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Skin-Melanocytic Tumors

Melanoma, invasive-General


Last major update: November 2008 - next update November 2009

Revised: 22 September 2009

Author: Nat Pernick, M.D., PathologyOutlines.com, Inc.

Copyright: (c) 2002-2009, PathologyOutlines.com, Inc.




● Incidence increasing worldwide

● 48,000 cases and 9,200 deaths in US in 2000

● Usually due to sun (UV light) exposure


Populations at higher risk:

● Whites with fair skin, red hair, tendency to burn or freckle from sun exposure, large number of melanocytic nevi, xeroderma pigmentosum, familial dysplastic nevi, melanosis, vitiligo, frequent sunburns at any age (Ann Epidemiol 2008;18:614), 5-10% familial (Surg Clin North Am 2008;88:897), possibly neurofibromatosis type I

● Blacks and Hispanics in US have low risk, their common melanoma sites are palms, soles, nail beds or mucous membranes; often poorer prognosis (Cancer Control 2008;15:248)

● Usually occurs after puberty, occasionally children - all have same morphology




● Head and neck, back, lower extremities (particularly in women)

● Also oral and anogenital mucosa, esophagus, meninges, eye

● Rarely subungual (“melanotic whitlow”), palm, sole


Clinical warning signs


● Change in color of pigmented lesion

● Enlargement of existing mole

● Itching or pain in preexisting mole

● Development of new pigmented lesion in adult life

● Irregular borders in pigmented lesion

● Variegation of color in pigmented lesion


Clinical features


● 5% are multiple, although prognosis is related to type and stage of largest lesion, not number of lesions

● Must distinguish multiple lesions from “hot nevi” / nevus activation

● Self assessment often inaccurate (Public Health 2008;122:1433)




● Cytotoxic T lymphocytes have difficulty killing melanoma cells due to delayed or ineffective apoptosis (J Cell Mol Med 2008 Nov 8 [Epub ahead of print])




● Partial regression is common, total regression may occur (Am J Dermatopathol 2008;30:178)




● Regional lymph nodes, liver, lungs, GI tract, bone, CNS, heart, skin (satellite tumors are considered intralymphatic metastases within 2 cm of primary tumor, termed in transit metastases if >2 cm from primary tumor but before the first echelon of regional lymph nodes), other sites

● Metastasis are occasionally S100 negative, but can still be identified as melanoma due to (a) negative workup for carcinoma, lymphoma and sarcoma, (b) HMB45+, MART1+, (c) clinical history of melanoma (Hum Path 2005;36:1016)

● Metastases may arise from unrelated clones (AJSP 2007;31:1029)

Molecular analysis can distinguish a second primary from metastatic disease (AJSP 2007;31:637)




● Overall 5 year survival is 60%, but behavior is variable, with occasional late deaths or long survival even with widespread satellite nodules


Poor prognostic factors


● Breslow (vertical) thickness in primary tumor

● Clark’s level

● Vascular invasion

● High stage (TNM)

● Male gender

● High mitotic rate

● Ulceration (AJSP 2006;30:1396)

● Microscopic satellites (tumor nests 50 microns or larger and separated from main tumor mass)

● Deeper level of invasion for T1 tumors

● Higher % tumor area/volume in sentinel node

● Positive nonsentinel lymph nodes (Ann Surg Oncol 2008 Nov 1 [Epub ahead of print])

● Regression

● Tumor-infiltrating lymphocytes


Possible poor prognostic factors:

● Patient age

● Site of primary melanoma

● Angiotropism (migration of melanoma cells along external surface of blood vessels (AJSP 2008;32:1396)

Tumor lymphangiogenesis (Mod Path 2005;18:1232)

Increased density of dendritic leukocytes in nodal paracortex (Mod Path 2004;17:747)


● For patients with localized melanoma, most important prognostic factors are tumor thickness and ulceration

● For patients with nodal metastases, most important prognostic factors are number of metastatic nodes, microscopic versus macroscopic tumor and presence or absence of ulceration of primary melanoma

● Note: there is excellent agreement between pathologists in assessing tumor thickness, ulcerative state and tumor mitotic rate (AJSP 2003;27:1571)


Case Reports


● Metastasis to basal cell carcinoma (AJSP 2006;30:133)

Malignant basomelanocytic tumor with subsequent metastatic melanoma (AJSP 2004;28:1393)

Presenting as leptomeningeal melanomatosis (Hum Path 2003;34:625)

With true epithelial component (Am J Dermatopathol 2007;29:395)

Myxoid stroma associated with patient use of phototherapy (Am J Dermatopathol 2008;30:185)

Angiomatoid periorbital tumor (Hum Path 2000;31:1520)

Presentation in 71 year old identical female twins at same time and location (Am J Dermatopathol 2008;30:182)

With dysplastic nevi and sebaceous-type cells (Am J Dermatopathol 2007;29:566)

With incipient follicular lymphoma in axillary node (Hum Path 2001;32:1410)

