SKIN PATHOLOGY

EDITED BY

Dr. JUSUF FANTONI

SpPA,MScPath (Glasg)

Epidemiology
Most common human cancer

600,000 to 800,000 cases per year in U.S.

Male:Female 2-3:1 80% arise in head and neck SCCa over 60 years old BCCa over 40 years old

Etiology
Ultraviolet radiation

ethnicity
ionizing radiation exposure chemical exposure - arsenic burns, scarring immunosuppression

Syndromes
Xeroderma pigmentosum

nevoid basal cell syndrome

albinism epidermodysplastic verrucoformis epidermolysis bullosa dystrophica dyskeratosis congenital

Skin
Largest organ

major functions

protection sensation thermoregulation metabolic

Skin structure
Epidermis

dermis
hypodermis epidermal appendages

Skin Histology
Stratum corneum

stratum lucidum
stratum granulosum stratum spinosum

stratum basale

DISORDERS OF PIGMENTATION and MELANOCYTES

VITILIGO Vitiligo is a common disorder characterized by partial or complete loss of pigment producing melanocytes within the epidermis. All ages and races are affected, but lesions are most noticeable in darkly pigmented individuals. Clinical lesions are asymptomatic, flat, welldemarcated macules and patches of pigment loss; their size varies from few to many cnetimeters. Vitiligo often involves the hands and wrists, axillae and perioral; periorbital and anogenital skin

Morphology

On histologic examination , vitiligo is indistinguishable from normal skin. However, it is characterized by loss of melanocytes. This is in contrast to some forms of albinism in which melanocytes are present but melanin pigment is not produced because of a lack of or defect in tyrosinase
Pathogenesis

Theories include: (1) autoimmunity, (2) neurohumoral factors toxic to melanocytes and released by nearby nerve endings, and (3) self-destruction of melanocytes by toxic intermediates of melanin synthesis.

Melanocytic Nevus ( Pigmented Nevus, Mole )

Most of us have at least a few moles. Clinically, common acquired melanocytic nevi are tan to brown, uniformly pigmented, small ( usally < 6 mm across), flat (macules) to elevated ( papules ) with well-defined rounded borders.
Morphology. Melanocytic nevi are initially formed by melanocytes that have been transformed from highly dendritic single cells normally intersperesed among basal keratinocytes to round cells that grow in aggregates, or nests. along the dermoepidermal junction. Nuclei of nevus cells are uniform and rounded in contour, contain inconspicuous nucleoli, and show little or no mitotic activity. Such lesions are believed to represent an early developmental stage in melanocytic nevi and are called Junctional nevi.

Eventually, most junctional nevi grow into the underlying dermis as nests or cords of cells ( Compound nevi ); in older lesions, the epidermal nests may be lost entirely to form pure Intradermal nevi. Clinically, compound and dermal nevi are often more elevated than junctional nevi. Progressive growth of nevus cells from the dermoepidermal junction into the underlying dermis is accompanied by a process termed maturation. Less mature, more superficial nevus cells are larger, tend to produce melanin, and grow in nests; more mature, deeper nevus cells are smaller, produce little or no pigment and grow in cords. The most mature nevus cells may be found at the deepest extent of lesions where they often acquire fusiform contours and grow in fascicl;es resembling neural tissue.

Malignant Melanoma

is a relatively common neoplasm, mostly arise in the skin; other sites of origin include the oral and anogenital mucosal surfaces, esophagus, meninges and notably the eye. Sunlight appears to play an important role in the development of skin ma;ignant melanoma. For example, men commonly develop the tumor on the upper back, whereas women have a relatively high incidence on both the back and the legs. Lightly pigmented individuals are at higher risk. Othe predisposing factors include : the presence of a preexisting nevus (dysplastic nevus), hereditary factors, or exposure to certain carcinogens.

Clinical Features.
Malignant melanoma of the skin is ususally asymptomatic, although itching may be an early manifestation. The majority of lesions are greater than 10 mm. The most important clinical sign of the disease is change in color, size, or shape in a pigmented lesion. On occasion, zones of white or flesh-colored hypopigmentation are also present. The clinical warning signs of melanoma are : (1) enalrgement of a pre-existing mole, (2) itching or pain, (3) development of a new pigmented lesion during adult life, (4) irregularity of the borders, (5) variegation of color within a pigmented lesion. Growth Patterns and Morphology Simply stated, radial growth indicates the tnedency of a melanoma to grow horizontally within the epidermal and superficial dermal layers, often for a prolonged time. During this stage of growth, melanoma cells do not have the capacity to metastasize., i.e. Lentigo maligna, superficial spreading and acral / mucosal lentiginous.

