Definition/General

Introduction:
-Vulvar melanoma is a rare but aggressive malignant tumor arising from melanocytes in the vulvar skin
-It represents 2-3% of all vulvar malignancies and 0.3% of all melanomas in women
-It has a poor prognosis compared to cutaneous melanoma
-Most cases occur in postmenopausal women aged 60-70 years.
Origin:
-Arises from melanocytes present in the vulvar epidermis and dermis
-Originates from neural crest cells that migrate to the vulvar skin during embryogenesis
-Can develop de novo or from pre-existing benign nevi
-The exact etiology remains largely unknown
-UV exposure is not a significant risk factor unlike cutaneous melanoma.
Classification:
-Classified according to AJCC staging system
-Clark levels and Breslow thickness are important prognostic factors
-Histological subtypes include superficial spreading melanoma (most common)
-Nodular melanoma
-Acral lentiginous melanoma
-Amelanotic melanoma
-Mucosal lentiginous melanoma.
Epidemiology:
-Peak incidence in 6th-7th decades
-Rare in women under 50 years
-No clear racial predilection
-Risk factors include increasing age
-Personal history of cutaneous melanoma
-Family history of melanoma
-Atypical nevi syndrome
-No association with HPV infection
-Indian population shows increasing incidence with improved healthcare access.

Clinical Features

Presentation:
-Pigmented lesion (70-80% cases)
-Ulcerated nodule or mass
-Pruritus (most common symptom)
-Bleeding
-Pain
-Change in pre-existing nevus
-Amelanotic variant (20-30% cases) presents as pink/red nodule
-May be asymptomatic in early stages.
Symptoms:
-Pruritus (60-70% cases)
-Bleeding (40-50%)
-Pain (30-40%)
-Burning sensation
-Discharge
-Change in pigmentation of existing lesion
-Rapid growth of vulvar lesion
-Ulceration with foul odor
-Inguinal lymphadenopathy (advanced cases).
Risk Factors:
-Age >60 years
-Personal history of cutaneous melanoma
-Family history of melanoma
-Atypical mole syndrome
-Immunosuppression
-Fair skin complexion
-Multiple dysplastic nevi
-Genetic predisposition (CDKN2A mutations)
-Previous history of vulvar cancer.
Screening:
-No specific screening guidelines
-Annual gynecological examination recommended
-Self-examination for vulvar changes
-ABCDE criteria for pigmented lesions (Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolution)
-Early referral for suspicious lesions
-Dermoscopy may aid diagnosis.

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Gross Description

Appearance:
-Pigmented nodular lesion with irregular borders and variegated coloration
-Size ranges from 0.5-10 cm
-Brown to black coloration with areas of regression (gray-white)
-May show ulceration and bleeding
-Cut surface shows hemorrhage and necrosis.
Characteristics:
-Irregular, raised lesion with asymmetric borders
-Variable pigmentation from light brown to jet black
-Areas of depigmentation (regression)
-Ulceration and crusting
-Satellite lesions may be present
-Firm to hard consistency.
Size Location:
-Size varies from 0.5-15 cm (mean 3-4 cm)
-Most commonly on clitoris and labia minora (40-50%)
-Labia majora (30-35%)
-Posterior vulva (10-15%)
-May involve multiple sites
-Multifocal disease in 10-15% cases.
Multifocality:
-Satellite lesions in 15-20% cases
-In-transit metastases may occur
-Bilateral vulvar involvement rare
-Inguinal lymph node involvement in 30-40% at presentation
-Skip metastases to pelvic lymph nodes possible.

Microscopic Description

Histological Features:
-Atypical melanocytes with epithelioid or spindle morphology
-Junctional activity with nesting at dermal-epidermal junction
-Pagetoid spread in epidermis
-Dermal invasion with desmoplastic reaction
-Variable melanin pigmentation
-Mitotic activity usually high.
Cellular Characteristics:
-Large epithelioid cells with prominent nucleoli
-High nuclear-cytoplasmic ratio
-Nuclear pleomorphism and hyperchromatism
-Abundant eosinophilic cytoplasm
-Variable melanin pigment
-Multinucleated giant cells may be present
-Spindle cell component in some cases.
Architectural Patterns:
-Junctional component with melanocyte nests along basement membrane
-Vertical growth phase with dermal invasion
-Pagetoid spread through epidermis
-Desmoplastic stroma in invasive component
-Lymphovascular invasion in advanced cases
-Perineural invasion may be present.
Grading Criteria:
-Grading based on Breslow thickness (most important)
-Clark level (anatomic depth)
-Mitotic rate (mitoses per mm²)
-Presence of ulceration
-Lymphovascular invasion
-Microsatellites
-Tumor-infiltrating lymphocytes
-Regression (histologic evidence).

