Definition/General

Introduction:
-Vaginal melanoma is an extremely rare malignant tumor accounting for 2-5% of all primary vaginal cancers and 0.2-0.3% of all melanomas
-It represents a subset of mucosal melanomas with distinct biological behavior from cutaneous melanomas
-Vaginal melanoma has an aggressive clinical course with high propensity for local recurrence and distant metastasis
-The prognosis is generally poor with 5-year survival rates of 10-25%.
Origin:
-Originates from melanocytes present in the vaginal mucosa
-These melanocytes are normally sparse in the vaginal epithelium compared to skin
-The tumor arises from malignant transformation of these mucosal melanocytes
-Junctional activity (melanocytes at epithelial-stromal junction) is often present
-The tumor typically develops in the lower third of the vagina near the introitus
-Melanosis vaginae (benign melanocytic proliferation) may be a precursor lesion.
Classification:
-WHO classification recognizes vaginal melanoma as a distinct entity within mucosal melanomas
-Growth patterns include superficial spreading, nodular, and acral lentiginous-like
-Histological variants include epithelioid, spindle cell, and mixed types
-Amelanotic melanoma lacks pigment production
-AJCC staging for mucosal melanomas differs from cutaneous melanomas
-Breslow thickness is not applicable
-staging based on size and extent.
Epidemiology:
-Accounts for 2-5% of primary vaginal malignancies
-Peak incidence in 6th-7th decades (median age 60-65 years)
-Rare in young women (<40 years)
-No racial predilection unlike cutaneous melanoma
-No association with sun exposure or UV radiation
-Extremely rare in Indian population with limited case reports
-Familial clustering is exceptional
-No established risk factors identified.

Clinical Features

Presentation:
-Vaginal bleeding (70-80% of cases), often the first symptom
-Visible pigmented lesion (60-70% of cases)
-Vaginal discharge (bloody or serous)
-Pelvic pain and discomfort
-Dyspareunia and post-coital bleeding
-Palpable mass or nodule
-Pruritus and irritation
-Amelanotic lesions may present as non-pigmented masses.
Symptoms:
-Postmenopausal bleeding (most common presenting symptom)
-Dark-colored discharge may contain melanin pigment
-Vulvar discomfort and burning sensation
-Dyspareunia due to tumor location near introitus
-Urinary symptoms (frequency, urgency) with anterior involvement
-Defecation difficulties with posterior wall involvement
-Constitutional symptoms (weight loss, fatigue) in advanced disease.
Risk Factors:
-Advanced age (peak in 6th-7th decades)
-Previous history of melanoma (cutaneous or other mucosal sites)
-Immunosuppression (theoretical risk)
-Chronic irritation (pessary use, infections)
-Fair skin phenotype (conflicting evidence for mucosal melanomas)
-Family history of melanoma (extremely rare association)
-No established environmental risk factors.
Screening:
-No specific screening guidelines due to rarity
-Annual pelvic examination for postmenopausal women
-Careful inspection of vaginal mucosa for pigmented lesions
-Dermoscopy may be helpful for pigmented lesions
-Biopsy of any suspicious pigmented or non-pigmented lesion
-Awareness among gynecologists about possibility of melanoma
-Patient education about reporting unusual vaginal symptoms.

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Gross Description

Appearance:
-Pigmented nodular or polypoid mass with irregular surface
-Dark brown to black coloration in pigmented cases
-Pink to gray appearance in amelanotic variants
-Friable, easily bleeding surface
-Irregular, asymmetric shape
-Ulceration may be present on surface
-Satellite nodules may be visible around main tumor.
Characteristics:
-Firm to soft consistency depending on cellularity
-Heterogeneous cut surface with areas of hemorrhage and necrosis
-Variable pigmentation from heavily pigmented to completely amelanotic
-Irregular margins with infiltrative borders
-Mucoid or gelatinous areas in some cases
-Calcification is rare
-Cystic changes may occur in larger tumors.
Size Location:
-Size ranges from small nodules (1-2 cm) to large masses (>5 cm)
-Lower third of vagina most commonly affected (70-80%)
-Anterior and posterior walls equally affected
-Near the introitus is characteristic location
-May extend to vulva making primary site determination difficult
-Upper vaginal involvement is less common.
Multifocality:
-Multifocal disease in 10-20% of cases
-Satellite lesions around primary tumor
-In-transit metastases along lymphatic channels
-Skip lesions may be present
-Concurrent vulvar melanoma in some cases
-Distinguishing primary from metastatic disease can be challenging.

