Incidence and mortality

Vulvovaginal (vulvar/vaginal) melanomas are often treated as one entity, but the incidence and mortality of each differs. Although we consider them “mucosal” melanomas, it is unclear whether vulvar and vaginal melanomas are true “mucosal” melanomas. In 2020, an estimated 6120 vulvar cancers were diagnosed in the United States ; and on average, 1350 vaginal cancers are diagnosed each year. Melanoma accounts for only 6% of vulvar cancers and 9% of vaginal cancers in the Unites States, totaling approximately 500 newly diagnosed cases of vulvovaginal melanoma per year. The median age at diagnosis for vulvovaginal melanoma is 68 years. The median age at diagnosis for vulvar melanoma is slightly younger than that for vaginal melanoma. The range of ages is much wider for vulvar melanomas, with cases reported in girls as young as 10 years old and women as old as 99 years of age. At least 85% of women with vulvar melanoma are white, 4%–12% are Hispanic, and approximately 1%–4% each are African-America, Asian, or of other races. It is more difficult to precisely ascertain race distribution for vaginal melanomas ; however, a large SEER dataset analysis noted that approximately 9.5% of women with vaginal melanoma are African-American, compared to 3.5% of those with vulvar melanoma. The age-adjusted annual incidence rates for vulvovaginal melanomas are 1.9 for whites and 1.0 for non-whites per million women.

Vulvovaginal melanoma is associated with a worse overall survival (OS) compared to other vulvar cancers, as well as compared to cutaneous melanomas. The 5-year OS rate for vulvar melanoma is 59% compared to 76% for squamous cell carcinoma and 92% for adenocarcinoma. Survival appears to vary based on race, as well as whether the primary site is the vulva or vagina ( Table 17.1 ). It is unclear, however, why African-American women have worse survival. Vulvovaginal melanomas seem to be diagnosed at more advanced stages compared to other vulvar cancers, as well as cutaneous melanomas, which may explain the differences in survival as a group overall. Individually, vaginal melanomas present at more advanced stages compared to vulvar melanomas, likely due to anatomic location, leading to delayed diagnoses and worse survival. For vulvar melanomas, survival seems to be worse stage-for-stage compared to squamous cell carcinomas and adenocarcinomas. It also seems that stage-for-stage, women with vaginal melanoma have a worse survival compared to those with vulvar melanoma.

Etiology/risk factors

Vulvovaginal melanomas are not associated with chronic sun damage (CSD) as are acral and other non-CSD skin melanomas and are generally categorized as mucosal melanomas. There are no known etiologic or well-established risk factors for vulvovaginal melanomas. There are a few reported inherited genetic mutations that increase the lifetime risk of cutaneous and uveal melanomas. These include CDKN2A, CDK4, POT1, TERT, BRCA1&2, BAP1, MITF, XPC, XPD, XPA, PTEN, and TP53. There are no reports, however, on the association of risk of vulvovaginal, or mucosal melanomas in general with these specific hereditary syndromes. A maxillary mucosal melanoma in a 21-year-old with Li–Fraumeni syndrome has been reported.

A retrospective analysis of 81 genital or anorectal mucosal melanomas (GAMMs) over a 33-year period compared to 293 cutaneous melanomas attempted to address the familial/hereditary risk of these mucosal melanomas. The majority of the GAMM cases were women (88%) and were vulvar/vaginal melanomas (68%). Other cases included anorectal, penile, and cervical melanomas. The rate of cases with multiple other primary melanomas was similar (6% for GAMM and 5.3% for cutaneous melanoma). A family history of any-type melanoma was noted in 18% of the GAMM cases compared to 7.5% of the cutaneous cases. Germline testing for CDKN2A was performed in 17 of the GAMM cases, and none of these patients had a germline mutation. Although a germline mutation was not identified, the authors suggested that GAMMs are part of familial/hereditary syndromes based on the increased family history of melanoma in GAMM patients. This very small retrospective series is far from conclusive or definitive. However, careful vulvovaginal examination along with the recommended whole-body skin examinations is prudent in patients with known germline mutations and strong familial history of any type of melanoma. Biopsy of any new or concerning (or even if not too concerning) vulvovaginal lesions should be performed in patients with these hereditary syndromes.

Gross features

In majority of the cases, primary vulvar melanomas are characterized by a lesion, which is frequently ulcerated. At least focal pigmentation is noted in majority of the cases. However, some cases may lack pigmentation. In those arising from preexisting melanosis or melanocytic lesion, a recent change in color, size, and shape is a clue to malignant transformation.

