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CHAPTER 3

Tumours of the Thymus

Tumours of the thymus account for less than 1% of all neo-


plasms and, therefore, do not contribute significantly to the
overall human cancer burden. However, their etiology is largely
unknown and the biology is complex. Thymomas often ma-
nifest clinically by causing autoimmune diseases, in particular
myasthenia gravis.
The histological typing of tumours of the thymus remains a
challenge for surgical pathologists. The Working Group
responsible for this volume largely followed the previous WHO
classification published in 1999. Some recently recognized
entities have been added, together with updated diagnostic
criteria.
WHO histological classification of tumours of the thymus
Epithelial tumours GCTs of more than one histological type (mixed GCT)
Thymoma1,2 8580/1 Variant: Polyembryoma 9072/3
Type A (spindle cell; medullary) 8581/1 GCTs with somatic-type malignancy
Type AB (mixed) 8582/1 GCTs with associated haematologic malignancy
Type B1 (lymphocyte-rich; lymphocytic;
predominantly cortical; organoid) 8583/1 Mediastinal lymphomas and haematopoietic neoplasms
Type B2 (cortical) 8584/1 B-cell lymphoma
Type B3 (epithelial; atypical; squamoid; Primary mediastinal large B-cell lymphoma 9679/3
well-differentiated thymic carcinoma) 8585/1
Thymic extranodal marginal zone B-cell lymphoma
Micronodular thymoma 8580/1 of mucosa-associated lymphoid tissue (MALT) 9699/3
Metaplastic thymoma 8580/1 T-cell lymphoma
Microscopic thymoma 8580/1 Precursor T-lymphoblastic lymphoma 9729/3
Sclerosing thymoma 8580/1 Precursor T-lymphoblastic leukaemia 9837/3
[Precursor T-cell acute lymphoblastic leukaemia
Lipofibroadenoma
(ALL)/Precursor T-cell lymphoblastic lymphoma (LBL)]
Anaplastic large cell lymphoma and other rare mature
Thymic carcinoma (including neuroendocrine epithelial T- and NK-cell lymphomas of the mediastinum 9714/3
tumours of the thymus) 8586/3
Hodgkin lymphoma of the mediastinum 9650/3
Squamous cell carcinoma 8070/3
Grey zone between Hodgkin and Non-Hodgkin lymphoma 9596/3
Basaloid carcinoma 8123/3
Histiocytic and dendritic cell tumours
Mucoepidermoid carcinoma 8430/3
Langerhans cell histiocytosis 9751/1
Lymphoepithelioma-like carcinoma 8082/3 Langerhans cell sarcoma 9756/3
Sarcomatoid carcinoma (carcinosarcoma) 8033/3 Histiocytic sarcoma 9755/3
Clear cell carcinoma 8310/3 Malignant histiocytosis 9750/3

Adenocarcinoma 8140/3 Follicular dendritic cell tumour 9758/1


Follicular dendritic cell sarcoma 9758/3
Papillary adenocarcinoma 8260/3
Interdigitating dendritic cell tumour 9757/1
Carcinoma with t(15;19) translocation Interdigitating dendritic cell sarcoma 9757/3
Well-differentiated neuroendocrine carcinomas Myeloid sarcoma and extramedullary acute myeloid leukaemia 9930/3
(carcinoid tumours)
Typical carcinoid 8240/3
Mesenchymal tumours of the thymus and mediastinum
Atypical carcinoid 8249/3
Thymolipoma 8850/0
Poorly differentiated neuroendocrine carcinomas
Lipoma of the mediastinum 8850/0
Large cell neuroendocrine carcinoma 8013/3 Liposarcoma of the mediastinum 8850/3
Small cell carcinoma, neuroendocrine type 8041/3 Solitary fibrous tumour 8815/0
Undifferentiated carcinoma 8020/3 Synovial sarcoma 9040/3
Combined thymic epithelial tumours, including Vascular neoplasms
neuroendocrine carcinomas
Rhabdomyosarcoma 8900/3
Leiomyomatous tumours
Germ cell tumours (GCT) of the mediastinum
Tumours of peripheral nerves
GCTs of one histological type (pure GCTs)
Seminoma 9061/3
Rare tumours of the mediastinum
Embryonal carcinoma 9070/3
Ectopic tumours of the thymus
Yolk sac tumour 9071/3 Ectopic thyroid tumours
Choriocarcinoma 9100/3 Ectopic parathyroid tumours
Teratoma, mature 9080/0
Teratoma, immature 9080/3 Metastasis to thymus and anterior mediastinum

__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {6} 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.
2 For thymus, designated as malignant; change from /1 to /3

146 Tumours of the thymus


TNM classification of malignant thymic epithelial tumours
TNM classification 1,2,3 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
T1 Tumour completely encapsulated Stage Grouping
T2 Tumour invades pericapsular connective tissue Stage I T1 N0 M0
T3 Tumour invades into neighbouring structures, Stage II T2 N0 M0
such as pericardium, mediastinal pleura, thoracic wall,
Stage III T1 N1 M0
great vessels and lung
T4 Tumour with pleural or pericardial dissemination T2 N1 M0
T3 N0, 1 M0
N Regional Lymph Nodes Stage IV T4 Any N M0
NX Regional lymph nodes cannot be assessed Any T N2, 3 M0
N0 No regional lymph node metastasis
Any T Any N M1
N1 Metastasis in anterior mediastinal lymph nodes
N2 Metastasis in other intrathoracic lymph nodes excluding
anterior mediastinal lymph nodes
N3 Metastasis in scalene and/or supraclavicular lymph nodes

__________
1
{899}
2
A help desk for specific questions about the TNM classification is available at http://www.uicc.org
3
This is not an official UICC TNM Classification.

TNM classification of thymic germ cell tumours


TNM classification 1,2,3 N1 Metastasis to regional lymph node present
N2 Metastasis in other intrathoracic lymph nodes excluding
T Primary Tumour anterior mediastinal lymph nodes
TX Primary tumour cannot be assessed N3 Metastasis in scalene and/or supraclavicular lymph nodes
T0 No evidence of primary tumour
T1 Tumour confined to the organ of origin (thymus and mediastinal M Distant Metastasis
fat) MX Distant metastasis cannot be assessed
T1a Tumour 5 cm M0 No distant metastasis
T1b Tumour > 5 cm M1 Distant metastasis present
T2 Tumour infiltating contiguous organs or accompanied by
malignant effusion Stage Grouping of the Pediatric Study Group1,3
T2a Tumour 5 cm Stage I Locoregional tumour, non-metastatic, complete resection
T2b Tumour > 5 cm Stage II Locoregional tumour, non-metastatic, macroscopic complete
T3 Tumour invades into neighbouring structures, resection but microscopic residual tumour
such as pericardium, mediastinal pleura, thoracic wall, Stage III Locoregional tumour, regional lymph nodes negative or
great vessels and lung positive; no distant metastasis; biopsy only or gross residual
T4 Tumour with pleural or pericardial dissemination tumour after primary resection
Stage IV Tumour with distant metastasis
N Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis

1
{167}
2
A help desk for specific questions about the TNM classification is is available at http://www.uicc.org/tnm
3
This is not an official UICC TNM Classification.

WHO and TNM classification 147


Tumours of the thymus: Introduction H.K. Mller-Hermelink
P. Engel
P. Mller
F. Menestrina
T.T. Kuo Y. Shimosato
Ph. Strbel H. Asamura
A. Marx A. Masaoka
N.L. Harris L.H. Sobin

Tumours of the thymus comprise neo- gin. In addition, some histiocytic and arise from mediastinal lymph nodes. In
plasms assumed to arise from or differ- myeloid neoplasias are of teratomatous children, the mediastinum is the site of
entiate towards thymic cellular con- derivation. By contrast, the origins of 1% of all tumours; most common are
stituents, including thymic epithelial thymic MALT, NK-cell and Hodgkin lym- non-Hodgkin lymphomas, while thymo-
tumours (thymomas, thymic carcinomas, phomas are less clear. The same holds mas are extremely rare.
neuroendocrine tumours), germ cell true for many mesenchymal tumours.
tumours, lymphoid and haematopoietic Etiology
neoplasms and mesenchymal tumours. Epidemiology The etiology of thymic tumours is largely
Tumours of the thymus are among the unknown. Some epidemiologic cluster-
Histogenesis and differentiation rarest human neoplasms, comprising ing of thymomas and neuroendocrine
Thymoma. It has long been assumed <1% of all adult cancers, with an inci- tumours has been observed among
that thymic epithelial cells originate from dence rate of 15 / million population / patients with multiple endocrine neopla-
both the ectodermal and endodermal year. Thymomas are the most frequent sia (MEN1) syndrome {461,1687}.
germ cell layers. However, a growing thymic tumours in adults, followed by Epstein-Barr virus (EBV) infection may
body of evidence suggests that the mediastinal lymphomas, some of which play a role in a minority of thymic carci-
diverse thymic epithelial populations all
develop from a common thymic epithelial
stem cell of endodermal origin {181, 684}.
This concept does not exclude the occur-
rence of more differentiated committed
stem cells with medullary, cortical or
other phenotypes {1671}. Tumours that
we know as thymomas derive from thymic
epithelium. In spite of morphological and
immunological evidence for tumour differ-
entiation towards a medullary or cortical A B
epithelial phenotype, available data do
not allow to unequivocally assign thymic
tumours to defined functional and
anatomical compartments of the normal
thymus {1691}.
Neuroendocrine thymic tumours. Both a
neural crest and thymic epithelial cell
derivation have been considered {316,
471,1139,2116,2137}. The latter hypo- C D
thesis is supported by combined (mixed)
thymoma-neuroendocrine tumours and
the occurrence of either thymomas or
thymic neuroendocrine tumours in MEN1
syndrome patients {461,1535,1687,
2094}.
Lymphomas. The thymus is the site of
the earliest stages of T-cell and natural
killer (NK)-cell development. Precursors
of dendritic cells, mature dendritic cells,
E F
and small numbers of B cells are also Fig. 3.01 Normal thymus. A Normal thymus in a child. Well developed cortical areas (Cort), thymic medulla
(Med) and Hassalls corpuscles (HC). The thymic cortex is divided by septa into lobules. The septa extend
found in the normal thymus. Among
to the corticomedullary junction and harbour vessels. The space between these vessels and the subcap-
thymic haematopoietic neoplasias, there sular epithelial cells that delineate thymic lobules is called "perivascular space". B Identification of thymic
is good evidence that T-lymphoblastic epithelial cells by the pan-cytokeratin antibody KL1. C Identification of immature CD1a positive T-cells.
lymphomas arise from lymphoid progen- D High Ki67 index in the cortex but not medulla. E The CD20+ B-cell compartment is largely confined to the
itors, while mediastinal large B-cell lym- thymic medulla. B-cells surround Hassalls corpuscles. F Myoid cells as revealed by anti-desmin staining
phomas are of putative thymic B-cell ori- (brown) in the thymic medulla (Med), one of them directly adjacent to a Hassalls corpuscle (HC).

148 Tumours of the thymus - Introduction


nomas, as well as some Hodgkin, rare Table 3.01
non-Hodgkin and NK/T-cell lymphomas. Autoimmune diseases associated with thymomas.
Rare manifestations are indicated by an asterisk.
Clinical features
Patients may exhibit symptoms due to Neuromuscular Diseases
local complications (pain, superior vena Myasthenia gravis
cava syndrome, respiratory insufficiency Neuromyotonia*, rippling muscle
or tachycardia because of pleural or disease*, polymyositis/dermatomyositis*
pericardial implants and effusions), as
Encephalitis* (limbic, cortical, and
well as systemic symptoms (fever or
brainstem)
weight loss).
In addition, thymomas can cause a large Intestinal pseudoobstruction*
A variety of autoimmune diseases (Table Haematologic Autoimmune Diseases
3.01) which are often typical for a specif-
Anaemia: pure red cell aplasia
ic tumour type and may precede or fol-
(in all thymoma subtypes) {168}
low thymoma resection {987}. Type A, AB pernicious anaemia, haemolytic anaemia,
and B thymomas exhibit an unrivaled fre- aplastic anaemia
quency and spectrum of autoimmune
Other isolated cytopenias, eg eosinophils,
phenomena, comprising neuromuscular,
basophils, neutrophils
haematopoietic, dermatologic, rheumat-
ic/vasculitic, hepatic and renal diseases. Immunodeficiencies:
Hypogammaglobulinaemia +/- T-cell
Myasthenia gravis is by far the most fre-
deficiencies (Good syndrome)
quent and preferentially associated with
B type AB and B2, B3 thymomas, while Dermatologic Diseases*
hypogammaglobulinaemia (Good syn- Pemphigus (foliaceus, paraneoplastic)
drome) is more typical for type A thymo- Lichen planus
ma. Pure red cell aplasia is also a rare
Alopecia areata
complication of type A thymomas,
though recent data find a less specific Endocrine Disorders
association with this thymoma subtype Addison disease, Cushing disease
{1096}. Thymic carcinomas are not asso- Graves disease
ciated with myasthenia gravis or
hypogammaglobulinaemia, but occa- Renal and Hepatic Diseases
sionally with other autoimmune diseases. Glomerulonephritis, autoimmune hepatitis
C Cytopenias and/or hypogammaglobuli-
Systemic Autoimmune Diseases*
naemia can result in serious bacterial
Fig. 3.02 A Cartoon of the non-lymphoid cellular
and opportunistic infections. Lympho- SLE, Sjgren disease, systemic sclerosis
components of the normal thymic cortex and
cytosis and thrombocytosis can occur. Graft-versus-Host-Disease
medulla, including Hassalls corpuscle (HC).
Various thymic epithelial cells, dendritic cells (DC), Whether the increased incidence of sec-
macrophages (MA), and myoid cells (MC). ond cancers in thymoma patients is relat-
Subcapsular and medullary epithelial cells delin- ed to genetic or environmental etiologies
eate septa and perivascular spaces (PvS) at the or thymoma-induced immunodeficiency Histopathological classification
corticomedullary junction. B Electron micrograph is unknown {1395,1537}. Thymomas
showing cortical and subcortical thymic epithelial Histological classification schemes for
cells (TEC), apoptotic bodies, and macrophages.
thymomas traditionally have been
C Electron micrograph of thymic medulla, depict-
descriptive (predominantly spindle, pre-
ing a medullary epithelial cell , a dendritic cell
and a Hassalls corpuscle (HC). dominantly lymphocytic, predominantly
epithelial, mixed lymphoepithelial) {158,
1086,1134,1172,1732}, or were based on
the combined consideration of morphol-
ogy (spindle, polygonal, mixed tumour
cells) and lymphocyte content {1086,
1808}. Except for the spindle cell type,
these classifications largely lacked prog-
nostic significance independent of stage
{1172,1253,1808}.
The histogenetic or functional classifica-
A B tion included terms (medullary, cortical)
Fig. 3.03 Epidemiology of mediastinal tumours A in children (< 15 years), and B in adults (45-75+ years). that reflected the normal differentiation of
Thymomas are exceedingly rare in children, while they are the most common mediastinal tumours in adults. the major functional and anatomic com-

Introduction 149
Table 3.02 entiation, resembling carcinomas outside long-standing cases. but may exception-
Comparison of Masaoka tumour stages and corre- the thymus. This category includes neu- ally be the first clinical manifestation of
sponding TNM classification. Modified, from roendocrine epithelial tumours. the tumour.
K. Koga et al. {1043}.
Germ cell, lymphoid, haematopoietic
Masaoka stage T N M and mesenchymal tumours With distant metastases.
The classification of these tumours fol- A thymoma with metastases to distant
I 1 0 0 lows the WHO Classification of gonadal site(s), most commonly lung, liver, and
II 2 0 0 germ cell tumours {526}, tumours of skeletal system. This excludes metas-
haematopoietic and lymphoid tissues tases to lymph nodes and local extension
III 3 0 0
{919} and tumours of soft tissues and into adjacent organs.
IVa T4 0 0
bone {590}.
IVb any T N1 or M1
Grading of malignancy
Useful morphological terms Thymic epithelial tumours consist of sev-
partments of the thymus {1245,1404}. Encapsulated. eral histological subtypes, i.e., thymoma
This classification proved to be of inde- A thymoma completely surrounded by a types A, AB, B1, B2 and B3, and thymic
pendent prognostic value {341,856, fibrous capsule of varying thickness carcinomas, in increasing order of malig-
1017,1540,1630} and was highly repro- which is not infiltrated by tumour growth. nancy {1691} Thymoma type A and AB
ducible {378}. However, although some Thymic tumours that infiltrate into, but not generally behave like a benign tumour,
morphological and immunological stud- through, the capsule still belong in this type B1 as a low-grade malignant tumour
ies have supported the histogenetic con- category. (10-year survival rates of over 90%), type
cept {235,859,1015,1086,1452,1510, B2 has a greater degree of malignancy,
1886}, it has not been generally accept- Minimally invasive. and type B3 in the advanced stage
ed {1058,1691,1917}. A thymoma surrounded by a capsule shows a poor prognosis, just like thymic
In 1999, a WHO Working group suggest- which is focally infiltrated by tumour carcinoma and malignant tumours of
ed a non-committal terminology, preserv- growth with invasion of the mediastinal other organs {1511}. Among the various
ing the distinct categories of the histoge- fat. The capsular invasion needs to be subtypes of thymic carcinoma, squa-
netic classification, but using letters and complete in order for the tumour to be mous cell carcinoma, basaloid and
numbers to designate tumour entities placed in this category. Minimally inva- mucoepidermoid carcinoma have a bet-
{1690}. The rationale for the concept to sive thymomas are usually identifiable as ter prognosis than other histological sub-
label thymomas as type A, AB, and B is such only after microscopic examination types. The malignancy grade of thymic
derived from a growing body of morpho- in so far as they generally appear to the neuroendocrine tumours (carcinoids) is
logical, functional and genetic evidence surgeon indistinguishable from encapsu- intermediate between thymoma and
{235,859,896,1510,1631,2242}, suggest- lated thymomas at the time of excision. thymic carcinoma. The rare small cell
ing that these thymoma subgroups form and large cell carcinomas tend to be
distinct entities both in morphological Widely invasive. highly malignant.
and clinical terms. A thymoma spreading by direct exten-
In recent years, this WHO classification sion into adjacent structures such as TNM Classification and
{1690} has been well accepted and is pericardium, large vessels or lung. This stage grouping
largely retained in the current WHO clas- type of thymoma usually appears inva- The TNM Classification and stage-group-
sification as it provides an easy compar- sive to the surgeon at the time of exci- ing has been applied to malignant
ison of clinical, pathological and sion, which may be incomplete as a tumours of many organs {2045}, but
immunological studies {235,318,1196, result. there is currently no authorized TNM sys-
1511,1744,1886}. tem for thymic epithelial and neuroen-
Thymomas of type A, AB, and B exhibit Implants. docrine tumours. In the TNM Supplement
organotypic (thymus-like) architectural A thymoma in which tumour nodules sep- 2nd edition {899}, a tentative classifica-
features. These tumours have not been arate from the main mass are found on tion of malignant thymomas appeared for
observed in organs other than the thy- the pericardial or pleural surface. These testing. It is mainly based on the
mus, though they may arise from hetero- implants tend to be small and multiple Masaoka system and its revised versions
topic thymic tissue in the head and neck and their microscopic appearance is {1255,2036,2184}. While the tentative
region, anywhere in the mediastinum, usually, but not always, similar to that of classification applies only to malignant
pleura and lung {1691}. By contrast, the the parent tumour. thymic epithelial tumours {899}, it has in
heterogeneous thymic carcinomas this chapter been extended to include
(called type C thymomas in the previous Lymph node metastases. neuroendocrine tumours.
WHO classification) exhibit morphologies A thymoma that involves one or more
that are encountered also in organs other lymph nodes anatomically separate from Invasion
than the thymus. the main mass. This excludes direct Crucial points in defining the T-cate-
Thymic carcinomas comprise malignant, extension into the node by the tumour. gories are invasion through the capsule
usually invasive epithelial tumours with The nodes most commonly involved by and invasion into neighbouring struc-
clear-cut atypia, largely absent organ- metastatic thymoma are mediastinal and tures. Although invasive growth outside
otypic features and a very diverse differ- supraclavicular. It is a rare event even in the thymus detected by the surgeon at

150 Tumours of the thymus - Introduction


the time of thoracotomy has been repeat- Table 3.03
edly reported to have significant impact Malignant potential in terms of mortality, combining WHO histologic type and tumour stage, according to
on the prognosis {693,1043}, the prog- Shimosato et al. {1808}. Stage IV thymomas should be considered as tumours of high malignant potential,
although metastatic type A or AB thymomas with long-term survival have been reported.
nostic significance of minor degrees of
invasion detected by histological exami- Histology Tumour Stage Malignant potential
nation remains controversial. Many
reports on thymoma have shown little or
no difference in survival between Type A, AB, (B1) thymoma I and II None (very low)1
Masaoka stage I and stage II thymomas III Low
{693,1043,1130,1511,1579,1645}.
Furthermore, some thymomas and most Type B2, B3 thymoma I Low
thymic carcinomas are devoid of a cap-
II and III Moderate
sule entirely or in part, which makes the
definition of encapsulation meaning-
Thymic carcinoma:
less. Therefore, the current and pro-
posed categories T1 (completely Low-grade squamous Stage I and II Moderate
encapsulated) and T2 (with invasion of cell, basaloid or Stage III High
pericapsular connective tissue) may not mucoepidermoid
be biologically meaningful and may be carcinoma, carcinoid
impossible for pathologists to use.
Criteria for minimal invasion need to be Other histological types Any stage High
better defined.
1These tumours amount to 40-50% of all thymomas {341,1511,1631}.
Tumour size
On the other hand, tumour size has been
used as an important parameter to resectable and curable ones and non- Stage-Grouping
define T-categories; critical dimensions resectable ones with a poor prognosis The most important issue in stage-group-
of 11 cm and 15 cm have been reported is desirable, especially for planning ing is the definition of stages I and II. The
{183,1172}. Especially in Blumbergs treatment. survival curves of patients with thymo-
report, tumour size was one of the signif- mas of stages I and II are superimposed
icant parameters for survival by multivari- Lymph node metastasis at around 100% at 5 and 10 years after
ate analysis {183}. Critical size may be This is rare in thymoma, and the basis for surgery {693,1511}. In other reports, a
quite different among thymoma and the definition of stage IVB (Masaoka) for minimal difference has repeatedly been
thymic carcinoma, including neuroen- thymomas with lymph node metastasis reported {1043,1130,1579,1645}. If the
docrine tumours. This consideration of {1255}. In the tentative TNM classifica- definition of the T-category remains
tumour size might also be necessary in a tion, N1 (metastasis to anterior mediasti- unchanged, the present stages I and II
revised definition of the T-category. nal lymph nodes) is defined as stage III. could be merged into a new stage I;
However, the prognostic equivalence however, no data are available on thymic
Surgical resectability between T3 and N1 has not yet been carcinoma with respect to stages I and II.
The present T denominator includes assessed. The appropriateness of the Stage III in the present tentative system,
tumours with different characteristics: nodal grouping N1 to N3 needs to be which is a heterogeneous group, is rec-
one extreme is an easily resectable investigated further. Depending on the ommended to be divided into a poten-
tumour with minimal invasion into the tumour location in the anterior medi- tially resectable group with a favourable
pericardium and a good prognosis and astinum, the lymphatic pathway by which prognosis and an unresectable group
another extreme is a non-resectable tumour cells spread might be different. with a poor prognosis, respectively.
tumour with invasive growth into multi- Consequently, the sentinel lymph node
ple neighbouring organs. A further divi- might be located elsewhere other than
sion of T3 tumours into potentially the anterior mediastinum.

Stage grouping 151


Thymomas A. Marx
Ph. Strbel
N.L. Harris
T.T. Kuo
A. Zettl Y. Shimosato
J.K.C. Chan P. Engel
H.K. Mller-Hermelink

Definitions Epstein-Barr virus appears to play an eti- 3. Thymomas combining type A with B1-
Thymomas (type A, AB, B thymomas) are ologic role in subsets of lymphoepithe- like or (rarely) B2-like features are desig-
neoplasms arising from or exhibiting dif- lioma-like, poorly differentiated squa- nated type AB.
ferentiation towards thymic epithelial mous and undifferentiated thymic carci- 4. Thymic carcinomas are termed
cells, regardless of the presence and rel- nomas both in Asian {343,1174,1265, according to their differentiation (squa-
ative numbers of non-neoplastic lympho- 2174} and Western countries {785,894, mous cell, mucoepidermoid, etc.). In the
cytes {1691}. Their malignant potential is 1234,1876}. There is no increased risk of 1999 WHO classification {1690}, the term
either absent or low to moderate. developing thymomas in patients receiv- WHO type C thymoma was the headline
Thymic carcinomas are malignant ing radio-chemotherapy for mediastinal designation to stress their thymic
epithelial tumours because of overt cyto- Hodgkin lymphoma {1455} or breast can- epithelial origin. In the current classifica-
logical atypia, almost invariable invasive- cer {1498}. tion, this term was eliminated since all
ness and lack of organotypic (thymus- non-organotypic malignant epithelial
like) features. Principles of thymoma classification neoplasms other than germ cell tumours
Combined thymoma, combined thymo- 1. There are two major types of thymoma are designated thymic carcinomas.
ma/thymic carcinoma. These terms are depending on whether the neoplastic 5. Combined thymomas are specified by
used for a combination of thymoma sub- epithelial cells and their nuclei have a the WHO histology and approximate per-
types and of thymomas with thymic car- spindle or oval shape, and are uniformly centage contributed by each component
cinomas, including thymic neuroen- bland (Type A thymoma) or whether the of the combined thymoma.
docrine carcinomas, within one tumour cells have a predominantly round or 6. Traditionally, the term malignant thy-
mass. polygonal appearance (Type B) {1691}. moma has been used for (i) thymomas
Thymoma (type X) with anaplasia is the 2. Type B thymomas are further subdivid- with advanced stage, i.e. local invasive-
suggested diagnostic term for a very ed on the basis of the extent of the lym- ness, pleural or pericardial implants or
uncommon group of tumours with bor- phocytic infiltrate and the degree of atyp- metastasis, irrespective of tumour histol-
derline morphological freatures between ia of the neoplastic epithelial cells into ogy or (ii) thymic epithelial tumours with
thymoma and thymic carcinoma. three subtypes B1 (richest in lympho- marked atypia (thymic carcinomas), irre-
cytes), B2, and B3 (richest in epithelial spective of tumour stage {1170,1691,
Epidemiology cells). 1841,1924}. The use of the term malig-
Thymomas and thymic carcinomas are
uncommon tumours with an annual inci-
dence of approximately 1-5 per million Table 3.04
Differential diagnosis of thymomas types A, AB, B and thymic carcinomas
population. There are only very limited
epidemiologic data, but cautious inter- Feature Thymomas Thymic carcinomas
pretation of data from the Danish
National Board of Health suggests that Organotypic (thymus-like) Almost always present (lobular None or abortive
the incidence has not changed signifi- histological features pattern, perivascular spaces,
cantly over the last three decades. immature, TdT+ / CD1a+ /
Thymomas and thymic carcinomas occur CD99+ T-cells)
at almost all ages (range 7-89 years) with
a peak incidence between 55-65 years. CD5, CD70 and CD117 expres- No Frequent (~ 60%)
They are exceedingly rare in children sion in epithelial cells
and adolescents {1577,1876}. There is
no pronounced sex predilection Invasion Variable Almost always
{318,341,1016,1630}. Patients exhibit an
increased incidence of second cancers Myasthenia gravis Variable: 1080% No
irrespective of the histology of the thymic
epithelial tumour {1537}. Other autoimmune diseases Common Rare

Etiology Clinical behaviour Often curable by surgery; Often unresectable {318};


The etiology of thymomas is still largely metastases are rare. metastases are frequent
unknown. They have been repeatedly Usually long survival due to Often short survival due to pro-
observed in patients with MEN1 syn- indolent clinical course gressive disease
drome {461,1535,1644,1648,2094}.

152 Tumours of the thymus - Thymomas


nant thymoma as a synonym for a local- Table 3.05
ly invasive thymoma irrespective of the Genetic alterations reported for the different WHO histological thymoma subtypes.
WHO histological type is discouraged, WHO Type Chromosomal Gains Chromosomal Losses Source
since it may not properly reflect the
excellent prognosis of type A and AB thy-
momas of advanced stage {318,341, Type A none -6p {437,1325,2065,2238,
2242}
1510,1511,1630}.
Type AB none -5q21-22, -6q, -12p, -16q {699,896,897}
Prevalence of thymoma subtypes
The predominant histological subtypes in
most published series are type B2 and Type B3 +1q -6, -13q {896,897,2238,2242}
AB thymomas (each 20-35% of all
cases), while type B1 and type A thymo- Thymic squamous cell
mas count among the rare types (5-10%
in most studies) {856,1510,1967}. The carcinoma +1q, +17q, +18 -3p, -6, -13q,-16q, -17p {896,897,1848,2238}
percentage of thymic carcinomas has
been reported to be about 1025% {318,
341,541,1404,1510}. 6 and 13q. Type B2 thymomas are genet- very low malignant potential; rare local
In children, type A, B1 and B2 thymomas ically related to type B3 thymomas {896}. recurrences or late metastases may
have been observed, in addition to undif- Thymic squamous cell carcinomas fre- occur {318}. Type B2 and B3 thymomas
ferentiated and EBV-positive lymphoep- quently show gains of chromosomes 1q, and thymic carcinomas, are clear-cut
ithelioma-like thymic carcinomas {274, 17q and 18 and losses of chromosomes malignant tumours. B2 and B3 thymomas
1577,1876}. The morphologically hetero- 3p, 6, 16q, and 17p {2238}. The shared and well differentiated squamous, basa-
geneous and rare carcinomas with genetic abnormalities underline the close loid and mucoepidermoid carcinomas
t(15;19) translocation typically occur in relationship between type B3 thymomas follow a more favourable course than
children and young adults {1081,1148, and thymic squamous cell carcinomas. poorly differentiated squamous cell car-
2072}. cinomas and other thymic carcinomas
Prognosis and predictive factors {1924}. The prognosis of combined thy-
Genetic features The most relevant prognostic factors in momas may be determined by the most
Recurrent genetic alterations have so far thymoma are tumour stage {341,1511, malignant component {1093,1912}.
been reported for type A and B3 thymo- 1630,1808}, WHO histologic type {341, Paraneoplastic pure red cell aplasia,
mas as well as for thymic squamous cell 1511} and completeness of resection other cytopenias, or hypogammaglobuli-
carcinomas {896,1567,2238,2242}. Type {318,1419}. naemia (Good syndrome) have an
A thymomas only show few genetic alter- Type A and AB thymomas in stages I and adverse effect {987} whereas paraneo-
ations, with deletions of chromosome 6p II virtually always follow a favourable clin- plastic myasthenia gravis had no or a
reported as a recurrent genetic alteration ical course {341,476,1511}, and even at positive factor on survival {318,341}.
{437,2065,2238}. Type A areas in type higher stages may not be fatal due to a
AB thymomas are genetically distinct very slowly progressive course {1808}.
from type A thymoma {699,896}. Type B3 They are considered benign tumours
thymomas frequently show gains of chro- {784,1404} or neoplasms of low malig-
mosome 1q and losses of chromosomes nant potential. Type B1 thymomas have a

A B C
Fig. 3.04 Kaplan-Meyer survival statistics of patients with thymic epithelial tumours. A Survival of patients with thymomas or thymic carcinomas according to stage.
Masaoka tumour stage is the most important and statistically most significant independent prognostic parameter for survival in almost all clinico-pathological stud-
ies. From G. Chen et al. {341}. B Survival of patients with thymomas or thymic carcinomas according to histological type. WHO-based histology was a statistically
significant prognostic parameter for survival in most clinico-pathological studies. In some studies, B3 thymomas and thymic carcinomas had a significantly worse
prognosis than B2 thymomas (L. Quintanilla-Martinez et al. {1631}; M.Okumura et al. {1511}), but not in others (G. Chen et al. {341}). C WHO-based histological sub-
type is an independant prognostic marker in patients with thymomas and thymic carcinomas infiltrating beyond the tumour capsule into the mediastinal fat
(Masaoka stage II). A no/low-risk group of tumours (type A, AB, B1 thymomas) is distinguished from a moderate/high-risk group (B2 and B3 thymomas and thymic
carcinomas). From G. Chen et al. {341}.

Thymomas 153
Type A thymoma T.T. Kuo
K. Mukai
T. Eimoto
R.H. Laeng
K. Henry
J.K.C. Chan

Definition
Type A thymoma is an organotypic
thymic epithelial neoplasm composed of
bland spindle/oval epithelial tumour cells
with few or no lymphocytes. The tumour
cells can form a variety of histologic
structures.

ICD-O code 8581/1

Synonyms
Spindle cell thymoma, medullary thymo-
ma

Epidemiology
Type A thymoma is a relatively uncom-
A
mon type of thymoma and accounts for
4-19% of all thymomas {541,1510,1511,
1808}. The age at manifestation ranges
from 32 to 83 years, with a mean age of
61 years {1538,1540,1630}, which is
higher than the mean age of 50 years of
all thymoma patients {341,1095}. No con-
sistent gender predilection has been
reported {318,1511,1540,1630}.

Clinical features
Approximately 24% of type A thymomas
are found in patients with myasthenia
gravis {318,341,1511,1538,1540,1630}.
Others are found because of local symp-
toms or incidentally discovered on imag- B
ing examination. Association with pure Fig. 3.06 Type A thymoma is composed of spindle cellls (A) or oval cells (B) with bland nuclei arranged in
red cell aplasia may occur, but in con- solid sheets without any particular pattern (B) or in a storiform patern (A).
trast to earlier reports, pure red cell apla-
sia may also occur in other thymoma (17%) and rarely stage III (3%) {341,541,
types {1096}. 1095,1510,1511,1538,1540,1630,1631,1
808}. Single exceptional cases of stage
Macroscopy IV type A thymoma have been reported
Grossly, type A thymoma is usually well {1403}.
circumscribed and encapsulated. The
cut surface is tan white and shows vague Histopathology
lobulation with less distinct dissecting Histologically, the tumour has few or no
white fibrous bands than is seen in other lymphocytes and shows neither distinct
types. Cystic change or calcification of lobules nor dissecting fibrous bands as
the capsule may be seen. Average seen in other types of thymoma. The
tumour size is 10.5 cm. tumour cells are spindle and/or oval-
shaped with bland nuclei, dispersed
Tumour spread and staging chromatin and inconspicuous nucleoli;
Fig. 3.05 A well encapsulated type A thymoma with The majority of type A thymomas (80%) they are arranged in solid sheets without
vaguely lobulated appearance and thin white occurs as Masaoka stage I in the anteri- any particular pattern or in a storiform
fibrous bands. or mediastinum, followed by stage II pattern {1403,1691}. Type A thymoma

154 Tumours of the thymus - Thymomas


cells can form cysts of various size, glan- and/or mitotic figures indicating the pres- medullary cells are also expressed in type
dular structures, glomeruloid bodies, ence of carcinoma {1093}. A thymoma cells {798,1087}. The few lym-
rosettes with or without a central lumen, phocytes, if present, are T cells positive for
Massons haemangioma-like papillary Immunophenotype CD3 and CD5. CD1a+ and CD99+ imma-
projections in cystic spaces, or menin- The tumour cells are strongly positive for ture T cells may be present but comprise a
gioma-like whorls {1086,1095,1403, AE1-defined acidic cytokeratins (CKs), minority of the T cells. CD20+ B cells are
1538,1691,1808}. Extremely elongated and negative for AE3-defined basic CKs. usually absent except in focal micronodu-
fibroblast-like spindle cells may be seen Other CKs of different molecular weights lar areas with a lymphoid stroma, if these
focally. Vessels in the background may show variable expression except that are present.
impart a haemangiopericytoma-like CK20 is negative {1086}. In general, the
appearance {1538}. Perivascular spaces cystic and glandular structures express Histogenesis
are less commonly seen than in other stronger CK {1808}. CD20-positive tumour Type A thymoma has been postulated to
types of thymoma {318}. Although type A cells may be detected focally {354,1403, derive from the normal thymic medullary
thymoma is a lymphocyte-poor tumour, 1538}. There is no expression of CD5 epithelial cells {1403,1404}. Evidence in
spindle cell micronodules in a lymphoid {1538}, and BCL-2, CD57 and EMA are support of this postulate include their
stroma may be present at places {1981}. variable and usually only focally expressed similar immunohistochemical expres-
Most tumour cells are individually sur- {227,1631,1808,1872, 1981}. Most tumour sions of CD20, cytokeratins, metalloth-
rounded by reticulin fibers {1086,1691}. cells are surrounded by basement mem- ionein, and PE-35 as well as the relative
Cells in mitosis are seldom found, but brane-like deposits as demonstrated by paucity of immature T cells {354,798,
lobular infarcts can occur. Rarely, thymic anti-laminin and anti-type IV collagen anti- 1086,1087,1095,1452,1538,1631}.
carcinoma can arise in type A thymoma. bodies. TP53 protein and Ki-67 show only
Areas of necrosis may be a clue to this low or no expression {1539,1872,
phenomenon; examination of these areas 1980,1981}. Two antigens, metallothionein
reveals hyperchromatic anaplastic nuclei and PE-35, found in normal thymic

A B

C D
Fig. 3.07 Type A thymoma. A Type A thymoma cells can form cysts of various size. B Type A tymoma cells with haemangiopericytoma-like appearence. C Rosettes
without a lumen. D Anaplastic malignant cells arising in type A thymoma.

Type A thymoma 155


A B
Fig. 3.10 Type A thymoma. CGH hybridization of a
WHO type A thymoma shows loss of chromosome
6p21-pter revealed by an excess of red hybridiza-
tion signal of normal DNA as compared to the
green hybridization signal of tumour DNA (high-
lighted by the arrows).

C D
Fig. 3.08 Different histological patterns in type A thymoma. A Glandular structures. B Glomeruloid bodies.
C Rosettes with lumens. D Perivascular spaces.

Somatic genetics type A thymoma {2242}, which could be can be completely removed surgically
Type A thymoma has been found to have the genetic basis for its generally benign {1095,1403,1404}. However, exceptional
t(15;22)(p11;q11) {438} or a partial loss clinical course. case reports of local recurrence or dis-
of the short arm of chromosome 6 {2238}. tant metastasis have been documented
Consistent loss of heterozygosity has Prognosis and predictive factors {1043,1403, 1538}. Rarely, type A thymo-
been found only in the region 6q23.3- The overall survival of patients with type ma can undergo malignant transforma-
25.3, which is common to type A and B3 A thymoma has been reported to reach tion into thymic carcinoma {1093}. The
thymomas and squamous cell thymic 100% at 5 years and 10 years {1403, association with myasthenia gravis has
carcinomas {897,2242}. Unlike type B3 1511}, even though approximately 20% been reported to have either a better or
thymomas and squamous cell thymic of them have stage II or stage III no effect on prognosis {318,1511,1630}.
carcinoma, no aberrations in the APC, tumours. Generally, type A thymoma is
RB1, and TP53 gene loci or in regions regarded as a benign tumour without
3p22-24.2 and 8q11.21-23 are found in having a risk of recurrence if the tumour

A B C
Fig. 3.09 Immunophenotype of type A thymoma. A Immunopositivity for AE1-defined acidic cytokeratins. Note the stronger expression of cytokeratin by the glan-
dular structures. B Focal epithelial expression of CD20. C Tumour cells are surrounded by abundant type IV collagen as demonstrated by immunostaining.

156 Tumours of the thymus - Thymomas


Type AB thymoma T.T. Kuo
K. Mukai
T. Eimoto
R.H. Laeng
K. Henry
J.K.C. Chan

Definition
Type AB thymoma is an organotypical
thymic epithelial neoplasm composed of
a mixture of a lymphocyte-poor type A
thymoma component and a more lym-
phocyte-rich type B-like component. The
tumour cells in the type B-like component
are composed predominantly of small
polygonal epithelial cells with small
round, oval or spindle pale nuclei show- A B
ing dispersed chromatin and inconspicu- Fig. 3.11 A Macroscopic appearance of a type AB thymoma showing multiple nodules separated by fibrous
ous nucleoli, and are smaller and paler bands. B Type AB thymoma composed of lymphocyte-associated type B nodules and diffuse lymphocyte-
than those of B1 or B2 thymomas. poor type A areas.
Lymphocytes are more numerous than in
the type A component, but may be less
numerous than in B1 thymomas. There is Macroscopy type B component. All histological fea-
a great variation in the proportion of the Grossly, type AB thymoma is usually tures of type A thymoma can be seen in
two components, and while usually both encapsulated and the cut surface shows the type A component. However, the type
components are present in most sec- multiple tan coloured nodules of various B areas are distinctive and different from
tions, either type A or type B areas can size separated by white fibrous bands. either B1, B2, or B3 thymoma. The
be scanty. Average tumour size is 7.7 cm. tumour cells in the type B component are
composed predominantly of small poly-
ICD-O code 8582/1 Tumour spread and staging gonal epithelial cells with small round,
The majority of type AB thymoma oval or spindle pale nuclei showing dis-
Synonym (71.7%) occur in the anterior medi- persed chromatin and inconspicuous
Mixed thymoma astinum as Masaoka stage I followed by nucleoli {1086,1403,1691,1808}. The
stage II (21.6%) and stage III (5.6%) large, vesicular epithelial cells with
Epidemiology {341,437,1404,1510,1511,1539,1540, nucleoli that are characteristic of B2 thy-
Type AB thymoma is either the most or 1691}. Rare cases of stage IV type AB moma are only rarely seen {1086}. The
the second most common type of thymo- thymoma (1.1%) have been reported type A and type B components either
ma and accounts for 15-43% of all thy- {1325,1404,1510,1539,1691}. form discrete separate nodules or inter-
momas {341,541,1095,1510,1511,1538, mix together {1403,1691}. The type A
1540,1631,1808}. The patients ages Histopathology component in the latter areas may form
range from 29-82 years with a slightly Histologically, type AB thymoma shows a bundles of extremely elongated fibrob-
younger mean age of 55 years than type nodular growth pattern with diffuse areas last-like spindle cells. Type B areas har-
A thymoma {1538,1540,1630}. A slight and is composed of a variable mixture of bour lymphocytes in variable numbers
male predominance has been noted in a lymphocyte-poor type A thymoma and medullary differentiation is rarely
most reports {1511,1538,1540,1630}. component and a more lymphocyte-rich observed. In particular, Hassall corpus-

Clinical features
The clinical presentation is similar to that
of type A thymoma. Approximately 14%
of type AB thymomas are associated with
myasthenia gravis {341,541,1510,1511,
1538,1540,1630,1808}. Paraneoplastic
pure red cell aplasia has also been
reported {1096}. Other tumours manifest
by local symptoms or can be asympto-
matic and are found incidentally upon
imaging examination. A B
Fig. 3.12 Type AB thymoma. A Medullary differention in type B component. B The lymphocytes in the focus
of medullary differentiation are distinctively CD5+ T cells.

