protein-15. Epidemiology
exophytic lesion, most commonly locat- Immunostains for S-100 protein and Mixed tumours most often occur as soli-
ed on the labius majus. high-molecular-weight keratins are nega- tary slowly growing nodules on the head

Benign tumours with apocrine and eccrine differentiation 147

Fig. 3.34 Mixed tumour (chondroid syringoma). A Well-circumscribed mixed tumour with branching tubules and myxochondroid stroma. B Mixed tumour with
epithelial tubules embedded in a myxoid and hyaline stroma. C Predominately ductal epithelial pattern of mixed tumour.

and neck of adults, although other sites tumours contain hyaline cells character- entities such as myxoma. In other lesions
may be affected. There is a male ized by an ovoid shape, dense ground- with abundant epithelial elements, the
predilection. Most lesions are between 1- glass or hyaline-like cytoplasm, and an differential diagnosis includes benign
3 cm in diameter, although examples as eccentric nucleus {85}. The cells resem- adnexal tumours such as hidradenoma
large as 6 cm have been reported ble plasma cells, and have been called and syringoma, depending on the pat-
{1182}. plasmacytoid cells. In some cases, hya- tern of epithelial growth.
line cells are the predominant cell type,
Clinical features leading to the term hyaline-cell rich Histogenesis
Cutaneous mixed tumours present as chondroid syringoma {735}. The pres- It is generally accepted that there are
asymptomatic dermal nodules, with no ence of hyaline cells appears to be of no both apocrine and eccrine variants of
specific distinguishing clinical character- prognostic significance, although such mixed tumours. Ultrastructural studies
istics. cells may present a diagnostic challenge confirm that myoepithelial cells surround
to the unsuspecting pathologist {735}. the epithelial cells, and appear to pro-
Histopathology duce the stromal components of the
At low power, cutaneous mixed tumours Immunoprofile lesions {2423}. The stroma of mixed
are well-circumscribed lesions located in Immunohistochemical studies reveal tumours contains matrix components
the dermis and/or subcutis. A biphasic staining of the inner layer of epithelial such as types II and IV collagen,
growth pattern can be readily detected, cells with cytokeratin, CEA, and EMA, tenascin, fibronectin, and laminin {773}.
with epithelial elements embedded with- and staining of the outer cellular layer Ultrastructural and immunohistochemical
in a myxoid, chondroid, or fibrous stro- with S100 and vimentin {2559}. studies of hyaline cells in mixed tumours
ma. The epithelium often shows a pattern The stroma of mixed tumours usually suggest these cells derive from both the
of branching tubules, sometimes with comprises at least half of the lesion, and epithelial and stromal components of the
decapitation secretion suggesting apoc- may show variable patterns of differenti- lesions, possibly representing a regres-
rine differentiation. Solid cords and ation, including myxoid, fibroblastic, sive process {85}.
islands of epithelium as well as single fibrocartilagenous, chondroid, and even
cells may also be present. In some osteoid components. Combinations of Prognosis
cases, the epithelial elements are com- matrix components are the rule. Despite Cutaneous mixed tumours are benign
posed of small non-branching tubules the name chondroid syringoma, chon- lesions cured by simple excision.
that may contain eosinophilic cuticles. droid areas may be absent in the stroma.
Follicular differentiation occurs in some The stroma stains strongly for alcian blue
mixed tumours, in the form of follicular with hyaluronidase resistance.
germinative cells, shadow cells, or sebo-
cytes. Mixed tumours may exhibit clear Differential diagnosis
cell change within the epithelial cells. In In mixed tumours where stroma predom-
an estimated 40% of cases, mixed inates, the differential diagnosis includes

