Skin melanocytic tumor
Melanoma
Invasive melanoma


Topic Completed: 1 May 2013

Minor changes: 3 November 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed Search: melanoma skin invasive

Christopher S. Hale, M.D.
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Cite this page: Hale CS. Invasive melanoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/skintumormelanocyticmelanoma.html. Accessed December 5th, 2020.
Definition / general
  • 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
Epidemiology

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
Sites
  • Head and neck, back, lower extremities (particularly in women)
  • Also oral and anogenital mucosa, esophagus, meninges and eye
  • Rarely subungual ("Hutchinson sign / melanotic whitlow"), palm or sole
Pathophysiology
Clinical features

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

Regression:
Survival:
  • 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)

Superficial spreading melanoma:
  • Traditionally considered most common type of melanoma (50 - 75%) but lentigo maligna may actually be more common in patients with extensive sun exposure (J Am Acad Dermatol 2008;58:1013)
  • Recently diagnosed tumors are thinner with less ulceration than in the past (Cancer 2008;113:3341)
  • Note: can be in situ or invasive
  • Risk factors:
    • Extensive sun exposure during childhood, family history of melanoma, large numbers of benign nevi and dysplastic nevi
    • Recommended to evaluate vertical growth phase as prognostic factor for thin (< 0.76 mm) tumors (Am J Surg Pathol 2003;27:717)
  • Variegated, black, brown, tan, blue, pink or white
  • Slightly elevated, flat and irregular margins, often with an indentation or notch
  • May have white areas of tumor regression or nodular areas of deep dermal invasion
  • Exon 15 BRAF mutations in 29% (J Invest Dermatol 2005;125:575)
  • Selective downregulation of seven microRNAs (let-7g, miR-15a, miR-16, miR-138, miR-181a, miR-191 and miR-933, J Invest Dermatol 2012;132:1860)

In situ melanoma:
  • Malignant melanocytes in epidermis, without dermal invasion
  • Variants include lentigo maligna, superficial spreading (which can be in situ or invasive) and acral melanoma
  • Cases in sun damaged skin may resemble benign lichenoid keratosis (Hum Pathol 2003;34:706)
  • Characterized by pagetoid spread, confluence and nesting of atypical melanocytes
  • May be associated with invasive malignant melanoma (Hum Pathol 2000;31:705)
  • Large pigmented lesions, irregular margins and irregular pigmentation
  • Hutchinson sign: periungual extension of brownish black pigmentation from longitudinal melanonychia (pigmented stripe within length of nail bed) onto the proximal and lateral nailfolds
  • Treatment:
Metastases
  • 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:
    1. Negative workup for carcinoma, lymphoma and sarcoma
    2. HMB45+, MART1+
    3. 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)
Diagnosis
  • 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)
Prognostic factors
  • High Breslow (vertical) thickness in primary tumor
  • High Clark 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
Clinical images

Images hosted on other servers:

Thickened plaques on the nipple

Superficial spreading melanoma



Melanoma in situ

Various images

Figs 2 - 3: acral lesion with parallel ridge pattern (B)


Before and after Imiquimod cream (A, B)

Fig 1 and 3: various images

Dermoscopy
  • 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: bluish white veil, scar-like depigmentation, multiple bluish gray dots, irregularly shaped depigmentation, irregular brown dots / globules, 5 - 6 colors and predominant central vessels are suggestive (Arch Dermatol 2008;144:1120)
  • Melanoma in situ:
  • Superficial spreading melanoma:
    • Multicomponent pattern, asymmetry and multiple colors
    • Also atypical reticular pattern (irregular holes and thick lines) with a sharp demarcation, bluish white veil, irregular linear vessels, central ulceration and irregularly distributed dots
Microscopic (histologic) 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 Ki67 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

Melanoma in situ:
  • Atypical melanocytes in epidermis with no dermal invasion
  • Usually epidermal effacement (absences of rete ridges in some foci, J Drugs Dermatol 2007;6:708)
  • Predominance of individual unit melanocytes over nests
  • Confluent growth of melanocytes along dermoepidermal junction
  • Pagetoid spread
  • Involvement of adnexal structures

Superficial spreading melanoma:
  • Classified based on radial growth component (has nothing to do with level of dermal invasion)
  • Noninvasive areas have asymmetry and poor circumscription, irregular acanthosis, irregular lentiginous and nested proliferation, uniform atypical melanocytes with nests and pagetoid cells
  • Also transdermal migration, nuclear pleomorphism, dusty pigmentation, apoptosis of individual melanocytes and pigmented parakeratosis
  • A variant composed predominantly of large nests has been described (Mod Pathol 2012;25:838)
Microscopic (histologic) images

Contributed by Jijgee Munkhdelger, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.

Dermal nodule with prominent pigmentation

Nodular melanoma

Loss of rete ridges

Cutaneous melanoma, HMB45

Metastatic melanoma


Lymph node metastatic melanoma



Contributed by various sources

Regression in melanoma

Tumor infiltrating lymphocytes

Subcapsular lymph node metastasis

Lymphatic invasion

Spindle cell melanoma with mitotic figures



Contributed by Angel Fernandez-Flores, M.D., Ph.D.

Pagetoid extension

Follicular growth


 Contributed by Epitomics

PMEL17



Images hosted on other servers:

Thin and thick melanoma

Vascular invasion

Ulceration

Satellite metastasis

Tumor infiltrating lymphocytes


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



Superficial spreading melanoma

Beta catenin expression in primary


Melanoma in situ

Hyperkeratotic keratosis with coexisting melanoma in situ and MITF staining

Frozen section from Mohs procedure (fig 4)

Limited pagetoid spread in nail (fig 2)

Cytology description
Positive stains
Distinguish melanocytes from nonmelanocytes but not malignant cells from benign cells:
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
  • See also topics in Molecular Pathology chapter:
  • 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)
Videos

Melanoma in situ

Differential diagnosis

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
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