Type AB thymoma 157


A B C
Fig. 3.13 Type AB thymoma. A Type B component cells are immunopositive for cytokeratin 14. B CD20+ tumour cells in type B component. C Abundant laminin pro-
duction is seen in type A component (immunostained with anti-laminin antibody).

cles are absent. There is a great variation CD57 are variably and usually weakly been described in individual cases
in the proportion of both components expressed {227,1631,1808,1872,1981}. {699}. Loss of heterozygosity at 5q21-22
and in particular, type A areas can be TP53 protein and Ki-67 are extremely low (APC), as seen in type B thymoma, has
extremely scanty to almost absent or absent {1539,1872,1980,1981}. In been detected in a minority of type AB
{1086,1403,1691}. Unlike type A thymo- contrast to type A thymoma areas, the thymoma {897}.
ma areas, type B areas show reticulin type B areas show less production of
fibers around tumour nodules rather than laminin and type IV collagen. Prognosis and predictive factors
around individual tumour cells. The overall survival rate of patients with
Histogenesis type AB thymoma is 80-100% at 5 years
Immunophenotype The cellular origin of the type A compo- and 10 years {1403,1511}. Although type
The patterns of cytokeratin (CK) expres- nent, like in type A thymoma, has been AB thymomas may present as stage II or
sion of type AB thymoma are essentially postulated to derive from or differentiate stage III tumours, they can be usually
similar to those of type A thymoma, towards thymic medullary epithelial cells cured by radical surgery {1095,1403,
except that the epithelial cells in type B {798,1087,1403,1404}. The type B com- 1404}. Therefore, they are generally
areas are usually CK14+ {1086}. CD20+ ponent ultrastructurally resembles regarded as clinically benign tumours
tumour cells can be seen in both type A epithelial cells at the corticomedullary {1403,1404}. Recurrence and metastasis
and type B areas, and the associated junction {1017}, but is similar to thymic are exceptionally rare {1043,1403,1538}.
lymphocytes are T cells positive for CD3 subcapsular epithelial cells in expression An association with myasthenia gravis
and CD5, including varying proportions of CK14 {1086}; thus its normal counter- has been reported to have either a better
of CD1a+ CD99+ immature T cells. The part is uncertain. or no effect on prognosis {318,1511,
lymphocytes in the foci of medullary dif- 1630}.
ferentiation are distinctively CD5+ T Somatic genetics
cells. B cells are usually absent. The Deletion of chromosome 6 with or without
fibroblast-like elongated type A cells are formation of ring chromosome 6 has
strongly positive for vimentin and EMA been found in type AB thymoma {437,
and may show weak CK staining. There 1043,1076,2065}. In addition, complex
is no expression of CD5. BCL-2 and multiple chromosomal aberrations have

A B C
Fig. 3.14 Type AB thymoma. A The lymphocyte-associated type B component and the lymphocyte-poor type A component intermix together. The type A component
cells appear as elongated fibroblast-like spindle cells. B The type B component is composed of predominantly small polygonal cells with small round or oval pale
nuclei with pale chromatin and inconspicuous nucleoli. C Type A component is poor in lymphocytes (left), while type B component is lymphocyte-rich (right).

158 Tumours of the thymus - Thymomas


Type B1 thymoma G. Palestro
R. Chiarle
A. Marx
H.K. Mller-Hermelink
I. Sng

Definition Tumour spread and staging densely packed population of small lym-
Type B1 thymoma is a tumour of thymic B1 thymoma is considered to have a low- phocytes, which have clumped chro-
epithelial cells with a histological appear- grade malignant potential being com- matin. Tingible-body macrophages may
ance practically indistinguishable from pletely encapsulated (stage I) in about be scattered throughout giving rise to a
the normal thymus, composed predomi- 53-58% of the cases or invading only the starry-sky appearance. Perivascular
nantly of areas resembling cortex with mediastinal fat (stage II) in another 24- spaces are not as frequent as in the other
epithelial cells scattered in a prominent 27% of the cases {341,1511}. Less fre- B thymomas. Cystic spaces and areas of
population of immature lymphocytes, quently it can invade the pleura, peri- necrosis, when present, are usually
and areas of medullary differentiation, cardium, great vessels or adjacent small.
with or without Hassalls corpuscles, sim- organs; metastases are exceedingly rare Pale areas of medullary differentiation
ilar to normal thymic medulla. {318,341,1511,1631}. Staging is done are always present, composed of more
according to the Masaoka Classification. loosely packed lymphocytes; Hassalls
ICD-O code 8583/1 corpuscles may be seen but are less
Histopathology numerous than in normal medulla. They
Synonyms Type B1 thymoma has also been called range from poorly formed epithelial
Lymphocyte-rich thymoma; lymphocytic predominantly cortical, organoid or lym- groupings to large structures with promi-
thymoma; organoid thymoma; predomi- phocyte-rich thymoma because it con- nent keratinised centres.
nantly cortical thymoma tains predominantly expanded areas
closely resembling the normal functional Differential diagnosis
Epidemiology thymic cortex. The neoplastic epithelial Type B1 thymoma is distinguishable from
B1 thymoma is a relatively rare tumour of cells are scant, small, with very little atyp- the normal non-involuted thymus mainly
the adult age (mean of 41-47 years) with ia, and are surrounded by non-neoplastic based on architectural differences,
no significant difference in the distribu- T lymphocytes. B1 thymomas may grow including the large excess of cortical
tion of genders {318,1511,1631}. B1 thy- in expansile sheets or more often display areas compared to small areas resem-
moma corresponds to 6% to 17% of all a highly organoid lobular architecture bling the thymic medulla, fewer Hassall
thymomas {318,341,1095,1405,1511, recapitulating the normal thymic cortex corpuscles, less regular lobulation and a
1630,1631}. with prevalence of the lymphocyte-rich thick fibrous capsule or irregular fibrous
inner cortical zone. Lobules may be of septa.
Localization varying size and separated by thin or B1 thymoma must be distinguished from
B1 thymoma arises in the anterosuperior thick acellular fibrous bands. The neo- B2 thymoma.
mediastinum, but rare localizations are plastic epithelial component is relatively B1 thymoma with a high predominance
described in the neck, pleura or lung inconspicuous and appears as inter- of T lymphocytes may simulate T lympho-
{632,1238}. spersed oval cells with pale round nuclei blastic lymphoma. An infiltrative pattern
and small nucleoli, although some cells of lymphocytes into septa and capsule
Clinical features may be large and occasionally have con- would favour lymphoma. The presence
B1 thymoma is often diagnosed because spicuous nucleoli. The epithelial cells are of a prominent cytokeratin meshwork and
of associated immunological diseases dispersed and do not form cellular low CDK6 expression in T lymphocytes
such as myasthenia gravis (18-56% of the groupings. The lymphoid component is a favours B1 thymoma {355}.
cases) {318,341,1511}, but local symp-
toms such as cough, dyspnoea and pain
may occur. Rare associated syndromes
are hypogammaglobulinemia and pure
red cell aplasia {987,1088, 2000}. It can
be detected by X-ray, CT or MRI imaging
as an enlarged mediastinal area or mass.

Macroscopy
B1 thymoma is usually a well-defined or
encapsulated greyish mass. Thick
fibrous capsule and septa can be pres- A B
ent, as well as cystic spaces or small Fig. 3.15 Type B1 thymoma. A CD1a staining highlights immature T-cells in the cortex-like areas. B CD20
haemorrhagic and necrotic areas. staining highlights B-cells in the medullary areas.

Type B1 thymoma 159


A B

C D
Fig. 3.16 Type B1 thymoma. A Medullary island (MI) showing Hassall corpuscles. The abnormal localization of MI adjacent to septa or the tumour capsule is very
typical. B High-power of cortex-like areas in B1 thymoma showing a vast majority of lymphoid cells compared to few inconspicuous epithelial cells characterized
by vesicular, clear nuclei and distinct but small nucleoli. C Small medullary island (light), that is devoid of Hassall corpuscles is surrounded by a predominant, cor-
tex-like component rich in immature T-cells (dark). This patttern has been the rationale for labelling B1 thymoma as organoid thymoma. D Cytokeratin 19 stain-
ing labels a network of epithelial cells which is more delicate than in B2 thymoma (compare with fig. 3.18D)

Immunophenotype Histogenesis Actuarial 10-year survival rates are more


The neoplastic epithelial cells express a The postulated cell of origin is a thymic than 90% due to the frequent stage I or II
cytokeratin pattern similar to normal cor- epithelial cell capable of differentiating presentation {318,341,1511}. Staging is
tical epithelial cells (CD19 diffuse, CK7, towards both cortical and medullary the most important prognostic indicator,
CK14, CK18 focal positivity, CK20, CD5, type. whereas age, gender and myasthenia
CD20 and CD70 negative) {354, gravis are not significant prognostic
851,854, 1086} and have a low fraction Prognosis and predictive factors parameters {318,341,1511,1631}.
of growth {1290}. Admixed cortical T B1 thymoma is slightly more aggressive
lymphocytes are CD1a+, CD4+, CD8+, than A and AB thymomas, but less
CD5+, CD99+ and TdT+, with high pro- malignant than B2, B3 thymomas and
liferation rate, whereas lymphocytes in thymic carcinomas. In B1 thymoma,
medullary islands are mostly mature T complete surgical resection is possible
cells: CD3+, CD5+, CD1a-, CD99-, TdT- in 91-94% of the cases {318,1511}, with
{355}. less than 10% of recurrences {318,1511}.

160 Tumours of the thymus - Thymomas


Type B2 thymoma H.K. Mller-Hermelink
I. Sng
R.H. Laeng
N.L. Harris
G. Palestro P.J. Zhang
T.J. Molina A. Marx

Definition {1088,1651}, hypogammaglobulinaemia Histopathology


Type B2 thymoma is an organotypical (Good syndrome) {987} and other There are usually large, coarse lobules of
thymic epithelial neoplasm composed of autoimmune phenomena . tumour with delicate septa, somewhat
large, polygonal tumour cells that are resembling the lobular architecture of the
arranged in a loose network and exhibit Macroscopy normal thymic cortex. Neoplastic cells
large vesicular nuclei with prominent Grossly, type B2 thymomas are encapsu- are large and polygonal, and their large
large nucleoli, closely resembling the lated or vaguely circumscribed and nuclei display an open chromatin pattern
predominant epithelial cells of the normal show a mean diameter of 6.3 cm {318, with prominent central nucleoli, similar to
thymic cortex. A background population 1630}. They can invade mediastinal fat or the appearance of normal cortical thymic
of immature T cells is always present and adjacent organs. The cut surface is soft epithelial cells. The neoplastic epithelial
usually outnumbers the neoplastic or firm and exhibits tan-coloured nodules cells form a delicate loose network, form-
epithelial cells. separated by white fibrous septae. There ing palisades around perivascular
may be cystic changes, haemorrhage, spaces and along septa; large, confluent
ICD-O code 8584/1 and fibrosis. sheets of tumour cells are not a usual
feature, but may occur. If such foci are
Synonyms Tumour spread and staging present, they should be examined close-
Cortical thymoma; lymphocytic thymoma The majority of type B2 thymomas occur ly to make sure that the tumour cells are
(obsolete); mixed lymphocytic and in the anterior mediastinum as Masaoka of B2 and not B3 type. Small epidermoid
epithelial thymoma (obsolete) stage I (10-48%), stage II (13-53%) or foci resembling abortive Hassalls cor-
stage III (19-49%) tumours. Metastatic puscles {1016} may occur in up to 25%
Epidemiology stage IV B2 thymomas are less common of cases, but medullary islands are miss-
Type B2 thymoma accounts for 18-42% (mean 8.9%) {318,341,1511,1630}, and ing or inconspicuous, and typical
of all thymomas {318,341,776,1016, distant metastases (stage IVB) are rare Hassalls corpuscles are exceptional find-
1540,1630,1631,1967}. Differences in (up to 3%) {1511}.
the prevalences of type B2 thymomas
among different institutions reflect the
strong correlation with myasthenia gravis
(MG) rather than real demographic dif-
ferences. Patients ages range from 13-
79 years, with a mean of 47-50 years
{318,1016,1631}. There is no consistent
gender predominance {341,1016,1511,
1630}.

Localization
B2 thymomas are almost always located A B
in the anterior mediastinum. Ectopic
cases are on record, including cases
with extensive pleural involvement
(pleural thymoma). Similarly to all types
of thymoma, they may arise ectopically in
the head and neck region, pleura or lung
{632,1238,1500}.

Clinical features
The most frequent manifestations are C D
symptoms of MG (30-82% of cases)
Fig. 3.17 Type B2 thymoma. A Lobular growth pattern and invasion into mediastinal fat (Masaoka stage II)
{318,341,1016,1511,1630}. Local symp- B Medium power of B2 thymoma resembling B1 in terms of the very high number of lymphoid cells.
toms (chest pain, dyspnoea, cough) However, the nuclei and nucleoli are larger and more conspicuous here than in B1 thymoma. C Medium
occur in about 20% of cases. Rare com- power showing a relatively high number of large tumour cells among a slightly more numerous lymphoid
plications are superior vena cava syn- component. Note inconspicuous cytoplasm but prominent large nuclei of tumour cells with prominent medi-
drome {1651}, pure red cell aplasia um-sized nucleoli. D High magnification of the former illustration.

Type B2 thymoma 161


A B

C D
Fig. 3.18 Type B2 thymoma. A Lymphoid follicle with prominent subcapsular germinal centre, associated with myasthenia gravis. B Type B2 thymoma after mas-
sive corticosteroid treatment: paucity of lymphoid cells, shrinkage of tumour cell nuclei and prominent infiltration of macrophages. C Perivascular space with promi-
nent palisading of elongated large tumour cells. High number of lymphoid cells in the perivascular space (center) and in an intraepithelial position (periphery of
image). D Cytokeratin 19 immunoreactivity of neoplastic epithelial cells highlights the lobular growth pattern of B2 thymoma.

ings. Tumour cells are usually outnum- size is often apparent in condensed or Differential diagnosis
bered by non-neoplastic lymphocytes. sponge-like postnecrotic areas. B1 thymoma is also lymphocyte-rich but
Areas of B3 thymoma occur in associa- epithelial cells are inconspicuous, small-
tion with B2 thymoma in 17-29% of the Immunophenotype er, and less numerous than in B2 thymo-
cases {341,541}. These are recognized Immunophenotypically, neoplastic cells mas. In addition, the nuclei and nucleoli
as lymphocyte-poor areas in which the are cytokeratin (CK) 19+ (100%), CK5/6+ are smaller and the medullary islands are
tumour cells are often smaller, with more (90%), CK7+ (80%), CK20-, EMA-; anti- more prominent than in B2 thymomas.
nuclear irregularity, less conspicuous bodies AE1/3, Cam5.2 and Leu7 (anti- B3 thymoma, in contrast to B2 thymoma,
nucleoli, and distinct cell borders. If any CD57) are almost always reactive is relatively lymphocyte-poor. Neoplastic
component is of B3 type, it should be {367,1016,1086,1631}. CD5, CD20, epithelial cells form confluent sheets and
classified as combined B2/B3 thymoma. CD70 are not expressed by epithelial solid areas with a small but distinctive
cells of B2 thymoma {354, 851,854}. population of intraepithelial immature T-
Lymphoid follicles in perivascular spaces Intraepithelial lymphocytes are predomi- cells. The neoplastic cells are usually
or septa are more frequent in MG-associ- nantly immature T-cells: CD1a+, CD4+, slightly smaller than those of B2 thymo-
ated cases. Regressive changes, either CD8+, CD5+, CD99+, TdT+ with a high ma, with irregular nuclear membranes,
spontaneous or induced by immunosup- Ki67 index of 70-90%. Lymphocytes in smaller nucleoli, nuclear grooves, and
pressive treatment, include necrosis and rare medullary islands are mostly mature less vesicular chromatin. T-lymphoblastic
lymphocyte depletion followed by col- T-cells: CD3+, CD5+, CD1a-, CD99-, lymphoma (T-LBL) may exhibit the same
lapse of the epithelial network and infil- TdT-, and significantly less proliferative immunophenotype and proliferative
trates of histiocytes and lipidized {327,355,1016,1631}. activity of lymphoid cells as those of
macrophages. A decreased tumour cell type B1 and B2 thymomas. However, the

162 Tumours of the thymus - Thymomas


A B Fig. 3.21 Anaplastic thymoma (B2 thymoma with
anaplasia). Metaphase with t(1;8)(p13;p11) translo-
cation. G-banded karyotype showing 46, XY,
t(1;8)(p13;p11).

epithelial network is destroyed in T-LBL,


and lymphoblasts usually infiltrate
beyond the epithelial compartment into
thymic septa and mediastinal fat. Very
high CDK6-expression is a distinguishing
feature of T-LBL {355}.
C D Histogenesis
Fig. 3.19 Type B2 thymoma. A Relatively high number of tumour cells with medium-sized nucleoli among a The postulated cell of origin is a thymic
majority of small lymphocytes. B Differential diagnosis B2 thymoma versus lymphoblastic lymphoma epithelial cell capable of differentiating
(T-LBL): CD1a expression in a rare initial T-LBL that is in a pre-infilrative phase without infiltration of thymic
towards cortical-type epithelial cells.
septum (top of image). C CD1a-positive immature T-cells between B2 thymoma tumour cells with large clear
nuclei and conspicuous nucleoli. D High Ki67 index. Note the non-infiltrated septum at top of image.
Somatic genetics
Recurrent genetic aberrations have not
been reported. More than 80% of B2 thy-
momas are aneuploid {743}. In a single
case with marked anaplasia and giant
cell formation, a t(1;8)(p13;p11) translo-
cation has been reported {1722}.

Prognostic and predictive factors


Type B2 thymoma is a tumour of moder-
ate malignancy, with higher malignant
potential than B1 thymoma, but appears
to be slightly less aggressive than type
B3 thymoma {1016,1511,1630}. It is often
A B invasive, thus non-resectable at presen-
tation in 5-15% of cases. Recurrences,
even after complete resection, are
reported in 5-9%, and metastases in up
to 11% {341,1511,1630}. Recurrences
typically occur after 1-7 years, but are
compatible with long-term survival (>10
years) {1510}. The most relevant prog-
nostic factors are tumour stage and
resectability, while gender, age, and MG
have no adverse effect on survival
{318,341,1645}. Reported 10 year sur-
C D vival rates range between 50-100%
Fig. 3.20 Thymoma with anaplasia. A Anaplastic giant epithelial cells in a B2 thymoma with few intraep- {341,1511,1540,1630}.
ithelial lymphocytes. B Anaplastic giant cells are cytokeratin 19+ but not histiocytes. Note unusual down-
regulation of cytokeratin 19 expression in many other neoplastic epithelial cells. C Anaplastic thymoma har-
bouring a significant population of CD1a+ immature T-cells like other thymomas but in contrast to thymic
carcinomas. D Ki-67 immunohistochemistry showing proliferations of anaplastic giant cells.

Type B2 thymoma 163


Type B3 thymoma H.K. Mller-Hermelink
K. Mukai
T.J. Molina
R. H. Laeng
I. Sng N.L. Harris
G. Palestro A. Marx
A. Zettl

Definition Clinical features bridges are, however, not a feature of B3


Type B3 thymoma is an organotypic The most frequent manifestations are thymoma. In the majority of cases,
thymic epithelial tumour predominantly symptoms of myasthenia gravis (30-77% tumour cells are polygonal, medium-
composed of mediumsized round or of cases) {318,341,1016,1511,1630}. sized, and the round or elongated nuclei
polygonal cells with slight atypia. The Local symptoms like chest pain, dysp- are often folded or grooved and charac-
epithelial cells are mixed with a minor noea or cough are common, while supe- teristically smaller with less prominent
component of intraepithelial lympho- rior vena cava syndrome {1651}, pure nucleoli than in B2 thymomas. Palisades
cytes, resulting in a sheet-like growth of red cell aplasia {1088,1651}, hypogam- around perivascular spaces and along
epithelial cells. maglobulinaemia (Good syndrome) septa are often conspicuous. While
{987} or other autoimmune phenomena medullary islands are usually absent,
ICD-O code 8585/1 are rare. small foci of keratinization mimicking
Hassall corpuscles may be present.
Synonyms Macroscopy
Well-differentiated thymic carcinoma Grossly, type B3 thymomas are usually Variants
(ICD-O code 8585/3); epithelial thymo- not encapsulated but show a vaguely In a minority of cases, slightly more atyp-
ma; squamoid thymoma infiltrative border with extension into ical, enlarged and hyperchromatic nuclei
mediastinal fat or adjacent organs. occur focally. Other rare variants show
Epidemiology Diameters range from 2-13 cm (mean: either polygonal cells with nuclei and
Type B3 thymoma accounts for 7-25% of 7.6 cm) {318,1016,1630}. The cut sur- nucleoli more similar to those in B2 thy-
all thymomas {318,341,1016,1540,1630, face is typically firm and exhibits grey to momas (large cell variant) or partial clear
1967}. Patients age ranges from 14-78 white nodules separated by white fibrous cell changes with focal loss of interep-
years, with a mean age of 45-50 years septa. Soft yellow or red foci, cyst forma- ithelial lymphocytes. Focal or extensive
{318,1016,1511}. There is no consistent tion or hard calcified regions indicate spindle cell formation may also occur.
sex predominance {341,1016,1511, regressive changes that are particularly
1630}. frequent among large and, paradoxically,
small (<3 cm), encapsulated or sclerotic
type B3 thymomas {1085}.

Tumour spread and staging


The majority of type B3 thymomas occurs
in the anterior mediastinum as Masaoka
stage II (15-38%) or stage III tumours
(38-66%), while stage I cases are rare
(mean: 4.2%) {318,541,1016,1511,1540}. Fig. 3.23 Type B3 thymoma with invasion of pleura
Stage IV type B3 thymomas, comprising and pericardium.
cases with either pleural spread (stage
IVA) or distant metastases (stage IVB),
occur in 6-26% (mean: 15%) {318,341,
1016,1511,1630}. Distant metastases
have been reported in up to 7% of cases
{1511} and preferentially involved the
same organs as in type B2 thymomas:
lung, liver, bone and soft tissues.

Histopathology
Histologically, tumour cells form lobules
that are separated by thick fibrous and
hyalinized septa. A major diagnostic cri- Fig. 3.24 Macroscopy of B3 thymoma (left) and rem-
terion is the paucity of intraepithelial lym- nant thymus (right). The cut surface of the tumour
phocytes, resulting in the formation of is white, lobulated and shows infiltration into the
Fig. 3.22 Type B3 thymoma. CT scan showing a well tumour cell sheets with a vaguely solid or surrounding mediastinal fat. Focal regressive
circumscribed tumour in the anterior mediastinum epidermoid appearance. Intercellular changes just left from the tumour centre.

164 Tumours of the thymus - Thymomas


A B

C D
Fig. 3.25 Type B3 thymoma. A Lobular growth pattern and infiltration into mediastinal fat (Masaoka stage II). B Clear cell areas (top and right) adjacent to an area
with a common histology (darker region in lower left part of image). C Ground glass appearance of tumour cells. Low number of intraepithelial lymphocytes.
D Large cell variant with B2-like large nuclei and prominent nucleoli: by its atypia the case appears "borderline" to squamous cell carcinoma of the thymus.

None of these variants has been shown type B2 thymomas, focal EMA positivity Histogenesis
to affect the biological behaviour of type is a characteristic feature. CD5, CD20, The postulated cell of origin is a thymic
B3 thymomas. CD70 {354,851,854} and TTF1 are not epithelial cell capable of differentiating
Combined thymomas exhibiting B2 and expressed in epithelial cells. towards a less differentiated cortical-type
B3 areas are common (17-29%) {341, Most intraepithelial lymphocytes are epithelial cell than in B2 thymoma.
541}, while tumours combining features immature T-cells: CD1a+, CD4+, CD8+,
of type B3 thymoma and thymic carcino- CD5+, CD99+ and TdT+. Somatic genetics
ma are rare (3%) {341}. In a series of 16 B3 thymomas investigat-
As in B2 thymomas, lymphoid follicles Differential diagnosis ed by comparative genomic hybridiza-
inside septa or perivascular spaces may B2 thymoma, in contrast to B3 thymoma, tion (CGH), all tumours showed genetic
occur particularly in myasthenia gravis- is lymphocyte-rich. Neoplastic epithelial imbalances. Recurrent genetic gains
associated cases. Steroid treatment may cells are scattered among lymphocytes were observed on chromosome 1q in
produce a sponge-like appearance and and do not form confluent sheets or 69%, recurrent losses on chromosome 6
accumulation of foam cells in intraepithe- extensive solid areas. B2 thymomas do in 38% of cases, and on chromosome
lial microcysts {1016}. Anaplasia can not express epithelial membrane antigen 13q in 31% {2238}. In microsatellite
occur in type B3 thymomas: a small (EMA). analysis, two major pathways in the
group of tumours show a high degree of Low-grade squamous cell carcinoma of tumorigenesis of B3 thymoma were
atypia with the maintenance of organ- the thymus shows more pronounced epi- described, one characterized by losses
otypic features that is characteristic of dermoid differentiation, usually with read- of 6q (6q23.3-q25.3), the other by losses
thymomas. B3 Thymoma with anapla- ily detectable intercellular bridges. of chromosome 3p (3p22-p24.2; 3p14.2,
sia is the suggested diagnostic termi- Significant numbers of immature intraep- FHIT locus), 5q (5q21, APC locus), 13q
nology. ithelial lymphocytes are absent. (13q14, RB1 locus) and 17p (17p13,
Type A thymoma may resemble the spin- TP53 locus) {896,2242}. Virtually 100% of
Immunophenotype dle cell variant of B3 thymoma. In type A B3 thymomas are aneuploid by DNA
The epithelial cells are positive for cytok- thymoma, there is usually a significant cytometry {743}.
eratin (CK) 19, CK5/6, CK7, CK10, CK 8, reticulin network around individual
as well as for AE1/3 and Leu7 (anti- tumour cells, the degree of atypia is Prognosis and predictive factors
CD57), while CK20 is not expressed lower, and perivascular spaces with B3 thymoma is a tumour of intermediate
{367,1016,1086,1631}. In contrast to epithelial palisades are absent. malignancy. It is almost always invasive,

Type B3 thymoma 165


A B C

D E F
Fig. 3.26 Type B3 thymoma. A Large cell variant: large nuclei and conspicuous nucleoli and paucity of intraepithelial lymphocytes. B Typical perivascular spaces
(PVS) with tumour cell palisading. C Large cell variant, lobular growth pattern; few intraepithelial lymphocytes. D High power of fig. 3.26C. E Hassall corpuscle in
a B3 thymoma (usually rare). F Abortive formation of Hassall corpuscles and vague spindling of tumour cells.

A B C
Fig. 3.27 Immunohistochemistry in type B3 thymoma. A Cytokeratin 19 immunohistochemistry showing the solid sheet pattern of tumour cells and palisading around
perivascular spaces. B CD1a staining showing a low number of immature intraepithelial lymphocytes and immature lymphocytes in a perivascular space.
Predominance of epithelial cells is obvious. C Type B3 thymoma with unusually high number of desmin and myoid cells.

shows frequent local recurrences (15-


17% of cases) {1016,1630}, is often unre-
sectable at presentation (17-47%)
{318,1511,1630} and metastasizes in up
to 20% of cases {341,1511}. Recur-
rences typically occur after 1-6 years,
but late recurrences (after 14 years) have
been reported {1016}. Some authors
{1016,1511,1630} but not others {341,
1540} found B3 thymomas slightly more
A B
aggressive than B2 thymomas in terms of
Fig. 3.28 A CGH hybridization of a type B3 thymoma shows gain of chromosome 1q and loss of chromosome
survival. The most relevant prognostic
6 as the typical genetic alterations of this thymoma type (red hybridization signal corresponding to loss,
factors are tumour stage and resectabili- green hybridization signal corresponding to gain of chromosomal material). This case in addition showed
ty, while gender, age, and MG status loss of chromosome 18q and a high-level amplification on chromosome 8p12 (white arrows).
have no adverse effect on survival B Chromosomal ideogram showing gains and losses of chromosomal material in 23 cases of type B3 thy-
{318,341,1645}. Reported 10 year sur- momas. The most frequent recurrent genetic imbalances in type B3 thymoma are gains of chromosome 1q
vival rates range between 50-70% (60%) and losses of chromosome 6 (43%) (Bars on the right side: gains of chromosomal material, bars on
{341,1511,1540,1630}. the left side: losses of chromosomal material).

166 Tumours of the thymus - Thymomas


Micronodular thymoma with A. Marx
Ph. Strbel
lymphoid stroma M. Marino
T. Eimoto
N.L. Harris
R.H. Laeng

Definition
Micronodular thymoma (MNT) is an
organotypic thymic epithelial tumour
characterized by multiple, discrete
epithelial nodules separated by an abun-
dant lymphocytic stroma that usually
contains prominent germinal centres.
The epithelial component is composed of
bland, oval to spindle-shaped cells with
few intraepithelial lymphocytes. The
epithelial component is similar to type A
thymomas.

ICD-O code 8580/1

Synonym
Micronodular thymoma with lymphoid
B-cell hyperplasia

Epidemiology
MNT is a rare entity accounting for only Fig. 3.30 Micronodular thymoma. Micronodular pattern of nodules of spindle epithelial cells in a lympho-
about 1-5% of all thymomas. The age at cyte-rich stroma but with few intraepithelial lymphocytes.
diagnosis ranged between 4595 years
{1914}. While the mean age in a pub- MNT is not associated with paraneoplas- epithelial nodules are composed of slen-
lished series was 58 years {1914}, in a tic myasthenia gravis. Other autoimmune der or plump spindle cells with bland
recent unpublished series of 33 cases it phenomena that are common in other looking oval nuclei and inconspicuous
was 70 years. There was no sex predilec- thymoma types have not been reported. nucleoli. Rosette formation of epithelial
tion. cells may be seen. Nodules contain few
Macroscopy interspersed lymphocytes. There are no
Localization Size of MNT varies between 3-15 cm in Hassall corpuscles or perivascular
All published cases occurred in the ante- diameter. Cystic tumour areas of variable spaces. Mitotic activity is absent or mini-
rior mediastinum. We have observed a size are common macroscopic findings. mal. Micro- and macrocystic areas, par-
single ectopic MNT in the lateral cervical ticularly in subcapsular localization, are
region {1294}. Tumour spread and staging common.
MNT is encapsulated (>90%) or minimal-
Clinical features ly invasive {1914}. Local excision has Immunohistochemistry
Clinical features usually are related to the been unproblematic and curative {1914}. The epithelial component in MNT stains
size and local extention of the tumour. In our own series, two advanced tumours positive for cytokeratins 5/6 and 19.
With very few exceptions (<5%) {1538}, with infiltration of the pericardium and CAM5.2 and CD57 are positive in about
pleura, respectively, were encountered. 60% each. CD20 is generally not
No tumour-associated deaths have been expressed in the epithelium of MNT
reported. {1538}, in contrast to the epithelial com-
ponent in about half of conventional type
Histopathology A and AB thymomas. Cysts in MNT stain
Microscopically, MNT is characterized by positive for CK 5/6, 7, 8, 19, EMA, and
multiple, discrete or focally confluent CAM5.2.
epithelial nodules separated by an abun- The majority of the lymphocytes in MNT
dant lymphocytic stroma that may con- are CD20+ B-cells, but mature
tain follicles with prominent germinal CD3+CD5+ T cells can outnumber B
centres surrounded by mantle and cells focally. Moreover, immature, Ki67+,
enlarged marginal zones. There is a vari- CD1a+, CD10+, TdT+ and CD99+ thy-
Fig. 3.29 Cystic micronodular thymoma. able number of mature plasma cells. The mocytes are almost always present

Micronodular thymoma 167


A B

C D
Fig. 3.31 Micronodular thymoma. A Epithelial micronodules are composed of bland looking spindle epithelial cells. Few intraepithelial lymphocytes but abundant
lymphocytes around epithelial micronodules. B CD1a staining showing a few intraepithelial immature T-cells inside the epithelial nodules and in the direct periph-
ery (outside) of the nodules. C Histoarchitectural hallmarks are cohesive micronodules of neoplastic epithelia surrounded by a lymphocytic stroma with hyperplastic
lymph follicles. D CD20 staining of a lymphoid follicle between epithelial micronodules in a case of micronodular thymoma.

{1981} restricted to a narrow band sur- grade lymphoma (MALT type and follicu- {1538,1630}. Single combinations with
rounding the epithelial cell nodules, while lar lymphoma) {P. Strbel et al., submit- B2 thymoma have been observed {452}.
intraepithelial lymphocytes are scarce. ted}.
B-cells frequently form follicles with or Histogenesis
without germinal centres with a well Differential diagnosis A medullary epithelial cell origin has
developed network of follicular dendritic MNT should be differentiated from con- been postulated {452}.
cells and a population of CD57+ T-cells. ventional type AB thymomas, which in
Germinal centre B-cells are CD10+ and rare cases may also contain single lym- Prognosis and predictive factors
bcl-2-. Mantle zones consist of IgD+ B- phoid follicles. In contrast to type AB and There have been no reports on recur-
cells, while marginal zones are IgD- and other organotypic thymomas, the lym- rences, metastasis or tumour-related
CD23-. Plasma cells are usually poly- phocytic-rich areas in MNT do not con- deaths.
clonal. In a recent series of 18 MNTs, tain epithelium. Of note, MNT may rarely
expansion of monoclonal B cell popula- (10%) occur together with an otherwise
tions was observed in 33% of cases, with typical type A and AB thymoma
half of them showing features of low

168 Tumours of the thymus - Thymomas


Metaplastic thymoma J.K.C. Chan
A. Zettl
M. Inoue
D. de Jong
S. Yoneda

Definition Localization infiltration of adjacent tissues {2210} and


Metaplastic thymoma is a circumscribed The tumour has not been described out- may recur {2211}.
tumour of the thymus in which anasto- side the thymus.
mosing islands of epithelial cells are Histopathology
intermingled with bland-looking spindle Clinical features The tumour is well circumscribed, some-
cells. Most patients are asymptomatic, being times with a narrow rim of residual thymic
incidentally found to have an anterior tissue incorporated in its peripheral por-
ICD-O code 8580/1 mediastinal mass, while some present tion. Occasional cases can show inva-
with cough. None of the patients have sion of the surrounding tissues. In con-
Synonyms myasthenia gravis or other paraneoplas- trast to conventional thymomas, it does
Metaplastic thymoma has been reported tic syndromes. not show a lobulated growth pattern.
in the literature under the designations Typically, the tumour exhibits a biphasic
thymoma with pseudosarcomatous stro- Macroscopy architecture comprising epithelial islands
ma, low grade metaplastic carcinoma The tumour is well circumscribed to intertwining with bundles of delicate
and biphasic thymoma, mixed polygo- encapsulated, but can exhibit invasive spindle cells. The two components are
nal and spindle cell type {1808,1919, buds. The cut surfaces show homoge- present in highly variable proportions
2210}. neous, rubbery, grey-white tumour. The from area to area of a single tumour and
reported maximum dimensions of the from case to case.
Epidemiology tumours range from 6-16 cm. The epithelial component takes the form
This rare tumour occurs in adult patients, of anastomosing islands to broad trabec-
with a median age of 53 years and mean Tumour spread and staging ulae, and often exhibits a squamoid qual-
age of 50.9 years. There is male pre- The Masaoka stage distribution at pres- ity or whorled configuration. The con-
dominance (M:F ratio 3:1) {1485,1919, entation is as follows: 75% stage I, 17% stituent cells are polygonal, ovoid or
2210,2211}. stage II, 8% stage III {1485,1919,2210, plump spindle, with oval vesicular nuclei,
2211}. Occasional tumours can show small distinct nucleoli and a moderate

A B

C D
Fig. 3.32 Metaplastic thymoma. A The tumour is well circumscribed. A thin rim of residual thymic tissue is incorporated into the peripheral portion. B Anastomosing
rounded islands of epithelial cells are disposed among spindle cells. C Broad trabeculae of epithelium are separated by narrow zones of spindle cells. D A stori-
form growth pattern is seen.

Metaplastic thymoma 169


cinosarcoma). The latter often shows
prominent coagulative necrosis, signifi-
cant atypia in the spindle cells and read-
ily identified mitotic figures.

Histogenesis
Biphasic metaplastic thymoma is a
tumour of thymic epithelial cells. The
spindle cell component probably arises
A B as a metaplastic phenomenon, rather
than a stromal reaction in view of its
Fig. 3.33 Metaplastic thymoma. A The epithelial component (right field) is fairly well delineated from the
spindle cell component. The latter comprises slender cells that are bland-looking. B The squamoid epithe- marked predominance and presence of
lial island shows enlarged atypical nuclei that are either hypochromatic or hyperchromatic. It is richly tra- genetic aberrations in a recurrent case.
versed by twigs of collagen fibrils. Tumour circumscription, relatively bland
cytology and usually good prognosis
amount of lightly eosinophilic cytoplasm. predominance of one component to the suggest that the tumour is benign.
Some cells can exhibit large empty-look- exclusion of the other in some or most However, lack of association with myas-
ing nuclei, large hyperchromatic nuclei areas. A diagnosis of such cases can be thenia gravis, tumour lobulation and
or nuclear pseudoinclusions. Despite the difficult without extensive sampling to perivascular spaces suggest some rela-
nuclear atypia, mitotic figures are rare. identify the typical biphasic pattern. tion to thymic carcinoma. Molecular stud-
Twig-like hyaline or sclerotic material ies, however, favour interpretation of this
may be abundant around and within the Immunophenotype tumour as a thymoma.
epithelial islands. Epithelial cells show strong staining for
The spindle cells show a short fascicular cytokeratin and variable staining for Somatic genetics
or storiform growth pattern. They are epithelial membrane antigen, and they Comparative genomic hybridization and
often separated by small amounts of do not show cell membrane staining for microsatellite studies on a limited num-
loose tissue or delicate collagen fibrils. CD5. The spindle cells show focal weak ber of cases have shown no or few
They are always bland-looking and often or negative staining for cytokeratin and genetic alterations, suggesting a closer
mitotically inactive, with fine nuclear epithelial membrane antigen, positive relationship with type A or type AB thy-
chromatin and slender bipolar cell staining for vimentin, and inconsistent moma than with thymic carcinoma or
processes. They may show sharp delin- staining for actin. CD20 is negative. type B3 thymoma. Tumour recurrence is
eation or gradual merging with the Proliferative fraction (Ki67 index) is low apparently associated with acquisition of
epithelial islands. In the rare recurrences, (<5%). The T lymphocytes within the multiple genetic aberrations.
the spindle cells can show nuclear atyp- tumour proper usually exhibit a mature
ia and mitotic activity, associated with immunophenotype (TdT negative). Prognosis and predictive factors
acquisition of additional genetic aberra- Ultrastructurally, the spindle cells may or Among 11 patients with follow-up infor-
tions {2211}. Lymphocytes are usually may not show epithelial characteristics mation, 10 have remained well after sur-
sparse, but some cases can exhibit a such as tonofilaments and cell junctions gical excision at 1.5-20 years (median 5
light infiltrate of small lymphocytes and {1485,1919}. years) {1485,1919,2210,2211}. One
plasma cells. There can be scattered foci patient developed local recurrence at 14
of stromal calcification. Differential diagnosis months, and died at 6 years {2211}.
While both the epithelial and spindle cell It is most important not to mistake meta-
components are readily recognizable in plastic thymoma for the vastly more
most cases, some cases show marked aggressive sarcomatoid carcinoma (car-

A B C
Fig. 3.34 Metaplastic thymoma. A Immunostaining for pan-cytokeratin shows strong staining of the epithelial islands. Very few spindle cells are positive.
B Immunostaining for epithelial membrane antigen shows that the spindle cells are weakly positive, while the epithelial component is only focally positive.
C Immunostaining for TdT highlights only the thin band of lymphocytes within the incorporated thymic tissue in the periphery. There are no TdT positive cells with-
in the tumour proper.

170 Tumours of the thymus - Thymomas


Rare thymomas A. Marx
G. Chen
Ph. Strbel
T.T. Kuo
P.J. Zhang

Microscopic thymoma
ICD-O code 8580/1

Microscopic thymoma is the term applied


to usually multifocal epithelial prolifera-
tions (<1 mm in diameter) that preferen-
tially occur in myasthenia gravis-associ-
ated thymuses (15% of cases) without a
macroscopically evident tumour {1580}. A B
Respective epithelial nodules occur at Fig. 3.35 Type B1 thymoma / Lipofibroadenoma. A Gross appearance of a composite thymic tumour. The left
lower frequency in 4% of non-myasthenic lower part is a B1 thymoma and the right upper attached mass is a lipofibroadenoma. Note the white yel-
control thymuses {1626}. Microscopic low colour of the latter. The right lower piece is the thymus. B Lipofibroadenoma. A thymic lipofibroadeno-
thymoma may arise in cortical or ma composed of interconnecting thin strands of epithelial cells forming animal-like figures in an abundant
medullary thymic compartments {1580}. fibrous stroma with scattered fat cells.
Histologically, it shows marked hetero-
geneity and can be composed of bland-
looking or more pleomorphic, polygonal and probably resulted from tumour occurred adjacent to a conventional type
or plump spindle cells, usually without regression {1085}, we observed a well B1 thymoma in a patient with pure red
intraepithelial immature T-cells. Though circumscribed B2-like thymoma with a cell aplasia {1096}. The tumour resem-
microscopic thymoma may occur adja- diameter of 18 cm exhibiting a collage- bles fibroadenoma of the breast, taking
cent to conventional thymoma, its role as nous, partially hyalinized stroma har- the paucity of lymphocytes and the
a precursor lesion of macroscopic thy- bouring scant and bland looking fibrob- extended narrow strands of epithelial
moma is unresolved {1580}. lasts. There was neither necrosis nor cells into account. With respect to the
haemorrhage, suggesting that the stro- predominance of stroma over the epithe-
ma resulted from a fibrogenic stimulus lial component (including rare Hassall
Sclerosing thymoma delivered by thymoma epithelium. The corpuscles), the tumour shares morpho-
18-year-old male, non-myasthenic logical features with thymolipoma. As
ICD-O code 8580/1 patient remained free of complications with thymolipoma, it is unknown whether
after complete resection. the epithelial, the fibrolipomatous or both
This is an exceedingly rare tumour (<1%) components are neoplastic or whether
exhibiting the features of a conventional the lesion is a hamartoma.
thymoma in terms of epithelial cell mor- Lipofibroadenoma
phology and lymphocyte content, but
with exuberant collagen-rich stroma. Lipofibroadenoma of the thymus is a
While some cases were small (<3 cm) recently described neoplasm that

A B
Fig. 3.36 Microscopic thymoma. Small nodule of oval Fig. 3.37 Sclerosing thymoma. A Higher magnification shows a residual B3 thymoma in the center of a scle-
and spindle epithelial cells in an atrophic thymus. rosing thymoma. B Cytokeratin 19 immunoreactivity of epithelial tumour cells resembling a B1 thymoma.
There are almost no intraepithelial lymphocytes.

