KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases.

BACKGROUND: Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas. The aim was to determine the KIT, NRAS and BRAF mutation frequencies in a large series of primary SNMMs. METHODS: Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing. RESULTS: Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56), whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1. Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity (P=0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than those with tumours in the paranasal sinuses (P=0.027). CONCLUSION: Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour alterations in genes other than KIT, NRAS and BRAF.

Primary sinonasal malignant melanoma: a nationwide study of the Swedish population, 1960-2000.

OBJECTIVE: To establish population-based trends for sinonasal mucosal melanoma (SNMM) in Sweden. METHODS: We identified 186 patients from the Swedish National Cancer Registry diagnosed with primary melanomas arising from the nasal cavity, paranasal sinuses, or both, during the period 1960 through 2000. Incidence, gender and age, primary anatomical sites, geographic distribution, treatment and survival were investigated. RESULTS: The age-standardized incidence of SNMM increased significantly during the 41-year-period, with a higher overall incidence for females than males, but with a more rapid increase for males than for females. The incidence increased with age, peaking after the eightieth year in both genders. About 70 % of the cases were clinically amelanotic. The most common primary treatment was surgery. Five-year, disease-specific survival rates were poor for all these patients, but women had a significantly better survival time than men. For both genders the survival rate lengthened during the study period, irrespective of therapeutic strategy. CONCLUSION: SNMM is a rare disease, but the incidence in Sweden has increased significantly from 1960 through 2000, although not at the same pace as that of cutaneous malignant melanoma. Both the incidence and the survival were significantly higher in females than in males, but the reason for these gender differences is unknown.

Importance of clear resection margins in anorectal malignant melanoma.

BACKGROUND: Anorectal melanoma is rare and surgery is the recommended primary treatment. There has been some debate whether abdominoperineal resection (APR) or local excision is most appropriate. The aim of this study was to provide a population-based analysis of symptoms, treatment and outcome. METHODS: From the Swedish National Cancer Registry, 251 patients with anorectal melanoma were identified from 1960 to 1999. Medical reports were collected and reviewed retrospectively. R0 resection was defined by clear macroscopic margins and a pathology report showing a margin greater than 10 mm. Survival was compared with the log rank test, and Cox multivariable analysis was performed. RESULTS: APR and local excision was performed in 66 and 86 patients respectively. Median survival after surgery was 14 months, with no statistically significant difference between the two groups. Seventy-two patients in whom an R0 resection was achieved, irrespective of approach, had a significantly better overall 5-year survival rate than patients with involved margins (19 versus 6 per cent; P < 0.001). Multivariable analysis showed resection status and tumour stage to be independent prognostic variables. CONCLUSION: Both APR and LE seem appropriate for anorectal melanoma provided clear margins can be achieved; prognosis is poor regardless of surgical approach.

N-ras mutations are common in melanomas from sun-exposed skin of humans but rare in mucosal membranes or unexposed skin.

Ras mutations, preferentially in codon 61 of the N-ras oncogene, are common in human cutaneous melanomas. In this study, we questioned the association between ras mutations in primary melanomas and sun exposure. DNA was extracted from formalin-fixed primary melanomas: 28 at chronically sun-exposed head and neck areas, 18 at sites subject to intermittent sun exposure, and 28 from unexposed mucosal membranes (vulva/vagina, anus/ rectum, palate). Mutations of both exons of H-, K-, and N-ras genes were examined by polymerase chain reaction/single-strand conformation polymorphism and by direct nucleotide sequencing of the polymerase chain reaction amplified exons. Thirty-two per cent of the head and neck melanomas and 11% of the melanomas from intermittently sun-exposed skin had N-ras codon 61 mutations; comparatively only 7% of the tumors from the unexposed areas had such mutations. One vulvar melanoma had an N-ras codon 12 mutation. No H-ras or K-ras mutations were detected in any sample. The frequency of N-ras exon 2 mutations in melanomas of typically sunbathed skin was compared for the first time with that in melanomas of areas completely protected from sun exposure. The significantly higher frequency (p = 0.04, chi square exact test) of these N-ras mutations on the head and neck demonstrates their UV-light induction in a subset of melanomas explaining one of the molecular effects of UV light in human skin.

Is there place for radiotherapy in the treatment of advanced ovarian cancer?

BACKGROUND AND PURPOSE: Irradiation of advanced ovarian cancer has been performed during the years 1976-1984 with six-field technique. Results of this treatment in a long follow-up have never before been evaluated. MATERIAL AND METHODS: Seventy-five patients with stage IIb-IV of invasive ovarian cancer have been treated with a combination of surgery, radiotherapy and chemotherapy. The results of the treatment were compared with 98 patients treated during the year 1991-1992 with surgery and chemotherapy only. RESULTS: After controlling for the differences in background factors between the groups considered, there was still a significantly better survival rate for the patients treated with radiotherapy. CONCLUSION: The results suggest that the role of radiotherapy in advanced ovarian cancer should be investigated in a prospective randomized trial.

Mutations in the TP53 gene in human malignant melanomas derived from sun-exposed skin and unexposed mucosal membranes.