Microscopic features

Primary melanomas of the vulva display histopathologic features akin to their cutaneous counterparts, and the American Joint Committee on Cancer (AJCC) recommends vulvar melanomas to be analyzed and staged according to the criteria established for primary cutaneous melanomas. The histopathologic features to be assessed and reported in vulvar melanomas are summarized in Table 17.2 . Majority of the primary vulvar melanomas are invasive. However, in rare instances, the patient may have long-standing melanoma in-situ before developing invasive disease. Multifocal disease and skip lesions are common in vulvar melanomas.

Primary vulvar melanomas are characterized by architectural and cytopathologic abnormalities. The growth pattern of primary vulvar melanomas is most commonly lentiginous: contiguous proliferation of atypical single melanocytes along the basal layer of stratified squamous epithelium interspersed by a few nests ( Fig. 17.2 ), or nodular: absence of a radial growth phase, in which the intraepithelial component is either absent or does not extend beyond the invasive component ( Fig. 17.3 ). Rare cases of superficial spreading type, characterized by proliferation of predominantly nests of varying sizes and shapes with pagetoid scatter of atypical melanocytes within the suprabasal layers of stratified squamous epithelium ( Fig. 17.4 ) may also be seen, particularly among those that arise from cutaneous surfaces. The in-situ/ intraepithelial component is typically characterized by poor circumscription as well as asymmetry ( Fig. 17.5 ) and often involves the adnexal structures such as vaginal glands and folliculo-sebaceous units extensively.

Primary vulvar melanoma with lentiginous pattern of growth, characterized by contiguous proliferation of atypical single melanocytes along the basal layer of stratified squamous epithelium.

Primary vulvar melanoma, nodular type. The intraepithelial component or in-situ melanoma is either absent or does not extend beyond the invasive component; i.e., there is no radial component.

Primary vulvar melanoma, superficial spreading type. (A) The in situ component is characterized by a proliferation of predominantly nests of varying sizes and shapes with pagetoid scatter of atypical melanocytes within the suprabasal layers of stratified squamous epithelium. (B) MART1/Ki67 cocktail immunohistochemical stain highlights the broad radial component, i.e., the in situ component extending beyond the invasive melanoma.

Vulvar melanoma-in situ. (A) Subtle proliferation of small single melanocytes along the basal layer of stratified squamous epithelium with poor circumscription. (B) Melanocytic cocktail (HMB45 and anti-tyrosinase) immunohistochemistry highlights the in situ melanoma.

The extent of dermal/submucosal involvement by melanoma may be evaluated using various methods including (i) Breslow/tumor thickness, (ii) Clark/anatomic level and (iii) Chung level ( Fig. 17.6 , Table 17.3 ). Of these, the AJCC has incorporated the Breslow/ tumor thickness in staging of primary melanomas. In view of the lack of well-defined papillary dermis in mucosae, Clark level is not applicable to primary vulvar melanomas; the term “anatomic” level is recommended instead ( Table 17.2 ). The invasive component is characterized by irregular proliferation of melanocytes within the dermis and/or submucosa with varying degrees of cytologic atypia, absence of maturation of melanocytes with deeper descent and mitotic activity, including atypical forms ( Fig. 17.7 ).

Methods for evaluating extent of dermal/subdermal involvement.

Invasive melanoma with epithelioid cytology, patchy cytoplasmic pigmentation and atypical mitotic figure with multipolar spindle (left lower).

The maximum depth of invasive tumor, referred to as Breslow thickness in primary melanomas of cutaneous origin and tumor thickness in melanomas of mucosal origin is the parameter of most prognostic importance. It is typically measured from the (i) top of granular layer in keratinized stratified squamous epithelium, (ii) top of nucleated layer in nonkeratinized stratified squamous epithelium or (iii) base of ulcer to the deepest extent of tumor. In particular, tumor thickness > 2 mm and mitotic rate of ≥ 2/mm ² of the invasive component correlated with poor disease-specific survival (DSS) in a retrospective analysis of 100 cases of primary vulvar melanomas.

Melanoma-associated ulceration ( Fig. 17.8 ) is more frequent in primary vulvar melanomas (in up to 50%) compared to primary cutaneous melanomas. Even though ulceration correlated with overall and DSS by univariate analysis, it did not emerge as an independent prognostic parameter of overall and disease-specific survival after multivariable analysis. Lymphovascular invasion (LVI) ( Fig. 17.9 ), neurotropism or perineural invasion (PNI) ( Fig. 17.10 ) and microscopic satellitosis may also be present.

Primary vulvar melanoma with spindled cytology and extensive ulceration.

Lymphovascular invasion in primary vulvar melanoma, characterized by presence of atypical cells within lumina lined by flattened endothelial cells.

Perineural invasion in primary vulvar melanomas. (A) Small caliber nerve fiber completely encircled by melanoma cells. (B) MART1 immunohistochemical study highlights the melanoma cells and perineural invasion.