148 Appendageal tumours

Malignant tumours with follicular S. Kaddu
L. Requena

Pilomatrical carcinoma occurs mainly in middle aged and elder- aggregations of basaloid cells (matrical
ly individuals, may represent an interme- and supramatrical cells) {28,804,954,
Definition diate precursor lesion. 2064}. Foci of cornified material contain-
Pilomatrical carcinoma is the malignant ing shadow cells are characteristically
counterpart of pilomatricoma. Localization observed within the basaloid cell aggre-
Pilomatrical carcinomas mostly occur in gations. Some neoplasms show a vari-
ICD-O code 8110/3 the head and neck, upper extremities able desmoplastic stroma surrounding
and buttocks. Rare tumours have been the basaloid cell aggregations. Focal
Synonyms reported in the axilla and inguinal connections of basaloid cell aggrega-
Pilomatrix carcinoma, matrical carcino- regions. tions to the overlying epidermis and/or
ma, invasive pilomatrixoma, malignant ulceration are often noted. Basaloid cells
pilomatrixoma, matrix carcinoma. Clinical features exhibit hyperchromatic nuclei, with one
The clinical appearance of pilomatrical or more prominent nucleoli and ill-
Epidemiology carcinoma is generally not distinctive. defined cytoplasmic margins as well as
Pilomatrical carcinoma is an extremely Patients show solitary, occasionally variable numbers of occasionally atypi-
rare tumour. Most cases present in adults ulcerated or fungating nodules ranging cal mitotic figures (up to 10 mitoses per
with a broad age range {28,804,954, in size from 1-10 cm in diameter. Skin high-power field). Foci of geographical
2064}. The mean age at the time of diag- nodules are often of long duration rang- necrosis, calcification and ossification
nosis is about 48 years. The male to ing from several months to years before are observed. Mitotic activity is not a reli-
female ratio is 2:1. diagnosis, although occasional cases of able indicator of malignancy, because
recent onset and a history of rapid mitoses are common in pilomatricoma.
Etiology growth have been reported. Other parameters, such as an infiltrative
The majority of pilomatrical carcinomas growth pattern, as well as angiolymphat-
develop de novo, although malignant Histopathology ic, perineural, and bone invasion, are
transformation from a pre-existing pilo- The tumour is a large, asymmetrical, more reliable features {804,2064}.
matricoma has been reported {2064}. It poorly circumscribed dermal or dermal-
is conceivable that proliferating pilomatri- subcutaneous mass composed of sever- Immunoprofile
coma, a variant of pilomatricoma that al, irregularly shaped and variously sized Immunohistological studies have previ-

Fig. 3.35 Pilomatrical carcinoma. A The neoplastic cells are present in apposition to the epidermis. B A large mass of shadow (ghost) cells is present. The clear
cells have more nuclear pleomorphism than in the pilomatricoma.

Malignant tumours with follicular differentiation 149

evidenced by involvement of regional
lymph nodes, lungs and/or bone.

Proliferating tricholemmal

Proliferating tricholemmal tumour is a
solid-cystic neoplasm that shows tric-
holemmal differentiation similar to that of
the isthmus of the hair follicle.

ICD-O code 8103/1

Synonyms and historical annotation

Epidermoid carcinoma in sebaceous
cyst {252,416} subepidermal acanthoma
{1458}, proliferating epidermoid cyst
{1152}, invasive hair matrix tumour of the
Fig. 3.36 Proliferating tricholemmal tumour. A large scalp {1910}, trichochlamydocarcinoma Fig. 3.37 Proliferating tricholemmal tumour. The
tumour on the scalp of an elderly woman. {1053}, giant hair matrix tumour {583}, lobules of the neoplastic epithelium show tricho-
proliferating tricholemmal cyst {321}, pro- lemmal keratinization, characterized by peripheral
liferating pilar cyst {68,92}, proliferating palisading of small basaloid cells and large ker-
ously revealed keratin staining in both follicular cystic neoplasm {23}, proliferat- atinocytes with ample eosinophilic cytoplasm that
basaloid and shadow cells {556}. ing tricholemmal cystic squamous cell develop abrupt keratinization without previous
granular layer, resulting in compact orthokeratotic
carcinoma {1631}, proliferating isthmic
eosinophilic keratin. This type of keratinization is
Prognosis and predictive factors cystic carcinoma. These different names similar to that of the outer sheath at the level of the
Treatment of choice is by surgical exci- reflect the distinct histogenetic and bio- isthmus of the hair follicle.
sion with adequate margins. Mohs micro- logic interpretations for this neoplasm
graphic surgery technique may be useful among different authors.
in treating some patients. Pilomatrical Localization
carcinoma is a mainly locally aggressive Epidemiology More than 90% of the lesions are situated
tumour which often recurs if not com- The neoplasm is more frequent in women on the scalp. Other described locations,
pletely removed but very rarely shows than in men and most patients are elder- in decreasing order of frequency, include
distant metastases. Metastatic spread is ly {2069}. face, trunk, back and forehead {2069}.

Clinical features
The tumour is a solitary, multilobular,
large, exophytic mass, which may devel-
op within a naevus sebaceous {866,
1874}. Multiple lesions are very rare. The
size ranges from 2-10 cm in diameter,
although lesions up to 25 cm in diameter
have been described {407}. Alopecia
and ulceration can be found.