Rare thymomas 171


Squamous cell carcinoma M. Fukayama
T. Hishima
T. Fujii
A. Zettl
Y. Shimosato

Definition Clinical features Most cases of thymic squamous cell car-


Thymic squamous cell carcinoma is a The most frequent symptom is chest cinomas belong to Masaoka stage III and
type of thymic tumour with features of pain. Other symptoms are cough, IV at the time of surgery.
squamous cell carcinoma as seen in other fatigue, fever, anorexia, weight loss, and
organs, with or without clear-cut evidence superior vena cava syndrome. There Histopathology
of keratinization in routinely stained sec- have been no reports on myasthenia There are two hallmarks for the diagnosis
tions {1094,1691,1806,1808, 1841,1924, gravis (MG) or pure red cell aplasia, but of thymic squamous cell carcinoma: the
2032,2143}. In contrast to thymomas of paraneoplastic polymyositis can occur. A clear-cut cytological atypia in the large
the A and/or B categories, thymic carci- few MG-associated thymomas have epithelial cells that are arranged in nests
nomas lack immature T-lymphocytes been reported to progress to thymic and cords, and the broad zone of fibro-
{632,1748}. squamous cell carcinoma {1808}. hyaline-stroma separating the tumour
Thymic squamous cell carcinoma can be cell nests {1094,1806,1808,1841,1924,
ICD-O code 8070/3 detected by imaging techniques. Cystic
changes and calcium deposits are rare.
Synonym A relatively larger size and the lack of
Epidermoid keratinizing and nonkera- septal or nodular structures within the
tinizing carcinoma. tumour support the diagnosis of carcino-
ma rather than invasive thymoma {501,
Epidemiology 946}.
Thymic carcinomas are rare. The inci-
dence of thymic carcinomas occurring in Macroscopy
combination with a thymoma has been Squamous cell carcinomas usually lack
reportedly 10-20%. Squamous cell carci- encapsulation or internal fibrous septa-
noma is the most frequent subtype of tion that are common in thymomas. They A
thymic carcinoma, and the frequency is are firm to hard with frequent foci of
higher in Asia (90%) {1510,1808} than in necrosis and haemorrhage.
the West (30%) {318,1094,1841, 1924,
2032,2143}. Most cases occur at middle Tumour spread and staging
age, and the male to female ratio varies Thymic squamous cell carcinomas fre-
from 1 to 2.3 {1808}. quently invade the lungs, pericardium,
and major vessels. The most frequent
Localization sites of metastases are the lymph nodes
Thymic squamous cell carcinoma exclu- (mediastinal, cervical, and axillary), fol-
sively presents as an anterior mediastinal lowed by the bone, lung, liver and brain
tumour, and frequently invades the adja- {1808}. B
cent lung tissue.

C
Fig. 3.39 Immunohistochemistry of squamous cell
carcinoma of the thymus. A Diffuse immuno-
staining to CD70. B CD5 is also expressed in near-
A B ly all neoplastic cells. Note the immunolabelling of
Fig. 3.38 A Squamous cell carcinoma occurring in multilocular thymic cysts. Papillary growth of the tumour lymphocytes in the stroma. C Neuroendocrine dif-
in a large and haemorrhagic cyst. B Well differentiated squamous cell carcinoma, showing papillary ferentiation in thymic squamous cell carcinoma.
growth in the cystic space and invasion of the underlying stroma. CD56-positive cells scattered in neoplastic cells.

172 Tumours of the thymus - Thymic carcinomas


anterior mediastinum. However, tumour
cells in nasophayngeal carcinoma and
Hodgkin lymphoma may be CD70+.
Neuroendocrine markers (chromogranin,
synaptophysin, GTP binding protein Go-
alpha subunit, or CD56/NCAM) alone or
in combination are positive in two-thirds
of thymic squamous cell carcinomas in
focal or dispersed distribution {852,853,
1139}. Some of these neuroendocrine
cells show positivity for alpha-subunit of
human chorionic gonadotropin or ACTH
{630}.

Differential diagnosis
It is sometimes difficult to exclude the
possibility of lung carcinoma showing a
prominent extra-pulmonary growth.
Palisading or radial arrangement of the
cells at the borders of nests as often
Fig. 3.40 Keratinizing squamous cell carcinoma of the thymus. Large polyhedral cells with cytological atyp- seen in squamous cell carcinoma of the
ia, arranged in nests and cords, in fibrohyaline stroma. lung and oesophagus, is not commonly
observed. In addition, immunohisto-
chemical evidence (CD5, CD70 and
2032,2143}. A lobular growth pattern and are frequently seen, as is the invasion of CD117 positivity) may support the thymic
some remnant perivascular spaces may intratumoural blood vessels. origin of the neoplastic squamous cells
be recognized. Lymphocytes, when {632,854}. Infiltration of immature T-cells
present, are mature and usually admixed Immunohistochemistry (CD1a+, TdT+, CD99+) as seen in thy-
with plasma cells. The epithelial cells of most thymic squa- moma is not observed in thymic carcino-
Squamous cell carcinoma is composed mous cell carcinomas are immunoreac- mas {327,632,1748}.
of large polyhedral cells arranged in tive to CD5, CD70 and CD117 {151,511, Well-differentiated squamous cell carci-
nests and cords, and shows evidence of 816,851,1059,1887,1978}. Thymomas noma may rarely occur in a thymic cyst
keratinization and/or intercellular are negative to CD5 except for some {633,1161}. This type of carcinoma
bridges. The nuclei are vesicular or cases of type B3. Squamous cell carci- needs to be differentiated from the
hyperchromatic, and nucleoli are usually nomas of other organs are negative to pseudopapillary growth found in the mul-
readily apparent. Cytoplasm is eosino- CD5 and CD70, and thus both markers tilocular thymic cyst {1907}, and should
philic. The number of mitotic figures is are quite useful to confirm the thymic ori- be classified in a different category.
variable. Foci of spontaneous necrosis gin of squamous cell carcinomas in the
Precursor lesions
Some cases of thymic squamous cell
carcinoma are thought to arise from pre-
existing thymomas based on the obser-
vation of combined thymic epithelial
tumours that harbour squamous cell car-
cinoma and conventional (usually B3)
thymoma components {1093,1386,
1912}. The two components may be
widely separated, or observed in admix-
ture or in a gradual transition within the
same tumour mass.
A B
Fig. 3.41 Thymic carcinoma. A CGH hybridization of a thymic squamous cell carcinoma shows gain of chro- Histogenesis
mosome 1q, loss of chromosome 6 and loss of chromosome 16q as the typical genetic alterations of this Thymic squamous cell carcinomas may
tumour type (highlighted by the yellow arrows; red hybridization signal corresponding to loss, green be derived from thymic epithelial stem
hybridization signal corresponding to gain of chromosomal material). This case in addition showed loss of
cells.
chromosome 17p, and gain of chromosomes 8 and 17q (highlighted by the white arrows). B Chromosomal
ideogram showing gains and losses of chromosomal material in 12 cases of thymic squamous cell carcino-
ma investigated by CGH. The most frequent recurrent genetic imbalances in thymic squamous cell carci- Somatic genetics
noma are losses of chromosome 16q (67%), gains of chromosome 1q (60%) and losses of chromosome 6 Trisomy 8 and der(16)t(1;16) have been
(50%). (Bars on the right side: gains of chromosomal material, bars on the left side: losses of chromosomal reported in a single case of thymic squa-
material). mous cell carcinoma {1847}. Loss of

Squamous cell carcinoma 173


chromosome 16q, 6, 3p, and 17p and
gain of 1q, 17q and 18 are frequently
observed by comparative genomic
hybridization {2238}. Deletion of chromo-
some 6 {896} and gain of 1q are common
alterations in type B3 thymomas, where-
as alterations at 3p, 16q, 17p, 17q and
18 are characteristic of squamous cell
carcinoma. TP53-overexpression has
been observed in most of thymic carci-
nomas, but the frequency of TP53-over-
expression in thymomas varies consider-
ably {339,835,1980,2118}. TP53 gene
mutation can be detected in 30% of
thymic carcinomas {339}. Inactivation of
p16 (CDKN2A) and methylation of pro-
moter region of p16 are relatively more
frequent in thymic carcinomas than in A
thymomas {835}. Bcl-2 expression is
observed in nearly all thymic carcino-
mas, while it is absent in most thymomas
except for type A {1979}.

Prognosis and predictive factors


The prognosis of squamous cell carcino-
ma is largely dependent on tumour stage
and grade {1808}. They have a better
prognosis than other types of thymic car-
cinomas with the exception of basaloid
carcinoma.

B
Fig. 3.42 A Thymic squamous cell carcinoma, nonkeratinizing type. In contrast to B3 thymoma, this tumour
shows moderate atypia and lacks intraepithelial immature T-cells. The prominent perivascular spaces hint
to to the thymic origin of this tumour. B Squamous cell carcinoma. Apparent evidence of keratinization, a
squamous pearl, within the tumour nest.

174 Tumours of the thymus - Thymic carcinomas


Basaloid carcinoma M.R. Wick
A. Zettl
A.S. Baur
H.K. Mller-Hermelink
A. Marx

Definition surrounded by a thin fibrous capsule with squamous epithelium in continuity with
Basaloid carcinoma is a thymic carcino- focal haemorrhage and cyst formation. In the basaloid cells are noted {886,1924}.
ma composed of compact lobules of about 60% of reported cases basaloid In some cases, globular eosinophilic
tumour cells with peripheral palisading carcinomas were found as a mural nod- deposits of basement membrane-like
and a basophilic staining pattern due to ule in a multilocular thymic cyst and/or material is observed {1663}. There may
a high nuclear-cytoplasmatic ratio. showed cystic changes in the tumour. be tumour areas with numerous poorly
Basaloid carcinoma shows a remarkable Microscopically, basaloid carcinoma is formed gland-like, cystic spaces lined by
tendency to originate in multilocular composed of rather monotonous, small basaloid tumour cells and containing
thymic cysts. to medium-sized, columnar, round to PAS-positive/mucicarmin negative stro-
oval, or vaguely spindled tumour cells mal mucin {1663,1924}.
ICD-O code 8123/3 with high nucleo-cytoplasmic ratios, The multilocular thymic cyst frequently
hyperchromatic round to oval nuclei with associated with basaloid carcinoma is
Synonym inconspicious nucleoli, scant amount of lined by benign appearing squamous
Basaloid squamous cell carcinoma of the amphophilic cytoplasm, and indistinct epithelium which may imperceptively
thymus {1663}. cytoplasmic borders. The cells are ha- blend with the basaloid tumour cells.
phazardly arranged in trabeculae, anas-
Epidemiology tomosing cords, islands and nests, and Immunohistochemistry
A very rare variant of thymic carcinoma typically show prominent palisading at On immunohistochemistry, basaloid car-
with only 10 cases reported in the litera- the periphery with the tumour cells being cinomas express keratin and EMA. As
ture so far {861,886,980,1266,1841, elongated and radially arranged similar other thymic carcinomas, they can
1924,1974}. In a large series of thymic to patterns seen in basal cell carcinoma express CD5 {511}. Basaloid carcinomas
carcinomas, only 5% were basaloid car- of the skin. Perivascular spaces can be are negative for S-100, neurendocrine
cinomas {1924}. Most cases occur in the prominent. Mitoses are frequent. markers (NSE, chromogranin and synap-
5th decade of life (reported age range 41 Occasionally, focal keratinization in the tophysin) {886,980}.
to 65), male and female partients are centre of the cell nests with concentric
equally affected. whorls of bland, metaplastic-appearing Differential diagnosis
A mediastinal metastasis of a basaloid
Clinical features carcinoma of other primary location, par-
The symptoms are non-specific. Patients ticularly of the upper and lower respirato-
may show symptoms related to a medi- ry tract needs to be excluded.
astinal mass, e.g. chest pain or dysp- Neuroendocrine carcinomas may histo-
noea. In asymptomatic patients, the logically mimic basaloid carcinoma.
tumour may be detected by routine X-ray
or during unrelated thoracotomy. No Genetics
paraneoplastic autoimmune phenomena CGH analysis of a single case of basa-
such as myasthenia gravis are observed. loid carcinoma of the thymus showed
multiple gains and losses of chromoso-
Etiology A mal material, among them gain of chro-
More than half of the reported cases of mosome 1q and losses of chromosomes
basaloid carcinoma were associated 6 and 13. These abnormalities strongly
with a multilocular thymic cyst {886,980, overlap with those previously found in
1841,1974}. Basaloid carcinoma of the thymic squamous cell carcinomas
thymus may thus incidentally arise within {2238}.
a preexisting multilocular thymic cyst or
may induce cystic changes in the non- Prognosis
neoplastic thymus as a reactive Initially regarded as low-grade malignan-
response {886}. cy {1924}, metastasis to lung and liver
B have been reported in 30% of cases
Morphology Fig. 3.43 Basaloid carcinoma of the thymus. {1266,1841,1924}.
The tumour size ranges between 5 and A Sharply outlined islands of basophilic tumour
20 cm. Basaloid carcinomas are mostly cells showing peripheral pallisading. B Strong CD5
well-circumscribed, grey to tan masses immunoreactivity in virtually all tumour cells.

Basaloid carcinoma 175


Mucoepidermoid carcinoma M.R. Wick
A. Marx
H.K. Mller-Hermelink
Ph. Strbel

Definition
Mucoepidermoid carcinoma of the thy-
mus is a rare morphologic variant of pri-
mary thymic carcinoma characterized by
the presence of squamous cells, mucus-
producing cells and cells of intermediate
type. Mucoepidermoid carcinoma of the
thymus closely resembles mucoepider-
moid carcinomas of other organs.

ICD-O code 8430/3

Epidemiology
This rare tumour comprises approximate-
ly 2% of published thymic carcinoma
cases {785,1841,1924}. It tends to occur
in aged individuals.

Clinical features A
Mucoepidermoid carcinomas are not
associated with myasthenia gravis and
may be asymptomatic {1924}.

Morphology
On macroscopy, the cut surface of
mucoepidermoid carcinomas is nodular
with fibrous bands and a mucinous
appearance {1663,1841}. On histology,
the mucous tumour cells are polygonal,
columnar or more goblet-like and form
solid masses or line cysts {1663,1841}.
Mucin-producing cells are strongly PAS-
positive {1841}. Areas with squamous
differentiation can be solid or form part of
a cyst linings. The squamous epithelial
cells show minimal to moderate atypia
with rare mitoses. The intermediate cells
are polygonal or spindle shaped with a
B
moderate amount of eosinophilic cyto-
Fig. 3.44 Mucoepidermoid carcinoma of the thymus. A Admixture of mucin-producing and squamous cells
plasm and round to oval nucleolus with
in a predominantly cystic neoplasms. B Higher magnification showing mucin producing cells surrounded
finely dispersed chromatin.
by squamous epithelial cells. From J. Rosai and L.H. Sobin {1690}.

Postulated cell of origin


Pluripotent epithelial stem cells of endo- al. {1841} described one case of nosis have been described {625,1094,
dermal origin have been postulated in mucoepidermoid carcinoma of the thy- 1264,1381,1946,1965,2009,2032,2098}.
the pathogenesis of mucoepidermoid mus with a low grade morphology that At the moment, it is not clear whether
carcinoma of the thymus by some was completely resectable and the these cases represent poorly differentiat-
authors {1841}. patient was alive after 28 months. ed mucoepidermoid carcinomas or form
However, a number of cases of thymic a separate tumour entity.
Prognosis and predictive factors adenosquamous carcinoma with focal
Only single case reports on the clinical mucin production but a high grade mor-
course have been published. Snover et phology {1663} and unfavourable prog-

176 Tumours of the thymus - Thymic carcinomas


Lymphoepithelioma-like carcinoma T.T. Kuo
J.K.C. Chan
K. Mukai
T. Eimoto
H. Tateyama

Definition
Lymphoepithelioma-like carcinoma
(LELC) of the thymus is a primary thymic
carcinoma characterized by a syncytial
growth of undifferentiated carcinoma
cells accompanied by a lymphoplasma-
cytic infiltration similar to undifferentiated
carcinoma of the nasopharynx. Thymic
LELC may or may not be associated with
Epstein-Barr virus (EBV). However, undif-
ferentiated carcinoma in a dense fibrous
stroma without a significant lymphoid
infiltration but positive for EBV is tenta-
tively included in this category.

ICD-O code 8082/3

Synonym
Lymphoepithelial carcinoma

Epidemiology Fig. 3.46 Lymphoepithelioma-like carcinoma of the thymus. Syncytial tumour cells are characterized by
Thymic LELC is a rare tumour. It occurs large nuclei with open chromatin, prominent nucleoli, and indistinct cytoplasmic membrane. Note the heavy
twice more commonly in male than infiltrates of lymphoplasmacytic cells.
female patients. The patients age ranges
from 4-76 years with a median of 41 liver, and bone are frequent sites for ulomas may be seen. The tumour cells
years and a bimodal peak age incidence metastasis {785,2143}. have large vesicular nuclei with open
at 14 years and 48 years {328,343, chromatin and one or more distinct
785,873,885,889,1094,1472,1876,1924, Clinical features eosinophilic nucleoli and show indistinct
2143,2174}. The patients usually complain of dull cytoplasmic membranes. The nuclei are
chest pain, cough, or dyspnoea and con- unevenly crowded and may appear to be
Localization stitutional symptoms, but some patients overlapping. Lymphocytes are not only
Thymic LELC occurs in the anterior medi- are asymptomatic and incidentally found present in the stroma, but are also inti-
astinum and usually extends into con- to have an anterior mediastinal mass mately admixed with the carcinoma cells.
tiguous structures. Lymph node, lung, upon imaging examination {785,2143}. Mitotic activity is variable but is often pro-
Superior vena cava syndrome is seen in nounced. Foci of tumour necrosis are
patients with more advanced disease usually observed. The histopathologic
{785,873,889,2143}. There is no associa- appearances of LELC may overlap with
tion with myasthenia gravis or other para- those of poorly differentiated squamous
neoplastic syndromes, but hypertrophic cell carcinoma with a lymphoplasmacytic
pulmonary osteoarthropathy has been stroma. Currently, with lack of molecular
reported in children {491,873,889,1472}. data on LELC and squamous cell carci-
noma of the thymus to determine their
Macroscopy relationship, if any, the diagnosis of
Grossly, the tumour is solid and yellow thymic LELC should be restricted to
white with areas of necrosis. It is usually tumours showing the typical histologic
incompletely encapsulated. appearances similar to that of nasopha-
ryngeal undifferentiated carcinoma (but
Histopathology allowing for presence of focal primitive
Fig. 3.45 Lymphoepithelioma-like carcinoma (LELC) Histologically, the tumour is composed of squamous cell differentiation in the form
of the thymus. A solid tumour with an irregular bor- nests or anastomosing cords of carcino- of eosinophilic mildly keratinizing cyto-
der and a yellow necrotic area. The tumour is ma cells in a lymphoplasmacytic stroma. plasm). Furthermore, since the so-called
growing into a multiloculated cyst on the left side. Germinal centres, eosinophils, and gran- undifferentiated carcinoma has not

Lymphoepithelioma-like carcinoma 177


been clearly defined for the thymus
{1691}, cases that do not show all classi-
cal appearances of LELC should not be
included under this category.

Immunohistochemistry
The tumour cells are strongly positive for
AE1-defined acidic cytokeratins (CKs),
and negative for AE3-defined basic CKs.
CK7 and CK20 are also negative. CD5 A B
may be expressed focally or not at all
{511}. The carcinoma cells also com-
monly express BCL-2 {338}. The majority
of lymphoid cells are CD3+, CD5+,
CD1a-, CD99-, and TdT- mature T cells
{327}. Smaller numbers of CD20+ B cells
are present in the stroma and among the
carcinoma cells. Plasma cells that are
present are polyclonal.

Histogenesis C D
Thymic LELC presumably arises from
thymic epithelial cells.

Somatic genetics
Overall, approximately 47% of cases of
thymic LELC show association with EBV
as demonstrated by EBER in situ
hybridization or DNA analysis {328,343,
491,873,1472,1876,2174}. EBV is almost
always positive in thymic LELC occurring
E F
in children and young adults, while EBV
Fig. 3.47 Lymphoepithelioma-like carcinoma of the thymus. A The carcinoma cells are strongly immunopo-
positivity rate is lower in adults over the
sitive for AE1-defined acidic cytokeratins. B The neoplastic cells are immunopositive for BCL-2.
age of 30 years. In two childhood cases C Abundant infiltrating lymphoid cells in lymphoepithelioma-like carcinoma are CD3+ mature T cells. D In
studied, the latent membrane protein-1 contrast, only few CD20+ B cells are present. E LELC without prominent lymphoid stroma but a syncytial
gene of EBV did not have a 30-base pair arrangement of large tumour cells with indistinct cell borders, large nuclei and conspicuous nucleoli.
deletion as seen in other EBV associated F Carcinoma cells showing strong nuclear signal of EBER (Epstein-Barr virus early RNA) by in-situ hybridization.
neoplasms {873,1089}. The association
with EBV is not related to geographic or
ethnic factors {885}. Based on the EBV
status, LELCs can be designated as with EBV {616,985}. This unique neo- mated average survival is 16 months in
either EBV+ LELC or EBV- LELC pending plasm is believed to be a different entity, 88% of patients {885}. The presence or
clinicopathologic and further molecular although no chromosomal genetic infor- absence of EBV does not seem to have
genetic investigation for their differences. mation is currently available for thymic prognostic significance.
The rare lethal carcinoma with t(15;19) LELC.
translocation {985,1876} occurring in the
mediastinum and respiratory tract of Prognosis
young people may share histologic fea- Thymic LELC is a highly malignant neo-
tures of LELC, but it is not associated plasm with a poor prognosis. The esti-

178 Tumours of the thymus - Thymic carcinomas


Sarcomatoid carcinoma A.C.L. Chan
J. K. C. Chan
T. Eimoto
K. Mukai

Definition tive necrosis. It shows intimate intermin- oli and frequent mitotic figures.
Sarcomatoid carcinoma is a thymic car- gling of carcinomatous and sarcomatoid Heterologous elements may be
cinoma in which part or all of the tumour components, but the carcinomatous observed, most commonly rhab-
resembles soft tissue sarcoma morpho- component can be subtle or demonstra- domyosarcomatous and occasionally
logically. ble only by immunohistochemistry or osteosarcomatous; the term carcinosar-
electron microscopy in some cases. The coma is sometimes applied for such
ICD-O code 8033/3 carcinomatous component usually com- cases {534,1478,1509,1841,1897}. In the
prises cohesive clusters and sheets of rhabdomyosarcomatous areas, spindle
Synonyms poorly differentiated epithelial cells with cells with cross striations and large cells
Carcinosarcoma, spindle cell thymic car- significant nuclear pleomorphism, and with abundant eosinophilic fibrillary cyto-
cinoma some cases may show obvious squa- plasm are found. In the osteosarcoma-
mous differentiation. The sarcomatoid tous component, osteoid production by
Epidemiology component frequently comprises fasci- tumour cells is seen.
Sarcomatoid carcinoma is uncommon cles and storiform arrays of discohesive Immunohistochemically, the carcinoma-
and accounts for only up to 7% of all spindle tumour cells with pleomorphic tous component expresses epithelial
thymic carcinomas {1924}. It is a tumour nuclei, coarse chromatin, distinct nucle- markers such as cytokeratin and epithe-
of late adulthood, predominantly fourth to
eighth decades.

Localization
The tumour is located predominantly in
the anterior mediastinum, with frequent
invasion of the adjacent structures.

Clinical features
The patients present with cough, dysp-
noea, dysphagia, chest pain, weight
loss, or superior vena cava syndrome
{1478,1897,2143}. Imaging studies
reveal the presence of a large anterior
mediastinal mass.

Macroscopy A
Grossly, the tumour is unencapsulated,
often with infiltrative borders. The cut sur-
faces show whitish or greyish fleshy
tumour with variable extent of necrosis
and haemorrhage. Microcysts may be
present.

Tumour spread and staging


The tumour is locally invasive, with fre-
quent invasion of the adjacent pleura,
lung and pericardium, and encroach-
ment on the major blood vessels in the
mediastinum. Metastases to mediastinal
lymph nodes and parenchymal organs
(especially the lungs) are common. B
Fig. 3.48 Sarcomatoid carcinoma of the thymus. A Usually spindle cells predominate, and there are areas
Histopathology of geographic necrosis. B A biphasic pattern is obvious in this case. The carcinomatous component takes
Sarcomatoid carcinoma is an infiltrative the form of a squamous cell carcinoma, and it gradually merges into a spindle cell (sarcomatoid) compo-
tumour often with large areas of coagula- nent.

Sarcomatoid carcinoma 179


A B

C D
Fig. 3.49 Sarcomatoid carcinoma of the thymus. A An elongated rhabdomyoblast with cross-striations is seen among polygonal carcinoma cells with pleomorphic
nuclei. B Skeletal muscle differentiation characterized by rounded rhabdomyoblasts with vacuolated cytoplasm are interspersed among the spindle sarcomatoid
cells. C Osteoid formation. D So-called spindle cell thymic carcinoma. The tumour comprises sheets and islands of compact atypical spindle cells.

lial membrane antigen. In the sarcoma- (e.g. cytokeratin, epithelial membrane entiation on immunohistochemical evalu-
toid areas, cytokeratin-positive tumour antigen) or electron microscopy. Sarco- ation {1509,1916}.
cells range from abundant to scanty or matoid carcinoma predominated by
even absent {534,1093,1478,1509,1841, rhabdomyosarcomatous component Differential diagnosis
1897,1916}. Variable expression of may have been confused with mediasti- Sarcomatoid carcinoma has to be distin-
myoid markers (e.g. desmin, actin, myo- nal rhabdomyosarcoma in the literature. guished from biphasic metaplastic thy-
genin, myoD1, myoglobin) is seen in the The latter sarcoma more commonly moma, which differs in showing good cir-
rhabdomyosarcomatous component affects children and young adults. cumscription of the tumour and bland-
{534,1478,1509,1841,1897}. The cases Although rhabdomyosarcoma can looking spindle cells, even though the
studied for CD5 have been negative for express cytokeratin, the positive tumour interspersed squamoid epithelial islands
this marker {1093,1916}. Only rare cells coexpress myoid markers, whereas may sometimes show nuclear pleomor-
tumours have been examined ultrastruc- at least some tumour cells in sarcoma- phism {1919,2210}.Spindle cell carcinoid
turally, but desmosome-like junctions toid carcinoma express cytokeratin only can be distinguished from sarcomatoid
have been described in the spindle cell {534,1509}. carcinoma by the presence of delicate
area of one case {534}. The entity reported as spindle cell fibrovascular septa, granular cytoplasm,
thymic carcinoma comprises lobules generally less striking nuclear pleomor-
Immunohistochemistry and compact sheets of atypical spindle phism, and usually presence of a con-
In a tumour where only sarcomatoid cells, and is probably an unusual form of ventional carcinoid component in some
component is identified despite exten- sarcomatoid carcinoma. There is fre- foci; the diagnosis can be further con-
sive sampling, distinction from a sarco- quent transition with thymoma with spin- firmed by positive immunostaining for
ma depends on the demonstration of dle cell (type A) morphology. The spindle neuroendocrine markers.
epithelial differentiation in at least some cells show epithelial characteristics and The biphasic pattern of sarcomatoid car-
tumour cells by immunohistochemistry no evidence of true mesenchymal differ- cinoma may raise the differential diag-

180 Tumours of the thymus - Thymic carcinomas


A B

C D
Fig. 3.50 Sarcomatoid carcinoma of the thymus. A In this example, pale-staining nodules are disposed among spindle cells. B The pale-staining nodules represent
areas with subtle epithelial differentiation. This field shows some resemblance to metaplastic thymoma. C The sarcomatoid component comprises closely packed
spindle cells with moderate nuclear atypia and frequent mitotic figures. D Immunostaining for EMA highlights nodular structures.

noses of synovial sarcoma and mesothe- Histogenesis Somatic genetics


lioma. Synovial sarcoma differs in show- The sarcomatoid component may arise Only one case has been studied by cyto-
ing more monotonous and uniform spin- from metaplasia of the carcinomatous genetics, with identification of a complex
dle cells and glandular differentiation in component, wherein the tumour cells chromosomal abnormality including
the epithelial component. The diagnosis often gradually lose epithelial character- der(16)t(1;16)(q12;q12.1) {534}. Interest-
can be further confirmed by the identifi- istics and simultaneously acquire mes- ingly, this chromosomal translocation has
cation of t(X;18)(p11.2;q11.2) or SYT- enchymal or mesenchymal-like features. also been previously reported in a case
SSX1 or SYT-SSX2 gene fusion. Alternatively, the tumour is derived from of thymic squamous cell carcinoma
Mesothelioma differs in being pleural or primitive cells with multidirectional differ- {1847}, suggesting a pathogenetic rela-
pericardial-based, showing papillary- entiation. tionship with thymic squamous cell carci-
glandular formation in the epithelial com- noma in at least some cases.
ponent, expressing mesothelial-associat-
ed markers (e.g. calretinin), and showing Prognosis and predictive factors
mesothelial differentiation ultrastructural- Sarcomatoid carcinoma is an aggressive
ly (e.g. bushy microvilli). tumour, with most patients dying of dis-
ease within three years of diagnosis
Precursor lesions despite aggressive multi-modality therapy.
Some cases show an identifiable compo-
nent of thymoma, most commonly with
spindle cell (type A) morphology, sug-
gesting transformation from an underly-
ing thymoma {1093,1897,1916}.
Fig. 3.51 G-banded metaphase spread shows a com-
plex karyotype, including der(16)t(1;16)(q12;q12.1).

Sarcomatoid carcinoma 181


Clear cell carcinoma M.R. Wick
A. Zettl
T.T. Kuo
J.K.C. Chan
A. Marx

Definition lular features which contrast their clinical express CD5 {511,1093}. They are nega-
Clear cell carcinoma is a thymic carcino- aggressiveness. Tumour cells are rather tive for PLAP, vimentin, CEA and S-100
ma predominantly or exclusively com- monotonous and polyhedral, and usually {797}, and do not contain a population of
posed of cells with optically clear cyto- display slight cellular pleomorphism with immature (CD1a- or CD99-positive)
plasm. Thymomas with clear cell features round to oval, vesicular nuclei, moderate T-lymphocytes.
are not included in this group. nuclear atypia, finely dispersed chro-
matin, and small discernible nucleoli. Differential diagnosis
ICD-O code 8310/3 They have abundant lucent, mostly clear When making the diagnosis of thymic
to granular, sometimes faintly clear cell carcinoma, metastatic clear
Synonym eosinophilic, cytoplasm which mostly, cell epithelial malignancies, particularly
Carcinoma of the thymus with clear-cell but not always is due to accumulation of renal, pulmonary and thyroid clear cell
features {797} glycogen. Clear cell carcinomas com- carcinoma have to be excluded. Other
monly show a lobulated architecture with differential diagnoses include mediasti-
Epidemiology nests, lobules or sheets of tumour cells nal diffuse large B-cell lymphoma, medi-
This is a very rare variant of thymic carci- being surrounded by a dense fibrous astinal seminoma, mediastinal parathy-
noma, with only 13 pure cases reported stroma, and lack the sinusoidal vascula- roid neoplasms, metastatic clear cell sar-
to date {797,1094,1877,1924,2032, ture characteristic of metastatic clear cell coma or melanoma, glycogen-rich alveo-
2166}. Clear cell carcinomas constitute carcinoma of the kidney. Rarely, few scat- lar rhabdomyosarcoma, and clear cell
only 3% of all thymic carcinomas {1924}. tered intratumoral lymphocytes, minute paraganglioma. Furthermore, thymoma
Clear cell carcinoma has also been foci of squamous differentiation or focal with clear cell features must be differenti-
reported as a high-grade component in a necrosis are observed. The tumour com- ated from clear cell carcinoma and from
combined thymoma/thymic carcinoma monly exhibits an infiltrative growth, with combined thymoma/thymic clear cell
that, in addition, showed areas of spindle tumour extending into the surrounding carcinoma {1093}. Clear cell features are
cell (WHO Type A) thymoma, squamous mediastinal fat and remnant thymus, common only in WHO Type B3 thymo-
cell carcinoma and undifferentiated car- even in cases which macroscopically mas and they are almost always focal
cinoma {1093}. The age range of the appear well-delineated. {797,2032}. Most tumours show a pre-
reported cases is 33 to 84 years, and the dominance of conventional B3 areas that
tumour tends to prevail in men (male : Special studies exhibit gradual transitions to foci of
female ratio 1.6) {797, 1663}. Tumour cells usually show strong cyto- bland-looking clear cells. While the con-
plasmic diastase-labile PAS positivity, ventional B3 areas harbour at least few
Clinical features but PAS negative cases have also been CD1a+ and CD99+ immature T-cells,
Patients may show symptoms related to reported {1877}. Clear cell carcinomas they may be absent in the clear cell
a mediastinal mass, e.g. chest pain or are keratin positive (cytokeratin 7 expres- areas. Significant PAS-positivity, necro-
dyspnoea. Some patients are asympto- sion may be absent), EMA is expressed sis, increased proliferative activity,
matic, with the tumour being detected by in 20% of cases studied {797}. As in desmoplastic stroma or TP53 overerex-
routine X-ray or during unrelated thora- other types of thymic carcinomas, a sub- pression are typically absent in clear cell
cotomy. There are no associated parane- group of clear cell carcinomas may foci of WHO B3 thymomas. By contrast,
oplastic autoimmune phenomena gravis. the clear cell carcinoma (with squamoid
features) arising in a WHO Type A thy-
Macroscopy moma (combined thymoma/thymic carci-
Macroscopically, the reported tumour noma) was PAS+, showed extensive
size ranges between 4 and 12 cm (aver- necrosis, cyst formation and a desmo-
age 9 cm). The tumours may appear plastic stromal reaction {1093}.
encapsulated and non-infiltrative, or may
extensively infiltrate the surrounding tis- Prognosis
sues. The cut-surface shows solid or Clear cell carcinomas are highly malig-
cystic tumour with or without haemor- nant, aggressive mediastinal neoplasms
rhage and focal necrosis. with frequent local recurrences and
metastases. Most reported patients died
Histopathology Fig. 3.52 Clear cell carcinoma. Tumour cells have of the disease. Deaths are related to
Microscopically, clear cell carcinomas of abundant, optically clear cytoplasm and well metastatic disease or local infiltration of
the thymus often show rather bland cel- defined cell membranes {1690}. organs in recurrence {797}.

182 Tumours of the thymus - Thymic carcinomas


Papillary adenocarcinoma Y. Matsuno
J. Rosai
Y. Shimosato

Definition but prominent nucleoli. Psammoma bod- phocytes are absent, but may be found
Papillary adenocarcinoma is a rare type ies may be present. Areas of coagulation in the coexisting thymoma portion.
of primary thymic carcinoma, character- necrosis, sometimes massive, are scat-
ized by a prominent papillary pattern of tered throughout the tumour. Invasion Differential diagnosis
growth. Although reports of this tumour into the adhesive extrathymic tissues Differential diagnosis of this rare type of
are rare, it may be the source of some accompanied by a dense collagenous thymic carcinoma includes mediastinal
metastatic papillary carcinomas with stroma may be seen. A small number of thyroid neoplasm (i.e. papillary carcino-
psammoma bodies in the cervical lymph tumour cells show positive staining for ma), malignant mesothelioma, germ cell
nodes of patients without tumours in the mucin. The mitotic count may vary from 1 tumour, metastatic adenocarcinoma, and
thyroid gland. to 7/10 HPF among cases. Permeation of adenocarcinoma of foregut cyst origin
tumour cells into lymphatics such as the {1915}.
ICD-O code 8260/3 subpleural or intrapulmonary perivascu-
lar lymphatics may be extensive. In the Histogenesis
Synonym majority of cases, type A thymoma is It has been suggested that papillary ade-
Papillary carcinoma found as a component within the tumour nocarcinoma originates from type A thy-
mass; one case showed high-grade his- moma as an expression of malignant
Epidemiology tology and a predominantly solid and transformation {1263}. This is based not
Papillary adenocarcinoma of the thymus sheet-like growth accompanied by well- only on the morphological similarities
is a rare neoplasm, and only five cases developed papillary structures, high- between the tubuloglandular or papillo-
have been reported {1263}. It affects eld- grade atypia and high mitotic rate. In tubular structures sometimes seen in
erly individuals in their sixth to seventh contrast to the other four cases, there type A thymomas and those of the carci-
decades of life. Males and females was no evidence of a type A thymoma noma, but also the occasional coexis-
appear to be equally affected. component. tence of a type A thymoma component
within the tumour.
Clinical features Immunophenotype
Papillary adenocarcinoma generally Papillary adenocarcinoma shows vari- Prognosis and predictive factors
presents as an enlarging anterior medi- able degrees of staining for LeuM1 and Since the number of reported cases is
astinal mass. The tumour may appear BerEP4. CEA and CD5 may also be pos- limited, specific information on the
cystic. Paraneoplastic symptoms such itive, but CD20, thyroglobulin, pulmonary histopathologic prognostic factors of
as myasthenia gravis or pure red cell surfactant apoprotein and calretinin are papillary carcinoma of the thymus is not
aplasia have not been described. negative. In addition, CD99-positive lym- available.

Macroscopy
The tumours are more or less encapsu-
lated, and usually large (measuring 5-10
cm). The cut surface is irregularly lobu-
lated, white and firm. Prominent cyst for-
mation containing serohaemorrhagic
fluid may be seen. Adhesion or direct
invasion to the adjacent lung, pleura or
pericardium is observed in most cases.
Pleural implants may be found.

Histopathology
The tumour shows a tubulopapillary pro-
liferation of uniform cuboidal to columnar
cells, mainly lying in a monolayer, but
occasionally showing a glomeruloid
arrangement. The tumour cells have
eosinophilic or clear cytoplasm. Their
nuclei are round to ovoid, with coarsely Fig. 3.53 Papillary adenocarcinoma of the thymus. Highly papillary configuration resembling papillary carci-
condensed chromatin, and a few small noma of the thyroid {1690}.

Papillary adenocarcinoma 183


Non-papillary adenocarcinomas H.K. Mller-Hermelink
A. Marx
T.T. Kuo
M. Kurrer
G. Chen
Y. Shimosato

There have been rare reports about non-


papillary adenocarcinomas in the thy-
mus. Among them are: an adenocarcino-
ma with glandular differentiation arising
in a thymic cyst {98}, as is also typical for
papillary carcinoma {541}; an adenoid
cystic carcinoma equivalent to the analo-
gous salivary gland carcinoma {1841};
and a mucinous (colloid) carcinoma of
the thymus {360}. The latter case arose in
a 15 year old boy and was CD5-negative
by immunohistochemistry.
An exceptional tumour in the thymus
exhibiting features of a hepatoid carcino-
ma was observed in a 78 year-old female
without an extrathymic neoplasm. The
tumour had a diameter of 10 cm, was not Fig. 3.54 Thymic adenoid cystic carcinoma. This salivary gland-type thymic carcinoma shows a glandular
encapsulated and virtually devoid of and cribriform pattern.
fibrous or inflammatory stroma. Respir-
atory distress was the only clinical symp-
tom. The tumour recurred locally two
years after surgery and responded to
radiotherapy. Considering the female sex
and protracted clinical course, lack of a
yolk sac component and absence of
alpha-fetoprotein in the tumour and the
patients serum, a diagnosis of hepatoid
carcinoma of thymus appears more like-
ly than a monophasic variant of hepa-
toid yolk sac tumour of the mediastinum
{606,1349,1355}.

B
Fig. 3.55 Thymic hepatoid carcinoma. A Tumour nodules composed of large polygonal tumour cells resem-
bling activated hepatocytes. No hepatic sinuses, no portal structures and absence of a tumour stroma.
B Large polygonal cells with abundant eosinophilic cytoplasm. PAS+ globules (immunorecative for alpha-
1-antitrypsin, not shown) occurred inside the cytoplasm and in between epithelial cells.

184 Tumours of the thymus - Thymic carcinomas


Carcinoma with t(15;19) translocation A. Marx
C.A. French
J.A. Fletcher

Definition
Carcinoma with translocation
t(15;19)(q13:p13.1) is a rare, aggressive
and lethal carcinoma of unknown histo-
genesis arising in the mediastinum and
other midline organs of young people.

Synonyms
Aggressive t(15;19)-positive carcinoma,
midline lethal carcinoma

Epidemiology
Six cases of t(15;19)-positive carcinoma
have been reported {439,616,985,
1081,1148,2072}. All occurred in chil-
dren or young adults (age range: 5-34
years), particularly females (F : M ratio =
A
5:1).

Etiology
The etiology of t(15;19)-positive carcino-
ma is unknown. Epstein-Barr virus does
not play a role {985,2072} .

Localization
Translocation t(15;19)-positive carcino-
ma has been reported to arise in supra-
diaphragmatic midline organs. Three of 6
cases arose adjacent to the thymus in
the mediastinum {985,1081,1148}. Other
primary locations were epiglottis {2072},
sinonasal region {616}, lung {439}, and
bladder (unpublished findings (C.A.F.,
J.A.F.)). B
Fig. 3.56 Aggressive carcinoma with t(15;19) translocation. A The typical undifferentiated morphology of the
tumour may mimic lymphoepithelioma or large cell lymphoma. B Focal squamous differentiation can be dif-
Clinical features
ficult to find, but is often present either histologically or ultrastructurally.
Aggressive local invasiveness is charac-
teristic. Intracranial extension occurred in
a sinonasal case. Pleural effusions and lymphoepithelioma {616}. Focal squa- Immunophenotype
superior vena cava syndrome are com- mous differentiation is common {616, The tumours consistently react, at least
mon in thoracic cases. Metastases are 1081,1148}, but not always seen, where- focally, with pan-cytokeratin markers
common and may involve lymph nodes, as glandular differentiation (mucoepider- {616,2072}. Inconsistent and usually
lung, bone, skin and subcutaneous soft moid carcinoma) {1148}) has only been focal positivity occurs for vimentin, EMA,
tissue {2027}. reported once. Electron microscopy and carcino-embryonic antigen (CEA)
revealed squamous differentiation (rare {985,2072}. CD30, CD45, PLAP, HMB45,
Histopathology desmosomes {1081,1148,2072}, tonofila- S100, and neuroendocrine markers are
The presence of undifferentiated, inter- ments {1148,2072}) in three cases. Care negative.
mediate sized, vigorously mitotic cells is must be taken not to confuse the disco-
characteristic. Commonly seen are hesive, undifferentiated round cells of Differential diagnosis
sheets of undifferentiated cells forming t(15;19)-positive carcinoma with large This lesion must be distinguished from
syncytia with inter-epithelial lympho- cell lymphoma or germ cell tumour {616, large cell lymphoma, germ cell tumour,
cytes, a pattern indistinguishable from 985,1081}. and t(15;19)-negative carcinomas, par-

Carcinoma with t(15;19) translocation 185


ticularly lymphoepithelioma-like, poorly
differentiated squamous cell, mucoepi-
dermoid, and undifferentiated carcino-
ma.