The melanoma cells may be of epithelioid or spindled cytology and are typically characterized by varying amounts of pale amphophilic or eosinophilic cytoplasm, fine-dusty pigmentation, ovoid nuclei, vesicular chromatin and prominent nucleoli. In some cases, cytoplasmic pigmentation may be completely absent. Infrequently, the melanoma cells may be of nevoid cytology in which the cytologic atypia is subtle with small ovoid hyperchromatic nuclei, condensed chromatin and inconspicuous nucleoli.

In limited biopsies or when the cytoplasmic pigmentation is minimal, melanocytic origin may be difficult to appreciate; thus, requiring use of immunohistochemical studies. Employing a panel of immunohistochemical markers, including melanocytic markers such as MelanA, HMB45, tyrosinase, MITF, S100 and SOX10; keratinocytic markers including cytokeratin cocktail(s), p63 and p40; as well as vascular markers including CD34, CD31, and ERG. Typically, primary melanomas of the vulva tend to be MelanA + HMB45-patchy + tyrosinase + MITF + S100 + SOX10 + cytokeratin cocktail(s)- p63- p40- CD34- CD31- ERG-. In some advanced cases, the tumors may have undergone de-differentiation resulting in loss of expression of melanocytic markers with acquisition of keratinocytic markers such as cytokeratin and less likely, p63. In such scenarios, SOX10 remains the most sensitive marker to demonstrate melanocytic differentiation. SOX10 may also be used as an ancillary test to determine margin status. Presence of LVI may be highlighted using endothelial markers such as D2-40 or CD31 as well as cocktails such as SOX10/CD31 and MITF/D2-40.

Differential diagnoses

Majority of vulvar melanomas are pigmented; therefore, the clinical differential diagnoses include all pigmented or dark lesions of the vulva of reactive and neoplastic origin ( Fig. 17.11 ). Pigmented vulvar lesions may be present in up to 12% of white women, of which 10%–19% may be melanocytic in origin. Documentation of the following features is important for optimal diagnosis, management and follow-up: type: rash vs. lesion and palpability; relationship with surrounding skin: well-defined vs. merging; the precise anatomic location(s); color: dark, reddish/ violaceous, brown-black and intralesional variability; multiplicity; size; shape; evidence of associated disease such as lichen sclerosus; nature of specimen submitted: excisional biopsy (recommended for small lesions to include a rim of normal skin) vs. partial biopsy and location of biopsy site (in large lesions). It is also imperative to document any underlying diseases such as lichen sclerosus, diabetes, systemic lupus erythematosus, lichen planus, etc.

Clinicopathologic differential diagnoses of pigmented vulvar lesions.

Molecular findings

When compared to primary cutaneous melanomas, genomic instability is more frequent in mucosal melanomas, manifesting in the form of copy number changes and structural variations, whereas point mutation burden is overall lower. Structural variations targeting TERT , CDK4 , and MDM2 genes are common. Whole-genome sequencing of mucosal melanomas has revealed almost 10-fold increased frequency of single nucleotide variants when compared to primary cutaneous melanomas. Commonly mutated genes include SF3B1 , NRAS , NF1 , KIT , TP53 , SPRED1 , BRAF , ATRX , HLA-A, and CHD8 of which NF1 and KIT co-mutations can also occur. Preferential mutations of TERT and ATRX correlated with shorter telomere lengths. BRAF mutations are more frequent in primary vulvar melanomas compared to other types of anogenital melanomas, likely due to cutaneous origin.

Signs and symptoms

The presenting signs and symptoms differ for women with vulvar compared to vaginal melanomas due to anatomic location. The most common presenting symptoms for vulvar melanomas are the presence of a vulvar mass or nevus/“mole” in 16%–25% of cases, pain in 5%–30%, bleeding in 17%–24%, and pruritis and/or irritation in 16%–24%. Many patients will have more than one “presenting” sign or symptom. The labia majora or minora alone will be the primary site in 40%–70% of cases. These masses can also be located primarily on the clitoris or perineum. Multiple sites are often involved, and the majority of cases are localized (51%–77%). Inguinofemoral nodal involvement occurs in 9%–34% of cases, but only 2%–3% are clinically suspicious.

Vaginal melanomas most commonly present with vaginal bleeding in 60%–100% of cases with vaginal masses, as well as pain or discharge. Approximately 10% of patients will have no symptoms, and the malignancy is discovered on physical exam. The anterior vaginal wall is the primary location in 45% of cases, the posterior wall in 32%, and the lateral walls in 24%, with larger tumors occupying greater aspects. The majority of cases (60%) are located in the lower third of the vagina. Pelvic and/or inguinal nodal involvement occurs in 25%–50% of cases. The majority of lesions are hyperpigmented.