The lesions often show a multilobular
appearance. The cystic structures often
contain compact keratin and calcified

Proliferating tricholemmal tumour occurs
on a morphologic continuum. On one
end of the spectrum, it consists of a well-
circumscribed solid and cystic neoplasm
Fig. 3.38 Proliferating tricholemmal tumour. At scanning power the neoplasm appeares as a well-circum- which involves the dermis and some-
scribed cystic neoplasm involving deeper dermis and subcutaneous tissue of the scalp. times extends to the subcutaneous tis-

150 Appendageal tumours

sue. In addition to the typical features of Differential diagnosis includes tricholem- unclear if proliferating tricholemmal
a tricholemmal (pilar) cyst, this tumour mal cyst, which lacks the multilobular tumours arise de novo or from pre-exist-
shows prominent epithelial infoldings into architecture, as well as proliferating epi- ing tricholemmal cysts {1631,1847}.
the cyst lumen. The epithelium shows dermoid (infundibular) cyst {2069}. The
peripheral palisading of small basaloid latter occurs most commonly in the Prognosis and predictive factors
cells arranged along a thick vitreous anogenital region of male patients and Proliferating tricholemmal tumours with-
membrane, differentiating towards large shows a cystic cavity lined by stratified out atypical features generally behave in
keratinocytes with ample eosinophilic squamous epithelium with infundibular a benign fashion {762}. Yet, complete
cytoplasm and abrupt keratinization with- keratinization. Up to 20% of the lesions excision is recommended to avoid recur-
out a granular layer. Often, areas of cal- may undergo malignant transformation rences, and to allow for complete
cification and abundant cholesterol crys- into squamous cell carcinoma {2069}. histopathological evaluation. Tumours
tals are seen within the compact Differentiation between proliferating tric- with an invasive growth pattern or cyto-
eosinophilic keratin. The neoplastic cells holemmal tumour and proliferating logic atypia have an unpredictable
are monomorphous without significant infundibular cyst is straightforward, course. They may be locally aggressive,
cytologic atypia and with only rare because the former shows tricholemmal recur, or metastasize {68,178,982,1017,
mitoses {1135,1724}. keratinization, whereas the latter has 1537,1572,1727,1728,1773,2311,2486}.
On the other end of the morphologic mainly infundibular keratinization. For this reason, it has been suggested
spectrum are neoplasms with malignant Tricholemmal carcinoma should also be that even the classical benign lesions are
features such as invasive growth extend- considered. squamous cell carcinoma {1631}.
ing beyond the confines of the cyst wall
coupled with nuclear pleomorphism and Immunoprofile
high mitotic activity. These areas may be Proliferating tricholemmal tumour
indistinguishable from squamous cell expresses fetal hair root cytokeratin, as
carcinoma. Additional findings include well as cytokeratin 7 {933}.
shadow cells as an expression of focal
matrical differentiation similar to that of Histogenesis
pilomatricoma {1726}, areas of seba- The pathogenesis remains unknown. In
ceous and apocrine differentiation some cases, human papillomavirus has
{2021}, and spindle cells {1649}. been implicated in the etiology {23}. It is

Malignant tumours with follicular differentiation 151

Benign tumours with follicular M. A. Hurt
S. Kaddu
B. Cribier
T. Schulz
differentiation H. Kutzner W. Hartschuh