Nipple melanoma resembling Paget’s disease (Dermatol Online J 2007;13(2):18)

With diffuse cutaneous melanosis (Dermatol Online J 2007;13(2):9)

Presenting as vitiligo-like patches (Am J Dermatopathol 2008;30:451)


Diagnosis and Treatment


● Initial biopsy should attempt to remove the entire lesion

● Punch biopsies for diagnosis are discouraged, since determination of depth may be inaccurate (Dermatol Online J 2005;11(1):7), but may be useful to define margins (Ann Surg Oncol 2008;15:3028)

Initial excision is usually down to subcutis with narrow margins, but then need wide local reexcision with 1-2 cm margins

Frozen sections for margins only

Lymphatic mapping and sentinel node biopsy for tumors with depth > 1mm

● Nodal block dissection (ANZ J Surg 2008;78:982)

Note: minimal metastatic risk if radial growth phase only; metastatic behavior occurs with vertical growth phase

Treatment for metastatic disease: Interleukin-2 and dacarbazine; possibly adoptive cell therapy with autologous antitumor lymphocytes in lymphodepleted hosts (J Clin Oncol 2008;26:5233); variable results for adjuvant radiotherapy (Ann Surg Oncol 2008;15:3022, Cancer Control 2008;15:233)


Clinical images




Scaly erythematous crusty pigmentation and thickened plaques on the nipple, spreading to surrounding areola                           




● More accurate than naked eye examination (Br J Dermatol 2008;159:669)

ABCD rule: asymmetry, border, color and differential structure (J Am Acad Dermatol 1994;30:551)

● Black dots represent pigmented cells at dermal-epidermal junction and within epidermis in heavily pigmented columns; brown dots are similar to black dots, but with less pigment; blue dots are due to melanophages surrounding superficial vascular plexus; depigmentation is due to intense fibrosis of papillary dermis; radial streaming and pseudopods are due to cells in nests or centrifugal linear extensions (Am J Dermatopathol 2006;28:13); blue-whitish veil is associated with melanoma (Am J Dermatopathol 2001;23:463); dermoscopy is less accurate if no significant pigment, but helpful features include blue-white veil, scarlike depigmentation, multiple blue-gray dots, irregularly shaped depigmentation, irregular brown dots/globules, 5-6 colors and predominant central vessels (Arch Derm 2008;144:1120)

Amelanotic/hypomelanotic lesions: blue-white veil, scarlike depigmentation, multiple blue-gray dots, irregularly shaped depigmentation, irregular brown dots/globules, 5-6 colors and predominant central vessels are suggestive (Arch Dermatol 2008;144:1120)


Micro description


● Features of melanoma in situ + dermal involvement of atypical melanocytes with cytologic atypia and no maturation

● Classic features are junctional activity with obscured dermoepidermal junction and pagetoid spread individually and in clusters throughout epidermis

● Prominent melanin pigmentation, invasion of surrounding tissue

● Large cells with abundant eosinophilic and finely granular cytoplasm

● Nuclear pseudoinclusions, folds or grooves

● Marked atypia with pleomorphic nuclei with large eosinophilic nucleoli

● Frequent mitotic figures


4 major subtypes

● Acral lentiginous

● Lentigo maligna

● Nodular

● Superficial spreading (described separately)


● Lack of a junctional component suggests a metastases, although epidermal component may have regressed or not been sampled, or melanoma may have developed from an intradermal nevus

Consumption of epidermis: usually (86%) present; thinning of epidermis with attenuation of basal and suprabasal layers and loss of rete ridges in areas of direct contact with neoplastic melanocytes; variable clefts separating epidermis and dermis, edema, telangiectasias (AJSP 2004;28:1621); is associated with increased Breslow depth and ulceration (Am J Dermatopathol 2007;29:527)

Lymphatic invasion identified in 5% on H&E but 33% using D2-40/podoplanin and S100 (Hum Path 2008;39:901)

● Subepidermal cleft present in 24% (Hum Path 2005;36:412)

● Angiotropism is suggestive of epidermotropic metastatic disease versus recurrent disease (Am J Dermatopathol 2006;28:429)

● Rarely paradoxical maturation occurs, but still have areas of cells with abundant cytoplasm and large nuclei, more mitotic figures, more confluence, high Ki-67 rate (AJSP 2000;24:1600)

Rarely CD68+ osteoclast-like giant cells (Am J Dermatopathol 2005;27:126), signet-ring cells (Am J Dermatopathol 2003;25:418), lipoblast like cells (Archives 2003;127:370)


Regressed melanoma:

● Dense lymphocytic infiltration similar to spontaneously disappearing nevi, variable melanin-laded macrophages

● May be complete or incomplete with residual tumor cells present

● May be confused with lichen planus-like keratosis


Other microscopic features


Growth patterns: pseudoglandular, pseudopapillary, peritheliomatous (around blood vessels), hemangiopericytoma-like, Spitz nevus-like, trabecular, verrucous, nevoid

