Prognostic factors in localized invasive primary cutaneous malignant melanoma: results of a large population-based study.

BACKGROUND: The prognostic impact of several histopathological prognostic features in cutaneous malignant melanoma (CMM) remains controversial. OBJECTIVES: To assess the independent prognostic value of mitotic rate, regression, tumour-infiltrating lymphocytes (TILs) and growth phase in primary stage I and II CMMs. METHODS: Clinicohistopathological data were obtained from the Stockholm-Gotland registry for 4237 patients diagnosed with an incident primary stage I or II CMM followed up to December 2011. The risk of CMM-specific death was evaluated by a Cox regression model. RESULTS: A mitotic rate of 1-10 mitoses per mm(2) [hazard ratio (HR) 1·69, 95% confidence interval (CI) 1·16-2·45] and > 10 mitoses per mm(2) (HR 2·27, 95% CI 1·46-3·52) were significant; TILs and regression were not. A more detailed analysis of data assessed between 1989 and 1995 confirmed significantly increased HRs for the presence vs. absence of mitoses (HR1-5/mm² 2·25, 95% CI 1·36-3·76; HR6-10/mm² 2·34, 95% CI 1·23-4·44; HR> 10/mm² 2·64, 95% CI 1·39-4·99). Other prognosticators were increasing T-stage vs. T1, presence of ulceration and presence of vertical growth phase (VGP). In T1 CMMs, an increasing tumour thickness vs. < 0·7 mm (HR0·7-0·8 mm 2·24, 95% CI 1·24-4·04; HR>0·8 mm  2·92, 95% CI 1·57-5·43) and presence of ulceration were significantly associated with higher HRs; mitotic rate, TILs, regression and growth phase were not. CONCLUSIONS: Determinants of increased risk of CMM death in stage I and II CMMs were increasing T-stage, presence of ulceration, presence of mitoses and VGP. This was not found for TILs or regression.

Trends in cutaneous malignant melanoma in Sweden 1997-2011: thinner tumours and improved survival among men.

BACKGROUND: Both patient survival and the proportion of patients diagnosed with thin cutaneous malignant melanoma (CMM) have been steadily rising in Sweden as in most Western countries, although the rate of improvement in survival appears to have declined in Sweden at the end of the last millennium. OBJECTIVES: To analyse the most recent trends in the distribution of tumour thickness (T category) as well as CMM-specific survival in Swedish patients diagnosed during 1997-2011. METHODS: This nationwide population-based study included 30,590 patients registered in the Swedish Melanoma Register (SMR) and diagnosed with a first primary invasive CMM during 1997-2011. The patients were followed through 2012 in the national Cause of Death Register. RESULTS: Logistic and Cox regression analyses adjusting for age at diagnosis, tumour site and healthcare region were carried out. The odds ratio for being diagnosed with thicker tumours was significantly reduced (P < 0·001) and the CMM-specific survival significantly improved in men diagnosed during 2007-2011 compared with men diagnosed during 1997-2001 (hazard ratio = 0·81; 95% confidence interval 0·72-0·91; P < 0·001), while the corresponding differences for women were not significant. Women were diagnosed with significantly thicker tumours during 2002-2006 and a tendency towards decreased survival was observed compared with those diagnosed earlier (during 1997-2001) and later (during 2007-2011). CONCLUSIONS: In Sweden, the CMMs of men are detected earlier over time and this seems to be followed by an improved CMM-specific survival for men. Women are still diagnosed with considerably thinner tumours and they experience a better survival than men.

Prognostic subclassifications of T1 cutaneous melanomas based on ulceration, tumour thickness and Clark's level of invasion: results of a population-based study from the Swedish Melanoma Register.

