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Sinonasal malignant melanoma (SNMM) comprises less than 1% of all melanomas and is located in the nasal cavity and the paranasal sinuses. The majority of SNMMs have unknown underlying oncogenic driver mutations. The recent identification of a high frequency of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in cutaneous melanoma led us to investigate whether these mutations also occur in SNMM. Our aim was to determine the TERT promoter mutation frequencies in primary SNMMs. Laser capture microdissection and manual dissection were used to isolate tumour cells from 49 formalin-fixed paraffin-embedded tissues. The tumours were screened for TERT promoter mutations by direct Sanger sequencing. Information on NRAS, BRAF and KIT mutation was available from an earlier study. Overall, 8% (4/49) of SNMMs harboured TERT promoter mutations. One of these mutated tumours had a coexistent NRAS mutation and one had a BRAF mutation. Our findings show that TERT promoter mutations are present in a moderate proportion of SNMM. No conclusion can be drawn on their potential influence on the clinical outcome or tumour progression.

Background/aim: Mucosal melanomas arise in non UV-light exposed areas and causative factors are yet unknown. Human polyomaviruses (HPyVs) are rapidly increasing in numbers and are potentially oncogenic, as has been established for MCPyV in Merkel cell carcinoma, an unusual skin cancer type. The aim of the present study was to investigate the association between TSPyV, MWPyV, HPyV6, 7 and 9 and mucosal melanoma., Materials and Methods: Fifty-five mucosal melanomas, were analyzed by a Luminex assay, for the presence of 10 HPyVs (BKPyV, JCPyV, KIPyV, WUPyV, TSPyV, MWPyV, HPyV6, 7 and 9) and two primate viruses (SV40 and LPyV)., Results: In 37 samples the DNA quality was satisfactory for analysis. However, none of the samples analyzed were positive for any of the examined viruses., Conclusion: None of the above-analyzed HPyVs were detected in mucosal melanoma samples, and they are for this reason unlikely to play a major role in the development of this tumor type.

Purpose: We have previously demonstrated an association of the human leukocyte antigen (HLA), HLA-A2 allele with ovarian and prostate cancer mortality as well as a segregation of the ancestral HLA haplotype (AHH) 62.1 [(A2) B15 Cw3 DRB1*04] in patients with stage III-IV serous ovarian cancer. The objective of the present study was to determine the role of the HLA phenotype on the prognosis in stage III-IV malignant melanoma patients., Patients and Methods: A cohort of metastatic malignant melanoma patients (n = 91), in stage III (n = 26) or IV (n = 65) were analysed for HLA-A, -B, -Cw and -DRB1 types by PCR/sequence-specific primer method. The frequencies of HLA alleles in the patients were compared to that of healthy Swedish bone marrow donors. The effect of HLA types on prognosis was defined by Kaplan-Meier and Cox analysis., Results: The presence of the AHH 62.1 in clinical stage IV patients was significantly and independently associated with the worst survival rate recorded from the appearance of metastasis (HR = 2.14; CI = 1.02-4.4; P = 0.04). In contrast, the period from the primary diagnosis to metastasis was the longest in patients with this haplotype (HR = 0.40; CI = 0.17-0.90; P = 0.02)., Conclusions: Melanoma patients in our cohort with 62.1 AHH which is associated with autoimmune diseases have an initial strong anti-tumour control with longer metastasis-free period. These patients have rapid progression after the appearance of metastasis, responding poorly to chemo- or/and immunotherapy. This apparently paradoxical clinical process could be due to the interplay between tumour clones escape and immune surveillance ending up with a rapid disease progression.

