KIT pathway alterations in mucosal melanomas of the vulva and other sites.

PURPOSE: A significant proportion of mucosal melanomas contain alterations in KIT. The aim of this study was to characterize the pattern of KIT, NRAS, and BRAF mutations in mucosal melanomas at specific sites and to assess activation of the KIT downstream RAF/MEK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in mucosal melanoma specimens. EXPERIMENTAL DESIGN: Seventy-one primary mucosal melanomas from various sites were studied. Mutation analysis was done by DNA sequencing. Expression of KIT, phosphorylated (p)-ERK, and p-AKT was evaluated by immunohistochemistry. RESULTS: KIT mutations were detected in 35% (8 of 23) of vulvar, 9% (2 of 22) of anorectal, 7% (1 of 14) of nasal cavity, and 20% (1 of 5) of penile melanomas. No KIT mutations were found in 7 vaginal melanomas. The difference in KIT mutation frequency between vulvar and nonvulvar cases was statistically significant (P = 0.014). The overall frequencies of NRAS and BRAF mutations were 10% and 6%, respectively. Notably, vaginal melanomas showed a NRAS mutation rate of 43%. KIT gene amplification (≥4 copies), as assessed by quantitative real-time PCR, was observed in 19% of cases. KIT expression was associated with KIT mutation status (P < 0.001) and was more common in vulvar than nonvulvar tumors (P = 0.016). Expression of p-ERK and p-AKT was observed in 42% and 59% of tumors, respectively, and occurred irrespective of KIT/NRAS/BRAF mutation status. NRAS mutation was associated with worse overall survival in univariate analysis. CONCLUSIONS: Results show that KIT mutations are more common in vulvar melanomas than other types of mucosal melanomas and that both the RAF/MEK/ERK and PI3K/AKT pathways are activated in mucosal melanoma specimens.

Spatial density of primary malignant melanoma in sun-shielded body sites: A potential guide to melanoma genesis.

UNLABELLED: UV radiation is a major factor in melanoma genesis, but non-UV linked factors are also operational, since primary malignant melanomas can emerge in body sites that never see the sun. The scarcity of melanomas in sun-shielded body sites reflects only the absolute number of melanomas, not the number of tumours per square unit of the surface in which they emerge. Studies on melanoma density conducted by us and others are here briefly reviewed. The access to reliable numbers along with measurable anatomical areas directed our choice of melanomas at the sun-shielded locations described here. Melanomas at the body surface. Calculations of surface areas bearing melanomas relative to the total body surface included sites on the vulva, subungual tissues, volar and palmar skin, and, for comparison melanomas of the face during the same period of time. The density of vulvar melanomas was identical to that in chronically sun-exposed facial skin. Subungual melanomas were almost nine times denser than expected whereas melanomas of palms and soles showed a lower density than expected. Melanomas beneath the body surface. The densities of melanomas in the vagina, anal canal and uvea, were calculated separately and compared to the average density of cutaneous melanomas (CMMs) during the same period of time. Melanomas of the anal canal displayed a density almost twice the average for CMMs, whereas the vaginal melanomas were similar in density to CMMs. In contrast, the density of the uveal melanomas was calculated as 50 and 41 times (men and women, respectively) the average density of CMMs. CONCLUSION: The high density of some melanomas in sun-shielded body areas indicates the presence of factors underlying the origins of these tumours that seem to be equivalent in strength to UV radiation and also implies that specific anatomical sites favour the emergence and proliferation of melanomas, independent of UV radiation.

Primary ano-rectal malignant melanomas within a population-based national patient series in Sweden during 40 years.