BACKGROUND: Survival and prognostic factors for thin melanomas have been studied relatively little in population-based settings. This patient group accounts for the majority of melanomas diagnosed in western countries today, and better prognostic information is needed. OBJECTIVES: The aim of this study was to use established prognostic factors such as ulceration, tumour thickness and Clark's level of invasion for risk stratification of T1 cutaneous melanoma. METHODS: From 1990 to 2008, the Swedish Melanoma Register included 97% of all melanomas diagnosed in Sweden. Altogether, 13,026 patients with T1 melanomas in clinical stage I were used for estimating melanoma-specific 10- and 15-year mortality rates. The Cox regression model was used for further survival analysis on 11,165 patients with complete data. RESULTS: Ulceration, tumour thickness and Clark's level of invasion all showed significant, independent, long-term prognostic information. By combining these factors the patients could be subdivided into three risk groups: a low-risk group (67·9% of T1 cases) with a 10-year melanoma-specific mortality rate of 1·5% (1·2-1·9%); an intermediate-risk group (28·6% of T1 cases) with a 10-year mortality rate of 6·1% (5·0-7·3%); and a high-risk group (3·5% of T1 cases) with a 10-year mortality rate of 15·6% (11·2-21·4%). The high- and intermediate-risk groups accounted for 66% of melanoma deaths within T1. CONCLUSIONS: Using a population-based melanoma register, and combining ulceration, tumour thickness and Clark's level of invasion, three distinct prognostic subgroups were identified.

Screening of germline mutations in the CDKN2A and CDKN2B genes in Swedish families with hereditary cutaneous melanoma.

BACKGROUND: Approximately 10% of human cutaneous melanomas occur in families in which several members are affected. The familial predisposition to this disease is often associated with dysplastic nevus syndrome, a condition in which afflicted family members have multiple dysplastic nevi (atypical moles). The chromosome region 9p21 and markers on chromosomes 1p and 6p have been linked to melanoma susceptibility. The tumor suppressor genes CDKN2A and CDKN2B have been mapped to the 9p21 region, and genetic analyses have revealed the presence of germline CDKN2A alterations in melanoma families. The reported frequencies of such alterations, however, vary among these families. PURPOSE: The present investigation was carried out to determine the frequencies of CDKN2A and CDKN2B germline gene mutations among members in a population-based cohort of Swedish melanoma families (i.e., melanoma kindreds). METHODS: DNA was prepared from blood samples obtained from 181 individuals belonging to 100 melanoma kindreds. The polymerase chain reaction (PCR) technique, followed by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses, were used to identify the types and frequencies of mutations in exons 1, 1beta, 2, and 3 of the CDKN2A gene and in exons 1 and 2 of the CDKN2B gene. RESULTS: CDKN2A gene aberrations were independently identified by both SSCP and nucleotide-sequence analyses. Nucleotide-sequence analysis identified a single point mutation leading to a substitution of leucine for proline in codon 48 of exon 1 in a family with a history of melanoma and several other cancers. A second abnormality, leading to an insertion of an extra arginine residue at codon number 113 of exon 2, was seen in four separate families. The CDKN2A exon-3 coding region had the wild-type sequence in all samples. No germline mutations were found in the alternative exon 1beta of the CDKN2A gene or in exons 1 and 2 of the CDKN2B gene. CONCLUSIONS: The present investigation demonstrates that CDKN2A germline gene mutations were observed in 7.8% of the 64 Swedish melanoma kindreds that each included at least two first-degree relatives with melanoma and dysplastic nevus syndrome. No CDKN2A exon 1beta or CDKN2B mutations were identified. The critical genes responsible for the inheritance of a susceptibility to develop melanoma among family members in this population have yet to be identified.

Serum S-100b protein as a prognostic marker in malignant cutaneous melanoma.