The single most important causative factor for malignant melanomas of the skin is UV radiation. However, this is not true for melanomas on body surfaces sheltered from the sun; thus, it is important to seek new causative factors of melanoma genesis. Human papillomaviruses and gammaherpesviruses are associated with human skin cancer; for example, human papillomavirus types 5 and 8 are associated with epidermodysplasia verruciformis, and human herpesvirus 8 is associated with Kaposi's sarcoma. Recently, a newly described human polyomavirus, Merkel cell polyomavirus (MCPyV), has been associated with Merkel cell carcinoma, an unusual form of neurotropic skin cancer. Moreover, melanocytes are of neuroepithelial origin. This background impelled us to investigate if human polyomavirus DNA could play a role in the development of extracutaneous melanomas. Sixty-four extracutaneous melanomas were initially collected and dissected. Of these, 38 could be successfully used for further testing for the presence of the five human polyomaviruses known so far-BK virus (BKV), JC virus (JCV), KI polyomavirus (KIPyV), WU polyomavirus (WUPyV), and MCPyV-and of simian virus 40 (SV40). No polyomavirus DNA could be detected in any of the samples tested by use of a nested PCR detecting BKV, JCV, and SV40; a newly designed PCR detecting KIPyV and WUPyV; or a newly designed PCR for MCPyV. We conclude that since no human polyomavirus DNA was detected in primary malignant melanomas on non-sun-exposed body surfaces, these polyomaviruses presumably are not major factors for the development of extracutaneous melanomas.

Background: UV-radiation is the most important causative factor for malignant melanomas of the skin. However, this is not the case for melanomas on sun-sheltered body surfaces. The aim of this study was to investigate if human herpes virus DNA could be found in malignant melanomas in sun-sheltered body areas and if these viruses play a role in the development of extracutaneous melanomas., Materials and Methods: Forty-one extracutaneous melanomas were dissected and used for further analysis. Quantitative PCR methods were used for detection of the eight human herpes viruses in melanoma samples., Results: Human herpes virus DNA was absent in 37/41 melanomas, however, cytomegalovirus DNA was detected in two samples, and one sample each exhibited presence of Epstein-Barr virus and Human Herpes virus-6 DNA respectively., Conclusion: Human herpes virus DNA is rarely detected in primary malignant melanomas in non-sun exposed body surfaces and is not a major factor for the development of extracutaneous melanomas.

Temozolomide is a rapidly absorbed chemotherapeutic agent, achieving significant central nervous system penetration. Previous clinical trials suggested that temozolomide in sequence with low-dose recombinant human interleukin-2 might be an efficacious and relatively non-toxic chemo-immunotherapeutic treatment, which may synergistically eliminate tumours. The primary objective was to determine the safety and tolerance of temozolomide administered orally 200 mg/m days 1-5, in sequential combination with subcutaneous injections of 4.5x10 IU recombinant human interleukin-2 on days 8-11, 15-18 and 22-25 in patients with measurable, progressive metastatic malignant melanoma without radiological signs of central nervous system metastases. The secondary objectives were to determine tumour response and time to progression. Twenty-seven patients were included, of which four were non-evaluable for response. Twenty-three patients tolerated the regimen with side effects below grade 3 according to the World Health Organization (WHO) scale. Three patients suspended the treatment because of WHO grade 3 side effects already during the first 3 days of the first course of temozolomide. Seven patients showed no tumour progression during the first four treatment cycles. Two patients had complete responses, three partial responses and two stable disease at the end of the four cycles defined by the protocol and they continued the treatment until signs of relapse or a maximum of 21 courses. Five of these patients are still alive. Thrombocytopenia was significantly more pronounced in patients with objective response and stable disease than in non-responders to therapy. The median time to progression for all patients was 3.1 months and for responding and stable disease patients was 15 months. Five of 23 treated patients (22%) developed brain metastases during follow-up. Temozolomide in combination with recombinant human interleukin-2 is a well-tolerated regimen for outpatient treatment and the bio-chemotherapy combination induced durable clinical responses. Thrombocytopenia might be a positive predictive factor for response to therapy.

Purpose: To investigate the occurrence of other primary malignancies before and after diagnosis of uveal melanoma in a Swedish population., Methods: In the Swedish Cancer Registry 2995 patients with uveal melanoma were notified during the period 1960 to 1998. In the same registry, a search for additional malignancies among these patients was performed. A matched case-control study with 2,916 patients and 14,577 population control subjects was set up for malignancies before diagnosis of uveal melanoma. Malignancies after diagnosis of uveal melanoma were evaluated in 2,995 patients through standardized incidence ratios (SIRs), based on the expected rates in the Swedish population., Results: Before the diagnosis of uveal melanoma, the odds ratio (OR) for the risk of cancer was 1.25 (95% CI: 0.98-1.59). No significantly increased risk was found for any specific malignancy. The OR for cutaneous melanoma was 1.74 (95% CI: 0.78-3.89). The risk of subsequent cancers was increased, SIR 1.13 (95% CI: 1.02-1.26). After reevaluation of archival specimens, the SIR of a cutaneous melanoma's developing after a uveal melanoma was found to be 1.75 (95% CI: 0.87-3.12)., Conclusions: An increased risk of second primary cancers was observed among Swedish patients with uveal melanoma. Metastases from uveal melanoma were found to be misclassified as cutaneous melanoma or as primary liver cancer.

