Melanomas are tumors that arise from the melanocytes or the pigment cells (Mihajlovic et al. 739). A common form of melanoma is the primary mucosal melanoma that is found in the mucosal lining of the urogenital tract, respiratory tract and the gastrointestinal tract (Mihajlovic et al. 739). Primary malignant vaginal melanoma is one such type of mucosal malignant melanoma that is very rare (Lin et al. 376) and very aggressive in nature (Androutsopoulos et al. 1). The first case of primary malignant vaginal melanoma was reported in 1887 and modern literature has noted about 500 cases, globally (Chen et al. 1585). This number constitutes 0.3% to 0.8% of melanomas in women, less than 3% of vaginal malignant tumors and less than 10% of female genital tract melanomas (Androutsopoulos et al. 1; Schmidt et al. 285). The disease is often observed in elderly women in their 6th or 7th decade of life (Moodley et al. 687; Baloglu et al. 819; Albareda et al. 50), where the lymph node infiltration and distant metastasis reach 50% and 20%, respectively (Kühn et al. 742). The disease presents poor prognosis even in case of localized lesions (Chauhan et al. 510), whereas lymph node and distant metastasis have been linked to reduced chance of survival (Chauhan et al. 510; Ng et al. 64). Though there is no effective treatment strategy yet in place (Androutsopoulos and Decavalas 1), current treatment plan includes radical surgery, chemotherapy, immunotherapy, combination therapeutics and palliative care (Lin et al. 377; Hardie and Siddiqui 206). Radiotherapy is used as adjuvant therapy, as data suggest that radiotherapy does not bring overall benefit being the sole therapy (Kirschner 1485). Evidence from case reports suggests that the overall five-year survival rate of primary malignant vaginal melanoma patients is 0-25% (Kühn et al. 742), irrespective of the type of treatment regime followed (Hinde et al. 280).
Epidemiology and associated risk factors
According to a review by Leitao et al., the authors found that a period of 29 years registered only 37 cases of malignant vaginal melanoma (S117). Similarly, in a study by the Gynecologic Oncology Group (GOG) spanning 17 years recorded only 43 primary malignant vaginal melanomas (Leitao et al. S117). The annual estimated incidence of primary malignant vaginal melanoma is 0.026 per hundred thousand women (Kühn et al. 740) and 0.46 per million women (Chaudhuri et al. 1). A statistical analysis by Shah et al. (1040) on the epidemiology of malignant vaginal cancer indicated that among the 2,531 cases taken under study, non-Hispanic whites constituted 66% of the registered cases. African American women, Hispanic women, Asian/Pacific Islanders and others constituted 14%, 12%, 7% and 1% of the total number of malignant vaginal cancer cases. Hu et al. (153) suggested that the low difference in the incidence rates of various racial and ethnic group indicates that race is not a risk factor for primary malignant vaginal melanoma.
The incidence rates have been found to be very high for post-menopausal women (Shah et al. 1040), ranging between 2.08/100,000 for 60-60 year old women and 4.43/100,000 for 80-90 year old women. The average age during first diagnosis is found to be 57 years (Androutsopoulos and Decavalas 1). Socioeconomic factors such as level of education, income and poverty seem to have no influence on the incidence rates (Shah et al. 1040). Human papilloma virus (HPV) 16 infection has been suggested as a risk factor for malignant vaginal cancer (Dittmer et al. 173).
Etiology and pathogenesis
Currently, the mechanism of pathogenesis and etiological factors are unknown for primary malignant vaginal melanomas (Androutsopoulos and Decavalas 1). This mystery extends to other types of melanomas. Whiteman et al. proposed a series of theories to elucidate the possible causes of melanomas. The difference in the incidence rate of occurrence of melanoma across sun-exposed and unexposed sites on the body suggest that the anatomic location of the melanocytes determines the mechanisms in which they interact with the UV radiation (Whiteman et al. 881). The theories suggested that even though UV radiation does not have a strong causal relationship with melanomas (Hu et al. 153), the marginally increased prevalence of the disease in Caucasians acts as a compelling evidence to reconsider the decision (881).
The theories also propose that melanomas with BRAF mutations could be spread out in multiple locations in the body, implicating the gene in triggering the formation of nevi (skin abnormalities), though not enough to cause melanomas (Whiteman et al. 885). However, primary malignant vaginal melanoma is a mucosal melanoma and mucosal melanomas are more often associated with KIT gene mutations rather than BRAF mutations, which are more often found in cutaneous melanomas (Whiteman et al. 885). KIT encodes for a protein called c-KIT (Mihajlovic et al. 740). 39% of the cases and 15.6% of the cases in 2 different studies on mucosal melanoma showed multiple copies of KIT (Mihajlovic et al. 740). Another theory suggests that the causative factor could be micro-environmental in nature and not associated with ultraviolet radiation (Hu et al. 155).
