Table of Contents
Definition / general | Terminology | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Additional referencesCite this page: Nagarajan P, Pernick N. Melanoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/vulvamelanoma.html. Accessed March 30th, 2023.
Definition / general
- Melanoma constitutes about 4 - 10% of all vulvar malignancies (Int J Gynecol Cancer 2013;23:1118)
- Second most common malignant vulvar neoplasm after squamous cell carcinoma
- Melanoma may originate in vaginal wall without involvement of vulva, uterine cervix or other surrounding structures (Gynecol Obstet 2013;3:183)
Terminology
- Also called primary malignant melanoma of vagina
Epidemiology
Vulva:
Vagina:
- Incidence: ~0.2 per 100,000 women (Gynecol Oncol 2011;122:612, Obstet Gynecol 2007;110:296)
- Caucasian women are more commonly affected
- Age at diagnosis:
- Fifth to seventh decade
- Median: 60.5 years
Vagina:
- Melanomas arising from female urogenital tract occur primarily in vulva (95%) and vagina (3%)
- Primary melanoma of vagina is extremely rare and aggressive
- Constitutes less than 3% of vaginal cancers and only 0.3 - 0.8% of all melanomas in women (Gynecol Obstet 2013;3:183)
- Occurs mainly in postmenopausal women, sixth and seventh decades of life (J Chin Med Assoc 2011;74:376)
- Rare cases in young patients (Int J Pathol 2009;7:102)
Sites
- In vulva, labia (minora and majora) are the most commonly affected sites, followed by clitoris in some studies (Ann Surg Oncol 2015;22:1959)
- In vagina, more commonly in the lower third of vagina and on anterior vaginal wall (Gynecol Obstet 2013;3:183, J Chin Med Assoc 2011;74:376)
Etiology
- In vulva, appears to originate from melanocytes present in vaginal mucosa (Gynecol Obstet 2013;3:183)
Clinical features
Vulva:
Vagina:
- May be discovered during routine gynecologic examinations
- Usually present as pigmented and sometimes nonpigmented lesions (macules, patches, nodules)
- May be ulcerated
- May present with multiple lesions (satellitosis)
Vagina:
- Vaginal bleeding or discharge (J Chin Med Assoc 2011;74:376)
Diagnosis
- In vulva, histologic examination is essential to diagnosis
- In vagina, diagnosis is based on biopsy / resection specimen with clinical history and imaging
Laboratory
- In vulva, serum lactate dehydrogenase levels > 200 to 225 U/L are associated with poor survival
Radiology description
Vulva:
Vagina:
- CT / MRI for staging
- Lymphoscintigraphy for identification of sentinel nodes (Wien Klin Wochenschr 2006;118:286, Cancer 2002;94:486)
Vagina:
- Small tumors can be difficult to assess on CT scan
- Use of fluorodeoxyglucose (FDG) as a glycolytic indicator in tumor altered metabolism in PET / CT study can aid in early diagnosis and staging
Prognostic factors
Vulva:
Vagina:
- Age: patients ≤ 68 years at diagnosis have a better prognosis
- Histologic parameters:
- Breslow depth (tumor thickness) and feasibility of complete resection with appropriate margins (J Am Acad Dermatol 2012;67:598)
- Mitotic rate
- Ulceration
- Margin status: free margin of ≥ 1.0 mm is associated with better prognosis (Ann Surg Oncol 2015;22:1959)
- Stage:
- Patients with localized disease (stage 0, I, II) have a better prognosis (Obstet Gynecol 2007;110:296)
- Higher number of positive lymph nodes is associated with worse prognosis
- Strong and diffuse c-kit expression may be associated with a worse prognosis (Int J Mol Med 2014;33:784)
Vagina:
- Common sites of recurrence of vaginal melanoma are vagina, vulva, groin
- Prognosis poorer than cutaneous melanomas
- 5 year survival rate of 13 - 19% is poor compared to vulvar and cutaneous melanomas
- 50% have positive lymph nodes and nearly 20 percent have distant metastases at presentation
- Mean survival is 8.5 months after recurrence (Gynecol Obstet 2013;3:183)
Case reports
Vulva:
Vagina:
- 23 year old woman with primary amelanotic melanoma of vulva (Indian J Surg Oncol 2012;3:36)
- 35 year old pregnant woman with recurrent vulvar melanoma (J Low Genit Tract Dis 2013;17:223)
- 50 year old woman with nodular vulvar melanoma (J Obstet Gynaecol India 2012;62:87)
Vagina:
- 31 year old woman with primary amelanotic melanoma (Onkologie 2008;31:474)
- 2 rare cases of malignant melanoma (Indian J Pathol Microbiol 2003;46:71)
- Primary amelanotic melanoma diagnosed by immunocytochemistry (Int J Gynaecol Obstet 1989;29:159)
Treatment
Vulva:
Vagina:
- Surgical resection with adequate margins is the principal management
- Radiation
- Chemotherapy
- Topical imiquimod therapy
Vagina:
- Many different treatment modalities have been tested but there is no standard therapeutic approach
- Surgery provides local control; procedures include wide local excision, radical surgery (total vaginectomy with or without vulvectomy), pelvic extenteration
- Sentinel lymph node biopsy (SLNB) provides important prognostic and staging data with minimal morbidity
- Routine lymph node dissection is not recommended because morbidity is high and prophylactic lymphadenectomy has not been shown to improve survival (J Chin Med Assoc 2011;74:376)
- Difficult to get negative surgical margins without pelvic exenteration due to multifocality and anatomic constraints
- Surgery may be combined with radiotherapy or chemotherapy
- Cytotoxic chemotherapy, IFNα, IL2, ipilimumab and vemurafenib have been used in some cases (Gynecol Obstet 2013;3:183)
- IFN is used as adjuvant therapy in patients without disease but at high risk of systemic recurrence (J Chin Med Assoc 2011;74:376)
Clinical images
Gross description
Vulva:
Vagina:
- Preservation of specimen orientation is critical for thorough evaluation of peripheral and deep tissue margins
Vagina:
- Can have raised, ulcerated and irregular appearance (Gynecol Obstet 2013;3:183)
- Can present as polypoid lesion or a nodule
- Usually pigmented with black to brown gross appearance but 40% cases are amelanotic
Microscopic (histologic) description
Vulva:
Vagina:
- Vulvar melanomas are evaluated and staged similar to cutaneous melanomas
- Most of the melanomas involving the cutaneous surface only are traditionally classified based on the histologic type (superficial spreading being the most common type at this site)
- However, when mucosal surfaces are involved, classifying them as mucosal lentiginous type would be most appropriate (CAP: Cancer Protocol Templates [Accessed 9 October 2017])
- Following histologic parameters should be included in the report:
- Histologic type
- Clark (anatomic) level
- Breslow thickness (primary tumor thickness, if completely mucosal)
- Presence of radial or nontumorigenic growth phase
- Presence of vertical or tumorigenic growth phase
- Mitotic rate per millimeter squared
- Presence of ulceration (the microscopic size of ulceration is often included)
- Must exercise caution in resection specimens as the ulceration might represent prior biopsy site
- Presence of regression (mention percentage of regression, is associated with a poor prognosis if > 75%)
- Presence of lymphovascular space invasion (the use of MART1 / MelanA plus D2-40 or CD34 immunostains is more sensitive)
- Presence of perineural invasion (size of nerves involved should be mentioned)
- Presence of microscopic satellitosis
- Presence of tumor infiltrating lymphocytes (presence or absence; brisk vs. nonbrisk)
- Presence of associated melanocytic nevi
- Predominant cytology of the tumor cells
- Status of surgical margins (for in situ and invasive melanoma)
- Sentinel lymph nodes:
- Examination of several H&E sections cut at various depth into the paraffin block and the use of immunohistochemistry for melanocytic markers are routinely employed to detect single cell metastases
Vagina:
- Diffuse infiltration of large, pleomorphic, epithelioid and spindle shaped tumor cells in vaginal mucosa
- Cells have eosinophilic cytoplasm, large oval or pleomorphic hyperchromatic nuclei, may have multiple nuclei with distinct nucleoli (J Clin Pathol 2004;57:986)
- Amelanotic melanomas can be difficult to diagnose on histology
- Junctional activity, if present, raises suspicion for melanoma (Int J Pathol 2009;7:102)
- Immunohistochemical stains are helpful if no melanin pigment or junctional activity (Gynecol Obstet 2013;3:183)
Microscopic (histologic) images
Contributed by Priya Nagarajan, M.D., Ph.D.
