Definition/General
Introduction:
Primary ovarian melanoma is an extremely rare malignant tumor representing less than 0.1% of ovarian malignancies
Most ovarian melanomas are metastatic from cutaneous or mucosal sites
Primary ovarian melanoma arises from ovarian teratoma or de novo
Highly aggressive tumor with poor prognosis.
Origin:
Arises from melanocytes in mature cystic teratoma (most common mechanism)
De novo development from primitive neural crest cells
Malignant transformation of pre-existing nevus in teratoma
Metastatic melanoma much more common than primary
Neural crest cell migration during embryogenesis explains ovarian location.
Classification:
WHO classification: Primary ovarian melanoma - arising in teratoma or de novo
Metastatic melanoma - from cutaneous, mucosal, or ocular primary
Amelanotic melanoma - lacks melanin pigment
Epithelioid melanoma (most common)
Spindle cell melanoma
Nevoid melanoma (rare).
Epidemiology:
Extremely rare - fewer than 100 primary cases reported worldwide
Age range 20-80 years (mean 45 years)
Associated with teratoma in 70% of primary cases
Unilateral involvement typical for primary
Bilateral suggests metastatic disease
Poor prognosis - 5-year survival <25%.
Clinical Features
Presentation:
Rapidly enlarging pelvic mass (90% cases)
Abdominal pain and distension (70% cases)
Constitutional symptoms prominent
History of cutaneous melanoma (important to exclude metastatic disease)
Ascites may be present
Advanced stage at presentation common.
Symptoms:
Pelvic/abdominal pain (80% cases)
Abdominal distension (60% cases)
Constitutional symptoms: weight loss (50%), fatigue (40%)
Menstrual irregularities (30% premenopausal)
Urinary symptoms from mass effect (20%)
Skin lesions should be carefully examined.
Risk Factors:
Previous cutaneous melanoma (most important - suggests metastatic disease)
History of teratoma
Fair skin, blue eyes
UV exposure history
Dysplastic nevus syndrome
Family history of melanoma
Immunosuppression
Age 40-60 years.
Screening:
No specific screening due to extreme rarity
Thorough skin examination essential to exclude cutaneous primary
Ophthalmologic examination for ocular melanoma
Complete blood count may show anemia
LDH often elevated
S-100 serum levels may be elevated
PET-CT for staging.
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Gross Description
Appearance:
Solid, dark brown to black masses with melanin pigmentation
Variegated cut surface - brown, black, tan areas
Soft to firm consistency
Hemorrhage and necrosis common
Amelanotic variants lack pigmentation (gray-white)
Associated teratoma may be evident.
Characteristics:
Dark pigmentation (melanin) in most cases
Soft, fleshy consistency
Variegated appearance
Hemorrhagic areas common
Necrosis in large tumors
Amelanotic forms lack pigment
May be cystic if arising in teratoma.
Size Location:
Variable size (5-25 cm, average 10-15 cm)
Unilateral involvement typical for primary tumors
Bilateral suggests metastatic disease
May involve ovarian surface
Associated with mature teratoma in primary cases
Peritoneal implants possible.
Multifocality:
Usually solitary when primary
Multiple lesions suggest metastatic disease
Widespread dissemination common
Peritoneal involvement frequent
Lymph node metastases common
Hematogenous spread to multiple organs.
Microscopic Description
Histological Features:
Malignant melanocytes with abundant melanin pigment
Epithelioid cell morphology most common
Large, pleomorphic cells with prominent nucleoli
Intracytoplasmic melanin (may be absent in amelanotic forms)
High mitotic activity
Invasion of ovarian stroma.
Cellular Characteristics:
Large, epithelioid cells with abundant cytoplasm
Pleomorphic, hyperchromatic nuclei
Prominent, cherry-red nucleoli
Intracytoplasmic melanin granules
High mitotic rate (>10/10 HPF)
Bizarre giant cells may be present
Nuclear pseudoinclusions.
Architectural Patterns:
Solid growth pattern predominant
Nested pattern less common
Alveolar pattern may be seen
Spindle cell areas in some cases
Pagetoid spread rare in ovarian location
Organoid pattern uncommon
Melanin deposits between cells.
Grading Criteria:
No formal grading system for melanoma
Ulceration (surface involvement) important prognostic factor
Mitotic rate >10/mm² poor prognosis
Tumor thickness not applicable in ovarian location
Clark level not applicable
Regression rare in ovarian melanomas.
Immunohistochemistry
Positive Markers:
S-100 protein (95-100% positive)
Melan-A (MART-1) (85-90% positive)
HMB-45 (80-85% positive)
SOX10 (95% positive, nuclear)
Tyrosinase (70-80% positive)
MITF (90% positive, nuclear)
Vimentin (positive).