Histogenesis
Despite various considerations {616,985,
1081,1148,2072}, derivation of this
tumour is unknown.

Somatic genetics
The specific t(15;19)(q13;p13.1) translo-
cation, which generates the 6.4-kb
BRD4-NUT fusion oncogenes, is often
the only demonstrable cytogenetic aber-
ration. The translocation fuses the 5 10
exons of the ubiquitously expressed
BRD4 bromodomain gene on chromo-
some 19 with nearly the entire transcript
of the 15q13 gene NUT (nuclear protein
in testis), that is normally exclusively
expressed in testis {617}. Cytogenetics,
fluorescence in situ hybridization (FISH),
Fig. 3.57 Aggressive carcinoma with t(15;19) translocation. Karyotype from a teenage girl with the t(15;19)
Southern blotting and RT-PCR studies
carcinoma. A reciprocal translocation involving chromosomes 15q13 and 19p13.1 has occurred. The der (19)
can identify the translocation {616,617}. contains the functional fusion oncogene.
Additional chromosomal aberrations are
rare {2027}.

Prognosis and predictive factors


All cases reported so far followed an
extremely aggressive clinical course
(average survival 18 weeks; range 8-38
weeks) {616}.

A B
Fig. 3.58 Aggressive carcinoma with t(15;19) translocation. A Schematic of the BRD4 and NUT genes dis-
rupted in the t(15;19)(q13;p13.1) chromosomal translocation. Exons are represented by horizontal bars, and
introns by connecting lines. All characterized breakpoints (N=2), represented by vertical arrows, occur in
intron 10 of BRD4 (gray), and intron 1 of NUT (green), splitting BRD4 roughly in half, and fusing to it nearly
the entire NUT transcript. Both bromodomains (pink) of BRD4 are preserved in the fusion oncogene. The
oncogenic mechanism is believed, at least in part, to result from unscheduled expression of NUT (normally
expressed only in testis) driven by the promoter of BRD4, which is ubiquitously expressed. B Fluorescent
in situ hybridization (FISH) depicting the t(15;19)(q13;p13.1) in a paraffin section. The red-green probe dou-
blet, which normally flanks the NUT gene on chromosome 15, is split apart by the translocation.

186 Tumours of the thymus - Thymic carcinomas


A. Marx
Undifferentiated carcinoma Ph. Strbel
of the thymus J.K.C. Chan
G. Chen
H.K. Muller-Hermelink

Definition
A thymic carcinoma growing in a solid,
undifferentiated fashion but without sar-
comatoid (spindle cell, pleomorphic,
metaplastic) features {1924}.

ICD-O code 8020/3

The diagnosis of this rare type of thymic


carcinoma is one of exclusion. Defining
its epithelial nature usually requires
immunohistochemistry. In children and
young adults, carcinoma with t(15;19)
translocation should be excluded by
cytogenetics or RT-PCR {617,1081}. The
most important differential diagnosis in
adults is large cell carcinoma in the lung
A
extending or metastasizing to the medi-
astinum.
Small cell carcinoma without (immuno-
histochemically) recognizable differentia-
tion is traditionally classified among the
neuroendocrine carcinomas of the thy-
mus.

B
Fig. 3.59 Undifferentiated thymic carcinoma. A A solid growth pattern composed of large polygonal to round
tumour cells, large nuclei and a slightly basophilic cytoplasm. No keratinization, no intercellular bridges, no
glandular differentiation, no sarcomatoid features and no EBER expression by in situ hybridization. The
prominent population of bland looking myoid cells with round inconspicuous nuclei and eosinophilic cyto-
plasm unequivocally identifies this carcinoma as a tumour of thymic differentiation. Myoid cells show no
significant proliferative activity (in contrast to rhabdomyosarcoma cells). B Desmin staining demonstrates
intratumorous myoid cells.

Undifferentiated carcinoma 187


Thymic neuroendocrine tumours A. Marx
Y. Shimosato
T.T. Kuo
J.K.C. Chan
W.D. Travis
M.R. Wick

Definitions Well differentiated lung {450,628,723,1361,1688,1808,


Thymic epithelial tumours that are pre- neuroendocrine carcinomas 2062,2140}. As a group, atypical carci-
dominantly or exclusively composed of noids more often show a diffuse growth
neuroendocrine cells are classified as In line with the nomenclature of neuroen- pattern, advanced stage disease, and a
neuroendocrine carcinomas (NECs) of docrine tumours occurring in other sites higher degree of cytologic atypia {723,
the thymus {1691}. They have to be dis- of the body, it is proposed that thymic 1362,1691,1808,2062}.
tinguished 1) from otherwise typical carcinoids be termed well differentiated Since virtually all thymic carcinoids are
thymic carcinomas, which may contain neuroendocrine carcinomas of the thy- atypical carcinoids (see epidemiology),
scattered or groups of neuroendocrine mus {349,1691}. The rationale for consid- most studies report thymic carcinoids to
cells {853,1091,1139}, and 2) from non- ering all these tumours as carcinomas have a worse prognosis compared with
epithelial neurogenic tumours, particular- {1691} is the observation that even inno- bronchial carcinoids {628,1361,1808,
ly paragangliomas. cent looking and encapsulated carci- 2136}. However, varying criteria have
noids bear a significant risk for recur- been used for definition of atypical carci-
Neuroendocrine differentiation can be rence, metastasis and tumour-associat- noids of the thymus in these series {628,
demonstrated by immunohistochemistry ed death {628,1845,2140}. The carci- 1361,1845,2062}. In fact, the only clinico-
(positivity for chromogranin, synapto- noids are further subdivided into typical pathological study applying WHO-
physin, neuron-specific enolase, CD56) and atypical carcinoids. defined criteria to classify atypical thymic
and/ or by ultrastructural identification of carcinoids {723} challenged the view that
neurosecretory granules. ICD-O codes thymic atypical carcinoids are clinically
Neoplasms combining features of NEC Typical carcinoid 8240/3 more aggressive than morphologically
and either thymoma or thymic carcinoma Atypical carcinoid 8249/3 identical carcinoids of the lung. A better
are included in the category of com- prognosis of atypical thymic carcinoids
bined thymic epithelial tumours. Typical and atypical carcinoids as compared to pulmonary carcinoids
Since the seminal work of Rosai and Following the introduction of the term was even suggested by a recent study
Higa, thymic neuroendocrine tumours atypical carcinoid by Arrigoni et al. in {1049} (5-year and 10-year survival rates
that are related to carcinoid tumours 1972 for a subgroup of moderately of 84% and 75% respectively, compared
have been distinguished from thymomas aggressive neuroendocrine neoplasms with 87% and 87% for pulmonary typical
{1686,1688,2144}. The epithelial neu- of the lung {75}, it became clear that the carcinoids and 56% and 35% for pul-
roendocrine tumours of the thymus com- vast majority of carcinoids in the thymus monary atypical carcinoids {2028}).
prise typical and atypical carcinoids, as correspond to atypical carcinoids when
well as large and small cell carcinomas. the same criteria are applied as in the

A B
Fig. 3.60 Typical carcinoid. A Solid and trabecular growth pattern. Note absence of necrosis and mitoses. B On high magnification, rosettes, and bland cytology
can be seen, but no mitoses.

188 Tumours of the thymus - Neuroendocrine tumours


Table 3.06 Small cell carcinoma, neuroendocrine
Classification of thymic neuroendocrine tumours (Neuroendocrine carcinomas, NECs) {1691}. type. A high-grade thymic tumour con-
sisting of small cells with scant cyto-
Neuroendocrine Carcinomas (NECs) plasm, ill-defined cell borders, finely
granular nuclear chromatin, and absent
Well-differentiated NEC Poorly differentiated NEC or inconspicuous nucleoli. The cells are
round, oval or spindle-shaped, and
Typical Carcinoid Atypical Carcinoid LCNEC* SCC** nuclear molding is prominent. The mitot-
ic count is high. The morphologic fea-
No necrosis; Necrosis present Non-small cell NEC Small cell cytology tures are indistinguishable from those of
<2 mitoses per 2 mm2 and/or 2-10 mitoses per with >10 mitoses per small cell carcinoma arising in the lung.
(10HPF) 2 mm2 (10 HPF) 2 mm2 (10 HPF) Variant: Combined small cell carcinoma:
Morphological Variants Variants A small cell carcinoma that also contains
a component of non-small cell carcinoma
Spindle cell type SCNEC combined with
Pigmented type Non-NECs
such as squamous cell carcinoma or
With amyloid (extrathyroidal medullary carcinoma) adenocarcinoma.
Oncocytic/oxyphilic type Large cell neuroendocrine carcinoma: A
Mucinous high-grade thymic tumour composed of
Angiomatoid type large cells with neuroendocrine morphol-
Combinations of the above variants ogy such as palisading, trabeculae, nest-
ing or rosette-like features; necrosis that
Thymic NECs with shared features of (atypical) carcinoid and LCNEC/SCC
is usually extensive; a high mitotic rate;
Carcinoid with sarcomatous change (metaplastic NEC)
*LCNEC,
and either neurosecretory granules by
large cell neuroendocrine carcinoma;
**SCC, electron microscopy or positive neuroen-
small cell carcinoma; HPF, high power field
docrine immunohistochemical markers.

Poorly differentiated Definitions Basis of the classification


neuroendocrine carcinomas Four major categories of thymic neuroen- Considering the paucity of data on clini-
Small cell carcinoma (SCC, neuroen- docrine neoplasms are recognized: copathological correlations in thymic
docrine type) and large cell neuroen- Typical (classic) carcinoid. A carcinoid NECs {723,1361,1845} as compared to
docrine carcinoma (LCNEC) of the thy- tumour comprised of polygonal cells with the statistically better analyzed pul-
mus are considered poorly differentiated granular cytoplasm arranged in ribbons, monary NECs {128,218,2023,2026}, the
neuroendocrine carcinomas of the thy- festoons, solid nests and rosette-like first edition of the WHO classification of
mus. glands. Tumours have less than 2 mitoses tumours of the thymus {1691} suggested
per 2 mm2 (10 HPF) and necrosis is thymic neuroendocrine tumours to be
ICD-O codes absent. classified using the same criteria applied
Large cell neuroendocrine Atypical carcinoid. A carcinoid tumour for NECs of the lung {218}. Although this
carcinoma 8013/3 with architectural features of the classic approach was not based on sufficient
Small cell carcinoma, type but exhibiting a greater degree of statistical data, it was meant to provide a
neuroendocrine type 8041/3 mitotic activity and/or foci of necrosis morphological basis from which pros-
(including comedonecrosis). pective and retrospective clinical studies

Fig. 3.61 Atypical carcinoid. Macroscopy of a well Fig. 3.62 Atypical carcinoid. Despite circumscription, there is lymphatic invasion outside the main tumour
circumscribed tumour. mass.

Neuroendocrine carcinomas 189


are launched to generate statistical data.
This approach is maintained in the pres-
ent edition of the WHO classification.

Epidemiology
Thymic NECs are rare, constituting 2-5%
of thymic epithelial tumours {723,1361,
1808,2062}. In contrast to the lung {218,
1128,2023}, the great majority of cases
are represented by atypical carcinoid. A B
MEN-1-associated thymic NECs have all
been carcinoids and occurred almost
only in male adults (31-66 years; mean
44 years) {1987,1989}.
Epidemiological data on typical carci-
noids are lacking. Atypical carcinoids are
mainly tumours of adults (1882 years;
mean 48-55 years in both males and
females) {723,1361,1845,2062}, but
have also been rarely observed in chil-
dren (8-16 years of age) {666,1185}. C D
There is a male preponderance (M:F = Fig. 3.63 Atypical carcinoid. A Striking rosette formation and a "punctate" area of necrosis (comedonecro-
1:2-7) {528,723,1361,1845}. sis). B Mitotic figures are seen. C Cytokeratin expression (Cam5.2; immunoperoxidase). D Strong chromo-
By contrast, small cell carcinomas show granin A staining.
no gender predilection and the patients
on average are slightly younger {1094,
2032,2143}. The case of thymic large cell well differentiated neuroendocrine carci- autoimmune disorders, such as the
neuroendocrine carcinoma reported by nomas exhibit local symptoms (chest Lambert-Eaton myasthenic syndrome, are
Chetty occurred in a 68 year-old male pain, cough, dyspnoea, or superior vena very rare.
patient {349}. cava syndrome) {723,1361,1845}.
Carcinoid syndrome is exceedingly rare Macroscopy
Etiology (<1%) {1845}. On the other hand, 17-30% Thymic carcinoids and poorly differenti-
About 25% of patients with thymic carci- of adult and >50% of childhood carcinoids ated thymic NECs are virtually identical
noids have a positive family history of of the thymus are associated with Cushing macropscopically. The majority are unen-
MEN-1 {1989}. Conversely, among MEN- syndrome due to ACTH production capsulated and can appear either cir-
1 patients, thymic carcinoids were found {456,1845,1918}. In fact, 10% of all cases cumscribed or grossly invasive. The size
in 8% of cases {681}. Since thymic NECs of ectopic ACTH syndrome are due to ranges from 220 cm (mean 8 -10 cm)
cluster with only a minority of MEN-1 fam- thymic carcinoids {162,2095}. Cutaneous {450,1361}. Cases associated with
ilies, exhibit diverse mutations and are hyperpigmentation due to tumour-derived Cushing syndrome tend to be smaller (3-
not associated with loss of heterozygosity alpha-MSH frequently accompanies and, 5 cm) due to earlier detection. They are
(LOH) at the 11q13 (MEN-1) locus, it rarely, precedes Cushing syndrome {666}. grey-white and firm on cut section, can
appears that genetic alterations in addi- Cushing syndrome is exceptionally rare in have a gritty consistency, and usually
tion to MEN-1 abnormalities (possibly thymic SCC {812}. lack the characteristic lobulated growth
involving a tumour suppressor gene(s) on Acromegaly (due to tumour-derived pattern of thymomas. Oncocytic/ oxy-
chromosome 1p) are required for thymic GHRH) {924}, and inappropriate produc- philic variants may show a tan or brown
carcinoids to develop {1988, 1989}. The tion of antidiuretic hormone or atrial natri- cut surface. Foci of haemorrhage and
role of a MEN-2 genetic background for uretic peptide {1507} are uncommon. necrosis are apparent in 70% of cases
the development of thymic carcinoids is Hypercalcaemia/hypophosphataemia in {2137}. Calcifications are frequent in
less clear {1239}. thymic carcinoid patients may result thymic NECs (30%) compared with
either from tumour production of PTHrP extrathymic NECs {924}.
Localization {2214} or from primary hyperparathy-
Thymic neuroendocrine carcinomas roidism in the context of the MEN-1 syn- Tumour spread and staging
occur in the anterior mediastinum. A sin- drome {1989}. Locally restricted atypical carcinoids
gle case occurring in an ectopic thymus MEN-1-associated thymic NECs are typi- (encapsulated pT1 or infiltrating the
adjacent to the thyroid has also been cally insidious tumours (carcinoids) that mediastinal fat or thymus pT2) make up
published {900}. manifest by local symptoms, metastases, 40-50% of cases, but half of them exhib-
disturbances of calcium/phosphate meta- it local metastasis (pN1) {723,2062}.
Clinical features bolism or, rarely, with acromegaly {196}, Invasion into adjacent organs (40-50%,
Most poorly differentiated neuroen- while Cushing syndrome has not been pT3) or pleural or pericardial cavity
docrine carcinomas and about 50% of reported {1988,1989}. Paraneoplastic (10%, pT4) is common {723,2062}.

190 Tumours of the thymus - Neuroendocrine tumours


A B

C D
Fig. 3.64 Atypical carcinoid. A Solid growth pattern. B Trabecular growth pattern. C Spindle cell variant of carcinoid. D Spindle cell carcinoid. Transmission elec-
tron microscopy showing distinct electron dense neurosecretory granules of variable size in the cytoplasm of a tumour cell.

Metastases are present in 30-50% of mitoses per 2 mm2 or 10 HPF using cer- diagnosis of atypical carcinoid.
cases {723,1845}. Lymph node metas- tain microscopes). The classic carci- Compared to typical carcinoids, atypical
tases can involve mediastinal, cervical noid can show a variety of organoid carcinoids more frequently show some
and supraclavicular lymph nodes {924} features: ribbons (trabeculae), festoons, degree of nuclear pleomorphism includ-
or they can be systemic {723}. Haemato- solid nests, rosettes, glandular struc- ing rare anaplastic cells {723}, a focal
genous metastasis to bone, liver, skin, tures, and nuclear palisades, accompa- diffuse growth pattern (so-called lym-
brain, kidney, heart, adrenals and soft tis- nied by a richly vascularized stroma. The phoma-like) {723,1361,1845,2062} or
sues have been reported {723,1013, trabecular and rosette patterns are the extensive desmoplastic stroma with
1845,2143}. Pericardial and pleural cavi- commonest, being found in over 50% of Indian filing of tumour cells {2136}.
ties can be sites of late NEC recurrences cases. The tumour cells are uniform and Calcifications are also more characteris-
(up to 9 years after resection) {2035}. polygonal, with relatively small nuclei, tic of atypical carcinoids (up to 30% of
Only very few cases of stage II SCC have finely granular chromatin, and eosino- cases) {924}.
been reported {1808,1841}, one with dis- philic granular cytoplasm. Lymphovas-
tant metastases {1841}. The vast majority cular invasion is common. Variants of thymic carcinoids
of SCC are in stage III or IV {812,1094, The morphologic variants should be
1841,2143}, and about half of them show Atypical carcinoids assessed as being typical or atypical
lymph node or haematogenous metas- These show (1) areas of necrosis and a using the criteria listed above. Among
tases {1094,2032}. maximum of 10 mitoses per 2 mm2 (10 the reported cases, almost all are classi-
HPF) of non-necrotic tumour area or (2) fiable as atypical carcinoids.
Histopathology of well differentiated absence of necrosis but a proliferation
neuroendocrine carcinomas rate of 2-10 mitoses/2 mm2 or 10HPF. All Spindle cell carcinoid
architectural features of typical carci- This is the commonest thymic carcinoid
Typical carcinoids noids can occur. Even small punctate variant, being predominantly or totally
By definition, these are devoid of necrot- area of necrosis (comedonecrosis) in an composed of spindle cells often
ic areas and exhibit a low mitotic rate (<2 otherwise typical carcinoid justifies a arranged in fascicles. Occasionally, spin-

Carcinoids 191
A B

C D
Fig. 3.65 A Atypical carcinoid. Rosette formation. B Atypical carcinoid. Small islands of tumour cells in oedematous stroma. C Pigmented carcinoid. Melanin is
present in the cytoplasm of some tumour cells. D Carcinoid with amyloid. Tumour cells are accompanied by deposits of extracellular amyloid.

dle cell carcinoid can be admixed with a (extrathyroidal medullary carcinoma). few reported cases have not been associ-
classic carcinoid {1169,1691,2141}. The histogenesis of this tumour is unclear. ated with Cushing syndrome.
A derivation from extra-thyroidal C-cells or
Pigmented carcinoid a thymic epithelial origin has been postu- Angiomatoid carcinoid
This variant of thymic carcinoid is charac- lated {1691}. This rare variant resembles haemangioma
terized by presence of intracytoplasmic macroscopically and microscopically due
melanin (neuromelanin) in a variable num- Oncocytic/oxyphilic carcinoid to the presence of large blood-filled cystic
ber of tumour cells. Melanosomes can be This is a rare variant that is composed of spaces. However, closer scrutiny shows
detected by electron microscopy. There polygonal, large tumour cells with that the spaces are lined by polygonal
can be admixed melanophages contain- oxyphilic cytoplasm due to accumulation tumour cells but not endothelial cells
ing phagocytosed melanin granules with of mitochondria {1362,2183}. Oncocytic {1360}.
a coarser appearance. Pigmented tumour carcinoid is rarely associated with MEN-1
cells can exhibit an otherwise classic or or Cushing syndrome {1362,2183}. Carcinoid with sarcomatous change
spindle cell morphology. This variant has Carcinoids in combination with a sarcoma-
also been reported to be associated with Mucinous carcinoid tous tumour areas have been described
Cushing syndrome {857,1028,1114}. This is a very rare variant that exhibits an rarely, and have pursued a highly aggres-
alcian blue-positive mucinous stroma sive clinical course {1090, 1557}. The sar-
Carcinoid with amyloid {1501,1911}. The tumours are often large comatous component shows fibrosarco-
This variant is accompanied by amyloid (>8 cm) and can resemble metastatic matous, myoid, osseous or chondroid dif-
deposition in the stroma that can be iden- mucinous carcinoma, such as from the ferentiation. The cases have been inter-
tified by Congo stain {2141}. The tumour gastrointestinal tract or breast. The stro- preted as examples of dedifferentiation or
cells are usually spindle shaped and mal mucin is believed to result from divergent development from a common
immunorective for calcitonin, so that the regressive changes rather than produc- precursor rather than collision of two clon-
tumour is indistinguishable from tion by the tumour cells. There can be a ally unrelated tumours.
medullary carcinoma of the thyroid focal component of classic carcinoid. The

192 Tumours of the thymus - Neuroendocrine tumours


Fig. 3.66 Sarcomatoid neuroendocrine carcinoma. Fig. 3.67 Sarcomatoid neuroendocrine carcinoma. Sarcomatoid neuroendocrine carcinoma exhibiting a
well differentiated and a sarcomatoid spindle cell components.

Carcinoids as components in other com- pathological correlation is essential to ably also LCNEC express at least two of
bined tumours distinguish between primary thymic these markers in >50% of tumour cells
Carcinoids can be admixed with thymic LCNEC and metastasis of an extrathymic {853,1362,1845,2062}.
small cell carcinoma (see below), and LCNEC to the mediastinum. Hormones can be detected in most
with thymoma or thymic carcinoma, par- thymic NECs in a variable (and some-
ticularly squamous cell carcinoma, Small cell carcinoma (SCC, neuroen- times very low) number of tumour cells.
adenosquamous carcinoma or undiffer- docrine type) of the thymus Expression of ACTH, HCG (alpha-sub-
entiated carcinoma {1094,1783, 1913}. In contrast to carcinoids and LCNEC, the unit more than beta-subunit {853}),
Three examples of carcinoid (including tumour cells of SCC are small (usually somatostatin, beta-endorphin, cholecys-
one goblet cell carcinoid {1124}) have <3x diameter of a lymphocyte) and cyto- tokinin, neurotensin, calcitonin {820,
been reported as components of mature plasm is very scant. Mitotic activity is 1808,2062,2140}, is quite common, while
cystic teratomas of the thymus {1124, usually higher than in other types of NEC. serotonin, gastrin, and parathormone are
1707,1787}. Two of the three patients Nuclei can be round, oval or spindly, the uncommon {1845,1953}. Multihormonal
(age: 4363 years) were females. The chromatin is finely granular, and nucleoli tumours appear to be frequent {820,
reported outcome was favourable after are inconspicuous. Apoptotic bodies are 853,1953}. Of note, there is no close cor-
complete surgical removal, but follow-up often numerous. Evidence of neuroen- relation between the hormones detected
time was short. docrine differentiation is usually support- by immunohistochemistry and the clini-
ed by immunohistochemistry (chromo- cal symptoms {820}.
granin; synaptophysin; NCAM/CD56). Nuclear expression of TTF-1 is absent in
Poorly differentiated neuroendo- Clinical imaging studies SCC are impor- the vast majority of thymic carcinoids
crine thymic carcinomas tant for distinction between primary {1513} and LCNEC (our experience),
thymic origin and mediastinal metasta- though more cases need to be studied
Large cell neuroendocrine carcinoma sis, which is much more frequent than under defined conditions. TTF-1 data on
(LCNEC) thymic SCC. thymic SCC are limited; three cases
LCNECs of the thymus are non-small cell studied have been negative {351,975}.
NECs with a mitotic rate of > 10 per 10 Immunophenotype
HPF {1691}. Necrosis is almost always NECs are virtually all immunoreactive for Postulated cell of origin
present and often extensive. The higher broad spectrum cytokeratins (AE1/3, Not definitively known. The relatively
mitotic rate is the essential differentiating CAM5.2), often showing a dot-like stain- common occurrence of mixed NECs,
feature of this tumour from atypical carci- ing. In contrast to Merkel cell carcinoma, squamous cell carcinomas of the thymus
noid. In addition, large tumour cell size, cytokeratin 20 is not expressed in small and the rare occurrence of neuroen-
including frankly anaplastic giant cells, cell carcinomas of neuroendocrine type docrine carcinoma associated with thy-
are more common than in atypical carci- (SCNECs) {326}. mom argue in favour for a common
noids {349,723,1361}. Neuroendocrine- Endocrine differentiation is revealed by thymic epithelial precursor as the pro-
type architectural features, such as nest- reactivity with antibodies to neuroen- genitor of thymic NECs {2137}.
ing, cribriform, trabecular, and rosetting, docrine markers: synaptophysin, chro-
may occur but are often less well devel- mogranin, neuron-specific enolase (NSE) Somatic genetics and genetic suscep-
oped compared with atypical carcinoids and NCAM/CD56. NCAM and NSE are tibility
{1691}. slightly more sensitive (about >90% Classical cytogenetic or comparative
LCNEC of the thymus cannot be distin- each) {1808} than chromogranin (70- genomic hybridization data on sporadic
guished from its pulmonary counterpart 90%) {1362,1845}, and synaptophysin thymic NECs have not been published.
by morphology alone. Careful clinico- (70%) {1362}. Most carcinoids and prob- In a small series of MEN-1-associated

Neuroendocrine carcinomas 193


NECs, 2 of 7 cases show losses in the 1p ers in a diffuse manner in >50% of are associated with a more favourable
region, while LOH at the MEN-1 locus at tumour cells, while reactivity is restricted prognosis. Sarcomatoid differentiation
11q13 is consistently absent {1989}. to scattered cells in thymic carcinomas may denote highly malignant clinical
Therefore, a tumour suppressor gene on {853,1139}. behaviour {1090}. It appears that the
1p, in addition to MEN-1 mutations, has Spindle cell carcinoids can resemble prognosis of LCNEC is worse than that of
been considered a candidate playing a other spindle cell tumours of the thymus, atypical carcinoid. Thymic SCNEC are
role in the oncogenesis of thymic NECs. including type A thymoma and synovial more aggressive than atypical carcinoids
In one study of atypical carcinoids, DNA sarcoma, which are also cytokeratin-pos- (median survival: 2536 months)
cytometry revealed aneuploidy in only 1 itive but lack finely granular chromatin {1094,1841,2032,2143}, although they
of 12 cases {723}. This aneuploid case pattern and neuroendocrine features. are said to have a slightly better progno-
was extensively metastatic (as were 3 Nerve sheath tumours can be positive for sis than their pulmonary counterparts
euploid cases). NCAM/CD56, but lack cytokeratin and {1808}. The poorly differentiated thymic
more specific neuroendocrine markers NECs (small and large cell types) and
Differential diagnosis like chromogranin or synaptophysin. NECs with combined features of carci-
NECs of the thymus are difficult to distin- Paragangliomas can closely mimic carci- noid plus SCC are similarly highly
guish from the much more frequent medi- noids by virtue of the similar architecture, aggressive, with patients dying of dis-
astinal metastasis of pulmonary NECs high vascularity, strong expression of ease within 1 to 4 years {1361,1363}.
{2137}. Immunohistochemical detection neuroendocrine markers, possible pig- Early and late recurrences (local or sys-
of TTF-1 expression might be helpful in mentation, and possible association with temic) are common (110 years) {528,
distinguishing carcinoids and LCNEC of Cushing syndrome {857,1028,1092, 1902,2035} and appear to be associated
the lung from their thymic counterparts, 1114,1350,1548}. In addition, carcinoids with a bad prognosis {628,723,1362,
since most thymic carcinoids {1513} and can occasionally show S100 positive 1845}. Local progression or local recur-
LCNECs are TTF-1 negative, while pul- sustentacular cells around nests of rence is observed in the majority of
monary NECs are TTF-1 positive in tumours cells {109,450}. The distinguish- patients that finally die {349,450,1094,
5075% of cases {272, 600,975}, ing features of carcinoids include: tra- 1841,2032,2136}. Since the thymic NECs
although the TTF-1 expression status in becular growth pattern, if present, and exhibit a poor response to chemo- and
pulmonary carcinoids has been ques- expression of cytokeratins. In morpho- radiotherapy, radical resection of the pri-
tioned recently {1894}. Of note, TTF-1 logically equivocal cytokeratin-positive mary tumour (together with local lymph
negativity of a carcinoid in the medi- neuroendocrine tumours, ultrastructural nodes) must be a major therapeutic goal
astinum does not exclude metastasis analysis may be helpful {2140}. {450,628,723}.
from a gastrointestinal or pancreatic pri
mary, since carcinoids in these locations Prognosis and predictive factors
are generally TTF-1 negative {272}. Tumour stage has been found in most
Whether TTF-1 is a useful marker to dis- studies to be an important prognostic
tinguish thymic SCNEC from the metas- factor {528,628,723,1845,2144}. Atypical
tasis of small cell carcinoma of lung can- carcinoids are clearly aggressive, with 5-
cer is unclear {27,351,975}. year and 10-year survival rates of 50-
Otherwise typical thymic carcinomas 82% and 30%, respectively {628,723,
with endocrine cells have to be distin- 1845,2141}. Among atypical carcinoids,
guished from thymic NECs. The latter a lower mitotic rate (<3/10 HPF), minimal
typically express neuroendocrine mark- atypia, and lack of necrosis {1361,1362}

A B
Fig. 3.68 Large cell neuroendocrine carcinoma (LCNEC). A Brisk mitotic activity distinguishes this LCNEC from atypical carcinoid, while the degree of necrosis and
cytologic atypia is not different. B Note cytological details on this high power magnification.

194 Tumours of the thymus - Neuroendocrine tumours


A B

C D
Fig. 3.69 Small cell carcinoma of the thymus. A Poorly differentiated neuroendocrine carcinoma: small cell carcinoma showing focal crush artifacts (low power).
B Photomicrograph of primary small-cell neuroendocrine carcinoma of the thymus. C Cytological details: cellular crowding, elongated nuclei with salt and pepper
chromatin structure, without recognizable nucleoli, scant cytoplasm, and high mitotic activity(high power). D Dense core granules are numerous in the cytoplasm
of the tumour cells.

Neuroendocrine carcinomas 195


Combined thymic epithelial tumours H.K. Mller-Hermelink
Ph. Strbel
A. Zettl
A. Marx

Definition bit more common (~1%). By contrast, Clinical features


Combined thymic epithelial tumours are various combinations of the type B thy- There are no differences in the clinical
neoplasms with at least two distinct moma subtypes B1, B2 and B3 account manifestations of combined thymomas
areas each corresponding to one of the for 10-15% of all cases in large series as compared to the individual compo-
histological thymoma and thymic carci- {341,541}. Combined B2/B3 thymoma is nents. Myasthenia gravis (MG) is by far
noma types, including neuroendocrine by far the most common comined thymo- the most common paraneoplastic mani-
carcinomas. The approximate percent- ma (8-12%), in accordance with the festation (60-72%). One patient in our
age of each component should be spec- close morphologic and genetic relations- series of 107 combined thymic epithelial
ified in the diagnosis. Type AB thymoma ship between B2 and B3 thymomas tumours presented with sarcoidosis,
is a separate entity by definition and {897}. another patient with amyotrophic lateral
does not fall under this category. Combined thymomas are not different sclerosis in addition to MG.
from the respective individual thymomas In combined neuroendocrine thymic car-
ICD-O code: Code the most aggressive in terms of age and sex association. cinoma-thymoma myasthenia gravis,
component. Combined neuroendocrine thymic carci- pure red cell aplasia {358,1336} and the
noma-thymoma are tumours of adults, carcinoid syndrome {1557} may occur.
Synonyms with most cases reported at age 50-60.
Composite thymomas; Composite thy- There is a male predominance. Macroscopy
moma-thymic carcinoma; Mixed neu- The size of combined tumours does not
roendocrine carcinoma-thymoma. Etiology differ from that of the respective non-
The etiology of these tumours remains combined individual components.
Epidemiology enigmatic. Unpublished genetic studies
Combined thymic epithelial tumours suggest that combined thymic epithelial Tumour spread and staging
showing either A or AB thymoma areas tumours can arise by dedifferentiation of All reported cases occurred in the anteri-
combined with one of the type B thymo- thymoma/ thymic carcinoma or by bipha- or mediastinum as Masaoka stage I
ma subtypes or thymic carcinoma com- sic differentiation of a multipotential (6%), stage II (45%), stage III (29%), or
ponents are exceptionally rare (<1%). thymic epithelial precursor. The concept stage IV (19%) tumours with intrathoracic
Likewise, combined neuroendocrine car- of tumour collision awaits genetic evi- metastases to pleura, lung and lymph
cinoma-thymoma, and combined neu- dence {1841}. nodes.
roendocrine/non-neuroendocrine thymic
carcinomas are exceedingly seldom Localization Histopathology
(<1%), while combined B3 thymoma- Almost all cases were observed in the Among thymomas and thymic carcino-
thymic squamous cell carcinomas are a anterior mediastinum mas, over 80% of combined tumours
have clearly distinguishable, circum-
Table 3.07 scribed areas showing typical B2 and B3
Combined neuroendocrine carcinomathymoma/thymic carcinomas reported in the literature. differentiation. Other common combina-
Type of thymoma: Corresponding Corresponding Source tions are those of B1 and B2 (10%) or of
descriptive terms WHO Classification neuroendocrine tumour B3 and non-neuroendocrine thymic car-
cinoma (5-7%). The carcinoma compo-
Spindle cell thymoma AB (?) Thymic carcinoid {358} nent in most cases is a squamous cell
carcinoma. Lymphoepithelioma-like, sar-
Lymphocyte-rich thymoma B2 Thymic carcinoid {1336}
comatoid/anaplastic or undifferentiated
Epithelial cell predominant B3 Thymic carcinoid {1808} carcinomas are uncommon. Rare cases
thymoma of combined AB and B2 thymoma
{341,1912}, and spindle cell (type A) thy-
Undifferentiated thymic C Thymic carcinoid {1783}
momas in combination with thymic squa-
carcinoma
mous cell {1912}, papillary {541,1263},
Sarcomatoid thymic carci- C Thymic carcinoid {1557} sarcomatoid or undifferentiated carcino-
noma ma have been observed, implying emer-
gence of thymic carcinoma from a
Squamous cell carcinoma C Small cell carcinoma {1841}
benign thymoma subtype.
Adenosquamous carcinoma C Small cell carcinoma {1094} Among neuroendocrine carcinomas
(NECs), tumours composed of a (usually

196 Tumours of the thymus


A B

C D
Fig. 3.70 Combined thymic epithelial tumours. A Combined B2 + B3 thymoma. Lymphocyte-rich B2 component (left) adjacent to lymphocyte-poor B3 component
(right). B Combined carcinoid and small cell carcinoma. Combined neuroendocrine carcinoma: carcinoid (right) and small cell carcinoma (left). C Combined neu-
roendocrine carcinoma/thymoma. Type B3 thymoma (right) adjacent to poorly differentiated (spindle cell) neuroendocrine carcinoma of the thymus (left).
D Combined small cell and keratinizing squamous cell carcinoma. Sharp segregation between foci of small cell carcinoma and the round clusters of keratinizing
squamous cell carcinoma.

atypical) carcinoid component and a Somatic genetics {341,1912}. In one case of combined
poorly differentiated NEC (small cell car- Genetic data have not been published. WHO Type B3 thymoma and thymic large
cinoma or large cell neuroendocrine car- CGH studies on single cases of com- cell neuroendocrine carcinoma, the
cinoma) component have been reported bined B2 and B3 thymomas or B3 and patient died of widespread metastasis of
{1362,1363,2142}. thymic carcinoma components suggest the neuroendocrine carcinoma compo-
To be designated combined neuroen- that the genetic alterations in these nent.
docrine carcinomathymoma/thymic car- tumours are identical to those of their
cinoma, both tumour components should non-combined counterparts {896,2238,
make up such a proportion of the tumour 2242} and that the individual compo-
that both components can be readily rec- nents are clonally related. In one case of
ognized on H&E staining. By immunohis- combined B3 thymoma and large cell
tochemical or ultrastructural studies, neuroendocrine carcinoma, shared
scattered epithelial cells or small epithe- genetic alterations were observed, sug-
lial cell clusters with neuroendocrine fea- gesting a common clonal origin of both
tures can be detected in rare conven- tumour components.
tional thymomas and many thymic carci-
nomas {39,853,1091,1139}. The term Prognosis and predictive factors
mixed neuroendocrine carcinoma thy- Available data on combined thymomas
moma should not be used for these suggest that the most aggressive com-
cases. ponent determines the clinical outcome

Combined thymic epithelial tumours 197


Germ cell tumours of the mediastinum M.R. Wick
E.J. Perlman
A. Zettl
U. Gbel
A. Orazi C. Bokemeyer
H.K. Mller-Hermelink J.T. Hartmann
A. Marx

The mediastinum is among the compart- has not been excluded to date with an NSGCT {199,721,790}. The distri-
ments of the body most frequently affect- {860,2116}. bution of the histologic types varies from
ed by germ cell tumours (GCT), second study to study. In some studies, mature
only to the gonads and ahead of other Basis of the classification teratoma is the most common single enti-
extragonadal GCT (EGGCT) that affect The terminology recommended for medi- ty, while seminoma represents the largest
the retroperitoneum, sacrococcygeal astinal GCT is the same as for germ cell histologic subentity among malignant
region and central nervous system. Like tumours of the gonads {526}. The close mediastinal GCTs {1954}. In other stud-
their gonadal counterparts, mediastinal embryologic relationship and generally ies, seminoma is the leading entity over-
GCT can contain more than one histolog- similar morphological, genetic, clinical all {721,1033}. In adults, mature ter-
ic type of GCT and have been catego- and biological features of GCTs support atomas {1356} and malignant mediasti-
rized for therapeutic purposes into pure this concept. However, GCTs associated nal germ cell tumours for all practical
seminomas, malignant non-seminoma- with haematologic malignancies are vir- purposes are restricted to males {1691},
tous germ cell tumours (NSGCT, includ- tually unique to mediastinal GCTs, while though rare exceptions occur {411},
ing embryonal carcinoma, yolk sac monodermal teratomas, which are well including germinomas in females {229,
tumour, choriocarcinoma, and mixed known in the gonads, have not been 1805,1954,2116}.
GCTs), and teratomas. Mixed GCTs observed in the mediastinum. In children (including adolescents),
account for 34% of all mediastinal GCT mediastinal GCT account for 4% of all
and are, therefore, relatively less frequent Epidemiology paediatric GCTs {1764}. Among extrago-
than gonadal mixed GCTs. Mediastinal germ cell tumours are rare nadal germ cell tumours mediastinal
As with the testicular germ cell tumours, neoplasms, representing less than 1% of cases are third only to sacrococcygeal
there is a separate group of mediastinal all malignancies and 3-4% of all germ and central nervous system GCTs
germ cell tumours that present in infancy cell tumours in both adults and children {721,1763}. In prepubertal children (<8
and early childhood that are comprised {1033,1764}. Mediastinal GCT account years), teratoma and yolk sac tumours
solely of teratomatous and yolk sac for up to 16% of mediastinal neoplasms are most prevalent, and other malignant
tumour components. in adults and for 19-25% of mediastinal histologic subtypes are virtually non-
The preference of germ cell tumours tumours in children {1356,1954}. existent {1764,1955}. The majority of
(GCT) for the mediastinum has been Although annual incidence rates for testi- these lesions present in infancy and early
explained by the distribution of fetal cal GCT are strikingly different between childhood. In prepubertal patients, ter-
germ cell precursors (primordial germ Caucasians (~10/100.000) and Africans atomas have no sex predilection, where-
cells) that migrate from the yolk sac to and Asians (1-2/100.000) similar inci- as yolk sac tumours demonstrate a
paired midline structures called germinal dence rates for mediastinal GCTs of female predominance in young children
ridges which during very early develop- about 0.1-0.2 per 100.000 can be calcu- with a 4:1 F: M ratio {1763}.
ment extend virtually throughout the axial lated from Japanese {1955} and
dimension of the body during fetal devel- European nation-wide data {674}. Etiology
opment {1204}. If arrested during migra- Mediastinal GCTs occur at all ages (079 The etiology of mediastinal germ cell
tion, some germ cell precursors may sur- years), though there is a bimodal age tumours is unknown. The only estab-
vive and serve as cells of origin for sub- distribution, with a distinct peak in infan- lished risk factor for mediastinal non-
sequent GCT development. Although cy {1356}. Children and adolescents seminomatous GCT development is
mediastinal NSGCTs exhibit a worse (<18 years) account for 16-25% of all Klinefelter (KF) syndrome (reported risk
prognosis than their gonadal counter- cases {1356,1954}. These can be divid- 50 to several hundred-fold) {793,795}.
parts {199} and can show virtually unique ed into post-pubertal mediastinal germ The underlying pathogenetic mecha-
biological features (like clonally related cell tumours (which simply represent the nisms are, however, not understood. In
haematologic neoplasms {315,1461, lower end of the age distribution of adult KF patients, NSGCT develop from early
2246}), recent genetic and epigenetic GCT) and prepubertal mediastinal GCT adolescence to the age of 30. The
data support the concept that most {1764}. This bimodal age distribution cor- increased frequency of GCTs is linked to
gonadal and mediastinal GCTs share a responds to differences in genetic aber- the 47, XXY genotype, while men with
common primordial germ cell ancestry rations, sex predilection, and clinical out- mosaic KF syndrome (46, XXY) have no
{257,316,1764-1766}. However, since come. significantly increased risk {480,793}. Of
thymic epithelial stem cells and their Post-pubertal mediastinal GCT account note, testicular GCTs are not increased in
plasticity have only partially been char- for 1-3% of all GCTs {721}. The mean age patients with Klinefelter syndrome {793},
acterized {181}, a somatic stem cell der- of affected adults is 33 years for semino- suggesting a unique oncogenic pathway
ivation of at least some mediastinal GCTs ma patients and 28 years for patients for mediastinal non-seminomatous germ

