Reduced Apaf-1 expression in human cutaneous melanomas

Malignant melanoma is a life-threatening skin cancer due to its highly metastatic character and resistance to radio- and chemotherapy. It is believed that the ability to evade apoptosis is the key mechanism for the rapid growth of cancer cells. However, the exact mechanism for failure in the apoptotic pathway in melanoma cells is unclear. p53, the most frequently mutated tumour suppressor gene in human cancers, is a key apoptosis inducer. However, p53 mutation is only found in 15–20% of melanoma biopsies. Recently, it was found that Apaf-1, a downstream target of p53, is inactivated in metastatic melanoma. Specifically, loss of heterozygosity (LOH) of the Apaf-1 gene was found in 40% of metastatic melanoma. To determine if loss of Apaf-1 expression is indeed involved in melanoma progression, we employed the tissue microarray technology and examined Apaf-1 expression in 70 human primary malignant melanoma biopsies by immunohistochemistry. Our data showed that Apaf-1 expression is significantly reduced in melanoma cells compared with normal nevi (χ2=6.02, P=0.014). Our results also revealed that loss of Apaf-1 was not associated with the tumour thickness, ulceration or subtype, patient's gender, age and 5-year survival. In addition, our in vitro apoptosis assay revealed that overexpression of Apaf-1 can sensitise melanoma cells to anticancer drug treatment. Taken together, our data indicate that Apaf-1 expression is significantly reduced in human melanoma and that Apaf-1 may serve as a therapeutic target in melanoma

Malignant melanoma of the vulva [Elektronisk resurs]

From a consecutive, nationwide series of 219 females with primary vulvar malignant melanomas diagnosed in Sweden during 1960 to 1984 and followed up until 1994, we analyzed epidemiological, clinical, histopathological, prognostic and molecular genetic data. The age-standardized incidence among these patients, 75 % of whom were 60 years old or more, decreased by 3.2 % annually compared to an increase of almost 6 % for contemporary cutaneous melanomas in Sweden. Relative 5-and 10-year survivals were 47 % and 44 %, respectively. The density of melanomas was roughly 2.5 times higher in the vulva than elsewhere; 46 % emerged in glabrous skin, 12 % in hairy skin, and 35 % extended in both. 57 % were mucosal lentiginous (MLM), 22 % nodular (NM), and only 2 % superficial spreading (SSM), an incidence reversing that of cutaneous melanomas. More than 94 % of the vulvar melanomas had a vertical growth phase; 27 % were macroscopically amelanotic, usually in the glabrous skin. Pre-existing nevocellular nevi were only in hairy skin and were adjacent to the SSM subtype, suggesting that glabrous skin melanomas emerge de novo. Of malignant melanomas, in clinical Stage I patients, tumor thickness, ulceration and clinical/macroscopical amelanosis predicted short survival according to multivariate analyses that evaluated all clinical, histopathological and therapeutical data. The relative risk (RH) for short survival increased 5 times when those variables were combined. Mutations in the Ras proto-oncogene family and in the TP53 gene of selected primary melanomas were traced in DNA extracted from tumor tissues dissected from histopathological archival materials. PCR/SSCP assays and nucleotide sequencing determined that 32 % of malignant melanomas from chronically sun-exposed skin, I I % from intermittently exposed and 7 % from unexposed skin displayed mutations in N-ras codon 6 1. The significant differences between those groups substantiate UV radiation as an inducer of N-ras mutation. 23 % of all melanomas from sun exposed and unexposed sites had TP53 mutations. C->T mutations at dipyrimidine sites, supposed to be typical of UV radiation -induced DNA damage, were found in melanomas from sun-exposed and unexposed areas, suggesting mutational factor(s) other than UV radiation. The diversity of surgical methods was too great to allow adequate analysis. However, wide local resection did not seem to shorten the prognosis as to survival compared to radical vulvectomy. We conclude that vulvar and cutaneous malignant melanomas differ markedly. Vulvar melanoma and its hairy and glabrous skin compartments are established here as a model for studying pathogenetic mechanisms of these tumors

Importance of clear resection margins in anorectal malignant melanoma

Abstract 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 &amp;lt; 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. </jats:sec

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.</jats:p

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

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