Contributed by Mayank Gupta, M.D.
Cytology description
Vagina:
- Loose aggregates of large, pleomorphic, polygonal to spindle shaped tumor cells with ill defined cytoplasmic borders, granular hyperchromatic nuclei and conspicuous nucleoli
- Multinucleated tumor cells and mitoses can be seen (J Clin Pathol 2004;57:986)
Positive stains
Vulva:
Vagina:
- S100: cytoplasmic and nuclear
- MelanA / MART1, gp100 / PMEL: cytoplasmic
- HMB45: cytoplasmic, patchy expression in epithelioid melanomas
- Tyrosinase: cytoplasmic
- MITF (microphthalmia associated transcription factor): nuclear
- SOX10: nuclear
- p75 NGFR, nerve growth factor receptor: cytoplasmic (J Am Acad Dermatol 2010;63:852)
- NKI-C3 (CD63): cytoplasmic, not specific and not commonly used
- NSE: cytoplasmic, not specific and not commonly used
- Vimentin, CD99: cytoplasmic, nonspecific but CD99 may be the only positive stain in some poorly differentiated melanomas (Am J Dermatopathol 2007;29:169)
- Spindle cell melanomas, desmoplastic melanomas and poorly differentiated melanomas may not express MelanA / MART1, HMB45 or tyrosinase but often express S100, SOX10 and p75 NGFR
- Melanomas, regardless of histology, may not express typical melanocytic markers (Hum Pathol 2005;36:1016, Dermatol Online J 2009;15:7)
Vagina:
- S100, HMB45, vimentin
- Melanin pigment can be demonstrated with Fontana-Masson silver staining (J Clin Pathol 2004;57:986)
- MelanA, tyrosinase, MITF
Negative stains
Vulva:
Vagina:
- Cytokeratins: usually negative; focal expression is not uncommon; should be interpreted with caution (Anticancer Res 2004;24:3203)
- Vascular / endothelial markers: CD34, D2-40
- Desmin
Vagina:
- Cytokeratin, epithelial membrane antigen (EMA), desmin, myoglobin, smooth muscle actin, CD34, CD68
- Amelanotic melanomas are negative for melanin pigment (J Clin Pathol 2004;57:986)
Molecular / cytogenetics description
Vulva:
Vagina:
- KIT mutations and amplifications appear to be more common in vulvar melanomas (Mod Pathol 2014;27:1386)
- NRAS mutations are also seen
- BRAF V600E mutations are rare (Biomed Res Int 2015;2015:303791); see also Stains - BRAF
- May have copy number alterations 1q and 6p (Acta Oncol 2004;43:421)
Vagina:
- NRAS mutations and KIT amplifications occur in both vaginal and vulvar melanomas
- KIT mutations appear to be more specific for vulvar melanoma
- BRAF mutations are absent in both vaginal and vulvar melanomas originating from the vulva or vagina (Mod Pathol 2014;27:1386)
Differential diagnosis
Vulva:
Vagina:
- Dermatofibroma:
- Epithelial induction with hyperpigmentation
- Other pigmented lesions:
- Including common or atypical vulvar nevi of the genital type
- Have architectural disorder but lack cytologic atypia, dermal mitosis and other features of melanoma including ulceration
- Pigmented epidermal neoplasms:
- Postinflammatory pigmentary alteration
- Vascular lesions:
- Such as angiokeratoma, Kaposi sarcoma
- Vulvar melanosis, mucosal melanotic macule (J Am Acad Dermatol 2014;71:1241, J Low Genit Tract Dis 2013;17:320)
Vagina:
- Hemangioendothelioma
- Malignant fibrous histiocytoma (MFH)
- Malignant peripheral nerve sheath tumor
- Sarcoma (Gynecol Obstet 2013;3:183)
- Undifferentiated carcinoma