PURPOSE: To analyze 251 patients (101 males and 150 females) diagnosed with ano-rectal malignant melanoma (ARMM) reported to the Swedish National Cancer Registry during 1960-1999. METHODS: Incidence, gender and age profiles, primary anatomical sites and density of the melanomas along with geographic distribution, and prognosis were investigated. RESULTS: The age-standardized incidence of ARMM was significantly higher for females (1.0 per 10(6) females) than for males (0.7 per 10(6) males) throughout the 40-year-period. The incidence increased with age peaking at 75-84 years in both genders. 54% of the tumours were primary in the anal canal, 24% engaged the whole ano-rectal unit and 10% were located at the anal verge (11% unknown primary site). Although ARMM were rare in absolute numbers, their density (number of tumours/square unit) was higher than that of cutaneous malignant melanomas (CMM) on average. No linkage between the geographic distribution of ARMM and population density was found. The prognosis was very poor albeit with a significant gender difference with a five-year survival rate of 10.6% for males and 15.7% for females. The survival rates for both genders improved during the 40-year-period but significantly more for females than males. CONCLUSION: The reason(s) for the difference in incidence and prognosis according to gender is unknown. The majority of ARMM emerged primary in the anal canal and a primary location exclusively in the colonic mucosa of the rectum is questionable. The higher density of ARMM as compared to the average density of CMM tallies with the result of our previous studies on vulvar melanoma and might be instrumental in exploring non-UV light associated factors in melanoma genesis. The concentration of patients with anal squamous cell carcinoma to population-dense urban areas, as previously reported, was not found in cases of ARMM.

Human papilloma virus (HPV) is rarely detected in malignant melanomas of sun sheltered mucosal membranes.

Human papillomavirus (HPV) has been associated with some types of human cancer. The aim of this study was to investigate if HPV could be associated with human primary malignant melanoma in non sun-exposed body areas like mucous membranes. Through the Swedish National Cancer Registry, in compliance with the rules of the Human Ethical Committee, histopathological specimens were collected from different pathological laboratories throughout Sweden. The histopathological diagnosis was reviewed, and from 45 primary melanomas, tumour tissue was micro-dissected and analysed further. A protocol for detection of HPV DNA using general HPV primers GP5 + /GP6+ or CPI/IIG, which together identify 36 different HPV subtypes, was developed. This protocol could detect presence of HPV DNA in less than 10 ng of DNA of a control cell that contained 1-2 copies of HPV type 16/cell. Before HPV testing the melanoma samples were examined for amplifiable DNA by a beta-microglobulin PCR and 39 were positive. Thirty-five of these could be evaluated for HPV DNA and no samples were positive according to all five defined criteria for HPV positivity although two were positive according to 4/5 criteria. In conclusion, HPV is rarely detected in primary malignant melanomas of non-sun exposed body areas.

Primary malignant melanoma of the vulva--an aggressive tumor for modeling the genesis of non-UV light-associated melanomas.

Malignant melanomas appear in such sun-shielded areas as the vulva, challenging conventional knowledge that they are associated with UV radiation. Based on 1442 patients with vulvar melanomas the tumors' epidemiology, clinical manifestations, histopathology, molecular genetics, treatment strategies, and prognosis were surveyed. Despite their sun-shielded location and rare incidence, vulvar melanomas were, on average, more dense than melanomas on the body surface and nearly the density of melanomas in chronically sun-exposed skin of the head and neck. Vulvar melanomas differed markedly from cutaneous melanomas, as evidenced by histopathological lesions and molecular genetics. Most melanomas were located on the glabrous skin as opposed to the hairy skin within the vulva and differed significantly in biological properties. The prognosis for the patients was poor, and in the 11 largest studies of surgical strategies, none offered a significant survival advantage. Tumor thickness and ulceration were usually significant predictors of (poor) prognosis in multivariate analyses along with macroscopic amelanosis, angioinvasion or DNA non-diploidy in some reports. Clear-cut biological differences between vulvar and cutaneous melanomas and between melanomas within different vulvar sites provide new paths for extensive research on melanomagenesis and for potential therapies. Additionally, studies of vulvar and other extracutaneous melanomas should characterize subgroups of cutaneous melanomas and identify their cause(s), which are apparently not linked to UV radiation.