Trichoblastoma The differential diagnosis is non-specific differentiate these lesion from trichoblas-
for solitary lesions, but includes the toma, one seems to be that the carcino-
Definition “angiofibroma” of tuberous sclerosis mas infiltrate through skeletal muscle or
Trichoblastoma is a benign neoplasm dif- when multiple. other deep structures while there is a
ferentiated toward the trichoblast, i.e., conspicuous absence of the usual stro-
the folliculo-sebaceous-apocrine germ, Histopathology ma present in a classic nodular tri-
or follicular germ, for short. In many Trichoblastic epithelial components choblastoma. Rare examples with this
cases, advanced follicular differentiation associated with stereotyped stroma, pattern have metastasized {1960}.
can be present also {28,989,1083}. chiefly the follicular papilla, must be Retiform trichoblastomas are reticulated,
present to establish the diagnosis with with large fenestrations containing follic-
ICD-O code 8100/0 surety. There are five patterns; these can ular stroma.
be mixed in any given neoplasm. Cribriform trichoblastoma is the most
Synonyms Large and small nodular trichoblastomas common pattern when the neoplasms
Trichoepithelioma, trichoblastic fibroma, are usually circumscribed, sometimes are multiple, characteristic of Brook-
trichogenic trichoblastoma, lymphadeno- subcutaneous, and contain a uniform Fordyce disease. The trichoblasts are
ma (adamantinoid trichoblastoma), tri- distribution of solid trichoblasts with fol- usually fenestrated, but with small fenes-
chogerminoma, sclerosing epithelial licular papillae. In some cases, the follic- trations compared to the retiform pattern.
hamartoma, Brooke-Fordyce disease, ular “papillae” are not papillary in that Racemiform trichoblastoma contains
Brooke-Spiegler disease. they fail to invaginate into the epithelial epithelial nests that simulate “clusters of
components of the germ. The epithelial grapes”. This results in stromal compo-
Clinical features cells are deeply basophilic, uniform, and nents that connect with the surrounding
Trichoblastomas, as a rule, are solitary, overlap each other usually. Melanocytes stroma rather than being isolated from it
small papules that occur on any hair fol- can be prominent within the epithelial in fenestrations.
licle-bearing location (usually head and areas in some cases. Some cases have Columnar trichoblastoma (desmoplastic
neck), at any age, and can affect either nodules that are lymphocyte-rich, a pat- “trichoepithelioma”) occurs most com-
sex. They can also present as multiple tern termed originally lymphadenoma monly as a solitary depression on the
centrofacial papules or nodules, particu- {1561,2053}. face of a young woman. As a rule, these
larly in the diseases of Brooke-Fordyce It should be noted that, rarely, lesions neoplasms are confined to the superficial
and Brooke-Spiegler. The size of an indi- with a pattern similar to nodular tri- dermis. They contain stereotyped, thin
vidual neoplasm can vary from a few mil- choblastoma are really trichoblastic strands of epithelium compressed by
limetres to several centimetres, but most (basal cell) carcinomas that mimic tri- dense stroma. Small trichoblasts can be
are less than 1 cm in diameter. Most are choblastoma. While it is not completely seen in some cases, but are less com-
skin-coloured and ulcerated only rarely. understood what are all the factors that mon compared to conventional forms of

Fig. 3.39 Trichoblastoma. A Large nodular trichoblastoma. Note the circumscription. Melanin pigmentation is present in this lesion. B Cribriform trichoblastoma. At
scanning magnification, there are small groupings of basophilic cells containing small fenestrations of stroma.

152 Appendageal tumours


Fig. 3.40 Trichoblastoma. A This trichoblast has a typical follicular "papilla" that does not extend cleanly into an invaginated epithelial component of the follicular
germ. B Compared to the usual types of trichoblasts seen in nodular trichoblastoma, this trichoblastic carcinoma has diminished mesenchymal stroma, specifical-
ly diminished mesenchyme of the follicular papilla. C Trichoblast containing a superficial follicular papilla that protrudes into an invaginated follicular germ. This
is a fundamental finding in trichoblastomas of any pattern. D Retiform trichblastoma. This reticulated pattern is seen often in large, solitary lesions. E This sieve-
like pattern is commonly present in the small centrofacial lesions of Brooke-Fordyce disease and is the pattern known classically "trichoepitheliom". F Groupings
of follicular germinative cells that branch out, mimicking a "cluster of grapes". Absence of sieve-like areas seen in the cribrifom pattern.

