GYNECOLOGICAL MELANOMA GENETICS

Melanoma arising from the mucosal membrane of the female urogenital tract is rare, and a new study shows that it is different from cutaneous melanoma.

A lack of solid data about gynecologic melanoma has made the management of patients with this disease challenging and unpredictable, say the authors of the new study, which was presented during a poster session at the recent Society for Melanoma Research (SMR) 2015 International Congress, held in San Francisco November 18 - 21.

The researchers, from the Cancer Centre of Southeastern Ontario, in Canada, report new histochemical and molecular findings for gynecologic mucosal melanoma that "set this devastating disease apart from its otherwise phenotypically identical cutaneous counterpart."

Mucosal melanomas are rarer and tend to be more aggressive than cutaneous disease, the authors note. Mucosal melanomas account for only 1.4% of all melanomas, and of these, only about 20% are diagnosed in the female genital tract, they point out. Overall, vulvar, vaginal, and cervical melanomas make up less than 1% to 3% of all melanomas in women.

"Gynecologic melanoma is treated similarly to all other mucosal melanomas, with surgery being standard first-line treatment," study author Tara Baetz, MD, assistant professor in the Department of Oncology at the Cancer Centre of Southeastern Ontario, told Medscape Medical News. "Once the disease is metastatic, there is no standard treatment aside from extrapolation of the treatment algorithm for cutaneous melanoma, although we know that these diseases are not identical."

Although treatment options for cutaneous melanomas are expanding and include systemic chemotherapy, BRAF and MEK inhibitors, and, most recently, immunotherapy with CTLA-4 and PD-1 inhibitors, the same has not held true for mucosal melanoma. It is a clinically distinct disease, Dr Baetz and her colleagues emphasize. It is driven by molecularly distinct mechanisms and does not appear to respond as well to these therapeutic options.

"Survival is known to be poorer overall, and this has been also seen in the SEER database, but we did not specifically compare survival of cutaneous vs gynecologic melanoma in this group of patients in our small study," she said. "But we do predict that it would also be significantly lower."

Because molecular targets in gynecologic melanoma are not as well defined and treatment options remain limited, the authors performed a retrospective analysis of the characteristics of patients who had been treated at their institution over the past 20 years.

Patient Characteristics

A total of 24 women were treated for gynecologic melanoma between 1995 and 2015 at their center; of these, 14 cases were further reviewed.

In the entire cohort, there were 12 melanomas of the vulva, nine of the vagina, two of the cervix, and one of unknown primary origin with liver metastasis for which biopsy was performed for initial diagnosis. In the 14 cases that were selected for further review, there were seven melanomas of the vulva, six of the vagina, and one with liver metastasis.

Of the 14 patients, 6 (42.9%) presented with metastatic disease at their initial diagnosis. The ages of the patients ranged from 19 to 97 years. The most common presentation was that of a symptomatic (enlarging/color changing/pruritic) vulvar lesion (57.1%), which was seen in more than half of patients, followed by vaginal bleeding or spotting (35.7%).

Five of the women were reported to have a significant history of smoking, two had a first-degree family history of melanoma, and eight had first- or second-degree relatives with other forms of cancer.

Four patients with metastatic disease at diagnosis did not receive any surgery; the remaining 10 underwent either a wide local excision with local lymph node biopsy and/or dissection or more extensive radical surgery. Disease-free survival for nonmetastatic patients ranged from 6 to 47 months regardless of whether or not the patient received any form of adjuvant therapy. Only one patient received up to three lines of therapy after initial recurrence.

For the cohort as a whole, 5-year survival was 29% (4/14); all four of these patients had undergone initial radical surgery. To date, three have remained disease free without recurrence; one underwent re-excision at recurrence and is also currently disease free. Only one patient received any form of adjuvant treatment (interferon therapy for 7 months).

Immunohistochemical and Molecular Analysis

Owing to the emerging interest in anti-PD1 and PD-L1 therapies, the team also performed immunohistochemical testing for PD-L1 expression and correlations between PD-L1 expression and survival.

Immunohistochemical staining for PD-L1 expression was positive (higher than 1%) in eight patients, but there was no statistical significance associated with PD-L1 positivity.

PD-L1 expression did not appear to be associated with a difference in survival, which may have been due to the small sample size, Dr Baetz noted. However, she believes that anti-PD1 treatments should definitely be investigated more fully in gynecologic mucosal melanoma. "We know in cutaneous melanoma that the PD1 expression is not required for benefit," she pointed out.

In their molecular analysis, the authors found that 3 of 14 cases were BRAF mutation positive, five were positive for NRAS mutation, and two were positive for KIT mutation. MET, p53, and FLT3 mutations were also identified in five, four, and one case, respectively; 2 cases did not carry any variants.

The authors point out that the frequency of NRAS mutations in their study (36%) was consistent with previous reports (12% to 43% in gynecologic melanomas). In similar fashion, KIT mutations are seen with a frequency of 7% to 45% in vulvar melanomas, whereas they are not reported in any vaginal melanomas. In this study, KIT mutations occurred at a frequency of 14%; none occurred in the vagina.

Contrary to previous reports that BRAF mutations are believed to be rare or even nonexistent in mucosal melanoma, the BRAF mutation frequency in the series was 12.5%.

Society for Melanoma Research 2015 International Congress. San Francisco, November 18 - 21.

Pigment Cell Melanoma Res. Abstracts