Negative Markers:
Cytokeratins (negative)
PAX8 (negative)
WT1 (negative)
Inhibin (negative)
Calretinin (negative)
CD45 (negative)
Desmin (negative)
CD34 (negative).
Diagnostic Utility:
S-100 and SOX10 most reliable markers (nuclear staining)
Melan-A confirms melanocytic differentiation
HMB-45 particularly positive in epithelioid melanoma
Panel approach essential for diagnosis
Negative epithelial markers exclude carcinoma
Ki-67 shows high proliferation (>50%).
Molecular Subtypes:
BRAF-mutated melanoma (40% cutaneous melanomas)
NRAS-mutated melanoma (20%)
c-KIT-mutated melanoma (mucosal/acral types)
NF1-mutated melanoma
Triple wild-type melanoma
Uveal melanoma (different molecular profile).
Molecular/Genetic
Genetic Mutations:
BRAF mutations (40% of melanomas, V600E most common)
NRAS mutations (20% of melanomas)
c-KIT mutations (mucosal and acral melanomas)
NF1 mutations (15% of melanomas)
CDKN2A loss (common)
TP53 mutations (variable)
TERT promoter mutations (70%).
Molecular Markers:
Ki-67 proliferation index (typically >50%)
p53 expression (variable pattern)
PTEN loss (IHC - 30% of cases)
β-catenin (cytoplasmic/nuclear)
Cyclin D1 expression
p16 loss (CDKN2A)
BRAF V600E (mutation-specific antibody).
Prognostic Significance:
Stage most important prognostic factor
Mitotic rate >10/mm² poor prognosis
Ulceration (surface involvement) adverse factor
Amelanotic melanoma worse prognosis
Primary vs metastatic affects treatment
BRAF mutation predicts targeted therapy response.
Therapeutic Targets:
BRAF inhibitors: vemurafenib, dabrafenib (BRAF V600E mutated)
MEK inhibitors: trametinib (combination with BRAF inhibitors)
Immune checkpoint inhibitors: ipilimumab (anti-CTLA-4), nivolumab, pembrolizumab (anti-PD-1)
c-KIT inhibitors: imatinib (c-KIT mutated melanomas)
Adoptive cell therapy: TIL therapy.
Differential Diagnosis
Similar Entities:
Metastatic melanoma (from cutaneous/mucosal sites)
Poorly differentiated carcinoma
Granulosa cell tumor (pigmented variant)
Steroid cell tumor
Malignant peripheral nerve sheath tumor
Leiomyosarcoma (pigmented)
Clear cell sarcoma.
Distinguishing Features:
Primary melanoma: associated teratoma, unilateral, S-100+, Melan-A+
Metastatic: cutaneous primary, bilateral, same morphology
Carcinoma: cytokeratin+, PAX8+
Granulosa cell tumor: inhibin+, Call-Exner bodies
Steroid cell tumor: inhibin+, lipid-rich cytoplasm
MPNST: S-100 focal, neural markers.
Diagnostic Challenges:
Distinguishing primary from metastatic melanoma (clinical correlation essential)
Amelanotic melanoma mimicking carcinoma
Spindle cell melanoma vs sarcoma
Small biopsy samples may be inadequate
Crush artifact in fragile tumors
Associated teratoma may be missed.
Rare Variants:
Amelanotic melanoma (lacks melanin pigment)
Spindle cell melanoma (desmoplastic variant)
Nevoid melanoma (deceptively bland appearance)
Balloon cell melanoma (clear cell morphology)
Rhabdoid melanoma (rhabdoid features)
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
[Laterality] salpingo-oophorectomy, measuring [size] cm
Diagnosis
[Primary/Metastatic] melanoma of ovary
Classification
[Epithelioid/Spindle cell/Mixed] melanoma, [melanotic/amelanotic]
Histological Features
Shows malignant melanocytes with [epithelioid/spindle] morphology, mitotic count [X]/mm², [pigmented/non-pigmented]
Size and Extent
Tumor size: [X] cm, [confined to ovary/extraovarian extension], [associated teratoma present/absent]
Surgical Margins
Surgical margins: [clear/involved]
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined
Special Studies
IHC: S-100 (+), SOX10 (+), Melan-A (+), HMB-45 (+), cytokeratins (-), Ki-67 [X]%
Molecular: BRAF [result], NRAS [result] if performed
Clinical correlation required to exclude metastatic melanoma from cutaneous/mucosal primary
Prognostic Factors
Type: [epithelioid/spindle]; Size: [X] cm; Mitoses: [X]/mm²; Primary vs metastatic: [status]
Final Diagnosis
[Primary/Metastatic] melanoma of [laterality] ovary