trichoblastoma. The differential diagnosis but is negative for CEA and S100 {2511}. Prognosis and predictive factors
includes morpheiform basal cell carcino- CK 5, 8, 14 and 15 have been identified Because these are benign neoplasms,
ma, microcystic adnexal carcinoma, and, in some cases {2555}. It can be differen- no treatment is required, in most cases, if
rarely, metastatic carcinoma from breast. tiated from morpheiform basal cell carci- the diagnosis is established with certain-
Thus, superficial biopsies of such lesions noma and microcystic adnexal carcino- ty. Because some trichoblastomas may
should be investigated thoroughly, and ma, in most cases, by applying CK20, occur, rarely, in association with basal
additional biopsy or excision should be which marks neuroendocrine cells in cell (trichoblastic) carcinoma, and
requested for cases in which the diagno- desmoplastic trichoepithelioma, but not because of the difficulty in establishing
sis is uncertain. in basal cell carcinoma or microcystic the diagnosis in superficial biopsies, in
adnexal carcinoma {13}. Furthermore, some cases, additional biopsy or exci-
Immunoprofile CK7 is usually positive in breast carcino- sion should be considered if there is
Trichoblastomas, as a rule, cannot be dif- ma metastatic to skin and in microcystic uncertainty about the diagnosis.
ferentiated from basal cell (trichoblastic) adnexal carcinoma, but not in desmo-
carcinoma based solely on specific plastic trichoepithelioma. Stromelysin 3
expression of cytokeratins. The presence has also been identified in the stroma of Pilomatricoma
of presumed Merkel cells within a neo- morpheiform basal cell carcinoma, but
plasm, however, does seem to favour tri- not in the stoma of desmoplastic tri- Definition
choblastoma over basal cell carcinoma choepithelioma {2346}. Pilomatricoma is a relatively common
{1349}. Some trichoblastomas can con- benign cutaneous adnexal neoplasm
tain zones of ductal differentiation; when Somatic genetics with differentiation towards the matrix
this occurs, markers, such as CEA will Multiple trichoblastomas (Brooke- and inner sheath of a normal hair follicle
highlight those areas {2398} but they will Fordyce disease) are transmitted as an as well as hair cortex {28,1169}.
not aid in establishing the diagnosis. autosomal dominant trait linked to chro-
Uncommonly, excessive pigmentation is mosome 9p21 {6,951}. Solitary (spo- ICD-O code 8110/0
seen in nodular trichoblastoma, and radic) trichoblastomas have been linked,
these lesions contain markers for in some cases, to 9q22.3 {1538}, the Synonyms
melanocytes {1199}, but they are non- same locus for the naevoid basal cell Pilomatrixoma, calcifying epithelioma of
specific for the diagnosis, as basal cell carcinoma syndrome {4}. Familial multi- Malherbe, benign calcifying epithelioma
(trichoblastic) carcinoma can have simi- ple trichoblastomas and cylindromas
lar findings. (Brooke-Spiegler disease) have been Epidemiology
Desmoplastic trichoepithelioma contains linked to chromosome 16q12-q13 Pilomatricoma accounts for up to 0.2% of
AE14, EMA, and Leu-M1 (CD15) focally, {5,722}. all routine dermatopathologic specimens

Benign tumours with follicular differentiation 153

Grossly, pilomatricomas occur mostly as
lobulated masses with variable amounts
of chalky white or yellow keratinous
material on their cut surfaces. Foci with
bone may be observed.

There is usually a relatively well-circum-
scribed, deep dermal or dermal-subcu-
taneous, cystic neoplasm surrounded by
a variable connective tissue stroma {28,
1169}. A spectrum of histopathologic
features reflecting mainly different stages
of development is observed in individual
lesions. Early and well-developed pilo-
matricomas are characterized by small
to large-sized, cystic lesions lined focally
by aggregations of basaloid cells (matri-
cal and supramatrical cells) and few
Fig. 3.41 Pilomatricoma. There is a growth component of basolid cells with transition to pilar ‘shadow cells’. squamoid cells and filled centrally with
large masses of eosinophilic cornified
material (faulty hair matrix) containing
in certain centres. The tumour occurs in skin-coloured, but may show a bluish- shadow (ghost) cells as well as a few
all age groups {1169}. About 30-50% of purple to reddish hue or pigmentation. keratin filaments. A transition zone of
cases present in young individuals less Unusual presentations include rapidly retained nuclei from basaloid cells to
than 30 years of age. Previous studies growing or giant tumours (measuring up eosinophilic cornified material containing
have shown a female predominance. to 15 cm in diameter), lesions with over- shadow cells is focally observed.
lying striae or anetodermic changes, and Basaloid cells exhibit deeply basophilic
Localization multiple tumours. Multiple pilomatrico- oval or round nuclei and a variable num-
Pilomatricomas favour hair-bearing mas are quite rare. They are a marker for ber of mitotic figures. Inflamed or
areas, with the majority of cases arising myotonic dystrophy, and may rarely be regressing pilomatricomas are relatively
in the head and neck region as well as associated with a number of different large cystic tumours with prominent
upper extremities. conditions including Rubinstein-Taybi areas of shadow cells and foci of basa-
syndrome, Turner syndrome, Goldenhar loid and/or squamoid cells surrounded
Clinical features syndrome, sternal cleft defects, coagula- by a variable, often dense inflammatory
Patients present with solitary, asympto- tive defects, and sarcoidosis. Piloma- infiltrate with histiocytic giant cells, and
matic, slowly growing, cystic or firm nod- tricoma-like features are an occasional occasionally siderophages and/or mela-
ules measuring 0.5-3 cm in diameter finding in cutaneous cysts removed from nophages. Areas of granulation tissue
{28,1169,1170}. Lesions are commonly patients with Gardner syndrome. may be present. Occasional lesions dis-

Fig. 3.42 Tricholemmoma. A Exo-endophytic tumour with wart-like silhouette and focal desmoplastic stroma. B Peripheral epithelia are arranged in a palisade.
Small central follicular microcyst.