198 Tumours of the thymus - Germ cell tumours


Table 3.08 or benign {2246}) histiocytosis {83,129,
Clinical categorization of mediastinal germ cell tumours helps to guide the decision about neoadjuvant 474,1112,1461}, myelodysplastic syn-
chemotherapy before radical resection and complete histological work-up. Clinical categories are derived
dromes (MDS) or myeloproliferative dis-
from the synopsis of (i) the patological diagnosis that is usually based on fine needle biopsies, (ii) serum
eases and haemophagocytic syndromes
tumour marker levels (AFP, beta-hCG) and (iii) imaging studies.
{83,1450,2055}. These haematologic pro-
Clinical category Therapeutic implication liferations occur in 2-6% of NSGCTs
{199,789}, are clonally related to the
Seminoma1,2 Chemotherapy and/or irradiation GCTs {315,1113,1461} and develop inde-
pendently of chemotherapy {474, 1461}.
Malignant non-seminomatous GCTs Chemotherapy, followed by resection of tumour
The NSGCT are most often yolk sac
Embryonal carcinoma remnants (irrespective of the histology)
tumours or harbour a yolk sac component
Yolk sac tumours
{83,315,1112,1461}, and can be associ-
Choriocarcinoma
Mixed germ cell tumours
ated with Klinefelter syndrome {129,490,
1461}.
Mature teratoma1 Resection Secondary MDS and AML that are relat-
ed to etoposide chemotherapy in
Immature teratoma1 Children: resection patients with mediastinal GCTs {100,
Adults: depending on tumour stage 1047} must be distinguished from clonal-
ly-related haematologic malignancies.
1 If patients with pure seminomas or pure teratomas as defined by fine needle biopsy exhibit elevated, Secondary MDS and AML occurred in
age-adjusted tumour marker levels {696}, tumours are included in the non-seminomatous category.
~1.0% of cases in a large series {1047}.
Sampling error is the most likely explanation for the discrepancy between histopathological diagnosis and
Chemotherapy-related AMLs usually
clinical category.
2 Elevated beta-hCG levels <100 IU/L (in adults) and <25 IU/L (in children) are compatible with a fine needle manifest later (2560 months after
biopsy-based diagnosis of pure seminoma {197,696,1764}. chemotherapy) than GCT-related AMLs
(median time to onset 6 months, range
0122) {789,1461}.
cell tumour (NSGCT) development in KF Respiratory compromise is more com-
patients. mon in neonates and children than in Metachronous testicular cancers in
Apart from the well established associa- adults, usually due to the extreme size of mediastinal GCTs. The risk for the devel-
tion between haematologic malignancies the lesion {1785,1954}, while the superior opment of metachronous testicular can-
and mediastinal NSGCTs, the frequency vena cava syndrome is more frequent in cer (MTC) is low in mediastinal GCTs (10-
of other neoplasms is not increased adults than children. Hydrops fetalis is a year cumulative risk ~6%) {199,787}.
{788} in patients with mediastinal GCT, typical complication of pericardial ter- MTCs are seminomas in ~70% of cases,
arguing against a role of common cancer atoma {1129,1834}. although the underlying extragonadal
susceptibility genes in the development Fever and formation of multilocular GCT usually is a NSGCT {787}.
of mediastinal GCTs. thymic cysts result from local inflammato- Intratubular germ cell neoplasia of the
ry reactions that frequently accompany testis is a rare accompanying finding in
Site of involvement GCTs and are most prominent in semino- mediastinal GCTs {757}.
The large majority of primary mediastinal mas.
GCTs arise within or adjacent to the thy- Precocious puberty due to increased Imaging
mus, but teratomas and yolk sac tumours beta-hCG levels can accompany medi- Pure seminomas, with few exceptions
{123} have also been described in the astinal NSGCTs or mixed GCT {1769}. {1810}, form uncalcified, homogeneous
posterior mediastinum {1955}, in an Children with Klinefelter syndrome and masses indistinguishable from lymphoma
intrapericardial location {172,1129, mediastinal NSGCTs have a particularly {1888}. By contrast, NSGCTs are usually
1293}, and sometimes even within the high frequency of precocious puberty heterogeneous masses, exhibiting cen-
myocardium {1764}. {795,1106}. tral attenuation and a frond-like periphery
Metastasis. Clinical symptoms related to {1888}. Since multilocular thymic cyst for-
Clinical features metastatic spread may dominate. Most mation is a stereotypic response of the
Signs and symptoms often symptoms are related to metastasis thymus to inflammatory stimuli, multilocu-
Mature teratomas are incidental findings to the bone, liver, brain {518}, retroperi- lar cystic lesions are not only typical for
in 50% of children and 66% of adults, toneum and heart {40}. mature teratomas but accompany many
while only 38% and 10% of patients with Paraneoplastic autoimmune diseases, other mediastinal GCT (particularly semi-
seminoma and malignant NSGCT, particularly myasthenia gravis, are virtu- noma), thymomas, thymic carcinomas,
respectively, are asymptomatic {1954}. ally non-existant. Hodgkin or non-Hodgkin lymphomas or
Presenting symptoms of GCTs are relat- Haematologic proliferations associated metastasis to the mediastinum.
ed to the local mass lesion and comprise with mediastinal GCT. An almost unique A diagnosis of primary mediastinal GCT
chest pain (52%), respiratory distress complication of mediastinal NSGCTs as requires absence of a testicular or ovari-
(48%), cough (24%), hoarseness (14%) compared to other extragonadal or testic- an tumour on physical examination, high
and the superior vena cava syndrome ular {1243} GCTs is the development of resolution ultrasonography, or MRI scan
(14%) {1954}. acute leukaemias {199,1132}, malignant {198}. A bilateral testicular biopsy is not

Germ cell tumours of the mediastinum 199


mandatory for diagnosis of mediastinal Table 3.09
GCTs. IGCCCG criteria for the prognostic factor-based clinical risk grouping of malignant GCT in adults {4}.
The criteria are not applicable to children before puberty.
Tumour markers IGCCCG Group Criteria
In patients with mature teratomas, tumour
markers are almost always negative in the Good Seminoma: No non-pulmonary visceral metastases AND normal AFP, any HCG,
serum. By contrast, a-fetoprotein (AFP) any LDH
and/or beta-human chorionic Non-Seminoma: no patients classified as good prognosis
gonadotropin (beta-hCG) are elevated in Intermediate Seminoma: non-pulmonary visceral metastases AND normal AFP, any HCG, any
80-90% of malignant GCTs {1764}. AFP- LDH
positivity is more frequent (~73%) than Non-Seminoma: no patients classified as intermediate prognosis
increased serum levels of beta-hCG
(~27%) {1955}. In adults, tumour marker Poor Seminoma: no patients classified as poor prognosis
levels at first presentation are citeria for Non-Seminoma: all patients with mediastinal Non-Seminoma are classified as
poor prognosis
the risk grouping (good, intermediate,
poor) of GCT according to the IGCCCG IGCCCG= International Germ Cell Cancer Collaborative Group
system {4} as given in Table 3.09. In addi-
tion, unsatisfactory decline of AFP and/or
beta-hCG levels during the early phase of for the aberrant migration pathways and have been identified at this site, these
chemotherapy appears to herald lack of the ability of the germ cells to survive at have not been substantiated or con-
tumour responsiveness and is therefore the extragonadal sites are largely firmed. Loss of distal 6q is of interest due
associated with a worse outcome {1273}. unknown. However, primordial germ cell to the location of the potential tumour
On the other hand, decline of tumour migration has been shown to be deter- suppressor gene insulin growth factor
markers in spite of persistence or mined by the ckit, stem cell factor recep- type II receptor. IGF2R has multiple activ-
enlargement of a mediastinal GCT on tor ligand pair. Abnormalities in expres- ities, one of which is to degrade IGF2, a
repeated imaging can be due to the sion of either the receptor or the ligand at potent growth promoter. Specific dele-
growing teratoma syndrome or somat- any site in this pathway may result in tions, mutations, or imprinting abnormali-
ic-type malignancy accompanying a abnormal migration or survival {1004}. ties of IGF2R have not been document-
chemosensitive GCT. The genetic changes that have been ed.
documented in primary mediastinal germ Malignant mediastinal germ cell tumours
Tumour spread and staging cell tumours vary with age at presenta- in adolescents and adults demonstrate
When all mediastinal GCT are consid- tion and parallel the genetic changes ploidy and genetic features similar to
ered, metastasis has been observed in found in germ cell tumours arising at those described in their gonadal coun-
~20% of cases {1356,1359}. While gonadal sites in comparable age groups. terparts. In contrast to the tumours of
mature teratomas do not metastasize, This results in three categories of genet- young children, tumours in this category
mediastinal seminomas show metastasis ic changes within mediastinal germ cell are usually aneuploid and demonstrate
in up to 41% of cases {197,199}. In medi- tumours: gain of chromosome12p, regardless of
astinal NSGCT, metastasis to at least one the histologic subtype {316,1765}. This
site is present in 85-95% of patients at Malignant mediastinal germ cell tumours observation correlates with the presence
presentation, and hematogenous metas- in infants and young children almost of an isochromosome 12p {1057,1392,
tasis is the predominant type of dissemi- exclusively show yolk sac tumour histo- 2230}, which has been found in 84% of
nation. In contrast, lymph node metasta- logy. These tumours may be diploid or 25 malignant mediastinal germ cell
sis is particularly common in seminomas. near-tetraploid and are uncommonly tumours in adults reported to date {316}.
Haematogenous metastases typically aneuploid {1517,1765}. Cytogenetic and The isochromosome 12p is formed by
involve lung (38%), bone, liver, brain comparative genomic hybridization the duplication and centromeric fusion of
{518}, retroperitoneum and heart {40}. (CGH) analysis of such tumours demon- the short arm of one chromosome, and
Metastasis is a major criterion for staging strate gain of chromosomes 1q, 3, and loss of the long arm. In other patients
and is an adverse prognostic factor in 20q and loss of chromosomes 1p, 4q, amplification of fragment of the chromo-
seminomas {790} and NSGCT {199, and 6q {1765}. The same genetic some 12p (double minutes, homoge-
790}. changes have been identified in infantile neously staning regions) can be
A modification of the TNM classification yolk sac tumours of the sacral region and observed. In testicular malignant GCTs,
of soft tissue tumours is recommended testis {1572,1573}. The two loci that have comparative genomic hybridization has
for staging of mediastinal GCTs. received additional attention and study been successful in identifying a small
are loss of distal 1p and loss of distal 6q region of high level amplification at
Genetics {874,1574,1881}. Loss of distal 1p has 12p11.2-12.1, providing an important
As indicated above, most GCT at extrag- been identified in 80% of infantile YST clue to the localization of candidate
onadal sites have been demonstrated to and is particularly intriguing due to its proto-oncogenes on 12p. Additional
arise in primordial germ cells that have established role in another embryonal recurrent changes seen in this category
undergone erasure of imprinting prior to tumour of infancy, neuroblastoma. While of germ cell tumours include loss of chro-
migration {1766}. The factors responsible candidate tumour suppressor genes mosome 13 and gain of chromosome 21

200 Tumours of the thymus - Germ cell tumours


{1765}, findings also reported in malig- ences between mediastinal GCT in indi- resection in all age groups. In infants,
nant testicular GCT {1057,1673}. viduals with and without Klinefelter syn- tumours may be quite large and associ-
Pure mediastinal teratomas (immature drome have been described, and the ated with developmental abnormalities
and mature) arising in all ages have underlying cause of the increased fre- due to compression of adjacent struc-
demonstrated no genetic gains or losses quency of GCT in patients with Klinefelter tures during development. Tumour-relat-
{258,860,1765}. This observation is simi- syndrome is unknown. Constitutional sex ed deaths almost never occur when the
lar to those described in mature tera- chromosomal abnormalities have not tumour is able to be resected {721,
tomas of the ovary, the infant testis, and been identified in mediastinal germ cell 1159,1955}.
other extragonadal sites in infants. tumours of young children. Following preoperative cisplatin-based
However, it is distinctly different from chemotherapies of malignant GCTs, com-
genetic reports of mature teratomas in Prognostic factors pleteness of resection {786,787, 1764}
the adult testis, in which aneuploidy and In the era of cisplatin-based chemother- less than 10% viable cells {588} and low-
the isochromosome 12p have been iden- apy for malignant GCTs, the most impor- risk features according to the IGCCCG
tified. Therefore, due to the extreme rari- tant natural prognostic factors in grouping system {4} are favourable prog-
ty of mature mediastinal teratomas in extragonadal GCTs are histology and nostic factors. Decreased survival is
post-puberty males, caution is recom- localization of the primary tumour {997, associated with failure to respond to cis-
mended prior to assuming a benign clini- 1461,1955}. platin and higher rates of relapses {790}.
cal behaviour in such cases. Supporting In NSGCTs, mediastinal localization is Unsatisfactory decline of AFP and/or
this is evidence provided by tumours that associated with a worse prognosis com- beta-hCG levels during the early phase of
contain a mixture of teratoma and malig- pared to their counterparts at other chemotherapy appears to herald a worse
nant germ cell histologies. In those extragonadal and gonadal sites {105, outcome {1273}. Treatment failure is
cases for which it was possible to ana- 790,1159,1233,1764}. However, recent among the worst prognostic factors and
lyze the teratoma component separately neoadjuvant strategies achieved dramat- is more common in mediastinal than other
from the malignant component, these ically improved outcomes also in NSGCTs GCTs and is significantly associated with
tumours demonstrated similar abnormal of children {1764} and adults {198,199, non-seminomatous histology and metas-
CGH profiles within both the teratoma- 588}. tasis to liver, lung and brain {790}.
tous and the malignant components Initial AFP levels >10.000 ng/ml indicate
{1765}. Similar findings have been a worse prognosis in children {105} while
reported at other sites {1205}. elevated beta-hCG is an independent
In addition to the above changes, post- adverse prognostic factor for survival in
pubertal malignant mediastinal GCTs adults {199}.
have long been associated with Seminomas show a favourable response
Klinefelter syndrome {480,793,795,1459, to radiotherapy and cisplatin-based
2246}. The majority of adolescent and chemotherapies, and their excellent prog-
adult mediastinal malignant germ cell nosis (~90% survival) is not different from
tumours arise in males {1359}, and up to the prognosis of seminomas in other loca-
half of these patients show an additional X tions {198,199,790,1159,1955}. Adverse
chromosome within their peripheral blood prognostic parameters in seminomas are
lymphocytes {258,1765}. Therefore, ado- liver metastasis or metastases to multiple
lescent males presenting with malignant other sites {790}.
mediastinal GCT should be evaluated for Mature mediastinal teratomas have an
Klinefelter syndrome. No genetic differ- excellent prognosis after complete

Table 3.10.
Interrelationship of age, tumour type, clinical behaviour and genetic alterations in mediastinal germ cell tumours. Data are derived from conventional cytogenetics,
CGH studies and DNA ploidity analysis.
Age at clinical presentation Histology Sex predilection Clinical behaviour Recurrent genetic aberrations

Prepubertal Teratoma M=F Benign if resectable None


(mature and immature)

Yolk sac tumour F>M Malignant del(6q), del(1p), gain 20q, gain 1p
(80% survival) diploidy or tetraploidy
Adolescents and Teratoma M>>F Benign None
Adults (mature and immature)

Malignant GCT M>>F Malignant (50% survival) i(12p), gain 21, loss 13, loss of Y, +Xc*,
(all histologic subtypes) aneuploidy
* +Xc, constitutional gain of the X-chromosome (Klinefelter syndrome)

Germ cell tumours of the mediastinum 201


Seminoma M.R. Wick
A. Zettl
J.K.C. Chan
C. Bokemeyer
J.T. Hartmann
E.J. Perlman
A. Marx

Definition 1371,1955}, with approximately two- metastases most commonly occur in cer-
A primitive germ cell tumour composed thirds of the cases occurring in the 3rd vical and abdominal lymph nodes (in one
of fairly uniform cells with clear or and 4th decade {197,1371}. series in 25% and 8%, respectively)
eosinophilic, glycogen-rich cytoplasm, {197}.
distinct cell borders, and a round nucle- Clinical features
us with one or more nucleoli, resembling Mediastinal seminomas typically arise in Etiology
primordial germ cells. Mediastinal semi- the anterior mediastinum, although a few The cellular origin of mediastinal semino-
nomas are morphologically indistinguish- cases have been reported to arise in the mas is controversial {316}. Apart from
able from their gonadal counterparts. posterior mediastinum {1955}. Clinical gonads, seminomas may occur at other
symptoms are non-specific. Patients may sites in the human body along the mid-
ICD-O code 9061/3 present with symptoms related to a medi- line, such as the pineal gland, retroperi-
astinal mass, e.g. chest pain, dyspnoea, toneum, or the sacral area. During
Epidemiology cough, superior vena cava syndrome. embryogenesis, migratory primordial
Seminomas are rare mediastinal germ Some patients are asymptomatic, with germ cells may become misplaced
cell tumours first described in 1955 the tumour being detected by routine X- along the midline on their way from the
{2170}. Only 2 to 5% of all adult germ cell ray or during unrelated thoracotomy yolk sac to the embryonic gonadal ridge
tumours arise in the mediastinum. {1371}. The size of the tumour may be {293,1356}. A derivation from thymic
Among extragonadal germ cell tumours, rather large due to slow constant growth myoid cells or from occult testicular
primary mediastinal seminomas account with overall little clinical symptoms. intratubular germ cell tumour has been
for 8% of cases {197,198}. In a large Moderate serum beta-hCG elevation discussed {316,1689}. Yet, in contrast to
series reported from Japan, only 1.6% of (100 IU/L in adults and 25IU/L in chil- patients with retroperitoneal seminomas,
primary mediastinal neoplasms are pure dren) may be found in up to one third of no testicular intraepithelial neoplasia is
seminomas {1955}. The reported fre- patients and is still compatible with the observed patients with mediastinal germ
quency of pure seminomas among pri- diagnosis of pure seminoma {197,696}. cell tumours {193,440, 441}.
mary mediastinal germ cell tumours At the time of diagnosis, the majority of The histogenetic relationship between
ranges from 9% to 39% {520,1356,1371, mediastinal seminomas are localized, mediastinal and gonadal seminoma is
1955}, ranking seminoma second in fre- circumscribed masses without macro- controversial. Genetic analysis of medi-
quency following teratoma {520,1356, scopic or microscopic evidence of inva- astinal seminomas have shown similar
1371}. sion into neighbouring organs such as patterns of non-random chromosomal
With the exception of single cases pleura, pericardium, and great vessels changes, in particular the presence of
{229,520,1955}, almost all reported {1371}. The preferential sites of distant i(12p), as in gonadal seminoma {314,
mediastinal seminomas have occurred in spread, if present, are the lung, chest 316}, suggesting a very close patho-
men {520,1356,1371,1955}. The age wall, brain, pleura, liver, adrenal gland, genetic relationship between seminomas
ranges from 13 to 79 years {520,1356, and bone {1349,1356}. Lymph node at either sites. However, other studies

A B
Fig. 3.71 Seminona. A Macroscopy of mediastinal seminoma. B Seminoma containing lymphoid follicle with prominent germinal center.

202 Tumours of the thymus - Germ cell tumours


A B

C D
Fig. 3.72 Seminoma. A Large tumour cells with broad clear cytoplasm, large nuclei and conspicuous nucleoli. A light infiltrate of lymphocytes is present among the
tumour cells and in the septa. B Mediastinal seminoma accompanied by lymphocytes and epithelioid cells including multinucleated giant cells.
C Syncytiotrophoblast in mediastinal seminoma. D Immunoreactivity for CD117 in thymic seminoma.

report significant differences between multinodular, tan-grey or pale cut sur- Frequently, there is a prominent inflam-
the two. Compared with testicular semi- faces. Punctate focal hemorrhage and matory cellular background infiltrate of
nomas, in one series, mediastinal semi- yellowish foci of necrosis may be small mature lymphocytes, plasma cells
nomas are reported to more frequently observed. The tumour size ranges from 1 and occasional eosinophils. The infiltrate
express CAM5.2 (80% vs 21%), keratin to 20 cm (median size 4.6 cm) {197, is typically most dense in and around the
(68% vs 0%), PLAP (93% vs 50%) and 1371}. fibrous septa, but is also intermingled
vimentin (70% vs 46%), possibly reflect- Microscopically, mediastinal seminomas with the tumour cells. A granulomatous
ing a more mature degree of tumour cell are composed of round to polygonal, reaction ranging from ill-defined clusters
differentiation in the latter {1920}. KIT fairly uniform tumour cells with round to of epithelioid histiocytes to well-defined
mutational analysis showed a different oval, central, slightly squared, non-over- epithelioid granulomas with Langhans
mutational pattern in mediastinal semino- lapping nuclei and one or more large giant cells may be present. Occasionally,
ma compared with testicular seminoma central nucleoli. The tumour cells com- germinal centers are present. The brisk
{1623}. monly have abundant glycogen-rich, inflammatory, granulomatous reaction
While Klinefelter syndrome is a risk factor clear to lightly eosinophilic cytoplasm and scar formation may obscure the
for nonseminomatous mediastinal germ and distinct cell membranes. Rarely, the underlying seminoma {1354,1371}.
cell tumours, seminomas have not been tumour cells may show a dense In some cases, large syncytiotrophoblas-
observed {794}. eosinophilic cytoplasm or a greater tic cells are scattered throughout the
degree of cellular pleomorphism. The tumour, often in close proximity to capillar-
Morphology tumour cells grow in confluent multinodu- ies and/or focal microhaemorrhage. These
Mediastinal seminomas are morphologi- lar clusters, sheets, cords, strands or giant cells are multinucleated, with abun-
cally identical to their gonadal counter- irregular lobules displaying a nesting dant basophilic cytoplasm and occasional
parts. Macroscopically, they are mostly pattern. Between the tumour cell aggre- intracytoplasmic lacunae. However, there
well-circumscribed, fleshy tumours with a gates, delicate fibrous septa are often are no cytotrophoblast cells or confluent
homogeneous, slightly lobulated to observed. nodules as in choriocarcinoma.

Seminoma 203
In a quarter of cases, remnants of thymic While it is prudent to rule out metastatic ciated with a higher recurrence rate, but
tissue can be found within or at the disease from a primary gonadal semino- most patients have been salvaged with
periphery {1356,1371}. In 10%, the ma, mediastinal metastases are rare in subsequent chemotherapy {197}. After
thymic remnants undergo prominent cys- gonadal seminomas, in particular in the completion of chemotherapy residual
tic changes similar to multilocular thymic absence of retroperitoneal lymph node lesions detectable by radiographic stud-
cysts, probably reflecting cystic transfor- metastasis {996}. Other differential diag- ies frequently persist, in most cases con-
mation of remnant thymic epithelium noses include metastatic melanoma, sisting of necrotic masses that will ulti-
induced by seminoma cells {1354}. In lymphoma, thymoma, thymic carcinoma, mately shrink over time. In contrast to
some cases, the thymic epithelium under- and in particular clear cell carcinoma mediastinal nonseminomatous germ cell
goes hyperplasia, and may lead to a mis- (primary or metastatic). tumours, surgical resection is usually not
diagnosis of thymic epithelial tumour. indicated. Investigation by positron emis-
Seminoma can also occur as a compo- Genetics sion tomography (PET) is helpful in dis-
nent in mixed germ cell tumours. The genetic changes that have been tinguishing viable from necrotic tumour
Spermatocytic seminomas have not described in mediastinal seminomas are residuals in seminoma patients {460}. In
been described in the mediastinum. the same as those reported in testicular a large international study on mediastinal
Mediastinal seminomas commonly show seminomas, with 69% demonstrating the seminomas, liver metastases, two or
diastase-labile PAS staining due to the isochromosome i(12p) characteristic of more metastatic sites, and the presence
presence of abundant glycogen. post-pubertal malignant germ cell of non-pulmonary visceral metastases
tumours at all sites. Mediastinal semino- have been identified as negative prog-
Immunohistochemistry mas are most commonly aneuploid, with nostic factors. Metachronous testicular
Immunohistochemically, 80-90% of medi- a minority having near-tetraploid DNA germ cell tumours in patients with medi-
astinal seminomas are reported to be content. astinal seminoma are exceedingly rare
positive for PLAP, and 70% show {198}.
vimentin positivity. CD117 positivity in a Prognosis
cell membrane or paranuclear Golgi pat- Compared with mediastinal nonsemino-
tern is common {1623}. Although up to matous germ cell tumours, pure medi-
70% of cases show staining for panker- astinal seminomas are associated with a
atin, the staining is often only focal, favourable prognosis. A 5-year survival
weak, and paranuclear. Immunostaining rate of 90% can be achieved with cis-
for beta-hCG highlights the scattered platin-based combination chemotherapy
syncytiotrophoblastic cells, if present, which has largely replaced radiotherapy
and also isolated seminoma cells in as the initial treatment in patients with
about 5% of cases. CEA, EMA, and AFP mediastinal seminoma {197,198}.
are negative {1356,1371,1920}. Primary radiotherapy seems to be asso-

204 Tumours of the thymus - Germ cell tumours


Embryonal carcinoma M.R. Wick
E.J. Perlman
A. Zettl
F. Mayer
J.C.K. Chan
A. Marx

Definition with seminoma is equally frequent in chil- Tumour spread


A germ cell tumour (GCT) composed of dren after puberty and adults (20-30%) Local tumour spread is common and can
large primitive cells of epithelial appear- {1764,1955}. lead to compression and infiltration of the
ance with abundant clear or granular lung. About 25% of pure or combined
cytoplasm, resembling cells of the Clincal features ECs already show pulmonary metastasis
embryonic germ disk and growing in Patients present with thoracic or shoul- at presentation {1955}. Further specific
solid, papillary and glandular patterns. der pain (60%), respiratory distress information on tumour spread in medi-
(40%), hoarseness, cough or fever astinal EC is not available. However,
IDC-O code 9070/3 (<10%), or superior vena cava syndrome since pure or combined ECs are among
(12%) {1955}. Gynaecomastia is uncom- the most frequent malignant mediastinal
Synonym mon and asymptomatic patients are rare GCTs, it is reasonable to assume that
Malignant teratoma, undifferentiated {1808}. A quarter of patients have pul- spread of ECs is similar to that of the
monary metastasis at presentation and whole NSGCT group, in that there is a
Epidemiology virtually all patients exhibit increased high rate (~50%) of haematogenous
Embryonal carcinoma (EC) of the medi- serum AFP levels, while HGG levels are metastasis (to lung, liver, brain and
astinum is a tumour of young males (M/F elevated in cases with a choriocarcino- bones), while lymphogenous metastasis
ratio, >10:1) {1033,1955}. It occurs in ma component {1955}. Imaging findings is apparently much rarer {199}.
pure form or as a component in mixed are not specifically different from those
germ cell tumours at about equal fre- reported for other NSGCT {1684}. A Macroscopy
quencies {1033,1369,1955}. ECs (pure minority of patients show features of ECs are described as large tumours with
or mixed) account for up to 12% of all Klinefelter syndrome {150,1290}. invasion of the surrounding organs and
mediastinal GCTs {1033,1356} and for structures. Grossly, the cut surface often
30-65% of all NSGCT {997,1356,1955}. Etiology reveals large areas of necrosis and
The mean age of adult patients is 27 The etiology of EC is unknown. The rare haemorrhage. Viable tumour tissue is
years (range: 18-67 years) {1032,1955}. association with Klinefelter syndrome soft, fleshy, grey or white to pink or tan. In
In the literature, EC in childhood is very {150,1290} suggests a similar (but unre- mixed GCT cystic spaces may be con-
rare before the age of 1 year and peaks solved) etiology as in other mediastinal spicuous.
(usually as part of a mixed GCT) NSGCT. A single reported familial case
between 1 and 4 years of age and again {34} might indicate a fortuitous coinci- Histopathology
after the age of 14 years {1764}. dence rather than a genetic predisposi- Pure ECs show a more solid growth pat-
However, as the pathologic features of tion. Risk factors for testicular GCTs tern than other NSGCTs. ECs form
solid yolk sac tumour (YST), and its dis- {1204} appear largely irrelevant for the sheets, tubules or vague papillary struc-
tinction from EC is increasingly recog- development of mediastinal GCTs {793}. tures composed of large polygonal or
nized, it is evident that the vast majority,
if not all, the tumours in prepubertal
patients previously classified as EC are
better classified as YST.
In adults, EC as a component of mixed
GCTs accounts for 9% of all mediastinal
GCTs and for 75% of all NSGCT {1955}.
EC is commonly associated with ter-
atoma (56%), choriocarcinoma (22%) or
seminoma (22%) {1032,1954}. The asso-
ciation with yolk sac tumour is very rare
in adults {1955} but more common in
adolescents {1369}.
In adolescents, combined EC accounts
for 15% of all GCT {1764} and for 27-33%
{1111,1764} or even more {1111} of the
non-seminomatous subgroup. EC in this
group is a component of most mixed Fig. 3.73 Embryonal carcinoma. Low power showing solid growth pattern on the left side and poorly formed
GCT (77%) {1111,1764}. The association glands on the right side.

Embryonal carcinoma 205


A B
Fig. 3.74 Embryonal carcinoma. A High power. Cytological details of a tumour with glandular growth pattern. B Strong membranous CD30 staining.

columnar cells. The nuclei are large, In addition, ECs are uniformly and AFP and beta-hCG) are distinguishing
round or oval, often vesicular, and can be strongly reactive with antibodies to low- features.
hyperchromatic or have a light chro- molecular weight cytokeratins, while Metastasis to the mediastinum from a
matin. They can be crowded and over- EMA, carcinoembryonic antigen (CEA), testicular EC or mixed GCT {932,996}
lapping. Prominent single or multiple and vimentin are usually negative. Alpha- has to be excluded.
nucleoli are common. The cell borders fetoprotein (AFP) {1369,1920} and pla-
are often indistinct, especially in the solid cental alkaline phospatase (PLAP) Genetics
areas. The cytoplasm is often {1808,1920} can occur in scattered The genetic changes that have been
amphophilic, but can be basophilic, tumour cells or small foci in about 30% of described in mediastinal EC are the
eosinophilic, pale or clear {1808}. As in cases. One third of cases show beta- same as those reported in their testicular
seminoma, scattered single or small hCG expression in scattered syncytiotro- counterparts and demonstrate the
groups of syncytiotrophoblasts can phoblastic cells. isochromosome 12p characteristic of
occur in EC. Mitoses are numerous and post-pubertal malignant germ cell
often atypical. Extensive necrosis can Differential diagnosis tumours at all sites. Mediastinal EC is
occur, and is particularly prominent in When syncytial areas are extensive, EC rarely associated with Klinefelter syn-
ECs combined with yolk sac tumour. The can mimic choriocarcinoma {1369}. drome {150,1290}. A single familial case
stroma is usually scant in viable tumour However, a biphasic plexiform pattern {34} cannot be taken as evidence for a
areas, but fibrotic adjacent to areas with produced by a mixture of syncytiotro- genetic predisposition.
regressive changes. Scattered lympho- phoblasts and cytotrophoblasts is lack-
cytes and a granulomatous reaction are ing, and pure ECs lack the extensive Prognostic factors
uncommon. beta-hCG immunoreactivity of choriocar- There are no reports focussing on the
In mixed GCTs, the EC component may cinoma {1369}. Yolk sac tumours can be prognostic factors of mediastinal EC.
be combined with a yolk sac tumour, distinguished from EC by a more varied However, since EC histology has not
teratoma, seminoma, choriocarcinoma, growth pattern (most commonly micro- been shown to be an adverse prognostic
or combinations of these GCTs, and cystic and reticular), smaller cell size, factor in several large clinical studies
uncommonly somatic-type malignancies presence of Schiller-Duval bodies, and {199,237,1462}, it is likely that the prog-
{1230}. lack of CD30 expression. EC can be dis- nostic factors described for NSGCT
tinguished from seminoma by showing a apply to EC. This conclusion is support-
Immunohistochemistry greater degree of nuclear pleomorphism, ed by a recent study: the long-term sur-
CD30 (Ki-1) is expressed in 85-100% of at least focal definite epithelial character- vival rate of ~50% in adult patients with
pure EC or EC components of mixed istics (such as gland formation), uniform mediastinal EC after cisplatin-based
germ cell tumours {1135,1534}, while strong staining for cytokeratin, frequent chemotherapy {1955} was very similar to
other germ cell tumours (with the excep- CD30 expression, and usual lack of the rates published for large series of
tion of rare cases of seminomas and yolk CD117 expression {1920}. adult NSGCT. Similar conclusions
sac tumours {855,1369}) and other non- Mediastinal metastasis from large cell appear justified for children with EC,
haematopoietic neoplasms are CD30- carcinoma of the lung can be a morpho- although 5-year survival rates are signifi-
negative {1534}. There is distinct cell logic mimic {1369}. The young age of cantly better (>80%) than for adults
membrane staining with variable cyto- most EC patients, CD30 expression, and {1764}.
plasmic positivity. the tumour markers in the serum (such as

206 Tumours of the thymus - Germ cell tumours


Yolk sac tumour E.J. Perlman
A. Marx
C. Bokemeyer
M.R. Wick

Definition YST presents exclusively in males. The lessens this diagnostic difficulty in this
A tumour characterized by numerous age at presentation ranges from 14 to 63 setting.
patterns that recapitulate the yolk sac, years {1369,1955}. A number of different histologic patterns
allantois and extra-embryonic mes- have been described; microcystic (reti-
enchyme. Clinical features cular), macrocystic, glandular-alveolar,
Patients with mediastinal YST often pres- endodermal sinus (pseudopapillary), myx-
ICD-O code 9071/3 ent with chest pain, dyspnoea, chills, omatous, hepatoid, enteric, polyvesicular
fever, and superior vena cava syndrome vitelline, and solid {1102, 1963,1990}. The
Synonym {1369,1955}. The site of involvement is majority of yolk sac tumours show more
Endodermal sinus tumour almost invariably the anterior medi- than one histologic subtype, and the dif-
astinum. Regardless of the age, alpha ferent subtypes often merge subtly from
Epidemiology fetoprotein (AFP) levels are elevated in one to another. These many different histo-
Mediastinal yolk sac tumours (YST) pres- over 90 percent of cases. logic types have not been shown to have
ent in two distinct age groups. In infants prognostic or biologic significance, but aid
and young children, YST is virtually the Macroscopy in the recognition of unusual YSTs.
only malignant germ cell tumour histo- Macroscopically, pure YSTs are solid, The reticular or microcystic variant is the
logic subtype seen and there is a strong soft, and the cut surface is typically pale most common histologic subtype, and is
predominance of females (F:M, 4:1) grey or grey-white and somewhat gelati- characterized by a loose network of
{1765}. In these patients it is usually the nous or mucoid. Large tumours often spaces and channels with small cystic
sole histologic subtype, however it may show haemorrhage and necrosis. spaces lined by flattened or cuboidal
occasionally be accompanied by ter- cells with scant cytoplasm. A variant of
atomatous elements. The age at presen- Histopathology the microcystic pattern is the myxoma-
tation ranges from the newborn period to The histology of YST is the same regard- tous pattern in which the epithelial-like
7 years of age, with over 75% of these less of the age of the patient or the site of cells are separated by abundant myxo-
patients presenting within the first three presentation. For detailed discussions of matous stroma. The endodermal sinus
years of life {1764}. In contrast, in post- the protean manifestations of endoder- pattern has a pseudopapillary appear-
pubertal patients YST is identified as the mal sinus tumour, several excellent ance and typically shows numerous
sole histologic element in approximately reviews are available {1102,1963,2050}. Schiller-Duval bodies. These are
10% of mediastinal tumours {1356,1369}. Cytologically, YSTs are composed of glomeruloid structures with a central
This is a much higher frequency than is small pale cells with scant cytoplasm blood vessel covered by an inner rim of
seen in testicular sites, which may be and round to oval nuclei with small nucle- tumour cells, surrounded by a capsule
due to the different cellular environments oli. Uncommonly, the cells may be larger lined by an outer (parietal) rim of tumour
in which the tumours develop {316}. In with prominent nucleoli, and may there- cells. The polyvesicular vitelline pattern
addition, YSTs are often seen as one ele- fore be difficult to distinguish from is composed of compact connective tis-
ment within a mixed germ cell tumour embryonal carcinoma or germinoma. sue stroma containing cysts lined by
{1369,1765,1955}. Like other mediastinal The virtual nonexistence of the latter two cuboidal to flat tumour cells. The solid
malignant GCT in post-pubertal patients, histologic subtypes in young children pattern is uncommon, and is usually

A B
Fig. 3.75 Mediastinal yolk sac tumour (YST). A Macroscopy of pure mediastinal YST, showing a grey-white Fig. 3.76 Mediastinal yolk sac tumour with strong
and gelatinatous cut surface. No haemorrhage, no necrosis. B Macroscopy of a YST with a variegated cut expression of AFP.
surface including areas of necrosis and haemorrhage.

Yolk sac tumour 207


Special studies
Strong positivity for AFP is helpful in
diagnosis of YST. However, the reaction
may also be variable. Therefore, negative
staining does not exclude the diagnosis.
YST also shows strong positive immuno-
cytochemical staining with low molecular
weight cytokeratin. Vimentin may show
focal positivity in a minority of YSTs, but
A B is negative in embryonal carcinoma
{1369}.

Genetics
The genetic changes identified in YST
depends on the age at presentation.
Prepubertal YST demonstrate the same
recurrent genetic abnormalities described
in infantile sacral and testicular YST,
including loss of the short arm of chromo-
some 1 (in particular the 1p36 region),
C D loss of the long arm of chromosome 6,
and gain of the long arm of chromosomes
1, and 20, and the complete chromosome
22 {671,1956}. In contrast, mediastinal
YST following puberty are aneuploid and
often demonstrate the isochromosome
12p characteristic of testicular malignant
germ cell tumours in the same age group.

Prognosis and predictive factors


It is difficult to accurately provide pro-
E F
gnostic information due to the rarity of
Fig. 3.77 Mediastinal yolk sac tumour. A Solid and microcystic pattern. B Hyaline globules. C High power
these lesions, the variability in staging
showing Schiller-Duval bodies. D Polyvesicular/vitelline pattern. E Endodermal sinus pattern. F Focus with
marked spindling of tumour cells.
parameters utilized, and the variability in
the chemotherapy provided. However,
the most important predictive factor of
seen only in small foci. This pattern may Schiller-Duvall bodies are present in only both pre- and post-pubertal YST is the
be difficult to distinguish from embryonal 50 to 75% of YST, and are seen predom- resectability of the primary lesion. This is
carcinoma or germinoma, however, the inantly in the microcystic and endoder- more often possible in prepubertal
cells of yolk sac tumour are smaller and mal sinus patterns. Therefore, these are patients due to a greater frequency of
less pleomorphic. Unfortunately, these not required for the diagnosis. Hyaline presentation at earlier stages. With cis-
foci may be negative or only weakly pos- droplets are commonly present in YST. platin based chemotherapy these chil-
itive for cytokeratin but usually retain However, these may also be found in a dren have an overall survival of over 90%
their AFP positivity. Hepatoid and enteric minority of embryonal carcinomas, as {1765}. In contrast, over half of post-
variants are other less common forms of well as in some other epithelial tumours. pubertal mediastinal YST have metastat-
yolk sac tumour {2050}. The hepatoid These are composed of a variety of pro- ic disease at presentation and the major-
pattern contains cells with abundant teins, and are PAS positive, resistant to ity of these die of their disease; stage 1
eosinophilic cytoplasm resembling fetal diastase digestion. The droplets may be and 2 patients are uncommon but often
or adult liver {1614}. The enteric and positive for AFP as well as alpha-1-anti- survive, particularly following aggressive
endometroid patterns show glandular trypsin, but often are not {1536}. chemotherapy {1369}.
features resembling the fetal human gut A spindle cell lesion has been described
and endometrial glands, respectively in YST-containing mediastinal germ cell
{377,386}. If these patterns are seen tumours in post-pubertal men. Histolog-
within an immature teratoma it may be ically, these tumours are composed pre-
difficult to determine whether they repre- dominantly of atypical spindle cells
sent immature fetal tissue or YST. admixed with areas of classic YST.
Fortunately, these unusual patterns of Immunohistochemical analysis demon-
YST are usually accompanied by other strates positive staining for keratin and
more common patterns. AFP in both the spindle cell and reticular
components of the tumour {1358}.

208 Tumours of the thymus - Germ cell tumours


Choriocarcinoma M.R. Wick
A. Zettl
J.K.C. Chan
C. Bokemeyer
E.J. Perlman
A. Marx

Definition carcinomas have also been observed in Syncytiotrophoblasts and cytotro-


Choriocarcinoma is a highly malignant the posterior mediastinum {1357}. phoblasts may grow intermingled in a bi-
neoplasm displaying trophoblastic differ- The patients present with symptoms due laminar plexiform pattern or in disor-
entiation. It is composed of syncytiotro- to the mediastinal mass, such as chest dered sheets. Occasionally, scattered
phoblast, cytotrophoblast and variably pain, dyspnoea, cough, superior vena clusters of syncytiotrophoblasts cap
intermediate trophoblast cells. Mediasti- cava syndrome. Patients may show cytotrophoblast nodules. Atypical mitosis
nal choriocarcinomas are morphological- gynecomastia due to elevated beta-hCG and cellular atypia are common. There
ly indistinguishable from their gonadal or levels {1356,1821}. Mediastinal chorio- can be sheets of nondescript mononu-
uterine counterparts. carcinomas are highly aggressive neo- clear cells that resemble intermediate
plasms with early haematogeneous dis- trophoblast. Choriocarcinomas are typi-
ICD-O code 9100/3 semination. In a series of 8 cases, metas- cally intimately associated with dilated
tases were observed in the lungs (88%), vascular sinusoids. Partial or complete
Epidemiology liver (50%), kidney (38%) and spleen replacement of the walls of blood vessels
Pure mediastinal choriocarcinomas are (25%). Metastatic disease to the brain, are common. There are often vast areas
exceedingly rare and virtually non-exis- heart, adrenals and bone has also been of haemorrhage and necrosis.
tent in children. Only 2.5 to 5% of medi- observed. {1033,1357,1821}. Mediastinal choriocarcinoma cannot be
astinal germ cell tumours are pure distinguished morphologically from
choriocarcinomas {997,1033,1356}. Pure Morphology metastatic choriocarcinoma. Since
choriocarcinoma constitute 9% of malig- Mediastinal choriocarcinomas are large gonadal choriocarcinoma often displays
nant mediastinal nonseminomatous tumours with soft consistency and exten- extensive regressive alterations but still
germ cell tumours, and 4.3% of nontera- sive hemorrhage and necrosis. may give rise to widespread metastasis,
tomatous germ cell tumours {1033,1349, Microscopically, they are composed of the exclusion of a primary gonadal
1356}. syncytiotrophoblast, cytotrophoblast and choriocarcinoma is particularily difficult,
intermediate trophoblastic cells. although mediastinal metastasis of
Clinical features Syncytiotrophoblasts are large multinu- gonadal choriocarcinoma seem to be
The patients` ages range from 17 to 63 cleated cells with numerous, pleomor- very rare {997,1356}.
(most commonly the 3rd decade of life), phic, dark-staining nuclei, distinct nucle- Trophoblastic neoplasms other than
and almost all reported cases were male oli, and abundant densly eosinophilic choriocarcinoma, such as monophasic
patients {520,1821,1955}. At diagnosis, cytoplasm which may contain cytoplas- choriocarcinoma and placental site tro-
mediastinal choriocarcinomas are mostly mic lacunae. Cytotrophoblasts are uni- phoblastic tumour have not been report-
large anterior mediastinal masses (aver- form, polygonal cells with round nuclei, ed in the mediastinum.
age size 10 cm) {1357}. Primary chorio- prominent nucleoli, and clear cytoplasm.

A B
Fig. 3.78 Choriocarcinoma. A High power showing multinucleated and eosinophilic syncytiotrophoblastic cells intertwined with mononuclear cytotrophoblastic
cells. B beta-hCG staining of syncytiotrophoblastic cells.