PURPOSE: To evaluate whether S-100B protein in serum is an independent prognostic marker in malignant melanoma. MATERIALS AND METHODS: S-100B protein in serum was analyzed in 1,007 consecutive patients with histologically verified cutaneous malignant melanoma. At the time of blood sampling, 876 patients were in clinical stage I, 35 were in stage II, and 96 were in stage III. The serum concentrations of S-100B protein were measured by a luminescence immunoassay (LIA). RESULTS: The mean serum concentration of S-100B protein was significantly related to clinical stage, with the lowest level in stage I and the highest in stage III. In a multivariate analysis, S-100B protein levels in serum showed the strongest prognostic impact of the factors analyzed with respect to disease-specific survival in clinical stages II to III, followed by clinical stage. Serum S-100B protein was not a significant independent prognostic factor in clinical stage I, where tumor thickness showed the strongest relation to melanoma-specific survival, followed by ulceration and satellites. CONCLUSION: This investigation contains the largest material of patients so far analyzed with the new LIA assay of S-100B protein in serum and confirms that S-100B protein in serum is correlated with clinical stage and is an independent prognostic marker in clinical stages II and III.

Factors associated with atypical nevi: a population-based study.

We conducted a case-control study to identify factors associated with the presence of clinically atypical nevi. Potential participants were selected, using a two-staged sampling scheme, from a population-based cohort of 50,000 Swedish women who had responded to a previous health survey questionnaire. Of 500 women sampled for study recruitment, 400 (80%) agreed to participate. Study participants underwent a physician-conducted skin examination, which identified 130 women who had at least one clinically atypical nevus (cases) and 270 women without these lesions (controls). The physician-conducted skin examination also assessed women for benign nevus counts; other risk factor information was based upon responses to a health survey questionnaire. We found a strong and highly statistically significant relationship between number of benign nevi and the presence of at least one clinically atypical nevus (P < 0.0001). Women with 100 or more benign nevi had a 26-fold increased likelihood of having an atypical nevus. We noted statistically significant interactions between number of benign nevi and other factors of interest; thus, the results are reported separately for women with low (<50) or high (> or =50) counts of benign nevi. Among women with low counts of benign nevi, the likelihood of having an atypical nevus increased with degree of freckling; there was also a suggested role for early sun exposure. Among women with high counts of benign nevi, difficulty tanning and lack of peeling sunburns between ages 10 and 19 appeared to increase the likelihood of case status; our data also suggested an inverse relationship between parity and atypical nevi in this subgroup.

Psychological reactions in patients with malignant melanoma.

Psychological and psychosomatic reactions to malignant melanoma were studied, comparing patients with tumour thickness < or = 0.8 mm versus > 0.8 mm and recurrent versus non-recurrent patients. Gender differences were also studied. Consecutive melanoma patients, Stage I (n = 144), were interviewed at their first postsurgery follow-up visit to an oncology clinic and completed questionnaires 7 and 13 months later. The questionnaire contained items regarding interest in nevi, sleeping problems, psychosomatic complaints, and the Hospital Anxiety and Depression Scale. Patients with a more unfavourable prognosis (tumour thickness > 0.8 mm), subjected to regular medical procedures, did not differ from those with a more favourable prognosis (< or = 0.8 mm), except reporting more sleeping problems. Women had considerably higher levels of problems than men. Amongst patients with an unfavourable prognosis, those with recurrence within 2 years showed lower levels of anxiety at the first visit compared with those free from recurrence after 2 years.

Psychological effects of participation in a prevention programme for individuals with increased risk for malignant melanoma.

The Swedish Melanoma Study Group runs a programme aimed at prevention and early detection of premalignant and malignant melanoma in families with two or more members having malignant melanoma. Psychological consequences of participation in this programme were studied. A questionnaire containing items concerning cognitive and emotional responses to the programme was completed by 115 consecutive individuals at their first visit to the clinic. The same questionnaire was administered by mail 7 months later. The levels of psychological and psychosomatic problems were relatively low at both points of assessment. No negative psychological effects were found, neither in the group with dysplastic naevus syndrome (DNS) with increased risk for malignant melanoma, nor in the group without dysplastic naevi. Only one variable, "emotional responses to the visit" differentiated between the groups, with higher scores in the group without DNS. A majority of the individuals expressed positive attitudes to the clinic.

Psychological reactions in public melanoma screening.

