Skin-melanocytic tumor
Invasive - general

Author: Christopher Hale, M.D. (see Authors page)

Revised: 29 October 2015, last major update May 2013

Copyright: (c)2003-2015,, Inc.

PubMed Search: melanoma skin [title] invasive
  • Malignancy of melanocytes, predominantly in skin, but also eyes, ears, GI tract, leptomeninges, mucous membranes (Wikipedia, eMedicine)
  • Only 4% of skin cancers but majority of skin cancer deaths

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% are familial (Surg Clin North Am 2008;88:897)
  • Possible increase in neurofibromatosis type I (Pigment Cell Res 2005;18:13)
  • 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 and eye
  • Rarely subungual ("Hutchinson’s sign / melanotic whitlow"), palm or sole
Clinical Features

Clinical warning signs:
  • Change in color of pigmented lesion
  • Enlargement of existing mole
  • Itching or pain in pre-existing mole
  • Development of new pigmented lesion in adult life
  • Irregular borders in pigmented lesion
  • Variegation of color in pigmented lesion
  • Change in color of pigmented lesion
  • Enlargement of existing mole
  • Itching or pain in pre-existing mole
  • Development of new pigmented lesion in adult life
  • Irregular borders in pigmented lesion
  • Variegation of color in pigmented lesion

  • Overall 5 year survival is 60%, but behavior is variable, with occasional late deaths or long survival even with widespread satellite nodules
  • 5 year and 10 year survival rates (TNM classification) range from 97% and 93% for T1aN0M0 melanomas to 53% and 39% for T4bN0M0 (J Clin Oncol 2009;27:6199)
  • Regional lymph nodes, liver, lungs, GI tract, bone, CNS, heart, skin and other sites
  • Isolated tumor cells or tumor deposits > 0.1 mm (within lymph nodes) that meet the criteria for histologic or IHC detection of melanoma should be scored as node positive (J Clin Oncol 2009;27:6199)
  • 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 (Br J Dermatol 2002;147:62)
  • Satellite and in-transit metastasis merged in 2009 AJCC Staging System (J Clin Oncol 2009;27:6199)
  • Site of metastasis and serum LDH (lactate dehydrogenase) are used to stratify stage IV melanoma
  • Metastasis are occasionally S100-, 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 Pathol 2005;36:1016)
  • Metastases may arise from unrelated clones (Am J Surg Pathol 2007;31:1029)
  • Molecular analysis can distinguish a second primary from metastatic disease (Am J Surg Pathol 2007;31:637)
Prognostic Factors
  • High Breslow (vertical) thickness in primary tumor
  • High Clark's level
  • Vascular invasion
  • High stage (TNM)
  • Male gender
  • High mitotic rate
  • Ulceration (Am J Surg Pathol 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 2009;16:186)
  • 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 (Am J Surg Pathol 2008;32:1396)
  • Tumor lymphangiogenesis (Mod Pathol 2005;18:1232)
  • Increased density of dendritic leukocytes in nodal paracortex (Mod Pathol 2004;17:747)
  • Presence of tumor-infiltrating lymphocytes may indicate better prognosis (J Clin Oncol 2012;30:2678)

  • 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 (Am J Surg Pathol 2003;27:1571)
Case Reports
  • 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;11:7), 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 (Clin Lab Med 2011;31:289)
  • 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)
  • 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
      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
  • Frequent mitotic figures

4 major subtypes: (described separately)
  • Acral lentiginous
  • Lentigo maligna
  • Nodular
  • Superficial spreading

  • 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 and telangiectasias (Am J Surg Pathol 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 Pathol 2008;39:901)
  • Subepidermal cleft present in 24% (Hum Pathol 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 (Am J Surg Pathol 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 (Arch Pathol Lab Med 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
Micro Images

Images hosted on Pathout server:


Regression in melanoma

Tumor infiltrating lymphocytes

Subcapsular lymph node metastasis

Lymphatic invasion

Spindle cell melanoma with mitotic figures

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

Pagetoid extension

Follicular growth

Images hosted on other servers:

Thin and thick melanoma

Vascular invasion


Satellite metastasis

Tumor infiltrating lymphocytes

Nipple melanoma, nodular type


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


Images hosted on

Primary melanoma and epidermotropic metastases

Confocal microscopy versus H&E

Cytology Description
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 Pathol 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 (MITF): sensitive, but also stains dermatofibroma and smooth muscle tumors; negative in spindle cell / desmoplastic melanoma
  • NKI-C3 and NSE: nonspecific
  • PHH3 and Ki-67: to assess proliferative activity, 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 Pathol 1999;12:1143)
  • Other positive stains: Fontana-Masson (detects melanin granules), vimentin; variable staining for Cam 5.2, CEA, EMA, alpha-1-antichymotrypsin, CD68
  • Rare reports of CK18+ melanocytic component (Am J Dermatopathol 1994;16:241)
Electron Microscopy Description
  • Melanosomes and premelanosomes
  • May be useful if stains are not confirmatory
  • May have well developed microvilli similar to adenocarcinoma
Molecular / Cytogenetics Description
  • 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
  • To date, no overlapping molecular signatures (Lancet Oncol 2012;13:e205)
Differential Diagnosis
  • Atypical fibroxanthoma: HMB45, MelanA and S100 are usually negative (but see Am J Dermatopathol 2007;29:551)
  • Benign fibrous histiocytoma
  • Granular cell tumor: negative for HMB45 and MelanA (Am J Dermatopathol 2007;29:22)
  • Amelanotic tumors resemble pyogenic granuloma
  • Hemangioma
  • 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)
  • Pigmented basal cell carcinoma
  • Pigmented seborrheic keratosis

Helpful features of melanoma that differentiate from benign lesions (from Rosai):
  • Asymmetry
  • Atypia
  • Band like chronic inflammatory infiltrate in dermis
  • Lack of maturation of dermal tumor cells
  • Lateral extension of individual melanocytes
  • Melanocytes with clear cytoplasm and finely dispersed chromatin, individual melanocyte necrosis (compared to eosinophilic hyaline bodies in Spitz nevi)
  • Mitotic figures in melanocytes (particularly atypical ones)
  • Pleomorphism of tumor cells
  • Poor circumscription of intraepidermal component
  • Presence of chromosomal gains or losses
  • Transepidermal migration of melanocytes