154 Appendageal tumours

play features of transepidermal elimina-
tion of shadow cells (perforating piloma-
tricoma) or a keratoacanthoma-like pat-
tern. Old pilomatricoma lesions reveal no
epithelial components but show irregu-
larly shaped, partially confluent, focally
calcified or metaplastically ossified
shadow cell areas embedded in a
desmoplastic stroma, with little or no
inflammatory infiltrate. Extramedullary A B
haematopoiesis has been observed in
some regressing and old pilomatricoma
A subset of pilomatricomas, also termed
“proliferating pilomatricoma”, is charac-
terized by the presence of relatively
large, solid or solid-cystic basaloid cell
areas with small foci of shadow cells
{1170}. This variant presents mainly in
middle aged and elderly individuals.
“Matricoma” represents another unusual C D
pilomatricoma variant characterized by Fig. 3.43 Tricholemmoma. A Thick PAS-positive basement membrane. B Focal necrosis within bulbous fol-
discrete, small, solid aggregations of licular hyperplasia. Thickened basement membrane. C Desmoplastic stroma with entrapped bizarre epithe-
basaloid cells with several connections lial strands (“pseudoinvasive interface”). D PAS-positive desmoplastic stroma and basement membrane.
to pre-existing infundibula at different
points {28}.

Molecular and cytogenetics Tricholemmoma Clinical features

Derivation of pilomatricomas from the Patients usually present with a solitary
hair matrix has been underlined by Definition asymptomatic exophytic centrofacial
recent biochemical studies demonstrat- Tricholemmoma (TL) is a benign folliculo- lesion which is either wart-like with verru-
ing prominent staining of tumour cells infundibular proliferation occurring fre- cous and keratotic features or dome
with antibodies directed against LEF-1, a quently but not exclusively on the face of shaped with a smooth surface. Individual
marker for hair matrix cells. Mutations in adults. Multiple tricholemmomas may be lesions are small, varying in diameter
the gene CTNNB1 have been detected in associated with Cowden disease. between 3 and 8 mm {28}. Multiple facial
up to 75% of pilomatricomas studied TLs are almost invariably associated with
implicating beta-catenin/LEF misregula- ICD-O code Cowden disease {2247,2249-2251}.
tion as a possible cause of hair matrix Tricholemmoma 8102/0
cell tumourigenesis {438}. In another Multiple tricholemmomas 8102/0 Histopathology
study, all 10 pilomatricomas examined Most cases of TL present as a sharply
were found to display strong bcl-2 Synonyms circumscribed superficial exo-endophyt-
immunostaining, a proto-oncogene well Trichilemmoma ic proliferation with a papillated surface.
known to help in suppressing apoptosis There is marked parakeratosis, hyperker-
in benign and malignant tumours {712}. Epidemiology atosis, and wedge-shaped hypergranu-
This finding supports a role for faulty sup- TL is a relatively common cutaneous pro- losis of the infundibula, in conjunction
pression of apoptosis in the pathogene- liferation that occurs mostly in adults and with a collarette of embracing adnexal
sis of pilomatricomas. affects both sexes equally {323}. Multiple epithelium {28,323}. TL does not involve
TLs, often in conjunction with acral ker- the interfollicular epidermis. The domi-
Prognosis and predictive factors atoses, palmar pits, and oral fibromas, nating histological pattern of TL is that of
Treatment is recommended mainly to are a cutaneous marker of Cowden dis- a bulbous infundibular hyperplasia with
avoid a foreign body reaction and inflam- ease (multiple hamartoma and neoplasia tricholemmal differentiation, akin to the
mation with eventual scarring. Surgical syndrome) {322,325,681,2025,2247, outer root sheath of the hair follicle {28}.
excision is usually curative, but occa- 2249-2251}. There are one or more bulbous lobules,
sional recurrences may be observed. always in continuity with the epidermis.
Spontaneous regression has been Localization These lobules consist of numerous pale
reported in a few cases. Malignant trans- TL arises on the head and neck, almost and clear isomorphic epithelia, most of
formation has only been suspected in a exclusively on the face, favouring the which are PAS positive. At the periphery,
single case of pilomatrical carcinoma centrofacial area. Rarely, TL may occur in pale columnar cells are arranged in a
{2064}. naevus sebaceous {410,1979}. palisade, bordered by a prominent PAS-

Benign tumours with follicular differentiation 155

ICD-O code 8101/0

TF represents a rare hamartoma mostly
occurring during adulthood (with a wide
range of ages between 11 and 77 years
{28}) without sex predilection {887}.