Microscopic Description

Histological Features:
-Malignant melanocytes with prominent nucleoli and abundant cytoplasm
-Junctional component with melanocytes at epithelial-stromal junction
-Invasive component extending into vaginal stroma
-Variable melanin pigment from abundant to absent
-Mitotic activity usually high (>5-10 per mm²)
-Pagetoid spread of melanocytes in overlying epithelium.
Cellular Characteristics:
-Large epithelioid cells with vesicular nuclei and prominent nucleoli
-Spindle-shaped cells in some areas or variants
-Abundant eosinophilic cytoplasm with or without melanin
-Pleomorphic nuclei with irregular contours
-Binucleated and multinucleated cells may be present
-Melanophages (pigment-laden macrophages) in stroma.
Architectural Patterns:
-Nodular growth pattern (most common) with expansile masses
-Superficial spreading pattern with lateral extension in epithelium
-Nested pattern with clusters of melanocytes
-Single cell infiltration into stroma
-Vertical growth phase with deep invasion
-Ulceration of overlying epithelium in advanced cases.
Grading Criteria:
-No standard grading system for mucosal melanomas
-Breslow thickness not applicable to mucosal sites
-Mitotic rate is important prognostic factor (>4 per mm² worse prognosis)
-Ulceration indicates aggressive behavior
-Tumor thickness measured from mucosal surface
-Level of invasion into vaginal wall structures.

Immunohistochemistry

Positive Markers:
-S-100 protein (nuclear and cytoplasmic, positive in >95% of cases)
-SOX10 (nuclear, highly sensitive and specific)
-Melan-A/MART-1 (cytoplasmic, positive in 70-80%)
-Melanoma cocktail (HMB45 + Melan-A)
-HMB45 (cytoplasmic, positive in 60-70%)
-Tyrosinase (cytoplasmic, positive in 50-60%)
-MITF (nuclear, positive in 80-90%).
Negative Markers:
-Cytokeratins (CK7, CK20, pan-cytokeratin negative)
-EMA (negative, helps exclude carcinoma)
-Vimentin (usually positive, but not specific)
-CD45 (negative, excludes lymphoma)
-CD117/c-kit (variable, may be positive)
-Desmin (negative, excludes sarcoma)
-CD34 (negative in melanoma cells).
Diagnostic Utility:
-S-100 and SOX10 are most reliable markers for melanoma diagnosis
-Melanoma cocktail (HMB45 + Melan-A) helps confirm melanocytic differentiation
-Negative cytokeratins help exclude carcinoma, especially in amelanotic cases
-MITF positivity supports melanocytic lineage
-Panel approach essential for accurate diagnosis
-Caution with HMB45 as it may be negative in some melanomas.
Molecular Subtypes:
-KIT-mutated type (c-kit mutations in 20-30% of mucosal melanomas)
-NRAS-mutated type (less common than cutaneous melanoma)
-BRAF-mutated type (rare in mucosal melanomas, <5%)
-Triple wild-type (no mutations in BRAF, NRAS, or KIT)
-Chromosomal instability type (complex karyotype)
-TERT promoter mutated type (associated with poor prognosis).