Choriocarcinoma 209
Immunohistochemistry cell tumour component is found), sarco- sites {316}. Such tumours are most com-
Syncytiotrophoblasts and cytotro- matous component in teratoma, and monly aneuploid, with a minority having
phoblasts react with pankeratin markers mediastinal metastasis from a carcinoma near-tetraploid DNA content.
and CAM5.2, whereas they are negative with choriocarcinoma-like features/dedif-
for PLAP, AFP, CEA, CD30 and vimentin. ferentiation. Prognosis
The syncytiotrophoblasts additionally In most of the reported cases, patients
express beta-hCG, while the cytotro- Genetics died of disseminated disease shortly
phoblasts are variably positive for human The genetic changes that have been after diagnosis (average survival time 1
placental lactogen {1357,1920}. described in mediastinal choriocarcino- to 2 months) {520,1357,1821}. However,
Apart from metastasis of an extramedi- ma are the same as those reported in the treament with cisplatin-based chemo-
astinal choriocarcinoma, the differential testis and demonstrate the isochromo- therapy may improve the prognosis
diagnoses include mediastinal mixed some i(12p) characteristic of postpuber- {1955}.
germ cell tumour (in which a further germ tal malignant germ cell tumours at all

Teratoma M.R. Wick


E.J. Perlman
P. Strbel
J.C.K. Chan
U. Gbel A. Marx
D. T. Schneider

Definitions components of non-germ cell malignant tomas occur almost exclusively in males
A germ cell tumour (GCT) that is com- tumour, which may be a sarcoma or a {1808}.
posed of several types of organoid carcinoma (ICD-O code 9084/3). The mean age of adults is 28 years
mature and/or immature somatic tissues (range 1860) {1171}. In children, tera-
derived from two or three germinal lay- ICD-O codes toma is the predominant mediastinal
ers (ectoderm, endoderm and meso- Mature teratoma 9080/0 tumour during the first year and has
derm). Immature teratoma 9080/3 been detected in fetuses as young as 28
weeks of gestation {708}. The proportion
Mature teratomas are tumours com- Epidemiology of immature teratomas (up to 40%) is
posed exclusively of mature, adult-type Mediastinal teratomas account for 7- much higher in the first year of life than
tissues. Dermoid cyst is a variant con- 9.3% of mediastinal tumours {708,1171} at older age (~4-6%) {1053,1356,2116}.
sisting of one or more cysts lined pre- and 5070% of all mediastinal germ cell Mature teratoma can be associated with
dominantly by keratinizing squamous tumours {466,520,759,1356,1458, classical (47, XXY) and very rarely,
epithelium with skin appendages. 1888,2116} Among teratomas of all mosaic Klinefelter syndrome {480}.
Monodermal teratomas analogous to sites, up to 27% occur in the medi-
struma ovarii have not been described in astinum in adults, and 4-13% in children Clinical signs and symptoms
the mediastinum. {708,1053,1763}. 30-59% of mediastinal mature tera-
Overall, there is an equal sex distribution tomas, particularly those in adults
Immature teratomas contain immature, {1171} or a slight female preponderance {1955}, are asymptomatic {708,1171,
embryonic or fetal tissues exclusively or (M:F =1:1.4) {1808}, but immature tera- 1337}. Other cases can be associated
in addition to mature tissues. Mature and
most immature mediastinal teratomas
are benign tumours {1053,1244,1764,
1808}.

Teratomatous component is the term


used to describe differentiated somatic
tissues associated with a seminoma,
embryonal carcinoma, yolk sac tumour
or choriocarcinoma. The teratomatous
component of mixed GCTs is very often
immature {1808}.
Fig. 3.79 Mature cystic mediastinal teratoma. The Fig. 3.80 Immature mediastinal teratoma with a var-
Teratoma with somatic-type malignancy yellow areas represent mature fat. iegated cut surface. Cystic areas are less promi-
is a teratoma containing one or more nent than in mature teratoma.

210 Tumours of the thymus - Germ cell tumours


A B
Fig. 3.81 Mature teratoma. A Dermoid cyst-like area (left), mature cartilage (top, right), mature intestinal type glands and villi (bottom, right). B High power of pan-
creatic tissue, including islets.

with chest, back or shoulder pain, dysp- fluid, fat and calcium {1337}. meter of 10 cm (range 3-25 cm) {1655,
noea, cough, and fever due to chronic Calcifications occur in in 26% {1171} to 2008,2116}. There can be adhesions to
pneumonia {708,1764}. Rare symptoms 53% {1337}. A shell-like tumour wall cal- the surrounding lung or great vessels.
include superior vena cava syndrome, cification or identifiable bone and teeth The cut surface is variegated, showing
erosion of bronchi or vessels, Horner occur in up to 8% each {1171, 1337}. cystic spaces with fluid or grumous
syndrome, or pneumothorax {696,708, Immature teratomas appear more often materials, hair, fat, flecks of cartilage,
1764,1808}. Due to the occurrence of solid {1888}. With rare exceptions {1244}, and rarely teeth or bone {1808,1888}.
exocrine pancreatic tissue, rupture is the usual serum tumour markers (AFP; Immature teratomas are often very large
more common in mediastinal teratomas beta-hCG) are not elevated. (up to 40 cm) {1975} and solid. They
than teratomas of other sites {1808,2038} exhibit a soft to fleshy consistency or are
and can result in pleural effusions or car- Site of involvement extensively fibrous or cartilaginous
diac tamponade. Endocrine pancreatic More than 80% of mature teratomas {1808}. Haemorrhage and necrosis can
component can cause hyperinsulinism occur in the anterior mediastinum, 3-8% be present.
and hypoglycaemia {1808}. Hydrops in the posterior mediastinum and 2% in
fetalis is a complication of congenital the middle mediastinum, while 13-15% Histology
intra- and extrapericardial mediastinal involve multiple mediastinal compart- Mature teratomas
teratoma {708}. ments {963,1337,1829}. Teratomas can These are characterized by a haphazard
extend deeply into one or both thoracic admixture of organoid mature tissues
Imaging cavities and elicit atelectasis. derived from 2 or 3 germinal layers. Skin
Mature teratomas show multilocular cys- and cutaneous appendages are consis-
tic structures in almost 90% of cases Macroscopy tent constituents and form cyst linings.
{1888}. Attenuation is heterogeneous Mature mediastinal teratomas are usually Bronchial, neural, gastrointestinal,
with varying combinations of soft tissue, encapsulated masses with a mean dia- smooth muscle and adipose tissue com-

A B
Fig. 3.82 Immature teratoma. A Immature neural tissue forming tubes. B Immature cartilage.

Teratoma 211
ponents are very frequent (>80%), while domyoblasts (desmin, myogenin), neural Differential diagnosis
skeletal muscle, bone and cartilage are components (S100; NSE) or immature The main differential diagnosis is mixed
less common {708,1808}. Salivary gland, cartilage (S100; GFAP) {1490}, and (ii) to germ cell tumour with a teratomatous
prostate, liver and melanocytes are even exclude other germ cell or somatic component. Immature teratoma may be
less frequent; thyroid tissue has not been malignancies. Pure teratomas are nega- difficult to distinguish from teratoma with
reported {1808}. Pancreatic tissue is typ- tive for PLAP, beta-hCG and CD30. AFP somatic type malignancy; the latter usu-
ical of mediastinal teratomas and found is usually negative, although liver cells ally shows frank cytologic atypia and
in up to 60% of cases, but is rare or and immature neuroepithelium in ter- invasiveness that are absent in pure
absent in teratomas of other sites {521, atomas may express AFP. immature teratomas.
1808}.
Regressive changes, such as rupture of Grading of immature teratoma Prognostic factors
cystic structures, can be accompanied There are insufficient data to support a Mature teratoma is a benign tumour irre-
by a granulomatous inflammation {1808, particular grading system for immature spective of the patients age. The prog-
2116}. Remnant thymic tissue is found teratomas of the mediastinum. Grading nosis of pure immature teratoma is age-
outside the capsule in 75% of mature ter- according to Gonzalez-Crussi {708} was dependent. In children, pure immature
atomas {708}. of no prognostic significance in children teratoma has an excellent prognosis with
{696,1244,1764,1808}. However, it is no risk of recurrence and metastasis
Immature teratoma important to realize the following: 1) the {1244,1764}. The presence of an
These lesions are characterized by more immaturity is present in a teratoma, admixed malignant germ cell tumour
embryonic or fetal tissues derived from the higher the risk to find a yolk sac component (detected in up 30% of
the various germinal layers, such as tumour component; 2) immaturity in a ter- immature teratomas after extensive sam-
immature glands lined by tall columnar atoma in an adolescent male is highly pling {1244}, and most commonly yolk
epithelial cells, fetal lung, immature carti- suspicious of a malignant i(12p)-contain- sac tumour) is associated with a recur-
lage and bone, rhabdomyoblasts, ing germ cell tumour. Therefore, the rence rate of 25%. In children, such
blastema-like stromal cells. The most pathologist should communicate clearly mixed GCTs have a good prognosis after
common immature components are neu- in the report the quantity (rough percent- cisplatin-based chemotherapy (>80% 3-
roectodermal tissues, with neuroepithe- age) of immaturity. years-survival) {695,1244}.
lial cells forming tubules, rosettes or reti- In adults, the prognosis of pure immature
nal anlage {708,1808,2116}. By defini- Genetics teratoma is more guarded but experi-
tion, pure immature teratoma should not The pure mature and immature tera- ence is limited {2116}. Apparently pure
harbour a morphologically malignant tomas analyzed and reported to date do immature teratomas with pulmonary
component. not show recurrent genetic gains and metasases have been reported in adults,
losses. This is in contrast to malignant with only the metastasis showing a germ
Immunohistochemistry germ cell tumours {1765}. Mature tera- cell and/or somatic type malignancy
The main role of immunohistochemistry toma can be associated with classical {1808}.
in teratomas is: (i) to define the nature of and very rarely mosaic Klinefelter syn-
immature components, such as rhab drome {480}.

212 Tumours of the thymus - Germ cell tumours


Mixed germ cell tumours M.R. Wick
E.J. Perlman
F. Mayer
Ph. Strbel
U. Gbel J.K.C. Chan
D.T. Schneider A. Marx

Definition Clinical features do not secrete AFP or beta-hCG; b)


A neoplasm composed of two or more Only ~10% of mixed GCTs are asympto- development of somatic-type malignan-
types of germ cell tumours (GCTs). The matic at diagnosis {1955}. Most patients cies; c) the growing teratoma syndrome
diagnosis should be complemented by present with general and local symptoms (GTS). GTS is a rare complication of
listing each component and its approxi- identical to those in other mediastinal mixed GCTs {24} and defined by 1) an
mate proportion. GCT: chest pain, cough, dyspnoea, increase in tumour size during or after
Polyembryoma represents a variant with hoarseness, superior vena cava syn- chemotherapy; 2) normalization of serum
a unique growth pattern that is charac- drome and cardiac tamponade {757, tumour markers; 3) identification exclu-
terized by the predominance of embry- 1955}. Precocious puberty and gyneco- sively of mature teratoma on histological
oid body-like structures. Embryonal car- mastia are rare in polyembryoma {150} analysis of the resected tumour specimen
cinoma, yolk sac tumour, syncytiotro- and other mixed GCTs {1106,1808}. In {1199}. The growing mediastinal mass is
phoblastic cells and teratomatous com- some cases, endocrinologic symptoms usually asymptomatic but can be accom-
ponents can usually be recognized in induced by beta-hCG production may panied by fever and dyspnoea {24,1256}.
polyembryoma. precede tumour diagnosis by years Lymphatic spread can involve mediasti-
Embryonal carcinomas or seminomas {1769}. nal and supraclavicular lymph nodes
containing scattered syncytiotrophoblas- A minority of patients present with symp- {56}. Late GTS complications are local or
tic cells do not qualify as mixed GCTs, toms attributable to metastases {709, metastatic development of malignant
but are classified as the respective 757,1955}. Clonally related leukaemias non-seminomatous GCTs and develop-
pure GCTs. are rare (~2%) {40,729,789,1518}. ment of GCT-related sarcomas, carcino-
Imaging studies typically show a large mas or leukaemias {56,1256}. The patho-
ICD-O code inhomogeneous mass with necrosis, genesis of GTS is largely unknown.
Polyembryoma 9072/3 hemorrhage and infiltration of adjacent
structures. Cystic spaces or adipose tis- Tumour spread
Synonyms sue hint to the presence of a teratoma- Most mixed GCT exhibit extensive infil-
Malignant teratoma intermediate, terato- tous component {757,1888}. tration into mediastinal structures and
carcinoma. The use of terms that do not Most cases (~90%) show elevated adjacent organs. Rates of metastasis at
precisely qualify the type and quantity of serum tumour marker levels {1005}. time of diagnosis vary widely in different
tumour components is discouraged. Raised AFP (~80%) is strongly correlated reports, from 20-36% {520,1356,1764,
with a yolk sac tumour component, 1955} up to >80% {997,2169}.
Epidemiology although teratomatous hepatoid cells Metastasis to lung, pleura, lymph node,
In adults, mixed GCTs account for 13- and teratomatous neuroepithelium can liver, bone and brain have been reported
25% of all mediastinal GCTs {466,520, also produce small amounts of AFP. {156,1005,1765,1955}. Metastases to
1005,1033,2116}, second only to ter- Increased beta-hCG (~30%) levels occur supraclavicular lymph nodes and lung
atomas (40-60%) and as common as in mixed GCTs with a choriocarcinoma due to occult mediastinal mixed GCTs
seminomas (15-20%) {520,1005,1356, component or with syncytiotrophoblast are rare {708}.
1808,2116}. Virtually all patients are male cells {2169}.
{1005,1356}. Macroscopy
In children, mixed GCTs account for Post-chemotherapy findings, inclu- The tumours are often poorly circum-
about 20% of cases, and yolk sac tumour ding the Growing Teratoma Syndrome scribed or frankly infiltrative, and show a
with mature or immature teratoma is the During or following chemotherapy, heterogeneous cut surface with solid
characteristic constellation. Other types patients with GCT can alternatively show areas, haemorrhage and necrosis. Cystic
of mixed GCTs are virtually nonexistent {2169}: (1) Normalization of tumour mark- spaces usually indicate presence of a
during the first four years of life {1764}. ers and resolution of the tumour mass teratomatous component. The size
Among children <8 years of age, some (10%), (2) persistence of elevated tumour ranges between 3 and 20 cm (mean 10
authors {1005,1765} but not others {167} markers and the tumour mass due to cm) {908}. Tumours in the context of the
see a preponderance of females, while resistance to chemotherapy (10%), or (3) growing teratoma syndrome measure
almost all adolescent patients > 8 years normalization of tumour markers with up to 28 cm {24}.
are males {1765}. residual tumour mass (80%).
After the onset of puberty, mixed germ In the latter group, 10-20% of patients Histopathology
cell tumours can be associated with exhibit tumour enlargement. This phe- Various types of GCTs can occur in any
Klinefelter syndrome {150,795,1106, nomenon can be due to a) chemo- combination in mediastinal mixed GCTs.
1290,1765}. therapy-resistant GCT components that Their morphologies are identical to those

Mixed germ cell tumours 213


of pure GCTs. The reported frequencies Immunohistochemistry cisplatin-based chemotherapies and
of the various GCT subtypes vary widely The immunohistochemical profiles reflect resection are the treatment of choice
in the literature, but the following conclu- those of the various germ cell tumour {199,236,1462,2172}.
sions can be drawn: components contributing to a given In children, mixed GCTs usually harbour
In adults, the two most frequent compo- mixed GCT. AFP is expressed in virtually only yolk sac tumour and teratomatous
nents are teratoma (50-73%; mean 65%) all mixed GCTs, at least focally, due to components and their prognosis is not
and embryonal carcinoma (22100%; the frequent occurrence of yolk sac different from the prognosis of pure yolk
mean 66%) {237,520,1005,1356,1955}. tumour components. sac tumour {1764}, suggesting that
Less common are yolk sac tumour 5-year overall survival rates of >80% can
(0-83%; mean 48%), seminoma (22-50%, Genetics be achieved with modern therapies
mean 38%), and choriocarcinoma In adults and children > 8 years old, gain {1764}. Local stage, distant metastasis
(1067%, mean 28%) {520,1005,1033, of 12p and sex chromosomal abnormali- and AFP levels have not been shown to
1356,1955}. The teratoma components ties (often associated with Klinefelter be of prognostic significance in a recent
are more often immature than mature {17, syndrome) are the most common recur- paediatric series of NSGCTs that includes
1033,1808}. The most common combina- rent abnormalities of mediastinal mixed 24% mixed GCTs {1764}. In young chil-
tion is teratoma and embryonal carcino- GCTs {258,1765}, including polyembry- dren, mixed GCTs exhibiting microscopi-
ma (previously called teratocarcinoma), oma {150}. Additional recurrent changes cally small foci of NSGCTs in teratomas
encounterd in 15-56% of cases (mean include gain of chromosome 21 and loss have a good prognosis after complete
40%) {237,1005,1808,1955}. of chromosome 13. These abnormalities resection and chemotherapy {1244}.
In children, a yolk sac tumour component are also encountered in the mature ter- Small series suggest that histology,
occurs in most (>90%) mixed GCTs, fol- atoma component and/or somatic-type specifically an extensive seminoma com-
lowed by teratoma (~30%), and, in ado- malignant components of mixed GCTs, ponent of mixed GCTs, has a beneficial
lescents, seminoma, choriocarcinoma while pure teratomas are typically devoid impact on survival {1349,1359}, while a
and embryonal carcinoma (~20% each) of genetic imbalances {1394,1765}. choriocarcinoma component might indi-
{709,1764}. In contrast to adults, the tera- In children < 8 years old, i(12p) does not cate a more aggressive clinical course
toma components in paediatric mixed occur {1765}, and gain of the X chromo- {466,2116}.
GCTs are more often mature than imma- some and trisomy 21 {258,1765} are rare
ture {167,1725,1765}. findings. Instead, gain of 1q, 3, and 20q Postchemotherapy prognostic factors
Polyembryomas {150} show a unique and loss of 1p, 4q, and 6q are common Postchemotherapy findings are the most
growth pattern mimicking embryoid bod- {258,1765} in yolk sac tumour; tera- important prognostic factors in the era of
ies. These GCTs are composed of EC, tomatous elements show no chromoso- multimodality treatments. Primary com-
YST, syncytiotrophoblast cells and tera- mal abnormalities. plete response, i.e. normalization of
toma. Adult, but not childhood, mediasti- tumour marker levels and disappearance
nal mixed GCTs are frequently associat- Postulated cell of origin of the mediastinal mass after chemo-
ed with non-germ cell malignancies (sar- Toti- or pluripotent primordial germ cell. therapy occurs in 10% of NSGCT patients
comas, carcinomas, and/or leukaemias). and is associated with 80% long-term
Differential diagnosis survival {587}. 20% of such patients
Histology of metastasis Embryonal carcinoma components may relapse usually within 2 years after
The histology of metastases usually be difficult to recognize against a back- chemotherapy and may be amenable to
reflects the histology of the primary GCT ground of yolk sac tumour due to the salvage therapy after early detection of
or one of its components {17} but other heterogeneity of yolk sac tumour growth the relapse {2169}.
GCT histologies and somatic type malig- patterns. CD30 staining is a helpful dia- Among patients that show normalization
nancies may occur, particularly after gnostic adjunct to resolve this differen- of tumour markers and a residual tumour
chemotherapy {56,406,1230,1256,2046}. tial. Due to the lack of cytotrophoblastic mass (80% of cases) {587,588,2169,
cells, scattered syncytiotrophoblasts in 2172}, completeness of resection is the
Postchemotherapy histology pure seminomas and embryonal carci- most important prognostic factor in
After chemotherapy, viable non-tera- nomas can be distinguished from the adults {199} and children {11,1764}: sal-
tomatous tumour occurs in up to 50% of choriocarcinoma components of mixed vage rates after incomplete resection are
cases even after normalization of serum GCTs. <10% in adults and <50% in children.
tumour markers {1808,2049}. In the In addition, postchemotherapy histology
remaining cases, areas of necrosis, ter- Prognostic factors has a bearing on prognosis {660,1655}:
atoma structures, inflammatory infiltrates In adults, mixed GCTs exhibit a long-term complete lack of viable tumour cells is
including xanthogranulomatous reac- survival rate of 40-45% {1359} and there associated with a 90% disease-free sur-
tions, and fibrosis can be encountered. appears to be no significant difference vival rate, while the rate drops to 60% if
Chemotherapy may unmask a previously between mixed and pure NSGCTs viable teratoma, including the growing
overlooked somatic-type tumour or a ter- {1955}. Therefore, tumour stage, particu- teratoma syndrome, is encountered.
atomatous component. Metastases do larly metastasis to brain, liver, lung, and Viable non-teratomatous GCT tumour or
not necessarily reflect the histology of bone, and elevated beta-hCG levels somatic-type malignant cells are associ-
remnant viable tumour cells in the pri- might be major risk factors for mixed ated with a 30% and <10% survival rate,
mary location {56,1256}. GCTs as for NSGCTs {199,790}. Modern respectively.

214 Tumours of the thymus - Germ cell tumours


Patients with persistently elevated
tumour markers have a worse prognosis
than patients with normalization of
tumour markers, although viable tumour
cells are detectable in only half of the
respective resection specimens {997}.
Relapses after chemotherapy and sur-
gery and primary resistance to chemo-
therapy are poor prognostic factors due
to low salvage rates {199}.

Mixed germ cell tumours 215


Germ cell tumours with somatic-type M.R. Wick
E.J. Perlman
malignancy Ph. Strbel
J.K.C. Chan
A. Marx

Definition 1356,1385}, with most cases occurring according to the malignant components
A germ cell tumour (GCT) accompanied between 20-40 years. that are present.
by a somatic-type malignant component The somatic-type malignancies may Imaging studies typically reveal a solid
of sarcoma, carcinoma or both. arise in the mediastinum or only in the mass (representing the sacoma or carci-
Leukaemias or lymphomas are also metastases {277,1394,1808}. They are noma component) associated either with
somatic-type neoplasms that can more common after chemotherapy and a cystic teratomatous structure or with a
accompany mediastinal GCTs in tumours of late recurences {1665}. lesion showing heterogeneous attenua-
After removal of apparently mature ter- tion, predominant areas of enhancing
Synonyms atomas, metastases with pure sarcoma- soft tisuue elements, calcifications and
Teratoma with malignant transformation tous features have been rarely reported massive necrosis {1888}.
{1394}; Malignant teratoma with nonger- {277,1808}.
minal malignant tumour {1808}; Teratoma Tumour spread
with non-germ cell malignancy. Clinical features Sarcoma and carcinoma components
Signs and symptoms can infiltrate into the mediastinal struc-
Comments The tumours show the same local symp- tures and the lung {1230}. Metastases
Tumours included in this category have toms as other mediastinal GCTs, but they have been reported in the majority of
been collectively called Teratomas with are more frequently symptomatic (~90%) cases {1230,1505} and can be com-
malignant components etc. in the litera- than pure teratomas (~50%) {1808}. posed either of the somatic-type tumour
ture. However, since somatic-type malig- Symptoms due to metastatic disease {406,1230}, the GCT or one of its compo-
nancies are more common in mixed may accompany or follow local symp- nents {1230}, or of both somatic-type and
germ cell tumours than in teratomas toms {1394}. germ cell tumour {1230,2046}. Metastatic
{709,1230,1515,1808,2046} and can Most but not all cases show elevated spread may involve lung {406,1394},
also occur in pure yolk sac tumours AFP and/or beta-hCG levels in the regional lymph nodes {40,997}, bone
{2048} and seminomas {879,2047}, the serum. Other tumour markers (e.g. carci- {1515,2186}, brain {2046,2186}, liver
germ cell tumour component that noembyonic antigen [CEA] or neuron- {40,2046} and spleen {1394,2046}.
accompanies the somatic malignancy specific enolase [NSE]) may be elevated
should be specified accordingly.
A minimum size of one low-power field Table 3.11
has been suggested as the threshold for Mediastinal germ cell tumours and associated somatic-type malignancies.
the diagnosis of somatic-type malignan-
cy in GCTs {1655,2047}. However, this Germ cell tumour component Frequency1 Somatic-type malignancies2
size criterion is arbitary. More important Teratoma (mature; immature) ~ 10-20% Sarcomas/Neurogenic Tumours
is the independent growth pattern Rhabdomyosarcoma
demonstrated by the somatic-type malig- Angiosarcoma
nancy. It would be helpful to estimate the Neuroblastoma
size and percentage areas occupied by Liposarcoma
the somatic malignancy and give this Leiomyosarcoma
information in the patholgy report. Non-teratomatous GCT of one < 5% Osteo-, Chondrosarcoma, Ewing
histological type (most commonly sarcoma/PNET3
seminoma or yolk sac tumour) Malignant fibrous histiocytoma
Epidemiology MPNST4
GCTs with somatic-type malignancies Glioblastoma
are rare (~ 2% of all male GCTs) {30}.
About 25-30% of cases occur in the Mixed germ cell tumours > 75% Epithelial Malignancies
mediastinum {2047}. They account for up (almost all cases contain Adenocarcinoma
to 29% of all mediastinal GCTs of adults teratoma components) Adenosquamous carcinoma
{40,199,1230,1394,1450,1808,1955}, but Squamous cell carcinoma
are almost non-existent in children Undifferentiated carcinoma
{277,406,428,1005,1232,1764}. With few Haematological malignancies
exceptions {277,428,1033}, the tumours 1Percentage of all mediastinal GCTs with somatic-type malignancies
2More than one type of sarcoma and/or carcinoma can occur in a single GCT, and haematologic neoplasias
occur in males. The age range is from 4-
66 years {277,406,1005,1033,1230, can accompany sarcomas {1394}
3PNET, primitive neuroectodermal tumour; 4 MPNST, malignant peripheral nerve sheath tumour

216 Tumours of the thymus - Germ cell tumours


A

B
Fig. 3.83 Germ cell tumour (GCT) with somatic-type malignancy: Seminoma (left) and angiosarcoma (right). Fig. 3.85 GCT with somatic-type malignancy (STM):
A Seminoma and B epithelioid angiosarcoma.

Macroscopy ciated with various sarcomas (63% of type of sarcoma or combinations {1230}
The tumours range in size from 6 to 30 cases) {428,2046,2047}, carcinomas may occur, including chondrosarcoma,
cm {1230,1356}. They usually exhibit a (37%) {1385,1808}, combinations of both osteosarcoma, malignant fibrous histio-
partially cystic and often variegated cut {1033,1808,2047} or carcinosarcoma cytoma, malignant peripheral nerve
surface with focally necrotic areas. The {1808}. The somatic malignancy can be sheath tumour, glioblastoma {1808}, and
carcinoma or sarcoma areas are firm and intimately intermingled with the GCT liposarcoma {1359}.
gray or haemorrhagic (e.g. angiosarco- component, or forms an expansile nodu- The non-mesenchymal component can
ma) and often adherent to adjacent lar proliferation of atypical cells, often be adenocarcinoma (usually of colonic
mediastinal structures {2046}. with increased mitotic rate and necrosis. type) {1385,1394,1808,2047}, adeno-
Embryonal rhabdomyosarcoma squamous carcinoma {2047}, squamous
Histopathology {428,1230,1450} is the single most fre- cell carcinoma {1655} or primitive neu-
Mature {277,428,1033,1385} and imma- quent somatic-type malignancy. roectodermal tumours (PNET) {1655}.
ture {520,1195,1505,2186} teratomas, in Angiosarcoma {1230,2046}, leiomyosar- Melanocytic neuroectodermal tumours
addition to seminomas, yolk sac tumours coma {1450} and neuroblastoma {49} and carcinoids {1707} are rare.
or mixed germ cell tumours can be asso- {397,1505} are also common. Any other
Immunohistochemistry
Somatic-type malignancies stain like
their counterparts occurring elsewhere in
the body. PLAP, AFP, beta-hCG, and
CD30 are generally not expressed, while
they can be detected in pure GCTs and
the respective components of mixed
GCTs. One should keep in mind that
rhabdomyoblasts, embryonal rhab-
domyosarcomas and leiomyosarcomas
can express PLAP {700} and that hepa-
toid carcinomas can be AFP-positive.

Genetics
An isochromosome i(12p) genotype
shared by the somatic-type neoplasia
and the associated germ cell tumour
component is typical {789,1113,1394}. In
a case of teratoma-associated rhab-
domyosarcoma, an add(2)q35-q37
Fig. 3.84 Germ cell tumour with somatic-type malignancy. Immature teratoma and angiosarcoma. genetic abnormality that is characteristic

Germ cell tumours with somatic-type malignancy 217


for rhabdomyosarcoma was detected in
the sarcoma but not the germ cell com-
ponent {1394}. Thus, tissue-specific sec-
ondary chromosomal aberrations may be
necessary for the development of somat-
ic-type tumour components in GCTs.
Klinefelter syndrome has been reported
in association with GCT with somatic-
type malignancy {2186}.
A B
Postulated cell of origin
Malignant transformation of mature ter-
atoma cells or divergent differentiation of
a pluri- or totipotent primordial germ cell
towards a germ cell tumour and the
somatic-type malignancy have been
suggested {314}. The latter hypothesis is
favoured by the finding that pure
mature mediastinal teratomas show no
chromosome 12 abnormalities {1765}
while a shared i(12p) abnormality is char- C D
acteristic of teratomas that are clonally Fig. 3.86 Germ cell tumour with somatic-type malignancy. A Angiosarcoma component of the case shown
related with somatic type malignancies, in Fig. 3.85. B CD31 expression of the same case. C Immature teratoma and rhabdomyosarcoma.
including leukaemias {1394}. D Adenocarcinoma component in immature teratoma.

Differential diagnosis
Immature teratoma may be difficult to ma is morphologically different form GCT 2047}, while the type of somatic malig-
distinguish from teratoma with somatic- and commonly expresses CD5, while the nancy in the primary biopsy has no major
type malignancy. Frank atypia and infil- rhabdomyoblasts are devoid of atypia impact on survival {1394}. Persistence of
trative growth favour the latter interpreta- and proliferative activity. viable tumour after chemotherapy her-
tion. Likewise, chemotherapy-induced alds an unfavourable outcome {660,
atypia is usually diffusely distributed Prognostic factors 997,2169}. The median survival is only
throughout the tumour, while somatic- Presence of somatic-type malignancy in approximately 9 months {406,520, 709,
type malignancy is a focal process often a GCT confers a dismal prognosis 997,1005,1230,1394,1515,1655, 2047}.
forming a recognizable mass and invad- {406,520,709,997,1005,1230,1394,1515,
ing adjacent structures {1888}. 1655,2047}. There is no response to
Scattered rhabdomyoblasts are a fre- chemotherapy used for treatment of
quent feature of mature and immature germ cell tumours. Only a minority of
teratomas and do not justify a diagnosis patients will survive after chemotherapy
of rhabdomyosarcoma unless they show and complete surgical removal of medi-
nodular tumour formation and/or infiltra- astinal tumour remnants {879,1394,
tion of adjacent structures. 2047}. Advanced local infiltration, meta-
Rhabdomyoblasts can rarely occur in static disease, and incomplete resection
thymic carcinomas. The thymic carcino- are bad prognostic factors {997,1230,

218 Tumours of the thymus - Germ cell tumours


Germ cell tumours with associated A. Orazi
M.R. Wick
haematologic malignancies J.T. Hartmann
A. Marx

Definition topenia, spleno-/hepatomegaly, or throm- plasias with a yolk sac component,


Germ cell tumours associated with bocytopenia in a range of 20 to 35% though immature teratomas and mixed
haematologic malignancies that are clon- each. Bleeding complications and infec- germ cell tumours with somatic-type sar-
ally related to the underlying GCTs. The tions arise due to cytopenias in myelodys- comas have been observed {83,315,
association represents a variant of plastic syndromes and acute leukaemias 1112,1394,1461}. In a series of 287
somatic-type malignancy that is unique are also common events. Thrombo- patients with nonseminomatous medi-
to mediastinal GCTs. The haematologic embolic complications due to thrombocy- astinal germ cell tumours, yolk sac and
malignancies can involve the medi- tosis and megakaryocytic hyperplasia teratocarcinoma histology have been
astinum or present as infiltration of bone {1461}, and mediastinal mass formation significantly associated with the occur-
marrow or lymphatic organs, leukaemia due to myelosarcoma is rare {1723}. Other rence of haematologic neoplasias {789}.
or myelosarcoma. Haematopoietic malig- clinical signs are leukaemic skin lesions, Categories of haematological malignan-
nancies that arise due to chemotherapy and flushing {789}, and the development cies reported are: acute leukemias
are not included in this category. of haemo-phagocytic syndromes {2055}. {199,1132}, malignant (and rarely benign
Haematological complications can {2246}) histiocytosis {83,129,474,1112,
Historical annotation accompany, follow {199,2055,2087} or 1461}, myelodysplastic syndromes {1450,
The association between mediastinal precede local symptoms. Leukaemias 1846,2087}, myeloproliferative diseases
GCTs and hematologic malignancies has most commonly become apparent within {315,1113,1461}, and mastocytosis {335}.
been recognized since the 1970s the first year after the diagnosis of GCTs Among acute leukaemias, acute mega-
{2599,2477}. Derivation from a GCT- (range 0122 months; median 6 months) karyoblastic leukaemia (AML M7) and
derived pluripotent cell {2592,1681, {474,789,1394,1461,1518}. There is no "malignant histiocytosis" (including AML
1698} and independence from previous increased overall risk for other second M4 {729,1113} and M5 {2074}) are most
radio-chemotherapy {1681,1698} were tumours in mediastinal GCT patients common and account for about half of the
suggested since the 1980s. Genetic {199,788}. cases {199,1461,1518}. In addition, AML
studies {1698,1735,1737} demonstrated M2 {2087}, M6 {1450,1729}, acute undif-
chromosomal aberrations that were Etiology and pathogenesis ferentiated leukemia (AUL) {1461}, and
shared between GCTs and associated The etiology is unresolved. It has been acute lymphoblastic leukaemia {1132,
haematologic malignancies, providing speculated that expression of haemato- 1461} have been described.
evidence for a clonal relationship. Extra- poietic growth and differentiation factors Myelodysplastic syndromes (MDSs)
medullary haematopoiesis in a subgroup in some mediastinal GCTs could drive dif- include refractory anaemia with excess
of mediastinal GCTs {1310} suggests that ferentiation of primordial germ cells into blasts {1846} or cases with megakary-
committed haematopoietic precursors haematopoietic progeny. The profile of ocytic hyperplasia {1460}, suggesting the
can be an alternative origin. The differentiation factors expressed may also 5q- syndrome {1394}. Myelodysplasia
predilection of the syndrome for medi- underlie the preferred commitment of can precede AMLs {2087}.
astinal GCTs has remained unexplained. transformed precusors to the megakaryo- Essential thrombocytemia and chronic
cytic and monocytic lineage {1450, idiopathic myelofibrosis are the charac-
Epidemiology 1518}. Concommittant mediastinal and teristic myeloproliferative disorders
Haematologic malignancies develop in extramediastinal leukaemias show a encountered in association with mediasti-
2-6% of malignant nonseminomatous comparable immunophenotype and nal GCTs {663,814,1461}.
mediastinal GCTs {789, 1450} (i.e. genotype, suggesting spread of haema- Leukaemias may diffusely or focally infil-
0.51,5% of all mediastinal GCTs) but vir- topoietic tumour cells from GCTs to trate the underlying GCT {1518} or can
tually never in GCTs of other sites {1243}. blood, bone marrow, and extra-medullary form tumorous lesions (granulocytic sar-
Patients are typically adolescents or sites {1113,1394}. comas) in the mediastinum {1723}.
young adults (age range 948 years) and Extramediastinal manifestations (organo-
virtually all are males {315, 474,1461}. Macroscopy megaly, leukaemia) can occur in the
About 10-20% of cases have been asso- Gross findings are identical to those of presence or absence of detectable
ciated with Klinefelter syndrome {129, non-seminomatous malignant GCTs. haematopoietic malignancy in the medi-
490,1461}. astinal GCT {1518}.
Histopathology
Clinical signs and findings The GCTs underlying the haematologic Immunohistochemistry
In a series of 17 patients the most com- malignancies typically are non-semino- Interpretation of cytochemical findings in
mon clinical features at the diagnosis of matous malignant GCT, most often yolk blood or bone marrow smears, and
the haematologic disorder include pancy- sac tumours or mixed germ cell neo- immunophenotypic profiles follows the

GCT with associated haematologic malignancies 219


A B

C D
Fig. 3.86a A-D Case of a mediastinal germ cell tumour with haematopoietic component. A, B Note the haematopoietic component in the yolk sac tumour blood ves-
sels. C Poorly differentiated myeloid precursors showing focal myleoid peroxidase immunoreactivity. Myeloblasts were also positive for CD34 (not shown).
D Subsequent bone marrow biopsy shows acute myeloid leukaemia.

criteria of the WHO classification of Postulated cell of origin months after chemotherapy) than germ
tumours of haematopoietic and lymphoid Toti- or pluripotent primordial germ cell. cell-related AMLs (median time to onset 6
tissues {919}. Useful immunohistochemi- Alternatively, the detection of non-neo- months, range 0122) {789, 1461}.
cal stainigs include myeloperoxidase plastic extramedullary haemotopoiesis in
(MPO), lysozyme, CD10, CD20, CD34, the yolk sac tumour component of some Prognostic factors
CD68, CD61, CD117, TdT, and gly- GCTs suggests that some haematologic The occurrence of a clonally related
cophorin. malignancies can arise from more com- acute leukaemia in a patient with medi-
mitted, somatic-type haematopoietic astinal GCT is among the most adverse
Genetics cells by malignant transformation {1518}. prognostic factors. In a recent series,
Isochromosome 12 [i(12p)] is the most none of the reported patients has sur-
specific and most common chromosomal Differential diagnosis vived for more than 2 years after the
marker shared by GCTs and the associ- Clonally-related haematologic malignan- onset of leukemia (median survival time:
ated haematologic malignancies {315, cies must be distinguished from secon- 6 months) {789}. These leukaemias
1394,1461}. In addition, the haematolog- dary MDSs and AMLs that are related to appear to be refractory to current treat-
ic malignancies can harbour genetic salvage chemotherapy regimens inclu- ment protocols including aggressive
alterations that are typical for specific ding etoposide in patients with mediasti- induction chemotherapy and allogenic
haematologic malignancies in general nal GCT {100,1047}. Secondary MDSs bone marrow transplantation. However,
(del(5q); trisomy 8), suggesting that ocurred in 0.7%, and AMLs in 1.3 % of the clinical course in patients with myelo-
GCT-unspecific aberrations determine cases in a large series {1047}. proliferative diseases may be more pro-
the phenotype of the associated haema- Chemotherapy-related AMLs do not show tracted {663,814}.
tologic malignancy {1394}. i(12p) and usually manifest later (2560

220 Tumours of the thymus - Germ cell tumours


Mediastinal lymphomas and E.S. Jaffe
N.L. Harris
haematopoietic neoplasms:
Introduction

Principles of classification of the thymus gland are relatively rare. indicative of the capacity of germ cell
The classification of haematological The most common of these is mediastinal neoplasms to differentiate along many
malignancies has undergone significant large B-cell lymphoma (PMLBCL), of pro- cell lines {159,729,1052,1518,1723}.
reappraisal in recent years. These posed origin from specialized thymic B-
changes have resulted from insights cells found in the medullary perivascular Epidemiology
gained through the application of space {22,906}. Classical Hodgkin lym- The epidemiology of haematopoietic and
immunological and genetic techniques, phoma, nodular sclerosis type, (HLNS) lymphoid neoplasms of the mediastinum
as well a better understanding of the clin- also arises in the thymus gland, and is and thymus gland is heterogeneous,
ical aspects of lymphoid and myeloid genotypically of B-cell origin, although B- reflecting the diversity of disease entities
neoplasms through advances in diagno- cell markers may be absent. Lymphomas presenting in this site. Precursor T-cell
sis, staging and treatment. A multifac- of mucosa-associated lymphoid tissue and NK-cell neoplasms are for the most
eted approach to both disease definition (MALT)-type may arise in the thymus part diseases of children and young
and diagnosis, as proposed by the gland, as well as in other mucosal or adults, with an increased male: female
Revised European and American epithelial sites, and reflect the intimate ratio. Mediastinal large B-cell lymphoma
Lymphoma (REAL) classification {783} functional relationship between epithelial and nodular sclerosis Hodgkin lym-
and updated in the WHO classification and lymphoid components in the thymus phoma share many epidemiological fea-
{919}, is now considered the state of the gland {891}. A functionally related lesion tures, including prevalence in young
art. is the multilocular thymic cyst seen in adult females, and propensity to present
While morphology is still the starting autoimmune disease and HIV-infection with localized disease. This observation,
point for pathologic diagnosis, immuno- {1051,1326,1923}. Lymphomas involving plus the fact that synchronous and
logic and genetic techniques have been the mediastinal lymph nodes reflect to metachronous instances of mediastinal
crucial in defining disease entities, and some extent the spectrum of systemic large B-cell lymphoma and nodular scle-
are often useful in differential diagnosis. nodal lymphomas. However, because of rosis Hodgkin lymphoma may be
The pathologist must also be cognizant its inaccessibility as a biopsy site, the pri- encountered, has suggested that these
of the clinical history, as the site of pre- mary diagnosis of lymphoma is uncom- neoplasms may share a common cell of
sentation and other clinical parameters monly made in mediastinal lymph nodes. origin {710,1575}. In addition, there are
are an important aspect of both disease Myeloid neoplasms rarely have primary rare grey zone lymphomas with features
definition and diagnosis. Finally, in many presentations in the mediastinum. A intermediate between both entities
instances, lymphoid and myeloid neo- recently described entity, precursor T- {1270,1704}.
plasms can be related to a normal cellu- lymphoblastic lymphoma with eosino-
lar counterpart in the haematopoietic and philia and t(8;13) typically presents with Clinical features
lymphoid systems. a mediastinal tumour with the With the exception of the relatively rare
Mediastinal lymphomas arise in either immunophenotype of T-LBL, but is asso- MALT-type lymphomas, most mediastinal
mediastinal lymph nodes or the thymus ciated with development of acute lymphomas and haematopoietic neo-
gland. Thymic lymphomas are unique in myeloid leukaemia in the bone marrow plasms are clinically aggressive; patients
many respects, as they reflect the func- {2179}. Acute myeloid leukaemias, often typically present with symptoms related
tion of the thymus gland as an organ with megakaryoblastic differentiation to a large mediastinal mass, or with peri-
involved in T-cell generation and differen- may develop in the mediastinum and cardial or pleural effusions in lym-
tiation {1863}. Precursor T-lymphoblastic bone marrow in association with non- phoblastic lymphoma. Other clinical fea-
lymphoma/leukaemia presents as a seminomatous germ cell tumours with an tures vary with the type of lymphoma.
mediastinal mass in 85% of cases, and i(12)p {159,315,474,506,729,1113,1460,
the immunophenotype of the neoplastic 1461,1723}. Genetic features
cells reflects the stages of cortical thy- Histiocytic and dendritic cell tumours are The genetic features of these neoplasms
mocyte differentiation {157,1604}. There rare tumours that occasionally may pres- for the most part are similar to their coun-
are also rare reports of natural killer (NK)- ent in mediastinal lymph nodes and the terparts presenting in other sites. One
cell tumours with an immature phenotype thymus gland. However, as with myeloid exception is mediastinal large B-cell lym-
arising in the thymus gland {1046}, and neoplasms, most histiocytic neoplasms phoma, which has genetic features dis-
the fetal thymus is one site of NK-cell presenting in the mediastinum are rela- tinct from that of other diffuse large B-cell
development {1863}. B-cell lymphomas ted to teratomatous germ cell tumours, lymphomas {148,404,1756}.