TF favours the head and neck region,
B foremost the face. Most lesions are situ-
ated around the nose {887}.

Clinical features
TF presents as a solitary asymptomatic
dome-shaped lesion with a smooth sur-
face and a widely dilated central ostium
from which a small tuft of delicate white
hairs emerges. Lesions are small, rang-
ing between 0.5 and 1.0 cm in diameter

A C Histopathology
Fig. 3.44 Trichofolliculoma. A Note reticulate pattern of vellus follicles in devolution. B Detail. Reticulate The main histological features of TF are
epithelial strands, sebaceous lobules and few vellus follicles. C Note sebaceous lobules and dense fibrot- reflected by its “Caput Medusae” pattern
ic stroma. Vellus follicles in different stages of devolution. {28}: embedded in a highly fibrocytic
stroma, large numbers of vellus follicles
with upper and lower segments like
and type IV collagen-positive basement Histogenesis those of normal follicles radiate from the
membrane. Central foci of epidermal / According to strict topographical anato- perimeter of a dilated infundibulum.
infundibular keratinization, occasional mical criteria, TL arises from the follicular TF is a symmetrical, well-circumscribed,
small and inconspicuous squamous infundibulum and differentiates toward vertically oriented lesion composed of
eddies, and keratinous microcysts in the outer [tricholemmal] root sheath {28}. three components: infundibulo-cystic,
larger lesions are occasional findings Its superficial folliculo-infundibular loca- follicular, and stromal {28}. The centre of
{28}. There are no mitoses. tion militates against the classification of the lesion is occupied by one or more
Desmoplastic tricholemmoma is a variant TL as a neoplasm of the lower portion of widely dilated infundibulo-cystic struc-
of TL characterized by a highly desmo- the hair follicle (i.e. the [outer] tricholem- tures that are continuous with the epider-
plastic stroma with broad zones of scle- mal sheath). mis and open to the surface of the skin
rosis and distinctive artifactual clefts. However, it is still a matter of debate through an ostium. The cystic lumina
Instead of “pushing” smooth lobular con- whether TL is of hamartomatous/neo- may be filled with innumerable corneo-
tours there may be a pseudoinvasive plastic {318,991,1906,1931} or of viral cytes and vellus hairs. From the epithelial
interface akin to pseudocarcinomatous origin {15,28,31}. The detection of HPV walls of the infundibular cystic spaces
epithelial hyperplasia, simulating carci- DNA in tricholemmomas by PCR {2688} smaller infundibula radiate, to which are
nomatous growth {1079,2333}. favours the latter view of TL as a resolv- attached vellus follicles in various num-
ing verruca vulgaris with tricholemmal bers. These vellus follicles are not asso-
Differential diagnosis differentiation {15,28, 31}. ciated with muscles of hair erection or
Warts, basal cell carcinomas, squamous with sebaceous ducts, albeit sebaceous
cell carcinomas, trichoblastomas, sebor- Prognosis and predictive factors cells arranged as solitary units or in lob-
rhoeic keratoses, and keratosis follicu- TL is an entirely benign cutaneous neo- ules may occur within the lining epitheli-
laris inversa may contain areas of tric- plasm. Multiple TLs are a hallmark of um of the central infundibulo-cystic
holemmal differentiation {31,1931}. The Cowden disease and should prompt a structure.
tumour of the follicular infundibulum search for internal malignancy. The morphology of the individual vellus
exhibits a plate-like pattern with inter- follicles may vary from normal to striking-
connecting horizontally oriented epithe- ly aberrant {28}. Normal vellus follicles
lial strands. Inverted follicular keratosis Trichofolliculoma may exhibit all stages of the follicular
consists of basaloid and squamous cycle {2106}. The whole lesion is embed-
epithelia, associated with large numbers Definition ded in a cellular connective tissue
of squamous eddies (i.e. concentric lay- Trichofolliculoma (TF) is a follicularly dif- sheath, which is separated from the adja-
ers of squamous cells in a whorled pat- ferentiated hamartoma generally appear- cent normal dermis by prominent shrink-
tern, sometimes keratinized). ing during adult life. age clefts. The highly fibrocytic stroma

156 Appendageal tumours

which surrounds the individual vellus fol-
licle resembles perifollicular sheath {28}.
The existence of considerable numbers
of Merkel cells in all trichofolliculomas
underlines their classification as hamar-
tomas with follicular differentiation {967}.