Individual melanoma cells are usually larger than nevus cells. They contain large nuclei with irregular contours and prominent nucleoli. These cells proliferate as poorly formed nests or as individual cells at all levels of the epidermis The nature and extent of the vertical growth phase determine the biologic behaviour of malignant melanoma.

Benign Epithelial Tumors Seborrheic Keratosis Occur frequently in middle-aged or older individuals. They arise spontaneously and may become numerous on the trunk; also the extremities, head, and neck may also be involved.

They appear as round, flat, coinlike, waxy plaques that vary in diameter from mm to several cms. They are uniformly tan to dark brown and show a velvety to granular surface.
Morphology Exophytic and demarcated sharply from the adjacent epidermis. They are composed of sheets of small cells that most resemble basal cells of the normal epidermis. Variable melanin pigmentation is present within these basaloid cells. Exuberant keratin production (hyperkeratosis occurs) and small keratin-filled cysts (horn cysts ) and invaginations of keratin into the main tumor mass ( invagination cysts ) are characteristic features. Interestingly, when seborrheic keratoses become irritated and inflamed, they undergo squamous differentiation and characterized by foci of whorling squamous cells resembling eddy currents in a stream. When sborrheic keratoses involve the epithelium of hair follicles, they may grow in an endophytic ( downward) fashion, and show the effects of inflammation; such lesions are termed : Inverted follicular keratoses

Premlignant and Malignant Epidermal Tumors

ACTINIC KERATOSIS Before the development of overt malignancy of the epidermis, a series of progressively dysplastic changes occur. Because this dysplasia is usualy the result of chronic exposure to sunlight and with build-up excess keratin , they are calleg actinic keratoses. Other causes : exposure to ionizing radiation, hydrocarbons and arsenicals. Ususally less than 1 cm, tan-brown, red, or skincolored, rough, sandpaper-like consistency. Some produce so much keratin that a cutaneous horn develop ( resemble the horn of animals ). Skin sites commonly exposed to sun ( face, arms, dorsum of hands ) are usually affected.

Morphology Cytologic atypia is seen in the lower-most layers of the epidermis and may be associated with hyperplasia of basal cells, or alternatively, with early atrophy of the epidermis. Thwe atypical basal cells usually have evidence of dyskeratosis with pink or reddish cytoplasm. Intercellular bridges are present, ( in contrast to basal cell carcinoma ). The dermis contains thickened, blue-gray elastic fibers ( elastosis) a probable result of abnormal dermal elastic fiber synthesis by sun damaged fibroblasts within the superficial dermis. The stratum corneum is thickened, and unlike in normal skin, nuclei in the cells in this layer are often retained ( = parakeratosis ).

Squamous Cell Carcinoma ( S C C ) = the second most common tumor arisin on sun-exposed aites in older people.

Except for lesions on the lower legs, these tumors have a higher incidence in men. Other factors : industrial carcinogens ( tars and oils ), chronic ulcers and draining osteomyelitis, old burn scars, ingestion of arsenicals, ionizing radiation ,and (in the oral cavity) tobacco and betel nut chewing.
Morphology S C Cs that have not invaded through the basement membrane is termed in situ carcinoma. When the oral mucosa is involved, a zone of white thickening may be seen ( caused by a variety of disorders ) referred to clinically as leukoplakia. S C C is characterized by cells with atypical ( enlarged and hyperchromatic ) nuclei ast all levels of the epidermis. When these cells break through the basement membrane, the process has become invasive. They are rangin from well-differentiated to poorlydiffenrentiated

Basal Cell Carcinoma ( B C C )

= slow-growing tumors that rarely metastasize. Tendency to occur at sites of chronic sun exposure and in lightly pigmented people. B C C rises sharply with immunsuppresion and in patients with inherited defects in DNA repair. Clinically, as pearly papules often containing prominent, dilated subepidermal blood vessels ( telangiectasias ). Some contain melanin. Advanced lesions may ulcerate, extensive local invasion of bone or facial sinuses may occur after many years of neglect (=rodent ulcers )

Morphology

Tumor cells resemble those in the normal basal cell layer of the epidermis. They arise from the epidermis or follicular epithelium and do not occur on mucosal surfaces. Two patterns are seen : multifocal growths originating from the epidermis and extending over several square cms or more fo skin surface and nodular lesions growing downward deeply into the dermis as cords and islands of variably basophilic cells with hyperchromatic nuclei, embedded in a mucinous matrix, and often surrounded by many fibroblasts and lymphocytes. The cells forming the periphery of the tumor cell islands tend to be arranged in approximately parallel alignment ( palisading ) The stroma shrinks away from the epithelial tumor nests, creating clefts or separation artifacts that assist in differentiating basal cell carcinomas from certain appendage tumors also characterized by proliferation of basaloid cells ( e.g. trichoepithelioma )/.