Participants in public screening for malignant melanoma (n = 190) completed a questionnaire containing items regarding cognitive and emotional responses to skin examination on two occasions, before screening and 7 months later. The results suggest subjective susceptibility to melanoma in participants in public screening, especially in women. No increase in psychosomatic problems, anxiety or depressive symptoms or signs of "false security" were seen as an effect of the screening, neither in the total sample nor in those who at the screening were recommended further medical procedures.

Primary prevention of malignant melanoma in the Stockholm Cancer Prevention Programme.

Malignant melanoma is the most rapidly increasing tumour in Sweden. Sunburns in childhood and adolescence are considered a major risk factor. The Stockholm Cancer Prevention Programme addresses strategies to establish sun awareness in the population of Stockholm county by using existing networks of standardized child health and preschool services, educational systems including schools, colleges of nursing sciences and preschool teaching (integration of sun awareness in curricula, and in a new syllabus for environmental theory), the Federation of Swedish Pharmacies, and media. Health education is designed for key persons in these organizations and the media, who in turn diffuse sun awareness via their respective organizations. The education programme only deals with primary prevention by behavioural changes in exposure to UV rays, ie excessive exposure to sun, and it is primarily intended to raise sun awareness. Experiences have shown that information diffusion was good in spite of limited staff resources.

Stereological estimates of nuclear volume in thin malignant melanomas.

Stereological estimation of nuclear volume was performed in a case control study of 72 malignant melanomas, thickness < or = 0.8 mm and Clark's level II-III. However, stereological measurements could be performed in only 57 thin melanomas due to too sparse cellularity. Thus, 21 thin metastasizing melanomas were individually compared with 33 thin non-metastasizing melanomas after individual matching of cases with one or two randomly chosen controls for site of primary tumour, tumour thickness, level of invasion, tumour regression and follow-up. Conditional logistic regression analysis showed no significant differences in nuclear volume between metastasizing and non-metastasizing thin malignant melanomas.

Nodular histogenetic type -- the most significant factor for thick melanoma: implications for prevention.

Tumour thickness is the most important prognostic factor in malignant melanoma. To reduce the melanoma-related mortality, factors related to the presentation of thick melanoma have to be identified. Three samples of melanoma patients (n=694) were studied for this purpose. Histogenetic type was the only factor which differentiated between 'thin' (< or = 0.8 mm) and 'thick' (> 2.0 mm) lesions. During a 10-year period only 3% of the nodular lesions were 'thin' at diagnosis. Differences in knowledge about melanoma or the location of the lesion (either 'easy' or 'difficult' for the patient to observe) did not explain differences in tumour thickness. The most common tumour site irrespective of histogenetic type and gender was 'back of the trunk'. 'Increase in diameter' and 'bleeding' were the symptoms most frequently reported by patients with 'thick' melanoma. 'Thick' lesions were diagnosed in older age groups and in men to a greater extent. Considering these results, melanoma prevention should also be targeted to older age groups and attention should be paid to symptoms such as 'increase in diameter' even in the absence of other characteristic symptoms of melanoma. An increased proportion of nodular melanoma diagnosed as 'thin' lesions can be interpreted as a step forward in secondary prevention.

Screening for cutaneous malignant melanoma: a feasibility study.

OBJECTIVES: To study two different procedures for inviting subjects to screening for malignant melanoma, and to study the role of specially trained nurses as primary examiners. METHODS: The study was carried out in Stockholm county and comprised 5000 randomly selected men and women aged 40 to 60, of whom 2,500 were invited with a personal invitation letter and with a set time of appointment and 2,500 were sent a questionnaire and instructions for self examination of the skin. To test the nurses' competence, a survey was made, comparing the judgments of skin examination between nurses and doctors. RESULTS: 1654 (66%) of those invited for a skin examination took part. 1507 (60%) replied in the questionnaire group, of whom 1024 (41%) requested and attended a subsequent skin examination. Of the subjects attending from both groups, the nurses judged 9% v 11% as having skin lesions suggesting malignant melanoma, whereas the two doctors referred 4% v 3% of the subjects for surgical biopsy. Two malignant melanomas were detected, both of them in the questionnaire group. In the study of nurses' screening competence, both nurses and doctors equally judged one case out of 19 as having a lesion suspicious for malignant melanoma. CONCLUSIONS: When the questionnaire method was used the results were achieved with one third fewer skin examinations, but it is difficult to conclude whether one of the procedures is better than the other. The results also indicate that nurses can be trained to be the primary examiners in a melanoma screening programme.