TF is a complex lesion with protean fea-
tures {28}. Some of these are caused by A B
the evolutionary and devolutionary alter-
ation of the vellus hair follicles in their
regular biological cycles {2106}. In this
context, folliculo-sebaceous cystic
hamartoma {1275,2187} may be inter-
preted as a TF at its very late stage with
nearly complete regression of the tran-
sient follicular epithelium, but with con-
current growth and maturation of seba-
ceous elements {2105}. Sebaceous tri-
chofolliculoma {1846} exhibits distinct C D
sebaceous lobules at its outer circumfer-
ence, but lacks vellus follicles that radi-
ate from the epithelial lining of the dilated
infundibulum. The latter criterion militates
against the classification of sebaceous
trichofolliculoma as a true TF {28}. Hair
follicle naevus is regarded as a TF that
was histologically sampled at its periph-
ery {28}. There is a striking predomi-
nance of mature vellus follicles and the
central infundibular lumen may be quite
Fig. 3.45 Pilar sheath acanthoma. A The characteristic infundibular and isthmic differentiation is stereo-
typed. Note the lack of a hair filament or inner root sheath. B The lobule contains red-pink corneocytes,
characteristic of the isthmus. C This pilar sheath acanthoma does not have the obvious widened ostium,
Prognosis and predictive factors but it does contain the lobules of isthmic epithelium. D The lobules have a nearly syncytial pattern. E This
TF represents an entirely benign cuta- lobule has clear-cell changes and syncytial, pink cell changes. Note the lack of inner sheath or hair fila-
neous hamartoma with no reports of ment. F The small, partly cornified cyst seen here contains no hair filament. Parts of the transient portion
tumour progression or aggressive clini- of the follicle are rarely seen in pilar sheath acanthoma.
cal course.

2 mm punctum, lacking hair filaments, Differential diagnosis

Pilar sheath acanthoma and will express corneocytes if Pilar sheath acanthoma should be differ-
squeezed. There are no known associat- entiated from dilated pore (Winer), tri-
Definition ed syndromes and no known genetic chofolliculoma, and fibrofolliculoma/tri-
Pilar sheath acanthoma is a follicular abnormalities within the neoplasms {29, chodiscoma. Dilated pore is an
neoplasm differentiated toward the per- 232,473,1570,2212,2402}. infundibular cyst that has proliferated
manent part of the hair follicle, to wit, the minimally, but lacks isthmic differentia-
infundibulum and the isthmus. [The Histopathology tion.
infundibulum is an extension of epider- The classical example consists of a pat- Trichofolliculoma is a hamartoma and
mis to meet the isthmus, but both func- ulous infundibulum that connects with contains fully formed vellus hair follicles
tion as part of the follicular sheath]. lobules of epithelium differentiated that radiate around a centrally positioned
toward both the infundibulum and the cyst. Fibrofolliculoma/trichodiscoma is
Synonyms isthmus. This differentiation results in also a hamartoma found characteristical-
Infundibuloisthmicoma blue-gray (infundibular) and pink (isth- ly in the Birt-Hogg-Dubé syndrome and
mic) corneocytes that fill the follicular that contains thin strands of infundibular
Clinical features canal. There can be a minor component epithelium connected so that fenestra-
Pilar sheath acanthomas affect adults of of stem or bulb (or both) differentiation in tions of delicate fibrous stroma are found
either sex, and are identified usually on some examples. Consequently there is, within. Additionally, considerable stroma,
the face. They are small, solitary papules as a rule, no evidence of hair filaments in lacking epithelium, is often identified (tri-
up to 5 mm in diameter, with a central 1- these neoplasms. chodiscoma).

Benign tumours with follicular differentiation 157

Trichodiscoma first was erroneously
thought to arise from or to differentiate
toward the hair disk (Haarscheibe) and
therefore bears this name {1836}.
Fibrofolliculoma was often used for peri-
follicular fibroma in the past. Neuro-
follicular hamartoma and trichodiscoma
are the same {2048}. ”Mantleoma” was
used as the overall term for both fibrofol-
liculoma and trichodiscoma {27}.

Fibrofolliculomas/trichodiscomas are
rare appendageal tumours, occurring
equally in males and females, usually not
before the third decade of life.
Fig. 3.46 Histopathology of a typical tumour of the follicular infundibulum, with horizontal proliferation of pale
keratinocytes in the papillary dermis. Note the connection with the overlying epidermi