Clinical symptoms and signs
A tumor is designated as primary malignant vaginal melanoma when the primary site of the tumor is the vagina, which commences from the vulva and ends upward at the uterine cervix (Hacker et al. S97). Primary malignant vaginal melanoma usually occurs in the anterior wall of the vagina, typically in the lower one-third region (Chaudhuri, et al. 2; Kühn et al. 740; Chauhan et al. 509; Alaoui et al. 1; Samolis et al. 233; Moodley et al. 685; ). However, there are several case reports that suggest the tumor could also be present in the upper one-third region (Ng et al. 63; Chen et al. 1585; Lin et al. 376; Baloglu et al. 820; Androutsopoulos et al. 1; Hinde et al. 279; Takehara et al. 1; ). In a study by Xia et al. (150), 54.6% of the patients had tumors in the distal one-third of the vagina. Gökaslan et al. (244) and Albareda et al. (50) have reported malignant vaginal melanoma cases presenting lesions on the posterior wall near the vaginal entrance while Shah (1040) reported the presence of pigmented tumors in the middle and lower thirds of the vagina. Common symptoms of primary malignant vaginal melanoma are abnormal vaginal bleeding (63.6%-80%), presence of vaginal mass that is easily palpable (15-15.9%), pain (2.3%-10%) and discharge from the vagina (15.9-25%) (Androutsopoulos et al. 2; Xia et al. 150).
Diagnosis
Upon visual inspection, the tumor may appear nodular (pigmented mass of brown, blue or black) or polypoid (polyp-like) in nature. The tumor usually bleeds on touch and is ulcerated in many patients (Mihajlovic et al. 741). Though the tumor is often found as a pigmented mass, amelanotic tumors have also been recorded in patients, which often leads to misdiagnosis and delayed treatment (Mihajlovic et al. 741; Androutsopoulos et al. 2). The tumor resected for biopsy or its contents aspirated using a fine needle. The analysis includes an immunohistochemical analysis, visual examination and the presence of mutations associated with melanomas (Kühn et al. 741). Histologically, the tumor cells are epithelioid in nature in 55% of the cases, spindled in 17% of the cases and mixed type in 28% of the cases (Androutsopoulos and Decavalas 1). Primary melanoma is confirmed by positive immunohistochemical staining of protein S-100, Melan A, Human melanoma black 45 (HMB-45) and vimentin (Chen et al. 1586; Albareda et al. 51; Lin et al. 377; Alaoui et al. 1; Samolis et al. 233). Differential diagnosis includes testing for cytokeratine, chromogranin, estrogen and progesterone receptors, which must be negative to confirm melanoma (Albareda et al. 51; Takehara et al. 2).
Pathological testing is done to determine the Breslow depth of the tumor in mm, mitosis number/mm2, ulceration, presence of microsatellites and the appearance of the margins (Leitao et al. S118). Imaging techniques such as computerized axial tomography (CAT) scan (Moodley et al. 687), thoracic-abdominal-pelvic CT scan, PET CT scan (Albareda et al. 50) and X-ray are used for diagnosis. Testing for genetic mutation in c-KIT, BRAF and NRAS are performed during initial diagnosis (Leitao et al. S118). To test metastasis, sentinel lymph node (SLN) biopsy is performed (Seifried et al. 1960).
Staging
Clinical staging of primary mucosal melanomas is based guidelines by the International Federation of Gynecology and Obstetrics (FIGO) while pathological staging is based on the American Joint Committee on Cancer’s (AJCC) TNM staging method (Edge et al. 388). TNM has been typically used for staging skin cancer lesions (Schmidt et al. 286); however, due to its detailed staging system and prognosis prediction, Seifried et al. (1959) found it to be a better staging system for malignant vulva and vaginal melanomas yet some literature show use both systems simultaneously (Albareda et al. 50; Schmidt et al. 286).
According to FIGO, the tumors are staged from I to IV A and IV B depending on the location and infiltration of the tumor. Stage I malignant vaginal tumors are confined to the vaginal wall while stage IV B have metastasized to distant organs (Hacker et al. S97). The TNM staging assesses the size of the primary tumor (T), infiltration of the nearby lymph nodes (N) and level of metastasis (M). Depending on the size of the tumor (no tumor to greater than 4 mm in thickness with ulceration), the tumor is classified from TX to T4b. Stages T1 to T4 are comparable to stages I to IVA of the FIGO system. Similarly, depending on the metastasis to the lymph nodes, the tumor is classified from NX (no lymph node metastasis) to N3 (metastasis to four or more regional nodes). Distant metastasis staging is done from MX (no metastasis) to M1c (metastasis to all visceral sites) (Greene et al. 211).