Immunohistochemistry

Positive Markers:
-S-100 protein (100% positive)
-Melanoma markers: HMB-45 (80-90%)
-Melan-A (85-95%)
-MITF (90-95%)
-Tyrosinase (70-80%)
-SOX10 (95-100%)
-MART-1 (85-95%)
-Ki-67 (high proliferation index).
Negative Markers:
-Cytokeratins (negative)
-EMA (negative)
-CEA (negative)
-p63 (negative)
-Vimentin (may be focally positive)
-CD68 (negative in tumor cells)
-Desmin (negative)
-Smooth muscle actin (negative).
Diagnostic Utility:
-Essential for differential diagnosis from carcinoma and sarcoma
-S-100 and SOX10 are most reliable melanoma markers
-HMB-45 may be negative in amelanotic variants
-MITF helps distinguish from other tumors
-Ki-67 correlates with prognosis
-BRAF and NRAS mutations tested for targeted therapy.
Molecular Subtypes:
-BRAF-mutated (20-30% of cases)
-NRAS-mutated (15-20%)
-KIT-mutated (10-15%)
-Triple wild-type (40-50%)
-c-KIT expression may be present
-PD-L1 expression for immunotherapy selection
-TERT promoter mutations common.

Molecular/Genetic

Genetic Mutations:
-BRAF mutations (20-30%, mainly V600E)
-NRAS mutations (15-20%)
-KIT mutations (10-15%, especially exons 11 and 13)
-TP53 mutations (40-50%)
-TERT promoter mutations (60-70%)
-CDKN2A deletions (30-40%).
Molecular Markers:
-Chromosomal aberrations common (complex karyotype)
-Copy number variations frequent
-CCND1 amplification
-MITF amplification
-MDM2 amplification
-Microsatellite instability rare
-Tumor mutational burden variable.
Prognostic Significance:
-Breslow thickness most important prognostic factor
-Ulceration indicates poor prognosis
-Mitotic rate >4 mitoses/mm² associated with worse outcome
-Lymphovascular invasion indicates high-risk disease
-BRAF mutations may have better response to targeted therapy
-High tumor mutational burden predicts immunotherapy response.
Therapeutic Targets:
-BRAF inhibitors: Vemurafenib, Dabrafenib (BRAF V600E mutations)
-MEK inhibitors: Trametinib, Cobimetinib
-Immunotherapy: Anti-PD-1 (Pembrolizumab, Nivolumab)
-Anti-CTLA-4: Ipilimumab
-KIT inhibitors: Imatinib (KIT-mutated cases)
-Combination therapies showing improved outcomes.

Differential Diagnosis

Similar Entities:
-Vulvar squamous cell carcinoma (especially pigmented variant)
-Vulvar sarcoma (leiomyosarcoma, angiosarcoma)
-Metastatic melanoma from other sites
-Atypical nevus
-Vulvar carcinoid tumor
-Clear cell carcinoma
-Aggressive angiomyxoma.
Distinguishing Features:
-Melanoma: S-100 and melanoma markers positive
-Melanoma: Cytokeratin negative
-SCC: p63 and cytokeratin positive
-SCC: Melanoma markers negative
-Sarcoma: Mesenchymal markers positive
-Nevus: Symmetry and maturation
-Metastatic: Clinical history important
-Carcinoid: Neuroendocrine markers positive.
Diagnostic Challenges:
-Distinguishing amelanotic melanoma from carcinoma or sarcoma
-Severely atypical nevus vs melanoma in situ
-Metastatic melanoma vs primary vulvar melanoma
-Regressed melanoma with minimal residual tumor
-Collision tumors (melanoma with other malignancies)
-Immunohistochemistry essential for accurate diagnosis.
Rare Variants:
-Amelanotic melanoma (20-30% of vulvar melanomas)
-Desmoplastic melanoma (spindle cell morphology)
-Clear cell melanoma (balloon cell change)
-Nevoid melanoma (deceptively bland appearance)
-Myxoid melanoma
-Signet ring melanoma
-Small cell melanoma.

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

Vulvar excision, [site], measuring [size] cm in greatest dimension

Diagnosis

Vulvar melanoma, [histological subtype]

Classification and Staging

Breslow thickness: [X] mm, Clark level: [I-V], AJCC stage: [stage]

Histological Features

Shows [growth pattern] with [cellular morphology] and [pigmentation status]

Invasion and Thickness

Breslow thickness: [X] mm, invasion to [anatomic level]

Margins

Margins are [clear/involved] with closest margin [X] mm from tumor

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Mitotic Activity

Mitotic rate: [X] mitoses per mm²

Special Studies

IHC: S-100: [positive/negative], HMB-45: [result], Melan-A: [result]

Molecular: [test performed]: [result]

[other study]: [result]

Prognostic Factors

Prognostic factors: Breslow thickness, ulceration status, mitotic rate, LVI

Final Diagnosis

Vulvar melanoma, [subtype], Breslow thickness [X] mm, [Clark level], [AJCC stage]