Mediastinal lymphomas and haematopoietic neoplasms 221


Primary mediastinal large F. Menestrina
N.L. Harris
B-cell lymphoma P. Mller

Definition without superficial lymphadenopathy or


Primary mediastinal large B-cell lym- hepato-splenomegaly. The thymus is typ-
phoma (PMLBCL) is a type of diffuse ically involved and rare cases of lym-
large B-cell lymphoma arising in the phoma confined to the thymus have
mediastinum, of putative thymic B-cell been reported, suggesting that the
origin, with distinctive clinical, tumour arises in the thymus and second-
immunophenotypic and genotypic fea- arily involves mediastinal lymph nodes
tures. {918,1121}. The mass is often bulky
(>10 cm in diameter) and is often locally
ICD-O code 9679/3 invasive, infiltrating lung, pleura, thoracic
wall and pericardium. Supraclavicular
Synonyms extension is sometimes observed {22,
Primary mediastinal clear cell lymphoma 1296,1341}. At progression, PMLBCL
of B-cell type {1341}, mediastinal large- disseminates predominantly to extran-
cell lymphoma of B-type with sclerosis odal sites, including lung and extratho- Fig. 3.87 Summary of the cytological variants
{1296}. REAL: Primary mediastinal racic organs {305}: liver, kidney, and encountered in a series of 109 mediastinal large
B-cell lymphomas (PMLBCL). From Paulli et al.
(thymic) large B-cell lymphoma {783} adrenal are the most frequent sites of
{1558}.
parenchymal involvement; gastro-intes-
Epidemiology tinal tract, ovary, CNS, and pancreas
It accounts for about 2-3% of non- {171} are other reported sites. Bone mar-
Hodgkin lymphomas and occurs pre- row involvement is extremely rare.
dominantly in young adults (third and ly widely infiltrative at the time of the
fourth decade), with a slight female pre- Clinical features diagnosis. In resected specimens, the
dominance {3,305,783,1143}. Both of Signs and symptoms are related to the cut surface has a fleshy appearance,
these factors distinguish PMLBCL from mediastinal mass: superior vena cava often with necrotic areas. Thymic cysts
other types of diffuse large B-cell lym- syndrome (most frequently), airway may be present. Diagnostic features may
phoma, which have a median age in the obstruction, pleural and/or pericardial be lacking in small (e.g., trans-thoracic
7th decade and a male predominance. effusion. B symptoms may be present needle) biopsies when only sclerosing
{1143}. Traditional or more sophisticated and/or necrotic tissue is obtained.
Etiology imaging techniques are important in
It is unrelated to EBV or other known detecting the mass, in documenting the Tumour spread and staging
tumour viruses {1340,2034}. It might be involvement of other intra-thoracic struc- PMLBCL most probably arises
driven by a still elusive oncogene, prob- tures and in deciding on the best intrathymically {22} and then aggressive-
ably located on chromosome 9p {941}. approach to obtain a diagnostic biopsy. ly invades adjacent structures and tis-
sues, including regional lymph nodes,
Localization Macroscopy whereas distant lymph nodes are rarely
At presentation, the disease affects the Radical surgery or debulking is rarely affected. Leukaemia is never observed;
antero-superior area of the mediastinum performed, because the mass is typical- however, haematogenous dissemination
occurs during progression, as evidenced
by distant organ involvement {305}.
Staging procedures must exclude a sec-
ondary mediastinal involvement by a sys-
temic diffuse large B-cell lymphoma;
extrathoracic lymph nodes or bone mar-
row involvement would suggest this
diagnosis.

Histopathology
The growth pattern is diffuse. PMLBCL
has a broad range of cytomorphology;
Fig. 3.88 Chest X-ray of a bulky mediastinal large B- Fig. 3.89 PMLBCL with fleshy, whitish tumour tis- however, individual cases tend to be
cell lymphoma (PMLBCL). sue, containing necrotic and pseudocystic areas. monomorphic. The cells range from

222 Tumours of the thymus - Lymphomas


A B

C D

E F
Fig. 3.90 Mediastinal large B-cell lymphoma. A High power view of mediastinal large B-cell lymphoma. B Note the clear cytoplasm and the very irregular nuclei
with inconspicuous nucleoli. C Polymorphic tumour cells including Hodgkin-like cells. D Silver stain highlights the pseudoalveolar compartmentalization of the neo-
plastic tissue by collagen fibrils and fibers. E CD20 expression. F CD30 expression.

medium-sized to large (2-5 times the size ble Hodgkin lymphoma or nonlymphoid but not consistent feature is a distinctive
of a small lymphocyte), have abundant, tumours. Mitotic activity is high, similar to fibrosis made up of irregular collagen
frequently clear cytoplasm and irregular- other large cell lymphomas. The centre bands compartmentalizing cellular areas
ly round or ovoid (occasionally multilo- of the lesion contains predominantly neo- of varying size {1296,1341,1558,2224}.
bated) nuclei, usually with small nucleoli plastic cells. However, at periphery of the The combination of different architectural
{1558}. Some cases may have more mass, a variable number of reactive cells patterns and cellular morphology might
pleomorphic nuclei and abundant such as lymphocytes, macrophages and raise the differential diagnosis of thymo-
amphophilic cytoplasm and may resem- granulocytes may be present. A frequent ma, seminoma or Hodgkin lymphoma.

Primary mediastinal large B-cell lymphoma 223


Depending on the surgical approach
and specimen size, thymic remnants can
be observed, usually better highlighted
by immunohistology. Cystic change may
be present in the thymic remnant. Lung,
pleura and pericardium can be included.
Rare cases of composite PMLBCL and
Hodgkin lymphoma are reported {1704}.

Immunophenotype
PMLBCL expresses B-cell lineage-spe-
cific surface molecules such as CD19,
CD20, CD22 {1344}, and the immunoglo-
bulin-associated CD79a {1595} mole-
cule, but not lineage-restricted T-cell anti-
gens, except for MAL {404}, which is
regarded as T-cell restricted and is not
observed in other diffuse large B-cell
lymphomas. CD10 has been detected in
some studies in 20-25%, similar to its fre- Fig. 3.91 Mediastinal large B-cell lymphoma. This tableau summarizes the data of the comparative genomic
hybridization (CGH) of 44 cases of PMLBCL. From M. Bentz et al. {148}.
quency in other large Bcell lymphomas
{448,1595}, but has not been detected in
other studies {1343,1344}. CD15 and medullary B-cells {862}. Genetically, approaches, including comparative
CD21 are always negative. BCL6 protein PMLBCL seems to be derived from B- genomic hybridization, FISH, arbitrarily
may be detected by immunohistochem- cells that have been activated by a spe- primed PCR fingerprinting and classical
istry in 50-60% of the cases. Molecules cific antigen, passed through the germi- cytogenetics have yielded a highly char-
often found in/on PMLBCL cells like nal centre and have shut down their acteristic pattern of genomic alterations
CD38, PC-1, MUM1 and PAX5 {1595} in mutational machinery before neoplastic in PMLBCL: chromosomal gains (2p, 6p,
the absence of CD138 favour a post-ger- transformation is completed {1158}. 7q, 9p, 12, and X) are much more fre-
minal centre stage of maturation. The Immunophenotypically, PMLBCL are at quent than losses {941,1661,1756}. Most
majority of PMLBCL do not express Ig post-germinal centre stage {1158,1344, important is gain of chromosome arm 9p
{1296,1341}. In fact, the discrepancy 1595}. (9p+), which is detectable in up to 75%
between the lack of Ig and the constitu- of cases {148}. This aberration is a chro-
tive CD79a {953} is characteristic of this Somatic genetics mosomal marker in PMLBCL, since 9+ is
disease. The lack of Ig expression is like- Antigen receptor genes and BCL6. As in very rare in other nodal and extranodal
ly not related to a defect in the Ig tran- other diffuse large B-cell lymphomas, Ig B-cell lymphomas but, interestingly, is
scriptional machinery since the Ig tran- heavy-chain and light-chain genes are detectable in about 25% of classic
scription factors Oct2 and BoB.1 are rearranged and have high loads of muta- Hodgkin disease {940}. In both tumours,
expressed {1595}. Furthermore, there is tions {872,1098,1158,1753}. Further, the the consensus region of the recurrent
frequently a defect of HLA class I and/or vast majority of heavy-chain V genes are aberrations on 9p is subtelomeric. A sec-
II molecule expression {1342}. potentially functional by showing evi- ond essential genomic region in PMLB-
CD30 expression, often weak and dence of selection for a functional anti- CL is the long arm of chromosome X.
restricted to a subset of the tumour cells, body. No bias towards particular gene Aberrations of Xq, including high levels
is often observed in PMLBCL, especially families (such as VH4) were observed, of DNA amplification, are present in up to
when antigen retrieval techniques are so selection by an autoantigen or super- 87% of cases of PMLBCL {148}. Recent
used {829}. CD30 expression is typically antigen is unlikely. Intraclonal variation molecular studies applying gene expres-
low compared with the strong CD30 was not detected in the PMLBCL cases sion profiling show that classical
expression in neoplastic cells of classic analysed so far, indicating that continu- Hodgkin lymphoma and PMLBCL are
Hodgkin lymphoma (HL) or in diffuse ing mutational activity is not a prominent closely related {1694,1752}.
large B-cell lymphoma (DLBCL) of feature {1158}. The data on frequencies
anaplastic type. This may result in differ- of BCL-6 mutations in PMLBCL are con- Prognosis and predictive factors
ential diagnostic problems between flicting, ranging from 6-50% {448,1532, There are no histological {1558},
PMLBCL, Hodgkin disease, and the so- 1595,2034}. immunophenotypic or genotypic features
called grey zone lymphomas of the Genetic abnormalities. BCL-2 is that have prognostic potential. Similarly
mediastinum, which have features inter- germline, suggesting that the regular to other DLBCL, response to initial thera-
mediate between HL and DLBCL {1704}. expression of bcl-2 protein in PMLBCL is py is a good marker for prognosis. The
regulatory {1595,2034}. BCL-1 and N-ras survival with aggressive therapy is simi-
Histogenesis are not altered while p16, c-MYC, and lar to that of other localized DLBCL
Histologically, PMLBCL has been attri- TP53 occasionally carry mutations {305,918,1143}.
buted to the asteroid variant of thymic {1595,1754, 1755}. Different genetic

224 Tumours of the thymus - Lymphomas


Thymic extranodal marginal zone B- A.C.L. Chan
J.K.C. Chan
cell lymphoma of mucosa-associated H. Inagaki
S. Nakamura
lymphoid tissue (MALT) P. Mller

Definition currently no evidence for a histogenetic ly many interspersed epithelium-lined


Primary thymic extranodal marginal zone link with mediastinal large B-cell lym- cystic spaces. Reactive lymphoid follicles
B-cell lymphoma of mucosa-associated phoma. are scattered within the lymphoid infil-
lymphoid tissue is a lymphoma consist- trate. There is a proliferation of small lym-
ing predominantly of small B-cells with a Localization phocytes and centrocyte-like cells
centrocyte-like or monocytoid appear- The bulk of the disease is in the anterior around and between these follicles. The
ance, which surround reactive follicles mediastinum, but the regional lymph centrocyte-like cells have small to medi-
and infiltrate the thymic epithelium to pro- nodes and other extranodal sites (e.g. um-sized irregular nuclei, indistinct nucle-
duce lymphoepithelial lesions. stomach, salivary gland, lung) may be oli, and a moderate amount of pale cyto-
involved concurrently. plasm. They show extensive invasion of
ICD-O code 9699/3 the Hassall corpuscles or the thymic
Clinical features epithelium lining the cystic spaces, form-
Synonyms Patients are usually asymptomatic, with ing lymphoepithelial lesions. The lym-
Mucosa-associated lymphoid tissue the mediastinal tumour being discovered phoid cells within and immediately
(MALT) lymphoma; MALToma incidentally on chest radiograph. A around the epithelial structures usually
minority of patients present with chest possess an even greater amount of clear
Epidemiology pain, shortness of breath, haemoptysis cytoplasm, reminiscent of monocytoid B-
Primary thymic extranodal marginal zone or back pain. In patients associated with cells. There are often interspersed aggre-
B-cell lymphoma is rare, with less than 30 autoimmune disease, the time interval gates of plasma cells, which are shown
cases having been reported in the litera- between the onset of autoimmune dis- on immunohistochemical staining to be
ture {493,778,891,905,1209,1279,1426, ease and the discovery of the thymic
1556,1700,1945,2188}. Most patients are tumour ranges from 2-25 years {891}.
in the fifth and sixth decades. There is Monoclonal gammopathy (frequently
female predominance (M:F = 1:3), and IgA, occasionally IgG or IgM) is com-
>60% of the reported cases are Asians. mon, and may sometimes result in hyper-
viscosity syndrome {891,1209}. An asso-
Etiology ciation with Sjgren disease is frequently
Primary thymic extranodal marginal zone observed.
B-cell lymphoma is strongly associated
with autoimmune disease (>50% of the Macroscopy
cases), especially Sjgren syndrome Grossly, the tumour is often encapsulat-
{891}. The autoimmune disease-associ- ed and comprises solid greyish-white
ated reactive lymphoid hyperplasia may fleshy tissue commonly interspersed with
provide a fertile ground for emergence of multiple variable-sized cysts. Invasion
the lymphoma. There is no association into the adjacent pericardium and pleura
with Epstein Barr virus {891}. There is is sometimes found.

Tumour spread and staging


Most tumours (>75%) are of low stage
(Stage I/II) at presentation {891}.
Concurrent extranodal marginal zone B-
cell lymphoma in other MALT sites (e.g.
salivary gland, stomach, lung) occurs in
about 20% of cases, probably related to
the homing characteristics of extranodal
Fig. 3.93 Primary extranodal marginal zone B-cell
marginal zone B-cell lymphomas {891}.
lymphoma of the thymus. Part of a reactive lym-
phoid follicle is seen at the top. The lower field
Histopathology shows thymic epithelium (including Hassall cor-
Fig. 3.92 Primary extranodal marginal zone B-cell The normal thymic lobular architecture is puscles), heavily infiltrated by lymphoma cells. The
lymphoma of the thymus. The cut surface shows effaced by an abnormal dense lymphoid cells within and immediately around the epithelial
fleshy, tan-coloured tumour tissue interspersed infiltrate, but residual Hassall corpuscles unit have abundant clear cytoplasm, resembling
with multiple cystic spaces. can still be identified. There are common- monocytoid B cells.

MALT lymphomas 225


A B

C D
Fig. 3.94 Primary extranodal marginal zone B-cell lymphoma of the thymus. A The thymic epithelium lining the cysts is extensively infiltrated by the lymphoma cells. Note
also the presence of small clusters of plasma cells. B The lymphomatous infiltrate comprises small lymphocytes, centrocyte-like cells and cells resembling monocy-
toid B cells. C Immunostaining for CD20 shows sheets of positive cells, confirming the B-cell lineage of the lymphoma. A residual Hassall corpuscle is seen in the left
middle field. Note that plasma cells do not react. D Many plasma cells are highlighted by immunostaining for immunoglobulin (lambda light chain in this case).

part of the neoplastic clone. Scattered cyte-like cells and monocytoid cells Prognosis and predictive factors
centroblast-like cells or immunoblasts are {1556}. Thymic extranodal marginal zone B-cell
frequently found. Transformation to dif- lymphoma is associated with an excel-
fuse large B-cell lymphoma has only Histogenesis lent outcome. Only one documented
been rarely reported {1209}. This lymphoma is derived from post-ger- tumour-related death has been reported
minal centre marginal zone B-cells. {891}. High tumour stage at presentation
Immunophenotype or concurrent involvement of other MALT
Immunohistochemically, the tumour cells Somatic genetics sites is not necessarily associated with a
express B-cell specific markers, such as Immunoglobulin genes are clonally poor prognosis. Most patients have
CD20 and CD79a. They are negative for rearranged {950}. Although API2-MALT1 undergone surgical resection both for
CD3, CD5, CD10, CD23, CD43, and fusion resulting from t(11;18) is present in diagnosis and treatment of low stage dis-
cyclin D1. They commonly express BCL2. up to 50% of extranodal marginal zone ease. Chemotherapy and radiotherapy
More than 75% of the cases express IgA B-cell lymphomas in general, this chro- have also resulted in complete remission
{891}. mosomal translocation is not detected in in some cases.
thymic extranodal marginal zone B-cell
Differential diagnosis lymphomas {891}. Only one case has
The main differential diagnosis is reactive been studied by cytogenetics, with the
lymphoid hyperplasia of the thymus. In finding of 46,X,dup(X)(p11p22) {778}.
reactive lymphoid hyperplasia, which is
most frequently associated with myas- Genetic susceptibility
thenia gravis, the thymic lobular architec- There is no known genetic susceptibility.
ture is preserved, and there is no band- It remains unclear whether this lymphoma
like or sheet-like proliferation of centro- type shows a predilection for Asians.

226 Tumours of the thymus - Lymphomas


Precursor T-lymphoblastic N. L. Harris
M. Borowitz
lymphoma / leukaemia E.S. Jaffe
J. Vardiman

Definition hood and 25% of adult ALL are of pre- effusions. Airway compromise is com-
Precursor T-lymphoblastic lymphoma/ cursor T-cell type {206}. Cases present- mon, and the presentation is often as a
leukaemia is a neoplasm of lymphoblasts ing without bone marrow and peripheral medical emergency
committed to the T-cell lineage, typically blood involvement (lymphoblastic lym-
composed of small to medium-sized phoma) comprise 85% of lymphoblastic Histopathology
blast cells with scant cytoplasm, moder- lymphomas, 25-30% of childhood non- The thymus and mediastinal soft tissue
ately condensed to dispersed chromatin Hodgkin lymphomas and only 2% of as well as adjacent lymph nodes are
and indistinct nucleoli, variably involving adult non-Hodgkin lymphomas world- involved. The epithelial meshwork is
bone marrow and blood (precursor T-cell wide {3}. Some studies indicate an destroyed, septa are effaced, and the
acute lymphoblastic leukaemia), thymus increased prevalence of precursor T-cell tumour cells spread through the capsule
and/or lymph nodes (precursor T-cell neoplasia in underdeveloped countries, into adjacent mediastinal tissue. In tissue
lymphoblastic lymphoma). while precursor B-cell neoplasms are sections, the cells are small to medium-
more common in industrialized countries sized, with scant cytoplasm, round, oval,
ICD-O code {2016}. or convoluted nuclei, with fine chromatin
Precursor T-lymphoblastic lymphoma and indistinct or small nucleoli.
9729/3 Etiology Occasional cases have larger cells. In
Precursor T-lymphoblastic leukaemia The etiology is unknown. No association lymph nodes the pattern is infiltrative
9837/3 with viruses or immune status has been rather than destructive, often with partial
demonstrated. Patients with ataxia preservation of the subcapsular sinus
Synonyms telangiectasia are at increased risk for and germinal centres. A starry-sky pat-
Precursor T-cell acute lymphoblastic development of T-ALL, but the ATM gene tern may be present, but is usually less
leukaemia (ALL) / Precursor T-cell lym- has not been implicated in sporadic prominent than in Burkitt lymphoma.
phoblastic lymphoma (LBL); T-cell lym- T-precursor neoplasia {1959}. In early Pleural or pericardial fluid may be the ini-
phoblastic lymphoma; T-cell acute lym- childhood T-ALL, the neoplastic clone tial diagnostic specimen. On smears,
phoblastic leukaemia; convoluted lym- can be detected at birth by clone-specif- lymphoblasts vary from small cells with
phocytic lymphoma (Lukes-Collins); lym- ic T-cell receptor gene rearrangement,
phoblastic lymphoma, convoluted cell suggesting that the transforming event
type (Kiel, Working formulation); poorly- occurs in utero {559}.
differentiated lymphocytic lymphoma
(Rappaport); leukosarcoma (Sternberg Localization
sarcoma) (historical term) {1878} The tumour typically involves the medi-
astinum, specifically the thymus, and
Epidemiology often mediastinal lymph nodes.
Precursor T-cell neoplasms occur most Supradiaphragmatic lymph nodes may
frequently in late childhood, adoles- also be involved, and tumour cells are
cence, and young adulthood, with a male often shed into the pleural fluid. The
predominance. Fifteen percent of child- bone marrow and peripheral blood are A
involved in the majority of the cases.
Central nervous system involvement is
also common. Clinically, a case is
defined as lymphoma if there is a medi-
astinal or other mass and <25% blasts in
the bone marrow, and as leukaemia if
there are >25% bone marrow blasts, with
or without a mass. This is an arbitrary dis-
tinction and should be regarded as stag-
ing rather than classification. B
Fig. 3.96 Precursor T-lymphoblastic lymphoma
Clinical features A Monomorphous infiltrate with a starry-sky pat-
Patients typically present acutely with tern. B Tumour cells have dispersed chromatin,
Fig. 3.95 Infiltration of the heart by a T-lymphoblastic symptoms related to a large mediastinal small nucleoli, and scant cytoplasm, such that the
lymphoma. mass, often with pleural or pericardial nuclei appear to overlap.

Precursor T-lymphoblastic lymphoma / leukaemia 227


Somatic genetics
Rearrangement of antigen receptor
genes is variable in lymphoblastic neo-
plasms, and may not be lineage-specific;
thus, precursor T-cell neoplasms may
have either or both T-cell receptor (TCR)
beta or gamma chain gene rearrange-
ments and immunoglobulin heavy chain
A B gene rearrangements {1939}. The major-
ity have T-cell receptor gamma chain
rearrangements, with either beta or delta
rearrangements in the majority of the
cases {1938}.
Chromosomal translocations involving
the TCR alpha and delta loci at chromo-
some 14q11 and beta and gamma loci at
7q34 are present in about one-third of
the cases {998,2044}; the partner genes
are variable and include the transcription
C D factors c-MYC (8q24), TAL1/SCL (1p32),
Fig. 3.97 Precursor T-cell acute lymphoblastic leukaemia (T-ALL). Flow cytometry of peripheral blood from RBTN1 (11p35), RBTN2 (11q13), and
an adolescent male with a mediastinal mass. A Cells are positive for CD1 and dimly for surface CD3. B Cells HOX11 (10q24) and the cytoplasmic
express both CD4 and CD8. C The cells express CD2 and CD10. D They are positive for CD5 and dimly for tyrosine kinase LCK (1p34). In an addi-
CD3. tional 25%, the TAL1 locus at 1p32 has
deletions in the 5 regulatory region
scant cytoplasm, condensed nuclear presentation may show earlier differentia- {136}. Deletions of 9p involving deletion
chromatin, and indistinct nucleoli to lar- tion stage than cases with thymic pres- of the p16ink4a tumour suppressor gene
ger cells with a moderate amount of cyto- entation {157,725}) there is overlap (CDK4 inhibitor) is also seen in T-lym-
plasm, dispersed chromatin, and multi- {1632}. Among cases that express T-cell phoblastic neoplasms {901,1601}.
ple nucleoli. Azurophilic granules may be receptor proteins, the majority are of the Cases associated with eosinophilia and
present. alpha/beta type and a minority express myeloid neoplasia have a t(8;13) involv-
Recently, cases of mediastinal precursor gamma/delta type; the latter appear to ing the fibroblast growth factor receptor
T-cell lymphomas with increased tissue have a more immature phenotype {1938}. gene on chromosome 8 and a novel
and bone marrow eosinophils have been Rare cases of lymphoblastic lymphoma zinc-finger gene on chromosome 13
described. Patients typically developed presenting in the mediastinum have the {2179}.
acute leukaemia with myeloid antigen immunophenotype of immature natural Analysis by gene expression array has
expression. These cases were found to killer (NK) cells {325,1046,1795}. shown that acute leukaemias of lymphoid
have a translocation t(8;13) in both the and myeloid types can be distinguished,
myeloid and lymphoid cells, indicating a Differential diagnosis as can precursor T and precursor B-cell
true biphenotypic malignancy {2179}. On biopsy specimens, the differential lymphoblastic leukaemias. The utility of
diagnosis may include thymoma with a these studies in diagnosis remains to be
Immunophenotype prominent immature T-cell population (B1 determined, however, some differentially
The lymphoblasts are positive for termi- or B2 thymoma). The immunophenotype expressed genes, such as TAL1/SCL can
nal deoxynucleotidyl transferase (TdT) in of T-LBL and of the normal precursor be detected by immunohistochemistry
virtually all cases, and variably express T-cells in thymoma can be identical. The and may provide a marker for T-precur-
CD2, CD7, surface or cytoplasmic CD3, infiltrative growth of the lymphoblasts sor neoplasia {552,706}
CD5, CD1a, CD4 and/or CD8. Only sur- with destruction of the epithelium and
face CD3 is considered lineage-specific. demonstration of clonality by molecular Prognostic factors
Minimal criteria for classification as T-LBL genetic analysis can be helpful in con- The prognosis with aggressive therapy is
are CD7+ and cytoplasmic CD3+. The firming the diagnosis of lymphoma. similar to that of precursor B-cell neo-
constellation of antigens defines stages In a patient with a mediastinal mass and plasms, and is not affected by immuno-
of differentiation, ranging from early or lymphocytosis, a diagnosis of peripheral phenotype or genetic abnormalities. In
pro-T (CD2, CD7 and cytoplasmic CD3), T-cell lymphocytosis associated with thy- children, treatment is generally more
to common thymocyte (CD1a, sCD3, moma has to be included among the dif- aggressive than that for precursor B-ALL,
CD4 and CD8), to late thymocyte (CD4 or ferential diagnoses {116,445}. and is typically the same for lymphoma-
CD8). tous and leukemic presentations {1361}.
Although there is some correlation with Histogenesis The median disease-free survival in one
presentation and differentiation stage Precursor T lymphoblasts at varying recent study of adult T-ALL was 28
(cases with bone marrow and blood stages of differentiation. months {206,2044}.

228 Tumours of the thymus - Lymphomas


Anaplastic large-cell lymphoma and S. Nakamura
T. Rdiger
mature T and NK cell lymphomas of A. Marx

the mediastinum

Definition
Mature T-cell and NK-cell neoplasms are
derived from mature or post-thymic
T cells and NK cells, respectively.
Because they share some immunophe-
notypic and functional properties, these
two classes of neoplasms are consid-
ered together.

ICD-O code A B
Anaplastic large-cell lymphoma Fig. 3.98 Anaplastic large-cell lymphoma. A Hallmark cells with embryoform or kidney shaped nuclei, broad
9714/3 cytoplasm, and pale staining Golgi region; numerous apoptotic bodies and mitoses. B CD30 expression in
the membrane and Golgi region.

Anaplastic large-cell
lymphoma (ALCL) granzyme B and TIA-1. They also may lymphoma primarily affecting the thymus,
exhibit positivity for other T-cell markers 5 of 142 cases registered in the NK Cell
ALCL mainly occurs in children and (CD43, CD45R0), EMA, while CD5 and Tumour Study Group in Japan showed
young adults, involving a variety of sites. CD7 are frequently negative. Anaplastic mediastinal involvement (unpublished).
The incidence of a mass presentation in lymphoma kinase (ALK) is expressed in In a patient with a mediastinal mass and
the thymus and/or mediastinum varies 40-70% of ALCL in various series. It may lymphocytosis, a diagnosis of peripheral
from 8-39% with or without lymph- be nuclear and cytoplasmic or cytoplas- T-cell lymphocytosis associated with thy-
adenopathy {231,1775,1930}. The higher mic only, depending on the translocation; moma has to be included among the dif-
figure of 39% likely results from inclusion it is more commonly expressed in pedi- ferential diagnoses {116,445}.
in some series of Hodgkin-like ALCL, atric cases, and is associated with an
which is now thought to be a variant of excellent prognosis {919}.
Hodgkin lymphoma in most cases {919}. ALCL may pose differential diagnostic
ALCL involving the thymus may be asso- problems from carcinoma, mediastinal
ciated with cyst formation, evident on large B-cell lymphoma or Hodgkin lym-
gross or microscopic examination. ALCL phoma. Immunophenotyping for CD15,
usually shows a cohesive growth pattern CD30, pan-B and pan-T antigens, cyto-
and cytologic features as follows: the toxic molecules, EMA, keratin, and ALK
cells are large, with round or indented protein may be essential for their exact
nuclei, often described as reniform, diagnosis.
embryo-, and horseshoe-shaped, multi-
ple nucleoli that vary in size, and abun- Somatic genetics
dant cytoplasm. The so-called hallmark ALCL is associated with characteristic
cell has an indented nucleus with a chromosome translocations involving the
paranuclear, eosinophilic region corre- ALK gene on chromosome 2, with the
sponding to the Golgi region. Reactive partner being the NPM gene on chromo-
cells may be numerous in rare cases, some 5 in most cases, and other genes
usually histiocytes or neutrophils; in a minority of the cases {919}.
eosinophils are not common.
The tumour cells are strongly and consis- Mature T cell lymphomas
tently positive for CD30. Although they
show T-cell receptor gene rearrangement Mature T-cell neoplasms are very rare in
on a molecular level, phenotypically their the thymus, despite the importance of
derivation from the T-cell lineage may be the thymus in T-cell ontogeny {1402,
difficult to prove. CD2 and CD4 are the 1610,1827,2195}. Only 0.2% of peripher-
markers most frequently positive. CD3 is al T-cell lymphomas are diagnosed from
often but not always positive. Most cases mediastinal biopsies. Although there is Fig. 3.99 High power magnification of typical hall-
express cytotoxic molecules such as no documented case of mature NK cell mark cells in ALCL.

Anaplastic large-cell lymphoma 229


Hodgkin lymphoma of the mediastinum H.K. Mller-Hermelink
T. Rdiger
N.L. Harris
E.S. Jaffe
A. Rosenwald
J.K.C. Chan

Definition at the third decade, and probably also a Macroscopy


Hodgkin lymphoma (HL) is a neoplasm second smaller peak in late life. The dis- The thymus or mediastinal lymph nodes
derived from B-cells in most cases, char- ease more commonly affects women involved by NSHL show multiple firm
acterized by large tumour cells scattered than men. Patients with a history of infec- greyish-white nodules, with or without
in a characteristic inflammatory back- tious mononucleosis have a slightly high- visible fibrous bands. The thymus com-
ground. It encompasses two entities dis- er incidence of HL. Both familial and geo- monly exhibits interspersed cystic
tinguishable by their phenotype and clin- graphical clustering have been spaces {988}.
ical presentation, namely nodular lym- described {1270}.
phocyte predominant Hodgkin lym- Tumour spread and staging
phoma (NLPHL) and classical Hodgkin Localization Hodgkin lymphoma typically spreads to
lymphoma (cHL) {50,496}. NSHL of the anterior mediastinum often contiguous lymph node regions, rather
Since HLs other than nodular sclerosis takes origin from the thymus or mediasti- than showing discontinuous dissemina-
are exceedingly rare in biopsies from the nal lymph nodes, or both may be tion. Mediastinal Hodgkin lymphoma
mediastinum, these should be referred to involved {988,1080}. may be restricted to the mediastinum
in the WHO Classification of Tumours of (stage I), associated with extension to
Haematopoietic and Lymphoid Tissues Clinical features adjacent lung (stage IE [E=extension]),
{919}. The patients present with symptoms due or may involve cervical or other lymph
to the presence of a large anterior medi- nodes (stage II [2 nodal groups on the
ICD-O code astinal mass, such as chest discomfort same side of the diaphragm] or III [nodal
Hodgkin lymphoma, nodular sclerosis or dyspnoea, or occasionally are asymp- groups on both sides of the diaphragm]),
9650/3 tomatic, being incidentally found to have and rarely spleen (stage III), bone mar-
a mass lesion on chest radiograph. row, or nonlymphoid organs such as liver
Synonyms Some patients have simultaneous (stage IV).
In older publications, thymic HL was involvement of supraclavicular or lower
often designated as granulomatous thy- cervical lymph nodes. A proportion of Histopathology
moma {968}. Since the tumour cells are patients also have systemic symptoms. The architecture of the lymph node or the
of lymphoid origin, the term Hodgkin lym- Myasthenia gravis has been described in thymus is effaced by a nodular infiltrate
phoma is preferred over Hodgkins dis- one case of thymic HL {1494}. that comprises variable numbers of
ease.

Epidemiology
Nodular sclerosis Hodgkin lymphoma
(NSHL) is especially predominant in
industrialized countries, in high socio-
economic groups and in urban areas
{782}. The age distribution shows a peak

Fig. 3.100 A 31 year-old female with cough and a


circumscribed thymic mass thought to be a thymo-
ma. Cut surface shows a lobulated, firm, yellow-tan Fig. 3.101 Hodgkin lymphoma. Nodular sclerosis (classical Hodgkin lymphoma) of the thymus. Fibrous colla-
mass. Microscopical examination disclosed NSHL. gen bands completely surround a cellular nodule in the mediastinal fat.

230 Tumours of the thymus - Lymphomas


Hodgkin and Reed-Sternberg cells asso-
ciated with a rich inflammatory back-
ground. Classical Reed-Sternberg cells
are large cells with apparently double or
multiple nuclei and abundant
eosinophilic or amphophilic cytoplasm.
The nuclei are often rounded in contour,
with thick nuclear membrane, pale chro-
matin, at least 2 eosinophilic nucleoli in 2
separate lobes, and perinucleolar clear- A B
ing. Mononuclear variants are termed
Fig. 3.102 Hodgkin lymphoma. A Hodgkin lymphoma, nodular sclerosis, BNLI Grade 2. A scalene lymph node
Hodgkin cells. Some tumour cells may biopsy from a 20 year-old female with a mediastinal mass shows a confluent infiltrate of large neoplastic
have condensed cytoplasm and pykno- cells with pleomorphic nuclei and pale cytoplasm, typical of lacunar variants of Reed-Sternberg cells.
tic nuclei, and are known as mummified B CD30 shows strong membrane and Golgi region staining of the neoplastic cells. The cells express CD15
cells. The lacunar variant of Reed- in a similar pattern but lack T and B-cell associated antigens.
Sternberg cells is characterised by rela-
tively small, lobated nuclei, often with
small nucleoli, and abundant, pale cyto- um mimicking thymoma on small biop- cHL not further classified, with a note that
plasm that is retracted in formalin-fixed sies. The cysts are lined by flat epitheli- the small specimen size precludes defin-
tissues. um which is frequently non-keratinizing- itive subclassification.
NSHL invariably shows sclerosis, which squamous, but may be columnar, ciliated Composite lymphomas with CHL and dif-
in lymph nodes begins in the capsule, or mucus producing {988,1080}. Tumour fuse large B cell lymphoma infiltrates
and divides the tumour into nodules of may be detected within cyst walls, some- side by side are rare.
varying size. At least one fibrous band times producing bulges into the lumen.
encapsulating a tumour nodule is con- Similar cystic changes can also occur in Immunohistochemistry
sidered to be the minimal criterion for the the thymus not involved by the lym- In cHL, tumour cells strongly and consis-
nodular sclerosis subtype. The inflamma- phoma itself. tently express CD30. CD15 is detectable
tory background of NSHL comprises In small biopsies, both the characteristic in more than 85% of the cases, although
lymphocytes, plasma cells, and granulo- pattern and tumour cells may be difficult sometimes only focally {2090}. CD20
cytes, especially eosinophils. Geo- to identify. To establish the primary diag- may be expressed in up to 20% of cHL
graphic necrosis is common, frequently nosis of cHL, either classical multinucle- {1760,2090,2248}, but it is usually weak-
accompanied by neutrophil infiltration ated Reed-Sternberg cells or lacunar er than in accompanying B-cells and
and concentration of tumour cells around cells showing the typical immunopheno- staining intensity varies among tumour
the necrotic areas. type should be identified, and this may cells {1705}. CD79a is negative in the
Involvement of the thymus by cHL often require examination of multiple levels of majority of cases. EBV is expressed in
results in cystic changes, and pseudo- the biopsy. If fibrous bands cannot be about 20% of NSHL, and may be detect-
epithelial hyperplasia of thymic epitheli- identified, the case may be classified as ed by immunohistochemistry for its latent

Table 3.12
Synopsis of mediastinal Hodgkin lymphomas

Classification of Hodgkin lymphomas Abbreviation Frequency diagnosed from media- ICD-O code
stinal biopsies with HL*

Nodular lymphocyte predominant NLPHL 1% 9659/3


Hodgkin lymphoma

Classical Hodgkin lymphoma CHL 99% 9650/3

Nodular sclerosis classical Hodgkin NSHL 80% 9663/3


lymphoma

Mixed cellularity classical Hodgkin MCHL 18% 9652/3


lymphoma

Lymphocyte-rich classical Hodgkin LRCHL 0% 9651/3


lymphoma

Lymphocyte-depleted classical LDHL 1% 9653/3


Hodgkin lymphoma

* German Hodgkin Study Group data based on 169 mediastinal biopsies, unpublished data.

Hodgkin lymphoma of the mediastinum 231


A B C
Fig. 3.103 Classical Hodgkin lymphoma of the thymus. A Hodgkin cells and granulocytes in thymic medullary region around Hassall corpuscle. B Strong CD30
expression in tumour cells. C CK19 staining reveals pseudoepitheliomatous hyperplasia around Hodgkin and Reed-Sternberg cells; this is frequently accompanied
by thymic cyst formation. When tumour cells are less conspicuous than here, epithelial hyperplasia can be mistaken for thymoma on small biopsies.

membrane antigen or EBER probes Somatic genetics long arm of chromosome 12 are fre-
{692}, while EBNA2 is not expressed On a single cell level, rearrangement of quently detected. An overrepresentation
{1991}. The incidence of EBV association the immunoglobulin genes can be of the REL-protooncogene (2p15-p16)
in NSHL is generally lower than in other demonstrated in almost all cases, indi- and the JAK/STAT signal transduction
subtypes and varies geographically cating B cell derivation of the Reed- pathway may play a major role in the
{692,782}. Vimentin {1705} and fascin Sternberg cells and variants {1096A}. In pathogenesis {115,939,940,1249}.
{1600} are generally expressed in cHL, cHL, the rearranged immunoglobulin Recent molecular studies applying gene
but rare in large B-cell lymphomas. The gene is not transcribed, either due to expression profiling show that classical
reactive background contains variable non-functional mutations in the Hodgkin lymphoma and PMLBCL are
numbers of B- and T-lymphocytes, with immunoglobulin genes {1099,1873} or closely related {1694,1752}.
the latter forming rosettes around individ- due to a lack in essential transcription
ual tumour cells. factors (such as OCT-2, BOB-1) {1874}. Prognostic factors
Rare cases with rearranged T-cell recep- Patients are usually treated with
Histogenesis tor genes have been observed {1414, chemotherapy with or without radiothera-
Post germinal center activated B cells 1776}. py, adapted to clinical stage. Stage is the
are the presumed cells of origin. In CGH-analysis, gains on the short arms single most important prognostic factor.
of chromosomes 2 and 9, and on the The various subtypes of cHL do not differ
in their prognosis, which has greatly
improved with recent protocols {495}. In
one study, cases that lacked CD15
expression had a worse prognosis than
CD15+ cases {2090}. Grading systems
for nodular sclerosis have been shown in
some studies, but not others, to predict
prognosis {574,825,1221,2069,2091}.

Fig. 3.104 Gene expression patterns shared between primary mediastinal large B-cell lymphoma (PMBL)
and Hodgkin lymphoma (HL). Several genes, including CD30, MAL, SNFT, Fas and TARC show expression in
PMBL and HL, in contrast to their low expression in the germinal center B-cell type of diffuse large B-cell
lymphoma (GC, DLBCL). From A. Rosenwald et al. {1694}.

232 Tumours of the thymus - Lymphomas


Grey zone between Hodgkin lymphoma H.K. Mller-Hermelink
T. Rdiger
and non-Hodgkin lymphomas (NHL) A. Rosenwald
N.L. Harris
E.S. Jaffe
J.K.C. Chan

Definitions
The term grey zone lymphoma has been
assigned to neoplasms exhibiting inde-
terminate features between classical
Hodgkin lymphoma (cHL) and large cell
non-Hodgkin lymphoma (NHL), such that
a definitive classification as cHL or NHL
is not possible.
Composite lymphomas exhibit clearly
separable lymphoma infiltrates with typi- A B
cal features of cHL and NHL side by
side. They may or may not be clonally
related. The different components and
their proportions should be stated in the
diagnosis.

ICD-O code
Composite Hodgkin and
non-Hodgkin lymphoma 9596/3
This code may also be used for grey
zone lymphomas. C D
Fig. 3.105 Hodgkin lymphoma. A Mediastinal lymph node with a composite classical Hodgkin lymphoma
Some tumours can exhibit indeterminate (dark staining areas on upper and left side of the lymph node) and PMLBCL (pale area in the lower, middle
and right side). Giemsa stain. B Pale area of the lymph node shown in A. PMLBCL, immunoblastic variant.
features of both cHL and large B cell lym-
Effacement of lymph node architecture by sheets of quite uniform medium-sized to large blasts showing
phoma, such that definitive classification prominent nucleoli. Giemsa stain. C Dark-staining area of the lymph node shown in A. Classical Hodgkin
as cHL or NHL is impossible even after lymphoma, mixed cellularity subtype. Note the absence of fibrous bands. Hodgkin cells are surrounded by
extensive immunophenotypic and molec- reactive lymphocytes and plasma cells. Note rosettes. Giemsa stain. D PMLBCL in mediastinal lymph node.
ular studies {1270,1704}. These lym- Presence of scattered Hodgkin-like cells among B-blasts is insufficient for a diagnosis of composite
phomas are termed grey zone lym- Hodgkin and Non-Hodgkin lymphoma. Note absence of a reactive infiltrate of lymphocytes, plasma cells
phomas. Their occurrence is not surpris- and eosinophils around the Hodgkin-like cells. Giemsa stain.
ing. Since Hodgkin lymphoma is a lym-
phoid malignancy derived from B-cells in
nearly all cases {1097,1099,1237}, its Finally, microarray-based studies have focal fibrosis. There are sheets of malig-
interface to B-cell NHL may not always documented largely overlapping gene nant cells, some of which resemble
be clear-cut. The interface between expression profiles in cHL and PMLBCL, Reed-Sternberg cells or lacunar variants.
NSHL and primary mediastinal large B- stressing their close keenship {1694, The inflammatory background may be
cell lymphoma (PMLBCL) is currently felt 1752}. However, as HL is treated differ- sparse or absent. The tumor cells typi-
to comprise a biological transition: apart ently than NHL, it is important to distin- cally all express CD20, and in addition
from their frequent mediastinal presenta- guish between them, if possible. strongly express CD30. CD79a and
tion, both tumours frequently lack func- NSHL and large B-cell lymphoma may CD15 may be variably expressed.
tional expression of HLA class I and occur metachronously {2233}, or syn- Retrospective clinical data suggest that
immunoglobulin genes. CHL is always chronously (composite lymphoma) {710, the mostly male patients respond poorly
CD30 positive, and primary mediastinal 1575}. to radiotherapy alone, and relapses in
large B cell lymphoma is also frequently abdominal and extranodal locations are
CD30 positive. CGH studies suggest that Histopathology. common {1704}.
they share an overrepresentation of Grey zone lymphomas, by definition,
genomic material on the short arms of have no specific morphology. They may
chromosomes 2 and 9 {148,1752}. manifest a vaguely nodular infiltrate with

Grey zone lymphomas 233


Histiocytic tumours J.K.C. Chan
T. Grogan
S.A. Pileri
E.S. Jaffe

Histiocytic tumours rarely occur as a pri-


mary tumour in the mediastinum. Details
are available in the WHO Classification of
Tumours of Haematopoietic and Lymph-
oid Tissues {919}. This section focuses
on cases located in the thymus or medi-
astinum. Exceptionally, Rosai-Dorfman
disease (Sinus Histiocytosis with Massive
Lymphadenopathy, SHML) can also
involve these sites.