Actinic Keratosis
Most common

progress to malignancy

in 5-20% cryotherapy, shave excision, 5-FU, TCA

Actinic Keratosis

Keratoacanthoma
Solitary or multiple

rapid growth
1 to 2.5 cm ulcer with keratinous

material spontaneous resolution observe, 5-FU, Mohs'

Keratoacanthoma

Bowens Disease
Carcinoma in situ

erythematous plaque
irregular borders non-exposed areas with

arsenic exposure

Bowens Disease

Basal Cell Carcinoma

Raised, with pearly

border prominent vasculature ulceration nodular most common

Pigmented Basal Cell

Produce brown pigment

often mistaken for

melanoma behave similar to nodular

Superficial Basal Cell

Scaly patches

irregular borders
extremities, less

common in head and neck

Morpheaform Basal Cell

Indistinct margins

flat macule
scar-like aggressive behavior

difficult to treat - Mohs

surgery

Morpheaform Basal Cell

Basal Cell Carcinoma

Cells resemble those of

stratum basale connective tissue stroma peripheral palisading stromal retraction

Keratotic Basal Cell

Differentiation toward

hair structures undifferentiated cells

Cystic Basal Cell

Differentiation towards

sebaceous glands cystic spaces within tumor

Adenoid Basal Cell

Pseudo-glandular

formation strands of epithelial cells in lace-like patterns

Basal Cell Biologic Behavior

Dependent upon stroma

locally invasive
spread along resistant planes metastasis rare - 0.0028% to 0.1%

adenoid and keratotic types more likely

Basal Cell Biologic Behavior

Embryonic fusion planes at risk for deep

invasion

inner canthus philtrum chin nasolabial groove pre-auricular retro-auricular sulcus

Squamous Cell Carcinoma

Sun exposure

erythematous,

ulcerated, crusting friable adjacent induration actinic vs. de novo

Squamous Cell Metastasis

Actinic lesions 3% to

5% de novo 8% scar or chronic inflammation 10% to 30% deep invasion higher grade perineural invasion

Squamous Cell Histopathology

Well, moderate and poorly differentiated

generic
adenoid bowenoid verrucous spindle cell or pleomorphic

Squamous Cell Histopathology

Adenoid Squamous Cell

Pseudoglandular

arrangement dyskeratosis acantholysis periauricular

Verrucous Squamous Cell

Rare on skin

cauliflower-like
well-differentiated marked hyperkeratosis,

parakeratosis, acanthosis invasion with pushing margins

Spindle Cell Squamous Carcinoma

Least common

poorly differentiated
anaplastic cells absent keratinization

pleomorphic giant cells

Staging

Treatment - ED&C
Most useful with BCCa <2 cm

92% to 98% cure

advantages

quick and easy open wound scarring

disadvantages

Treatment - Cryotherapy
Small, well-circumscribed lesions

-30 F to -50 F
advantages

quick in-office prolonged healing with potential for scarring no margins

disadvantages

Treatment - Excision
Most often used by head & neck surgeons

93% to 95% cure

advantages

specimen for evaluation control of margins (3 to 5 mm) expensive time-consuming

disadvantages

Treatment - Laser
Patients with medical diseases

multiple lesions
palliation

Treatment - Mohs Surgery

96% to 99% cure

Treatment - Radiation
Prolonged course

radiodermatitis
carcinogenesis useful in poor surgical patients no control of margins recurrence in 4.4% to 9.5%

Treatment - Photodynamic Therapy

Photosensitive drug concentrated in tumor

porphyrin, argon ion dye pump laser most

common still experimental

Treatment - Interferon
Interferon -

low dose, intralesional

3 times a week flu-like illness erythema, pain stimulation of macrophages and NK cells

Treatment - Chemotherapy
Retinoids

cis-platin - most widely used

bleomycin cyclophosphamide 5-fluorouracil vinblastine

Treatment - Regional Lymphatics

Deep invasion into muscle, bone, nerve

tumors >2 cm
recurrent tumors tumors arising de novo or in scarred areas

Treatment - Regional Lymphatics

Parotidectomy for

periauricular tumors spare uninvolved structures post op XRT as indicated

Treatment - Selection

Recurrence
BCCa 1-39% Nodular 1-6% Morpheaform 12-30% 3 years SCCa variable

recurrence rates

75% of recurrences occur within 2 years 95% of recurrences occur within 5 years

Recurrence
70% recurrence risk for:

Size greater than 2 cm invasion of bone, cartilage, muscle, nerve regional lymphatic involvement
47% recur 35% metastasize

perineural invasion

Mortality
Exact numbers not available - not consistently

reported 0.44 per 100,000 persons per year 2,000 to 3,000 deaths per year in U.S. patients 65-70 years old widespread SCCa arising in periauricular region

Conclusion
Common tumors

best chance for cure is early diagnosis and

treatment prevent new lesions with sun protection