Treatment
Surgery. For melanomas that can be resected, surgery is the preferred treatment (Leitao et al. S119; Schmidt et al. 286). Moreover, surgical treatment has been found to be positively associated with prolonged survival when compared to other treatment methods (Ng et al. 64; Alaoui et al. 1; Leitao et al. S118). A popular surgical method for early stages of the tumor is the wide local excision (WLE) method. WLE with a safety margin of 1 cm for tumors with a Breslow depth of 2 mm or less and 2 cm for tumors with a Breslow depth of more than 2 mm is performed along with pelvic radiotherapy (Xia et al. 150; Leitao et al. S118; Gökaslan et al. 246).
Radical surgery and lymphadenectomy with adjuvant chemo- or radiotherapy is used as an aggressive treatment for advanced stages (Samolis et al. 234; Moodley et al. 688; Albareda et al. 51; Gökaslan et al. 246; Lin et al. 377). However, lymphadenectomy is contraindicated in patients who show no lymph node metastasis (Leitao et al. S119; Gökaslan et al. 246). Reports show that radical surgery could include total hysterectomy, vaginectomy and/or vulvectomy depending on the location of the tumor (proximal, middle or distal to the vagina) (Xia et al. 150; Schmidt et al. 286; Baloglu et al. 821; Lin et al. 376).
Chemotherapy. In cases of inoperable tumor in advanced stages or deteriorating health conditions of the patients, palliative chemotherapy is preferred, which does not cure the disease but helps prolong the life of the patients while managing pain (Alaoui et al. 1; Hinde et al. 281; Albareda et al. 50). Chemotherapy is performed using dacarbazine (dimethyl-triazeno imidazole-carboxamide [DTIC]), temozolomide (oral analogue of DTIC) (Androutsopoulos et al. 3), paclitaxel, nitrosourea, imatinib, nidran and vincristine (Takehara et al. 2; Baloglu et al. 822). Paclitaxel, temozolomide and DTIC are sometimes used in combination with cisplatin and/or carboplatin (Leitao et al. S119).
Post-operative adjuvant therapy
Immunotherapy. Post-operative adjuvant immunotherapy using interferon alpha-2b (IFNα-2b) has been found to be effective in keeping the tumor from relapsing (Takehara et al. 2; Huang et al. 332; Lin et al. 377). It is also one of the first agents that was approved by the USFDA for treatment of metastasized melanoma (Leitao et al. S120). Immunotherapy has also been performed using agents such as measles vaccine, dendritic cells (DC-cells), interleukin-2 (IL-2), lymphokine-activated killer cells (LAK cells) and bacillus Calmette-Guérin (BCG) (Huang et al. 332).
Radiotherapy. Radiotherapy has been found to be effective as a post-operative adjuvant therapy (Androutsopoulos et al. 2) alongside immunotherapy (Lin et al. 377) but not as a sole treatment for primary malignant vaginal melanoma. However, the literature shows that radiotherapy is offered as a treatment regime if the patient refuses surgical intervention (Ng et al. 63; Chauhan et al. 509; Androutsopoulos et al. 2).
Topical treatment. Topical treatment with 5% imiquimod has been found to be effective as an adjuvant treatment in 6 patients by Smyth et al. (e809) and Prescott et al. (92) with no evidence of recurrence for a period of 18 months.
Targeted therapy. Targeted therapy using monoclonal antibody has been used for mucosal malignant prolonging survival and preventing recurrence of the tumor; however, no trials have been conducted specifically for malignant vaginal tumors (Leitao et al. S120).
Prognostic factors and survival
Patients with tumors less than 3 cm in size have a better prognosis (survival of 41 months, approximately) when compared to those who present tumors larger than 3 cm (survival of 12 months, approximately) (Mihajlovic et al. 741). A study by Kirschner et al. reported that the five-year survival rate is 17% when the tumor is restricted to the vaginal wall and 15% for all other patients with primary malignant vaginal melanoma, even when no lymph nodes have been infiltrated. The survival rate with lymph node involvement dwindles to 5% within a three-year period (1487). Patients who received surgical treatment have been shown to live longer when compared to those who received non-surgical treatments (Kirschner et al. 1486).
Summary
This review of current literature shows that primary malignant vaginal melanoma is a rare but aggressive melanoma that affects women in their 6th and 7th decade of life. The tumor appears as a dark node or spindle but can also be amelanotic. The size of the tumor is indicative of the prognostic factors. Surgery seems to be the only efficient treatment regime that significantly improves longevity of the person. Post-operative adjuvant therapy using chemotherapy, radiation therapy, topical creams, immunotherapy and targeted therapy might help in preventing recurrence of the tumor. The survival rate is largely dependent on nodal and distant metastasis of the disease after initial tumor resection. There is a dire need to form a proper therapeutic regime to control the disease without involving too many disfiguring surgical procedures.
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