Cell type: epithelioid, spindled or bizarre

Size: lymphocytes to multinucleated giant cells

Cytoplasm: eosinophilic, basophilic, foamy, signet ring, rhabdoid, oncocytic or clear

Stroma: desmoplastic, myxoid, bone or cartilage, osteoclast-like giant cells

Epithelium: pseudoepitheliomatous hyperplasia

Other differentiation: Schwann cells, ganglion cells, other neural structures


Micro images




Primary melanoma and                                    Thin and thick melanoma

epidermotropic metastases




Vascular invasion                                              Ulceration




Satellite metastasis                                          Tumor infiltrating lymphocytes




Confocal microscopy versus H&E




Nipple melanoma, nodular type                      HMB45+



Punch biopsy - depth of invasion was  incorrect since it was measured

along hair follicle that was not initially evident:


No hair follicle seen                           Hair follicle seen on recut                Excision



Contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain:


Pagetoid extension                            Follicular growth


Cytology description


● Metastases may have spindle cells resembling malignant peripheral nerve sheath tumor (Diagn Cytopathol 2008;36:754)


Positive stains


Distinguish melanocytes from non-melanocytes, but not malignant cells from benign cells:

● S100: nuclear and cytoplasmic staining, 90%+ sensitive but not specific (although usually negative in tumors considered in the differential)

● HMB45: cytoplasmic and weak nuclear staining (Mod Path 2008;21:1121), less sensitive but more specific than S100; negative in desmoplastic melanoma

● MelanA/Mart1: sensitive, but also stains steroid-producing cells in ovary, testis, adrenal cortex

● Tyrosinase: sensitive, but also stains peripheral nerve sheath and neuroendocrine tumors

● Microphthalmia transcription factor: sensitive, but also stains dermatofibroma and smooth muscle tumors; negative in spindle cell / desmoplastic melanoma

● NKI-C3 and NSE: nonspecific

● PHH3 and Ki-67: may distinguish melanoma from nevi (Am J Dermatopathol 2008;30:117); another marker is SM5-1 (Am J Dermatopathol 2005;27:401)

Azure blue counterstaining may be preferable to bleaching (Mod Path 1999;12:1143)

Other positive stains: Fontana-Masson (detects melanin granules), vimentin; variable staining for Cam 5.2, CEA, EMA, alpha-1-antichymotrypsin, CD68

● some melanomas, especially when metastatic, may stain with simple keratins (CK8)


Electron microscopy


● Melanosomes and premelanosomes

● May be useful if stains are not confirmatory

● May have well developed microvilli similar to adenocarcinoma


Molecular / cytogenetics


● Main altered pathways include RAS-RAF-MEK-ERK, p16(INK4A)-CDK4-RB and ARF-p53 (APMIS 2007;115:1161)

20% of melanoma prone families have point mutation in CDKN2A locus at 9p21 which encodes p16(INK4a) and p14(ARF) (Br J Cancer 2008;99:364)

● 10% of cases may be familial due to CMM1 gene at 1p36

● Microsatellite instability seen in pediatric melanoma (43%), adult melanoma (30%), nevi (9%) (Am J Dermatopathol 2005;27:279)

● Most melanomas have multiple chromosomal gains and losses, features that can be used to differentiate them from nevi, which do not have chromosomal alterations


Differential diagnosis


● Nevi - particularly Spitz nevi-desmoplastic type, halo nevi, activated and dysplastic nevi, vulval nevi and recurrent nevi after incomplete excision; features relatively specific for melanoma include absence of maturation, suprabasal melanocytes; also atypia, size >6 mm, mitotic figures, dermal lymphocytes and asymmetry, necrosis, asymmetrical melanin and melanin in deep cells (Melanoma Res 2008;18:253)

● Benign fibrous histiocytoma

● Hemangioma

● Pigmented seborrheic keratosis

● Pigmented basal cell carcinoma

● Atypical fibroxanthoma - HMB45, MelanA and S100 are usually negative (but see Am J Dermatopathol 2007;29:551)

Granular cell tumor - negative for HMB45 and MelanA (Am J Dermatopathol 2007;29:22)

Amelanotic tumors resemble pyogenic granuloma


Helpful features of melanoma that differentiate from benign lesions (from Rosai):

● Poor circumscription of intraepidermal component

● Lateral extension of individual melanocytes

● Transepidermal migration of melanocytes

● Pleomorphism of tumor cells

● Asymmetry

● Lack of maturation of dermal tumor cells

● Atypia

● Mitotic figures in melanocytes (particularly atypical ones)

● Melanocytes with clear cytoplasm and finely dispersed chromatin, individual melanocyte necrosis (compared to eosinophilic hyaline bodies in Spitz nevi)

● Band like chronic inflammatory infiltrate in dermis

● Presence of chromosomal gains or losses


Additional references


Wikipedia, eMedicine


End of Skin-Melanocytic Tumors > Melanoma, invasive-General




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