Langerhans cell histiocytosis


and sarcoma
Definitions
Langerhans cell histiocytosis is a neo-
A
plastic proliferation of Langerhans cells,
with expression of CD1a, S100 protein,
and the presence of Birbeck granules by
ultrastructural examination.
Langerhans cell sarcoma differs from
Langerhans cell histiocytosis in showing
overtly malignant cytologic features; it
can present de novo or progress from
antecedent Langerhans cell histiocyto-
sis.

ICD-O codes
Langerhans cell histiocytosis
9751/1
Langerhans cell sarcoma
9756/3
B
Fig. 3.106 Langerhans cell histiocytosis (LCH). A LCH presenting as a thymic mass. There is a diffuse infil-
Synonym
trate of cells with grooved nuclei and delicate nuclear membrane. Note some admixed eosinophils. B LCH
Langerhans cell sarcoma was previously
with CD1a expression in tumour cells. Macrophages are spared.
termed malignant histiocytosis X.

Epidemiology and clinical features nal structures. In adults, the thymic and eosinophilic cytoplasm. There are
Involvement of the thymus or mediastinal involvement is usually subtle, and is dis- commonly admixed multinucleated giant
lymph node by Langerhans cell histiocy- covered incidentally in thymus removed cells and eosinophils. Necrosis can be
tosis or Langerhans cell sarcoma is rare primarily for another indication; thus the present. The Langerhans cells typically
{1181}. It usually occurs in the setting of reported association with myasthenia express S-100 protein and CD1a.
disseminated disease {143,210,945, gravis is probably fortuitous {219,683, The thymus can be involved diffusely or
1596,1761}. 1578,2096}. focally. The involved areas show destruc-
Rare cases of Langerhans cell histiocyto- tion of the normal thymic parenchyma,
sis presenting with thymic involvement Histopathology damage to Hassall corpuscles, interlobu-
have been reported {219,683,1491, The key histologic feature of Langerhans lar connective tissue infiltration, and
1578,2096}. In children, the thymus is cell histiocytosis is a diffuse infiltrate of scattered calcospherites {1761,1823}.
often markedly enlarged and extensively non-cohesive Langerhans cells with Localized thymic involvement in adults
infiltrated by Langerhans cells; there can grooved or markedly contorted nuclei, often takes the form of scattered small
be invasion of the surrounding mediasti- thin nuclear membranes, fine chromatin nodular aggregates of Langerhans cells.

234 Tumours of the thymus - Lymphomas


This can be accompanied by reactive
lymphoid hyperplasia or multilocular
thymic cyst {2096}.

Differential diagnosis
An important differential diagnosis is his-
tioeosinophilic granuloma of the media-
stinum, which is a reactive lesion result-
ing from iatrogenic pneumomediastinum,
akin to reactive eosinophilic pleuritis
{762,1304}. Although both his-
tioeosinophilic granuloma and
Langerhans cell histiocytes feature
histiocytes and eosinophils, the histio-
cytes in the former are confined to the
capsule or septa of the thymus with spar-
A
ing of the parenchyma, the nuclei are
uncommonly grooved, and S-100 protein
and CD1a immunostains are negative.

Somatic genetics
In contrast to pulmonary eosinophilic
granuloma, which in most cases is a non-
neoplastic, reactive process in smokers,
most cases of Langerhans cell histiocy-
tosis occurring in non-pulmonary sites
are believed to be clonal neoplasms, as
demonstrated by X-chromosome inacti-
vation {2149}. Thymic cases have not,
however, been specifically studied.
B
Histiocytic sarcoma and Fig. 3.107 Histiocytic sarcoma. A The neoplastic cells are large, and possess abundant eosinophilic cyto-
malignant histiocytosis plasm. B The tumour cells show granular immunostaining for CD68 (PGM1).

Definition
Histiocytic sarcoma is a malignant proli-
feration of cells showing morphologic (including over 50 cases) {405,774,949, tive for CD45, CD4, CD43, CD45RO and
and immunophenotypic features similar 1140,1596}, there is only a single case HLA-DR; occasionally positive for S100
to those of mature tissue histiocytes. with predominant involvement of the protein; and negative for myeloid mark-
There is expression of one or more histi- mediastinum {949}. There are reports on ers, dendritic cell markers (CD1a, CD21,
ocytic markers without accessory/den- malignant histiocytosis or histiocytic sar- CD35), T lineage-specific markers, B lin-
dritic cell markers. Tumourous masses of coma associated with mediastinal non- eage-specific markers and CD30 {1596}.
acute monocytic leukaemia are exclud- seminomatous germ cells tumours, but
ed. The term malignant histiocytosis is they lack vigorous documentation
sometimes applied for histiocytic sarco- regarding the true histiocytic nature of
ma showing systemic disease, often with the neoplasm {83,473,474,789,1460,
liver, spleen and bone marrow involve- 1461,2246}.
ment.
Histopathology
ICD-O code Histiocytic sarcoma is characterized by a
Histiocytic sarcoma 9755/3 diffuse infiltrate of large cells with volumi-
Malignant histiocytosis 9750/3 nous eosinophilic, and sometimes finely
vacuolated, cytoplasm. The nuclei are
Synonyms round, oval, indented, grooved or irregu-
True histiocytic lymphoma, histiocytic larly folded, often with vesicular chro-
medullary reticulosis (obsolete) matin and small nucleoli. Nuclear pleo-
morphism can be significant.
Epidemiology The diagnosis has to be confirmed by
Among the recent series on histiocytic immunohistochemical staining: positive
sarcoma diagnosed using strict criteria for CD68 and lysozyme; frequently posi-

Histiocytic tumours 235


Dendritic cell tumours J.K.C. Chan
T. Grogan
S.A. Pileri
E.S. Jaffe

Follicular dendritic cell


tumour / sarcoma
Definition
Follicular dendritic cell (FDC) tumour/sar-
coma is a neoplastic proliferation of spin-
dle to ovoid cells showing morphologic
and phenotypic features of follicular den-
dritic cells. The terms tumour and sarco-
ma are both used because of the vari- A B
able cytologic grade and indeterminate
clinical behaviour of these neoplasms.

ICD-O code
Follicular dendritic cell tumour 9758/1
Follicular dendritic cell sarcoma 9758/3

Clinical features
These neoplasms are uncommon, with
only a small number of cases having
been reported to show primary involve- C D
ment of the thymus or mediastinal lymph Fig. 3.108 Follicular dendritic cell sarcoma of the thymus. A Fascicular to storiform growth pattern.
nodes {58,323,482, 560,1571,1596}. The Characteristic irregular clustering of nuclei and sprinkling of small lymphocytes. B This tumour comprises
spindle cells with indistinct cell borders, elongated pale nuclei and small distinct nucleoli. The nuclei
patients are adults with a mean age of 46
appear irregularly clustered. Sprinkling of small lymphocytes. C Membrane immunostaining for CD21 in a
years, being comparable to that of the meshwork pattern. D On the right a component resembling hyaline-vascular Castleman disease.
same tumour occurring in other sites
{323,1571}. However, they differ in show-
ing marked male predominance, but this ovoid, and the lightly eosinophilic cyto- because of the mediastinal location,
may be due to bias from the small num- plasm often exhibits indistinct cell bor- spindle cell growth and lymphocytic infil-
ber of cases. The patients are asympto- ders. The nuclei are elongated or oval, tration. To add to the confusion, follicular
matic, or present with cough, haemopty- with thin nuclear membrane, vesicular or dendritic cell sarcoma can exhibit jigsaw
sis or chest discomfort. granular chromatin, and small distinct puzzle-like lobulation and perivascular
nucleoli. There is often an irregular clus- spaces as commonly seen in thymomas
Etiology and precursor lesions tering of the nuclei, and occasional multi- {359}. In contrast to type A thymoma,
A proportion of cases of follicular den- nucleated tumour giant cells can be there is no focal glandular differentiation,
dritic tumour/sarcoma arise in the setting seen. Some cases can exhibit significant cytokeratin is negative, and follicular
of hyaline-vascular Castleman disease, nuclear pleomorphism, mitotic activity dendritic cell-associated markers are
often through an intermediary phase of and coagulative necrosis. The tumour is expressed.
follicular dendritic cell proliferation out- typically sprinkled with small lympho-
side the follicles {320,323,1186}. Both cytes, which can show clustering around Histogenesis
components of hyaline-vascular Castle- blood vessels. A diagnosis of follicular Follicular dendritic cells of the B-cell folli-
man disease and follicular dendritic cell dendritic cell sarcoma should be con- cle.
tumour/sarcoma may be identified in the firmed by immunohistochemical studies
same tumour mass in the mediastinum (positive for CD21 and CD35, and vari- Prognosis and predictive factors
{482}. ably CD23), and preferably also by ultra- Among 5 patients with mediastinal FDC
structural studies (numerous long slen- tumour/sarcoma with follow-up informa-
Histopathology der cytoplasmic processes and mature tion, two developed pulmonary meta-
Tumours are often large, with a broad. desmosomes). stases after two years, one developed
histologic spectrum. The growth pattern local recurrence at 3 years, and two were
can be storiform, whorled, fascicular, Differential diagnosis alive without evidence of disease after
nodular, diffuse or even trabecular. The Mediastinal follicular dendritic cell sarco- surgery and radiochemotherapy.
individual tumour cells are spindle or ma can be mistaken for type A thymoma

236 Tumours of the thymus - Lymphomas


Interdigitating dendritic cell Histopathology
tumour / sarcoma The tumour shows a fascicular, storiform,
whorled or diffuse growth pattern, com-
Definition prising spindle or plump cells with indis-
Interdigitating dendritic cell sarcoma/ tinct cell borders and abundant
tumour is a neoplastic proliferation of eosinophilic cytoplasm. The nuclei often
spindle to ovoid cells with phenotypic exhibit finely dispersed chromatin and
features similar to those of interdigitating distinct nucleoli. Cytologic atypia is vari-
dendritic cells. able.

ICD-O code Differential diagnosis


Interdigitating dendritic cell tumour The diagnosis should always be con-
9757/1 firmed by immunohistochemical staining,
Interdigitating dendritic cell sarcoma with or without ultrastructural studies
9757/3 (complex interdigitating cell processes
lacking well-formed macula adherens-
Epidemiology, localization and clinical type desmosomes and lacking Birbeck
features granules). The neoplastic cells strongly
Interdigitating dendritic cell sarcomas express S-100 protein, and often show
are very rare, and mediastinal involve- variable weak staining for CD68,
ment is even rarer. The few reported lysozyme, CD4 and CD45. They should
cases have involved the mediastinal be negative for CD1a, follicular dendritic
lymph nodes as a component of dissemi- cell markers (CD21, CD35), myeloperoxi-
nated disease {569,1309,1635,1698, dase, T lineage specific markers, B-cell-
2067}. There is a reported case of medi- specific markers and CD30.
astinal tumour showing hybrid features of
follicular dendritic cells and interdigitat-
ing dendritic cells {499}.

Dendritic cell tumours 237


Myeloid sarcoma and extramedullary A. Orazi

acute myeloid leukaemia

Definition the possibility of a local origin of the bility of a local origin of the myeloid sar-
Myeloid sarcoma is a mass forming neo- tumour should also be considered coma from haematopoietic precursor
plastic proliferation of myeloblasts or cells occurring within the germ cell
immature myeloid cells occurring in an Cytochemistry and immunophenotype tumour should also be considered
extramedullary site. It may occur de novo Cytochemical stains to detect myeloid {1278}.
or simultaneously with acute myeloid differentiation in AML can be applied to
leukaemia (AML), myeloproliferative dis- imprints of biopsy material. Flow cytome- Somatic genetics
orders, or myelodysplastic syndromes, try may demonstrate myeloid antigen AML with t(8;21) has an increased fre-
but may also be the first manifestation of expression. Myeloid associated markers quency of granulocytc sarcomas, as do
leukaemic relapse in a previously treated which that can confirm the diagnosis monocytic and monoblastic leukemias
patient {1518}. Interstitial infiltration of include lysozyme, myeloperoxidase, with 11q23 abnormalities.
myeloid blasts without a nodular mass CD43, CD117, CD68, and CD61. The The presence of genetic abnormalities in
can be termed extramedullary AML. lack of expression of lymphoid associa- myeloid sarcoma, can be detected by
ted antigens helps in the differential reverse transcriptase-polymerase chain
ICD-O code 9930/3 diagnosis versus large cell lymphomas reaction, conventional cytogenetics, or
and lymphoblastic lymphoma. The histo- fluorescence in-situ hybridization stu-
Synonyms chemical stain for chloroacetate esterase dies.
Extramedullary myeloid tumour; granulo- may be helpful in identifying promyelo-
cytic sarcoma; chloroma cytes and more differentiated myeloid Prognosis and predictive factors
elements in differentiated myeloid sarco- Mediastinal myeloid sarcoma is an
Clinical features ma subtypes. aggressive disease. Patients who pre-
Mediastinal myeloid sarcoma has been sented with a primary mediastinal MS
reported in association with a superior Differential diagnosis and were treated by local irradiation only
vena cava syndrome {1643}. Most The major differential diagnosis is with (prior to developing AML), eventually all
mediastinal cases occur simultaneously non-Hodgkin lymphomas, lymphoblastic relapsed as frank leukaemia and died
with AML or are followed by AML shortly. lymphoma and diffuse large cell lym- soon afterwards {369}. In contrast,
Patients who presented with primary phoma; in children, the differential patients who were considered to have
mediastinal granulocytic sarcoma with- includes various metastatic small round AML and given upfront systemic
out concurrent AML, all eventually cell tumours. Cases of myeloid sarcoma chemotherapy achieved better out-
relapsed as frank leukaemia {369}. with prominent sclerosis may closely comes, their prognosis being that of the
mimic sclerosing mediastinal (thymic) underlying leukaemia {369,919}.
Histopathology large B-cell lymphoma. In patients with
The most common type of myeloid sar- mediastinal germ cell tumours, the possi-
coma occurring in the mediastinum is
known as granulocytic sarcoma {2193}, a
tumour composed of myeloblasts and
promyelocytes. The degree of maturation
is variable in different cases. The blastic
subtype is entirely composed of
myeloblasts; in the more differentiated
subtypes, promyelocytes are also pre-
sent {919,2108}. Rare cases composed
of monoblasts (termed monoblastic sar-
coma), can also occur in this location.
Cases associated with acute transforma-
tion of an underlying myeloproliferative
disorder may show foci of trilineage
extramedullary hematopoiesis associa-
ted with the blastic proliferation.
In patients with mediastinal germ cell Fig. 3.109 Myeloid sarcoma (monoblastic). Sclerotic bands divide the neoplasm into irregular alveolar clus-
tumours with mediastinal myeloid sarco- ters and cords. Note the kidney shaped immature nuclei with vesicular or granular chromatin, multiple small
ma or extramedullary myeloid leukaemia, nucleoli, and pale abundant cytoplasm.

238 Tumours of the thymus


Soft tissue tumours of the A. Marx
T.T. Kuo
thymus and mediastinum Ph. Strbel
P.J. Zhang
Y. Shimosato
J.K.C. Chan

A variety of mesenchymal and neuro- Thymolipoma


genic tumours can arise in the media-
stinum. For those that occur in the anteri- Definitions
or mediastinum, it is often difficult to Thymolipoma is a well-circumscribed
ascertain whether they are of thymic ori- tumour consisting of mature adipose tis-
gin or derived from other mediastinal sue with interspersed islands of non-neo-
constituents {1529}. An exception is thy- plastic thymic tissue.
molipoma, since the intimate admixture
of lipomatous tissue with thymic ICD-O code 8850/0
parenchyma strongly supports its thymic
derivation. Some sarcomas arise in Synonym Fig. 3.110 Thinly encapsulated thymolipoma in a
mediastinal germ cell tumours {1230, Thymolipomatous hamartoma 6-year-old male child. The cut surface is yellow,
1932}. bulging, and lobulated, resembling lipoma. From
Epidemiology Y. Shimosato and K. Mukai {1808}.
Principles of the classification Thymolipomas are rare tumours (about
The classification of mesenchymal and 80-100 published cases) that may occur
neurogenic tumours of the thymus and at any age, but are most commonly quent (about 7% of cases {1352}), but sin-
mediastinum follows the WHO classifica- encountered in young adults (10-30 gle cases with other manifestations such
tions of tumours of soft tissues and bone years, mean age 33 years) {1352,1683}. as aplastic anaemia {113} and Graves
{590} and of tumours of the nervous sys- There is no sex predilection. disease {147} have been reported.
tem {1026}. Since thymolipoma is a
unique thymic tumour with a predomi- Localization Macroscopy
nant mesenchymal component, it is All documented cases arose in the ante- The size of thymolipoma ranges from 4 to
described and discussed here in more rior mediastinum. over 30 cm {1352}. The tumours are yel-
detail. low, soft, fairly well circumscribed with
Clinical features scattered white streaks or focal solid
Epidemiology Thymolipomas may remain asymptomatic areas on the cut surface.
Mesenchymal and neurogenic tumours for a long period. The majority of cases
of the thymus and mediastinum are all are incidental findings on routine chest Histopathology
very rare, constituting less than 10% of radiographs and may simulate car- Histologically, they consist of abundant
all mediastinal neoplasms. Almost all diomegaly {44,1818} or other mediastinal mature adipose tissue admixed with
neurogenic neoplasms of the media- neoplasms. Thymolipomas may become areas containing remnants of thymic tis-
stinum occur in the posterior media- symptomatic either due to the size of the sue. The fat cells show no cytologic atyp-
stinum. lesion, or, less frequently, due to associat- ia or mitotic activity {1352}. The thymic
ed autoimmune phenomena. Among tissue component may vary from strands
Clinical features these, myasthenia gravis is the most fre- of atrophic thymic epithelium to large
Mesenchymal and neurogenic tumours
of the anterior mediastinum or thymus
are frequently detected incidentally, but
may present as cough, chest pain, pleu-
ral effusion, respiratory distress or the
superior vena cava syndrome. Hypogly-
caemia is a rare complication of solitary
fibrous tumour {2164}. Tumours in the
middle and posterior mediastinum,
which are mostly neurogenic neoplasms,
often produce symptoms due to com-
pression of large vessels, heart, nerves A B
or spinal cord. Fig. 3.111 Thymolipoma. A Thymolipoma showing a delicate but distinct fibrous capsule and thin septae of
atrophic thymic tissue. B Strands of thymic epithelial cells within thymolipoma. The lymphocyte content is
virtually absent in this case, possibly related to the age of the patient. The content of fibrous tissue may be
extensive: Thymofibrolipoma {1372). Note single melanocytes scattered among thymic epithelial cells.

Thymolipoma 239
areas containing inconspicuous thymic authors favour a benign neoplasm {69, Lipoma is the most common benign mes-
parenchyma containing numerous, often 763,1352}. An origin from specialized enchymal tumour of the mediastinum
calcified, Hassalls corpuscles {1352}. thymic stroma has been postulated {69, {1529,1932}. In contrast to thymolipoma
Myoid cells are present {907}. The thymic 763}. it does not contain foci of thymic
compartment may show single lymph fol- parenchyma. Other rare benign lipoma-
licles. Prognosis and predictive factors tous tumours are lipoblastoma/lipoblas-
There have been no reports on recur- tomatosis {517}, hibernoma {31}, and
Differential diagnosis rences, metastasis or tumour-related angiolipoma {1031}.
Diagnosis of thymolipoma is usually not deaths, and local excision is curative.
problematic. However, due to the large
size of some lesions, careful sampling is Thymoma in thymolipoma Liposarcoma
necessary in order to rule out the possi- There is a single case report about thy-
bility of atypical or malignant areas. In moma within a thymolipoma occurring in ICD-O code 8850/3
rare cases, thymomas may arise within a 67 years old female patient without
thymolipomas {69}. Histologically, the myasthenia gravis {69}. The thymoma Liposarcoma is the most common sarco-
main differential diagnoses include lipo- was classified as cortical (type B2). ma in the anterior mediastinum, and
ma of the thymus (no thymic epithelial There was no recurrence within 10 years some cases may represent thymic stro-
component) and mediastinal liposarco- after radical surgery. We observed an mal sarcomas {801,938}, i.e. malignant
mas (scattered lipoblasts). almost identical case. counterparts of thymolipoma (thymoli-
posarcoma) {1030}. Mediastinal liposar-
Histogenesis Lipoma coma usually occurs in adults (mean age
The pathogenesis and biological nature of 43 years), and is rare in children {357}. In
thymolipoma are controversial, but most ICD-O code 8850/0 some cases, there is synchronous

A B

C D
Fig. 3.112 Thymoliposarcoma. A Macroscopy of a recurrent tumour (2 years after first treatment): well circumscribed and partially encapsulated tumour from the
anterior mediastinum. B Bland looking well differentiated (lipoma-like) liposarcoma adjacent to thymic remnant tissue with some lipoblasts (arrows).
C Multinucleated neoplastic lipoblasts and a heavy inflammatory reaction in the more fibrotic stroma of the recurrent tumour. D Higher magnification demonstrating
multinucleated tumour cells and the inflammatory reaction.

240 Tumours of the thymus - Soft tissue tumours


involvement of other sites such as the Table 3.13
retroperitoneum. Comparison of immunophenotype of solitary fibrous tumour (SFT) with other spindle cell tumours of the thy-
Well-differentiated liposarcoma is the mus and mediastinum.
most frequent subtype (60% of cases),
Diagnosis CD34 Bcl-2 CD99 CK1 S100 Desmin
including lipoma-like, inflammatory
{1030} spindle cell {1138,1835}, leiomy- SFT +++ +++ +++ - - -/+
omatous and dedifferentiated variants
{601}, followed by myxoid liposarcoma Type A Thymoma - - -2 +++ - -
(28%), and other subtypes (12%) {1030},
such as the highly aggressive pleomor- Spindle Cell Liposarcoma +++ + +/- - + -
phic liposarcoma {513}. In some cases,
the presence of heavy lymphoid infiltra- Synovial Sarcoma - +++ +/- +/++ - -
tion may result in mimicry of lymphoma or
Fibromatosis - - - - - -
an inflammatory process {1030}.
Like the same tumour occurring in other Leiomyoma - - -/+3 - - +++3
sites, mediastinal myxoid liposarcoma
shows TLS/FUS-CHOP fusion transcripts Nerve Sheath Tumour -4 +++ > - - -5 +++6 -
{1762}.
The tumours are curable by surgical 1CK, cytokeratin; 2Immature T-cells may be +; 3An identical phenotype is observed in some angiomatoid
excision in some patients {47,256, fibrous histiocytomas; 4S100-negative dendritic cells may be positive {1000,2121}; 5Rare glandular
357,740}, but recurrences develop in up structures may be +; 6Malignant peripheral nerve sheath tumours may be negative.
to 32% of cases after a mean interval of
36 months. Myxoid liposarcoma has a
worse prognosis than well-differentiated Histopathology atypia and coagulative necrosis occur in
liposarcoma {1030}. Solitary fibrous tumour (SFT) of the more than 50% of mediastinal SFT, sug-
mediastinum is identical to SFT of the gesting a high propensity for sarcoma-
pleura in terms of morphology and tous transformation {637,772,2164}. In
Solitary fibrous tumour immunophenotype [CD34+(>90%), such cases there is sometimes an identi-
CD99+ (>90%), bcl2+ (80-90%), cytok- fiable component of bland-looking SFT.
Definition eratin-] {772,791,999,1384,2063}.
Solitary fibrous tumour (SFT) is an In contrast to the usually bland-looking Differential diagnosis
uncommon, locally aggressive mes- pleural or thyroid SFT {1674,2164}, high The typical collagenous stroma around
enchymal neoplasm with highly variegat- mitotic activity (> 1-4/10HPF), cytologic individual tumour cells and the charac-
ing morphologic appearance, character-
ized by two basic elements encountered
in varying proportions: a solid spindle
cell component and a diffuse sclerosing
component.

ICD-O code 8815/0

Epidemiology
Mediastinal SFT is a rare tumour of adults
(28-78 years of age) {999}. Mediastinal
SFT on average account for 15% of all A B
SFT, and about 25% of extrapleural SFT
{772,791,999,1384}.

Localization
Some mediastinal SFT may represent
extensions from pleural SFT, but others
arise from the mediastinal (including
thymic) stroma {1685}.

Macroscopy C D
Mediastinal SFT can reach a large size, Fig. 3.113 Solitary fibrous tumour. A Characteristic unevenly distributed celluarity: hypocellular spindle cell
of up to 16 cm {2164}. area (on the right side), and a cellular area on the left. Note the inconspicuous vessels. B Patternless archi-
tecture composed of spindle cells in a haphazard arrangement. C Cellular area in the same tumour as
shown B. Bland looking spindle cells with inconspicuous cell borders and oval nuclei. D Characteristic
strong cell membrane CD34 expression in almost all tumour cells.

Solitary fibrous tumour 241


A

A B B
Fig. 3.114 Embryonal rhabdomyosarcoma. A Embryonal rhabdomyosarcoma of the mediastinum. B Desmin Fig. 3.116 Alveolar rhabdomyosarcoma. A Solid
expression with occasional cells showing cross-striations. variant in the anterior mediastinum in a 2 months-
old girl. Primitive round cells are arranged in solid
sheets, with focal alveolar pattern. Tumour cells
have a high N:C ratio and dense chromatin, many
teristic immunophenotype distinguish (>1/10 HPF) and necrosis herald an
apoptotic bodies and mitoses. B RT-PCR analysis
SFT from type A thymoma, synovial sar- aggressive course.
of solid variant of alveolar rhabdomyosarcoma
coma, low-grade spindle cell liposarco- (RMS) in a 2 months old girl (same case as A). Note
ma, leiomyomatous tumours and neural Rhabdomyosarcoma (RMS) the 409 bp PAX3-FKHR fusion product in frozen
tumours {1908}. tumour tissue (lower panel). Abbreviations: B,
ICD-O code 8900/3 blank; NC, negative control (tonsil); PC, positive
Somatic genetics control [t(2;13) positive RMS]; S1, specimen 1, cur-
Genetic findings in mediastinal SFT have RMS most commonly arise in thymic rent case; S2-S3, two other RMS specimens nega-
not been reported. germ cell tumour {1932}, or may occur as tive for t(2;13); WT, wild type FKHR segment (324bp;
a component of sarcomatoid thymic car- upper panel). Molecular size markers (ladder) on
the right side in the upper panel. For RT-PCR proto-
Prognosis and predictive factors cinoma {1509}, but can also rarely arise
col see refs {114,658}.
Primary mediastinal SFT are more de novo. Embryonal, pleomorphic and
aggressive than pleural or thyroid SFT alveolar RMS of the thymus, one with
{1674}. Local recurrences and tumour- unusual clear cell features, have been
related deaths occur in about 50% and reported {135,1922,1932}. The tumours has been observed in an example of
25% of cases, respectively {2164}. SFT can occur in adults and children, and fol- mediastinal alveolar RMS of the solid
may recur late (13 years after surgery) low a very aggressive clinical course variant {1742}. Rhabdomyomatous thy-
and can rarely develop intrathoracic {135,1922}. momas {1351,1730} with myoid cells,
metastases {2164}. High mitotic activity The t(2;13)(q35; q14) translocation should not be mistaken for RMS.
resulting in a PAX3/FKHR fusion gene

A B C
Fig. 3.115 Synovial sarcoma (SS). A Monophasic spindle cell SS focally with gaping vessels resembling haemangiopericytoma. B Spindle cell component calcify-
ing SS (30% of all SS cases ). Unusual biphasic type: solid epithelial cords and few spindle cells. C Round cell component. High power of the solid epithelial com-
ponent (if single component: = "monophasic epithelial SS").

242 Tumours of the thymus - Soft tissue tumours


A B
Fig. 3.117 A Capillary haemangioma of the anterior mediastinum. The tumour forms distinct lobules separated by a loose stroma. B Epithelioid haemangioen-
dothelioma. Cords of tumour cells with abundant eosinophilic cytoplasm. Occasional tumour cells show vacuolation. Some primitive vascular channels contain
blood. This case also shows interspersed osteoclastic giant cells.

A B

C D
Fig. 3.118 Angiosarcoma. A The tumour forms anastomosing channels, and the lining cells show significant nuclear pleomorphism and atypia. B Angiosarcoma can
show a solid growth, obscuring the vascular nature of this malignant tumour. C Typical immunostaining of tumour cell membranes for CD31. D Immunostaining of
remnant thymic epithelial cell network for cytokeratin 19.

Rhabdomyosarcoma 243
Synovial sarcoma (SS)
ICD-O code 9040/3

Several cases of SS have been reported


{871,2033,2163}. The tumours usually
occur in adults but rarely in children {871}
and manifest by pain, dyspnoea or supe-
rior vena cava syndrome. Most cases fol- A B
lowed an aggressive clinical course, with
Fig. 3.120 Angiomatoid fibrous histiocytoma of the central mediastinum involving the ascending aorta and
3 of 5 patients dying of tumour on follow- thymus. A The tumour typically comprises spindle cells that may raise the differential diagnosis of leiomy-
up of 10 months to 4 years. Detection of oma. In contrast to leiomyoma, AFH is typically accompanied in the tumour periphery by a dense inflamma-
SYT-SSX chimeric RNA transcripts, result- tory infiltrate composed of lymphocytes and plasma cells. B Desmin positivity in the neoplastic cells.
ing from the t(X;18) translocation is often Inflammatory cells are negative.
essential to distinguish SS from mesothe-
lioma, sarcomatoid (thymic and other)
carcinomas, malignant peripheral nerve thymic germ cell tumour {1230,1356}) dle cell features, and half of the cases
sheath tumour with glandular differentia- have also been described {962,1921, show desmin expression. However, it is
tion, germ cell tumour-associated sarco- 1932} often accompanied by an infiltrate of lym-
mas or metastases {71,2033}. phocytes and plasma cells, particularly in
the peripheral portion. Frequent coex-
Vascular tumours Leiomyomatous tumours pression of CD99, CD68 and EMA, and a
characteristic t(12;16)(q13; p11) translo-
Mediastinal lymphangioma is a common Leiomyomas, probably derived from the cation generating FUS/ATF1 fusion tran-
mediastinal tumour in children {1932}. aortic arch {1789}, and even rarer, scripts distinguish AFH from leiomyoma
Hemangiomas of the cavernous, and less leiomyosarcomas {96,1370} have been and leiomyosarcoma {590}.
frequently, capillary subtype have been reported in the mediastinum, including its
reported and may be complicated by the anterior compartment. They should be
Kasabach-Merritt syndrome {838,1353, distinguished from liposarcomas with
1932}. Hemangiopericytoma, epithelioid leiomyomatous differentiation {601}, and
hemangioendothelioma and angiosarco- angiomatoid fibrous histiocytomas (AFH)
ma (the latter usually arising from a of the mediastinum. AFH can exhibit spin-

A B C

D E F
Fig. 3.119 Paraganglioma. A Macroscopy of a well encapsulated paraganglioma of the anterior mediastinum with central scar formation. B The tumour comprises
packets of cells with abundant eosinophilic cytoplasm, traversed by a delicate vasculature. C Low power histology showing the "Zellballen-Pattern" of a mediasti-
nal paraganglioma. D High power of the same case shows marked variability of cell and nuclear size. E Typical strong cytoplasmic granular immunostaining for
synaptophysin. F Immunostaining for S100 protein reveals the delicate sustentacular cells that wrap around the tumour cell packets.

244 Tumours of the thymus - Soft tissue tumours


A B
Fig. 3.121 A Ganglioneuroma of the posterior mediastinum. Clusters of ganglion cells merge into a spindle cell component that resembles neurofibroma or schwan-
noma. Calcification is common. By definition, there should not be identifiable neuroblasts. B Differentiating neuroblastoma of the posterior mediastinum with abun-
dant neuropil. The latter should not be confused with the schwannian stroma required for a diagnosis of ganglioneuroblastoma.

Neurogenic tumours ically show a nesting pattern associated Other rare neoplasms
with a prominent vasculature. The tumour
Neurogenic tumours of the mediastinum cells are immunoreactive for synapto- Other thymic/mediastinal soft tissue
occur almost exclusively in the middle physin, and S100 protein positive susten- tumours include Ewing sarcoma which
and posterior compartments, where they tacular cells are often demonstrable usually extends into the mediastinum from
constitute the most frequent neoplasms. around tumour cell nests. In contrast to the thoracic wall {690}, malignant rhab-
However, benign schwannomas {1597}, neuroendocrine carcinomas, paragan- doid tumour {166,1160,1691}, inflammato-
and malignant peripheral nerve sheath gliomas do not form ribbons or rosette- ry myofibroblastic tumour (inflammatory
tumours, including malignant Triton like structures, and cytokeratin is usually pseudotumour) {422,467}, calcifying
tumours {1525} have also been negative. fibrous tumour {1443}, giant cell angiofi-
described in the anterior mediastinum, Tumours related to the sympathetic gan- broma {636}, elastofibrolipoma {455},
mainly in patients with neurofibromatosis glia include neuroblastoma, ganglioneu- desmoid fibromatosis {1036}, benign
{1726,1851}. roblastoma and ganglioneuroma. They mesenchymoma {2054}, rhabdomyoma
About 20% of mediastinal paragan- occur almost exclusively in the posterior {1315}, alveolar soft part sarcoma {593}
gliomas occur in the anterior compart- mediastinum, although neuroblastomas and malignant fibrous histiocytoma
ment {1365} and they may be pigmented {70} and ganglioneuroblastomas have {344,1932}.
{1350}. They tend to occur in older indi- also been rarely described in the thymus Primary malignant melanoma {42,642,
viduals (mean age 46 years). The {76,1964,2141}. In fact, neuroblastoma is 1804,2088} probably arises from thymic
patients are asymptomatic, or present the most common malignant tumour of nevus cell aggregates {642,1552}. Other
with compression symptoms, or rarely the posterior mediastinum in young chil- rare tumours include meningioma {553,
with Cushing syndrome {1548}. Posterior dren. Ganglioneuroblastoma and gan- 2150}, osteosarcoma {454,739,888},
mediastinal paragangliomas tend to glioneuroma occur mostly in adults. chondrosarcoma {1592}, giant cell
occur in younger patients (mean age 29 Primary ependymoma of the posterior tumour {622}, chordoma {32,1675,1910},
years), and about half of the cases have mediastinum in adults, is typically asso- myelolipoma {1008,1706,1884}, and
hypertension or other symptoms due to ciated with a prolonged indolent course extramedullary haematopoietic tumours
release of catecholamines by the {503,2153}. {449,834,1366,1400,1481,1788}.
tumours {1350}. They recur locally and
metastasize in 55% and 26% of cases,
respectively {1123}. Paragangliomas typ-

A B
Fig. 3.122 Fibromatosis (desmoid tumour) of the Fig. 3.123 A Ewing sarcoma of the mediastinum with B CD99 (MIC-2) expression.
thoracic wall and pleura.

Neurogenic tumours 245


Ectopic thyroid and J.K.C. Chan

parathyroid tumours

Ectopic thyroid tumour Histogenesis Genetics of Tumours of Endocrine


Thyroid tissue that has aberrantly migra- Organs). Parathyroid adenomas are cir-
Definition ted to the mediastinum during embryo- cumscribed or thinly encapsulated
Ectopic thyroid tumour is a thyroid neo- logic development is the cell of origin for tumours comprising sheets, cords and
plasm that occurs in sites other than the the ectopic thyroid tumours in the medi- acini of polygonal cells traversed by a
cervical thyroid gland proper. astinum. delicate vasculature. There is often a
mixture of tumour cells with clear, lightly
eosinophilic and oxyphilic cytoplasm.
Thyroid tumours occurring in the medi- Ectopic parathyroid tumour Some tumours have abundant inter-
astinum are often of cervical thyroid spersed adipose cells (lipoadenomas)
gland origin with extension into the medi- Definition {1444,2167}. Mitotic figures are absent or
astinum. Ectopic thyroid tumours arising Ectopic parathyroid tumour is a parathy- rare, and focal nucleomegaly is accept-
in the mediastinum without connection to roid cell neoplasm occurring in sites able. Parathyroid carcinomas often show
the cervical thyroid gland are very rare. other than the usual locations of the capsular or vascular invasion, sclerotic
They are either discovered incidentally, parathyroid glands in the neck {1889}. bands, and mitotic figures. If there are
or present with symptoms referable to a uncertainties whether a neoplasm is of
mediastinal mass. The nomenclature and Epidemiology, clinical features parathyroid origin, positive immunostain-
diagnostic criteria of these thyroid Approximately 10-20% of all parathyroid ing for parathyroid hormone would pro-
tumours should follow those of the World adenomas (including lipoadenomas) vide a strong support for the diagnosis.
Health Organization classification of occur in the mediastinum, most com-
tumours of endocrine organs {9}. monly the anterosuperior mediastinum in Histogenesis
Follicular adenoma and papillary carci- the vicinity or within the thymus gland Ectopic or supernumerary parathyroid
noma are the commonest, but other {376,399,1444,2103,2141}. The patients gland in the anterosuperior mediastinum
tumour types have also been described, present with symptoms due to hyper- is the cell of origin for the ectopic
such as follicular carcinoma, oncocytic parathyroidism. Ectopic parathyroid car- parathyroid tumours. Such a localization
(Hrthle cell) carcinoma and poorly dif- cinomas of the mediastinum are very for the parathyroid gland is not surprising
ferentiated insular carcinoma {507,966, rare, and they may or may not be func- since the inferior parathyroid glands
1191,1328,1527,1889,2133}. If there are tional {990,1412,1627}. share a common origin with the thymus
uncertainties as to whether the tumour is from the third branchial pouch {2141}.
of thyroid origin, positive immunostaining Histopathology
for thyroglobulin would provide a strong The nomenclature and diagnostic criteria
support for the diagnosis. Information on for ectopic parathyroid tumours should
the behaviour of these tumours is limited, follow those of the World Health
but it is likely that the outcome is similar Organization Classification of endocrine
to comparable stage tumours occurring tumours (see World Health Organization
in the cervical thyroid gland {2133}. Classification of Tumours: Pathology and

A B
Fig. 3.124 Ectopic papillary thyroid carcinoma of Fig. 3.125 Ectopic parathyroid adenoma of the anterior mediastinum. A The tumour cells form packets and
the anterior mediastinum. The tumour comprises acini, separated by a delicate vasculature. Many clear cells are evident. B Positive immunostaining for
papillae lined by cells with overlapping and pale parathyroid hormone provides confirmation that the tumour is of parathyroid origin.
nuclei.

246 Tumours of the thymus - Ectopic tumours


Metastases to thymus and H.K. Mller-Hermelink
Ph. Strbel
anterior mediastinum A. Zettl
A. Marx

Definition
Malignant tumours that metastasize to
the thymus or anterior mediastinum from
distant primary tumours. Neoplasms that
extend directly from adjacent organs or
tissues are also included in this category.

The most common primary tumours


involving these sites are lung, thyroid,
breast and prostatic carcinomas {948, A B
1188,1287,1288,1305}, while melanoma Fig. 3.126 Metastases to thymus and anterior mediastinum. A Summary of recurrent genetic gains and loss-
and various sarcomas (liposarcoma, es as determined by CGH discriminating between squamous cell carcinomas of the thymus, lung and head
osteosarcoma, rhabdomyosarcoma, & neck region. There is considerable overlap between the carcinomas arising in the lung and head & neck.
Kaposi sarcoma and malignant fibrous By contrast, the major genetic aberrations of thymic carcinomas are not shared with lung and head & neck
histiocytoma) are rare primary tumours carcinomas. B Diagnostic value of CGH-based genetic profiles for the distinction between squamous cell
{33,702,843,1852,1865}. carcinomas of the thymus and mediastinal metastases of primary lung and head and neck tumours.
Percentages indicate the probabilities for a primary lung or head and neck carcinoma in the presence of
The distinction between squamous and
highly discriminating genetic alterations {188,1267,1866,2238}.
neuroendocrine carcinomas of the thy-
mus and mediastinal metastases with
this differentiation can be difficult. In
about 50% of carcinomas, morphological
and immunohistochemical features can
clarify the thymic derivation, while clinical
staging procedures are required to clari-
fy the derivation of the other cases. The
different genetic characteristics of carci-
nomas of the thymus {896,2238,2242}
compared to those of lung and the head
and neck region {188,1582,1585,1866}
are of diagnostic value.
Clinical data is also necessary to distin-
guish primary thymic melanomas {42,
642,1804,2088} or sarcomas {256,1742,
1932} from metastasis with a respective
differentiation.
Fig. 3.127 Metastasis of an adenocarcinoma of the rectum to the thymus. Note the formation of thymic cyst
adjacent to and infiltrated by the metastatic tumour.
Table 3.14
Morphological and immunohistochemical criteria for the differential diagnosis of features of primary thymic carcinomas from metastases to the anterior medi-
astinum arising from carcinomas of the lung and head and neck region.

Tumour Primary of the thymus Primary of lung or head and neck

Squamous cell, basaloid, lympho- Lobular growth pattern 70% Lobular growth pattern rare
epithelioma-like carcinoma Perivascular spaces 50% Perivascular spaces very rare
CD5 expression 50% CD5 not expressed
CD70 expression 50% CD70 not expressed
CD117 expression 40-100%1 CD117 not expressed

Neuroendocrine carcinoma2 TTF-1 expression absent3 TTF-1 expression frequent

1Strbel et al. in a series of 34 thymic carcinomas (unpublished) 2Oliveira et al, 2001 {1513}; Pomplun et al. 2002 {1609}; 3Muller-Hermelink et al. in a series of 15 neuro-

endocrine carcinomas (unpublished).

Metastases to thymus and anterior mediastinum 247