Mutations in the p53 tumour suppressor gene ( ) have been linked to several types of cancer. We therefore investigated whether such mutations occur in malignant melanomas and, if so, whether they are linked to ultraviolet (sun) light exposure. For the first time, mutations in mucosal membranes and adjacent tissues shielded from sunlight were compared with those in cutaneous melanomas from sun-exposed skin. Archival tissues were obtained from 35 patients with a primary melanoma taken from unexposed mucosal areas and from 34 patients with a primary melanoma located in chronically sun-exposed head and neck skin. was characterized by means of polymerase chain reaction amplification and single-strand conformation polymorphism assay followed by nucleotide sequencing. The results showed that 17.6% of the primary cutaneous and 28.6% of the primary mucosal melanomas had point mutations in. Among the cutaneous melanomas, one showed three mutations in exon 7, and one had two mutations in exon 5; the mutation was in the same allele in both cases. One mucosal melanoma had two mutations in exon 7, both in the same allele, and another had two mutations, one in exon 7 and one in intron 6, both in the same allele. C<--T mutations at dipyrimidine sites, considered fingerprints for ultraviolet light-induced mutations, were about equally distributed among patients with melanomas from chronically sun-exposed areas (six out of nine; 67%) and those with melanomas from unexposed mucosal areas and adjacent skin (eight out of 14; 57%). Our data, demonstrating the presence of such mutations even in melanomas from mucosal membranes, clearly suggest that factors other than, or additional to, ultraviolet radiation are operational in the induction of mutations in melanomas.

Malignant melanoma of the vulva and vagina. Trends in incidence, age distribution, and long-term survival among 245 consecutive cases in Sweden 1960-1984.

BACKGROUND: Malignant melanomas of the vulva and vagina are rare tumors located in areas of the body not exposed to ultraviolet radiation. Investigations comprising large consecutive population-based series of patients with these diseases have not been published previously, to the knowledge of the authors. METHODS: Trends in incidence, age distribution, and prognosis were investigated among 219 consecutive cases of malignant melanoma of the vulva and 26 cases in the vagina, reported to the Swedish National Cancer Registry and representing virtually all primary tumors of that kind in Sweden during a 25-year period, 1960-1984. RESULTS: On average, 75% of the patients with vulvar melanoma and 73% with vaginal melanoma were older than 60 years of age. The mean age increased slightly but not significantly during the period. The age-standardized incidence of vulvar melanoma decreased from 0.27 to 0.14 per 100,000 Swedish women, or by 3% per year. The observed 5-year survival rate of patients with vulvar melanoma was 35%, and the relative survival rate was 47%. The observed and relative survival rates at 10 years were 23% and 44%, respectively. Observed and relative survival rates among patients with vaginal melanoma after 5 years were 13% and 18%, respectively. CONCLUSIONS: Accordingly, there was a decreasing incidence of vulvar and vaginal melanoma over the observed 25 years. This is in contrast to the trends in incidence for cutaneous melanomas in Sweden, which, during the same time period, increased almost 6% per year.

Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: clinical observations and histopathologic features.

BACKGROUND: Because the clinical and histopathologic features of vulvar melanoma had not been characterized completely in a large, homogeneous population, the authors retrospectively analyzed all such patients recorded in Sweden during a 25-year period. METHODS: The Swedish National Cancer Registry opened its records to the authors for review of all 219 females with primary vulvar melanoma reported from 1960 to 1984. Histopathologic specimens and clinical histories of the 198 patients who qualified for this study were reanalyzed and the tumors rigorously subtyped. RESULTS: Macroscopically amelanotic tumors were observed in 27% of patients, predominantly in glabrous skin; the clitoral area and labia majora were the most common primary sites. Of all melanomas, 46% emerged in glabrous skin, 12% emerged in hairy skin, and 35% extended to both areas. On average, approximately 2.5 times more melanomas appeared in the vulva than on the whole body surface. Overall, 57% were of the mucosal lentiginous (MLM) type, 22% were nodular melanomas (NMs), 12% were unclassified, and only 4% were superficial spreading melanomas (SSMs); this was the reverse of the order observed for cutaneous melanoma. Almost all vulvar melanomas underwent a vertical growth phase; other common features were marked thickness and ulceration, particularly in the glabrous skin. Preexisting nevi occurred in 11 cases, all in hairy skin, and 71% in conjunction with SSM but only 4% with MLM. CONCLUSIONS: Several clinical and histopathologic features indicated that the natural history of vulvar melanomas is at variance with that of cutaneous melanomas. Because preexisting nevi, which are often considered a precursor to melanoma, were significantly linked to SSM and only in the vulvar hairy skin, melanomas in the glabrous skin apparently emerged de novo.

Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: predictors of survival.

BACKGROUND: In an epidemiologic study of 219 Swedish females with vulvar melanoma, the authors previously established the incidence of this disease as 0.19 per 100,000 women, with a 3% annual decrease from 1960 to 1984 and a 5-year relative survival rate of 47%. After reviewing the medical histories of all of the 219 patients, the authors documented their precise clinical and histopathologic features, which, along with treatment, are assessed herein as predictors of survival. METHODS: Of 219 consecutive cases of vulvar melanoma collected from the Swedish National Cancer Registry, 21 were excluded because of inadequate data. Clinical and histopathologic materials from the remaining 198 cases were then reexamined. With a clinical three-stage system, lesion types and treatment modalities were assessed as survival factors in univariate and multivariate analyses. RESULTS: In univariate analysis, significant predictors of survival for patients at Stage I were tumor thickness, ulceration, number of mitoses, macroscopic amelanosis, preexisting nevi, extent of tumor invasion (lateral labia majora), and patient age. The mode of treatment was not significant. In multivariate analysis, staging (Stage I vs. II and III) and tumor thickness were independent predictors of survival. For Stage I only, tumor thickness, ulceration, and clinical amelanosis independently predicted survival time. CONCLUSIONS: To the authors' knowledge, this is the largest series of patients with vulvar melanoma ever reviewed, and an ethnically homogeneous and nationwide female population is represented. In this series, clinical stage, macroscopic amelanosis, and tumor characteristics such as tumor thickness and ulceration, rather than treatment mode, were the best factors for predicting the outcome of these patients.