Molecular/Genetic

Genetic Mutations:
-KIT mutations (20-30% of mucosal melanomas, exons 11, 13, 17, 18)
-NRAS mutations (10-15% of cases, less than cutaneous)
-BRAF mutations (rare, <5% of mucosal melanomas)
-NF1 mutations (10-20% of cases)
-TERT promoter mutations (40-60% of cases)
-TP53 mutations (variable frequency)
-CDKN2A deletions (common in advanced cases).
Molecular Markers:
-KIT overexpression (by immunohistochemistry, correlates with mutations)
-p53 overexpression (indicates TP53 mutations)
-Loss of p16 (CDKN2A deletions)
-High Ki-67 index (indicates aggressive behavior)
-TERT expression (associated with poor prognosis)
-PD-L1 expression (variable, potential immunotherapy target).
Prognostic Significance:
-KIT mutations may predict response to KIT inhibitors (imatinib)
-TERT promoter mutations associated with worse prognosis
-High mitotic rate (>4 per mm²) indicates poor prognosis
-Tumor thickness correlates with survival
-Ulceration indicates aggressive behavior
-Age at diagnosis influences prognosis (older patients do worse)
-Stage at presentation is most important prognostic factor.
Therapeutic Targets:
-KIT (imatinib for KIT-mutated cases)
-BRAF (vemurafenib/dabrafenib for rare BRAF-mutated cases)
-MEK (trametinib in NRAS-mutated cases)
-PD-1/PD-L1 (pembrolizumab, nivolumab for immunotherapy)
-Anti-angiogenic agents (bevacizumab)
-Adoptive cell therapy (TIL therapy under investigation)
-Radiation sensitizers for local control.

Differential Diagnosis

Similar Entities:
-Vaginal squamous cell carcinoma (especially amelanotic melanoma)
-Vaginal adenocarcinoma (clear cell type may be confused)
-Metastatic melanoma to vagina from other sites
-Poorly differentiated carcinoma (especially in amelanotic cases)
-Vaginal sarcoma (leiomyosarcoma, angiosarcoma)
-Benign melanosis (melanocytic hyperplasia)
-Blue nevus of vagina (extremely rare).
Distinguishing Features:
-Melanoma vs SCC: S-100/SOX10 positive vs p40/p63 positive
-Melanoma vs adenocarcinoma: Melanoma markers vs CK7/PAX8 positive
-Primary vs metastatic melanoma: Clinical correlation and absence of other primary sites
-Malignant vs benign melanosis: Nuclear atypia, mitoses, and invasion vs bland cytology
-Amelanotic melanoma vs carcinoma: Immunohistochemistry panel essential.
Diagnostic Challenges:
-Amelanotic melanoma may be confused with poorly differentiated carcinoma
-Small biopsy specimens may not show characteristic features
-Distinguishing primary from metastatic requires clinical correlation
-Rare occurrence may lead to misdiagnosis
-Mixed epithelioid and spindle morphology can be confusing
-Limited experience with mucosal melanomas among pathologists.
Rare Variants:
-Amelanotic melanoma (completely lacks pigment, difficult diagnosis)
-Spindle cell melanoma (predominantly spindle morphology)
-Balloon cell melanoma (cells with clear, vacuolated cytoplasm)
-Nevoid melanoma (resembles benign nevus but invasive)
-Desmoplastic melanoma (prominent fibrosis, neurotropism)
-Small cell melanoma (small cell morphology, very rare)
-Signet ring cell melanoma (signet ring morphology, extremely rare).

Sample Pathology Report

Template Format

Sample Pathology Report

Complete Report: This is an example of how the final pathology report should be structured for this condition.

Specimen Information

Vaginal biopsy/excision from [location] measuring [size] cm

Diagnosis

Malignant melanoma of vagina

Classification

[Pigmented/Amelanotic] melanoma with [epithelioid/spindle/mixed] morphology

Histological Features

Shows malignant melanocytes with [nuclear features], [pigmentation status], and [growth pattern]

Invasion and Extent

Depth of invasion: [X] mm from mucosal surface, extent: [local/regional]

Mitotic Rate

Mitotic rate: [X] mitoses per mm²

Ulceration

Ulceration: [present/absent]

Margins

Margins are [involved/uninvolved], closest margin [X] mm from tumor

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Special Studies

S-100: [positive/negative], SOX10: [positive/negative], Melan-A: [positive/negative]

MITF: [positive/negative], HMB45: [positive/negative]

Cytokeratins: [negative], EMA: [negative]

Molecular Testing

KIT mutation: [positive/negative/not performed], Other mutations: [specify if performed]

AJCC Staging

AJCC Stage: [I/II/III/IV] - [staging description]

Prognostic Factors

Mitotic rate: [X]/mm², Ulceration: [present/absent], Depth: [X]mm, Stage: [I/II/III/IV]

Final Diagnosis

Primary vaginal melanoma, [pigmented/amelanotic], AJCC Stage [I/II/III/IV]