Physical exam findings

The vast majority of vulvovaginal melanomas are hyperpigmented. There are, however, amelanotic cases. Any new hyperpigmented lesion or tumor-forming lesion on the vulva or vagina should be biopsied. Any preexisting nevi that have changed in appearance should also be biopsied. A careful inspection of the vulva, vagina, and cervix is critical. An assessment of the mobility of lesions should be performed, as well as involvement of the urethra and/or anus. The assessment of vaginal masses is more difficult. Careful palpation of inguinofemoral nodal regions should be performed. A full-body skin examination by a dermatologist is also recommended. Routine cystoscopy or proctoscopy is unnecessary unless there are symptoms that may warrant such examinations or if there is obvious involvement on physical examination.

Tumor markers

There are no known validated serum tumor markers in the diagnosis and/or surveillance of melanomas, including vulvovaginal melanomas.

Imaging

Routine imaging is not recommended for patients diagnosed with clinical stage I or II cutaneous melanoma in the absence of symptoms. Vulvovaginal melanomas are slightly different than cutaneous melanomas and present with regional or distant spread in 40%–60% of patients. Pelvic MRI may provide important information regarding the local extent of disease. However, this is not essential for smaller mobile vulvar melanomas that are unifocal and limited to the labia and/or clitoris. Pelvic MRI should be performed for vulvar melanomas that are large, are encroaching on other structures such as urethra and/or anus, are multifocal, or are fixed. Pelvic MRI should be performed for all vaginal melanomas, as physical examination is limited, and is possibly the best method to follow treatment responses.

Evaluation for distant metastasis can be accomplished with either multidetector computed tomography (CT) or PET/CT imaging in cutaneous melanoma and is recommended for stage III/IV cases or to assess symptoms. It is unclear whether the addition of PET scanning offers a greater value over good-quality CT imaging. CT +/− PET imaging is likely of low yield in melanomas confined the labia and/or clitoris that are unifocal. However, CT (+/−PET) imaging should be performed in all patients with vaginal melanomas, as they are associated with higher risk of distant metastasis at presentation. CT (+/−PET) imaging should also be performed in vulvar melanomas that are larger, fixed, involve other structures, or involve documented nodal metastases. Brain MRI should also be performed in patients with evidence of nodal metastases, other distant metastases, or symptoms.

Diagnostic tests

The key to proper diagnosis is biopsy with pathologic assessment by a dermatopathologists with expertise in melanoma. The following are important features to note in pathology reports for cutaneous melanomas: clinicopathologic type of melanoma, tumor thickness using Breslow depth (mm), presence or absence of ulceration, number of mitoses per square millimeters (mm ² ), presence of microsatellites, and the status of all margins. The significance of other features is less clear. Immunohistochemical testing may offer guidance in cases that are not clear-cut, as described in the “Pathology” section above.

Different melanoma subtypes harbor different molecular alterations. Acral melanomas, mucosal melanomas, and those associated with CSD have different molecular profiles than those arising from skin without CSD. BRAF and NRAS mutations are much more frequent in non-CSD melanomas and less common in the other melanomas, including mucosal melanomas. KIT alterations are seen more frequently in CSD-associated, acral, and mucosal melanomas ( Table 17.3 ). Curtin and colleagues noted BRAF mutations in 56% of non-CSD melanomas, and no KIT alterations were found in any of these melanomas. In contrast, BRAF mutations were seen in 3% of mucosal melanomas, with 39% having a KIT alteration, either mutation or amplification. In a phase 2 study, KIT alterations were seen in 25% of mucosal melanomas. Mutations in BRAF, NRAS, and GNAQ were detected in 9%, 12%, and 0% of mucosal melanomas, respectively. Hou and colleagues compared the molecular profiles of 51 vulvovaginal melanomas to 2253 nongynecologic melanomas and found BRAF mutations in 26% of the vulvovaginal melanomas, which is the highest reported rate KIT alterations were found in 22% of the vulvovaginal melanomas. Additional mutations were found in NRAS (4%) and APC (15%) and in other genes.

Molecular profiling is unlikely to assist in the management of patients with stage I or II melanomas. The National Comprehensive Cancer Network (NCCN) does not recommend routine molecular profiling for stages I and II resected melanomas but does recommended it for stage III/IV, unresectable, and/or recurrent melanoma to help guide treatment. This principle would apply to vulvovaginal melanomas, but considering the rarity of these tumors, it is reasonable to at least perform molecular analysis for KIT , BRAF, and NRAS in all cases. Broader genomic analysis when obtaining molecular testing, if possible, may provide a better understanding of this disease and also identify other potentially targetable mutations and/or triage cases for select clinical trials. The value of routine testing for programmed death-ligand 1 (PD-L1) expression in melanoma is unclear and not recommended by the NCCN.

The initial workup for newly diagnosed vulvovaginal melanoma is summarized in Table 17.4 .