Malignant Melanoma of Lower Female Genital Tract: A Histomorphological Review and Genotyping Analysis, Including BRAF, NRAS and C-KIT Mutations
Marjan Rouzbahman, Suzanne Kamel-Reid, Ayman Al Habeeb, Marcus Butler, Jason Dodge, Stephane Laframboise, Joan Murphy, Golnar Rasty, Danny Ghazarian. University Health Network, Toronto, Canada; University of Toronto, Toronto, Canada
Background: Though rare, melanoma is the second most common malignancy of vulva and vagina. The prognosis, even when localized at presentation, is poor. BRAF and NRAS mutations are reported in approximately 50% and 15% of cutaneous melanomas respectively. The presence of these mutations predicts aggressive tumor behavior. Clinical trials of the BRAF kinase inhibitor have shown response rates of more than 50% in metastatic melanoma harboring this mutation however the frequency of the mutations is not the same in different sites. Other studies suggest that C-KIT mutations are more common in vulvar melanomas however molecular characteristics of vulvar and vaginal melanomas have not yet been extensively explored.
Design: 33 cases of vulvar or vaginal melanoma were retrieved between 2002- 2012. The hematoxylin & eosin stained slides and clinical records were reviewed to record the size of the tumor, histological pattern, depth of invasion, tumor thickness, ulceration status, lymphovascular invasion and clinical outcome. Representative blocks were selected for genotyping studies to detect mutations in BRAF, NRAS, C-KIT as well as 45 other genes. Genotyping studies were performed either using a specific PCR based ARMS assay, Sanger sequencing or the Illumina TSACP Cancer panel on the Miseq platform.
Results: We identified 24 vulvar and 9 vaginal melanomas with mean age of 60 years (range 17-83). Tumor size varied from 0.4 to 6.2 cm. Breslow thickness ranged from 0.75 to 29 mm (mean: 10.9 mm). Ulceration was seen in 16 of 25 cases. The follow up period was 6 mo to 10 years. 10 patients were dead, 2 lost to follow up and 21 were alive at the time of the study. Preliminary data on 16 cases identified a BRAF mutation in 12.5% (2 of 16 cases- 1 by ARMS and 1 by Miseq), C-KIT mutation in 12.5% (2 of 16 cases- 1 by Sanger sequencing and 1 by Miseq; the case identified using Miseq had 2 C-KIT mutations) and NRAS mutation in 33% (2 of 6 cases- only Miseq). We detected a D594V BRAF mutation using the Miseq platform in one case which hadn't been detected by the ARMS PCR designed specifically for the V600E mutation.
Conclusions: Preliminary data identified BRAF mutations with less frequency as compared to non-genital cutaneous melanomas however NRAS mutations were detected in one third of our cases. More studies and with larger numbers of cases are necessary in order to increase the understanding of the pathological features and the molecular biology of melanoma of lower female genital tract. Such data may guide more therapeutic innovations.
Category: Gynecologic & Obstetrics
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 238, Tuesday Afternoon