In this paper, we compare the expression of the TP53 gene product, p53 protein (p53p), in primary malignant melanomas from sun-shielded mucous membranes and from chronically sun-exposed skin. Archival tissues from 29 patients with mucosal melanomas and from 27 with cutaneous melanomas in facial skin were subjected to immunohistochemical procedures using the monoclonal antibody DO-1. p53p expression did not differ significantly between the two groups of melanomas. A comparison with previously obtained data on TP53 mutations from the same tumours showed closer concordance amongst mucosal than amongst skin tumours. Primary mucosal melanomas and their satellites showed identical patterns, focal or diffuse, of p53p expression. Thus, expression of altered p53p could well participate in the clonal expansion of these mucosal melanomas and in tumour progression. The p53p characteristics recognized in our investigations are amongst the first hallmarks in the emerging molecular pathological profiling of mucosal melanomas, and may therefore be useful in exploring the aetiology of UV-independent melanomas.

Purpose: To investigate the crude and relative survival rates in patients with uveal melanoma in Sweden during the period from 1960 to 1998., Methods: A population-based national survey revealed 2997 cases of uveal melanoma in the Swedish Cancer Registry. The survival rates were calculated by the Hakulinen life-table method, using relative survival as an estimate for deaths due to uveal melanoma. The excess mortality rates were calculated with confidence intervals for the first 15 years after diagnosis. Multivariate regression analysis was undertaken to evaluate the influence of gender, age, and calendar period on relative survival the first 5 years after diagnosis. The underlying causes of deaths in the patients with uveal melanoma, as found in the Cause of Death Registry were also investigated., Results: Up to December 31, 1998, 2003 patients had died. The 5-year crude survival rate was 60.3% and the relative survival 70.1%. After 10 years, the rates were 42.5% and 59.4%, respectively. Significant excess mortality existed up to 5.5 years after diagnosis. In the multivariate model, younger age (P < 0.001) and later calendar period (P = 0.002), but not gender (P = 0.117), were associated with better relative survival. Deaths due to uveal melanoma were misclassified in the Cause of Death Registry in more than half of the cases., Conclusions: This study, covering more than 95% of the uveal melanoma cases in the Swedish population revealed an improvement in relative survival rates for patients with uveal melanoma over time and a significant excess mortality up to 5.5 years after diagnosis.

Purpose: To investigate the incidence of uveal melanoma in Sweden during the period from 1960 to 1998, with respect to age distribution, gender, and changes in incidence over time., Methods: The Swedish Cancer Registry was searched for patients with uveal melanoma and cross-checked against hospital files over patients where an eye-sparing treatment had been applied, to ensure inclusion in the Registry even when no histologic specimen was available. The crude and age-standardized incidence was estimated separately for each gender. The Swedish population of 1970 to 1974 was used as a standard, and the annual change in incidence was calculated by using a regression model with logarithmic incidence numbers., Results: In total, 2997 patients met the criteria, of whom 1542 were males and 1455 females. During the 39-year period, the age-standardized incidence of uveal melanoma declined significantly in the male population, from 11.7 cases/million to 8.4 cases/million (P = 0.002). The trend toward reduced incidence in females, from 10.3 to 8.7 cases/million did not reach statistical significance (P = 0.108). The annual relative change in incidence was 1% (95% CI, 0.8%-1.2%) in males and 0.7% (95% CI, 0%-1.3%) in females. The age-specific incidence revealed a significantly higher incidence among men older than 45 years (23.5 cases/million) compared with the incidence in women of the same age group (19.2 cases/million; P < 0.001)., Conclusions: A Swedish national survey performed to establish the incidence of uveal melanoma during the period from 1960 to 1998 revealed a decreasing incidence in the male and a stable incidence in the female population.

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.

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., (Copyright 1999 American Cancer Society.)

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., (Copyright 1999 American Cancer Society.)

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.