Chromosomal sensitivity to X-ray irradiation during the G2 phase in lymphocytes of patients with hereditary cutaneous malignant melanoma as compared to healthy controls.

Recent reports have suggested that elevated chromosomal aberration yields following X-ray irradiation of skin fibroblasts and peripheral lymphocytes in the G2 phase of the cell cycle are characteristic of affected members of cancer-prone families. These studies propose that the phenomenon is a consequence of impaired caffeine- and arabinofuranosylcytosine (ara-C)-sensitive DNA repair and might be a useful indicator of genetic susceptibility to cancer. We have tested G2 chromosomal X-ray sensitivity in peripheral blood lymphocytes from members of kindreds with hereditary cutaneous malignant melanoma (HCMM) combined with the dysplastic nevus syndrome (DNS), disorders in which susceptibility to skin cancer is inherited in an autosomal dominant pattern. In the assay lymphocytes from patients with HCMM/DNS exhibited responses indistinguishable from normal healthy controls. Furthermore, the radiation-induced aberration yields were potentiated to the same strong extent by post-treatments with caffeine, or a combination of ara-C and hydroxyurea, both in lymphocytes from individuals with HCMM/DNS and lymphocytes from healthy controls. Thus, lymphocytes of affected patients with HCMM/DNS do not have an increased sensitivity to X-ray irradiation in the G2 phase of the cell cycle.

A prospective population-based study of cutaneous malignant melanoma of the head and neck.

UNLABELLED: OBJECTIVES/HYPOTHESIS For cutaneous malignant melanoma (CMM) of the head and neck, neither prognostic factors in population-based groups, nor outcome with respect to surgical resection margins is clear. Therefore, we analyzed data in a regional registry to align treatment results for CMM of the head and neck with prognosis and survival times. STUDY DESIGN: Patient material collected prospectively for an 18-year period in a Swedish cancer registry underwent statistical analyses to establish the most reliable prognostic factors and the influence of surgical treatment on the survival of patients with CMM of the head and neck. METHODS: Data originated from the CMM database of the Stockholm-Gotland area of Sweden. Tumor thickness or invasiveness (Breslow or Clark's levels), extent of surgical margin, sex, histogenetic type, anatomic site, and ulceration were compared statistically for 469 patients. RESULTS: Male patients with head and neck CMM had a 68% 10-year survival rate; the 10-year survival rate for female patients was 87%. The corresponding figures for CMM at other sites were 83% and 90%, respectively. Tumor thickness (or Clark level of invasion) was the only statistically significant prognostic factor in a multivariate analysis (P < .001). The surgical resection margin seemed to be of no importance to outcome. CONCLUSIONS: Long-term survival after treatment for CMM of the head and neck is better than reported in most earlier publications, presumably because our evaluation used population-based materials, an important factor in accurate reporting of this kind. Tumor thickness is the main prognostic factor in estimating outcome.

Information to patients with malignant melanoma: a randomized group study.

An information programme for patients with cutaneous malignant melanoma, Stage 1, aiming at increasing satisfaction with information, was carried out at the Department of Oncology (Radiumhemmet). The programme consisted of a group meeting and a brochure. A total of 231 consecutive patients were included, and 149 (65%) reported interest in participation and were randomized to the Information group (n = 77) or to the Control group. A total of 67 patients (29%) were not interested (the NI-group). To evaluate the programme, the patients in the three groups completed questionnaires regarding satisfaction with information, knowledge of melanoma and psychological and psychosomatic variables before randomization and at the first visit for follow-up at Radiumhemmet. After the information programme, the Information group was significantly more satisfied with information, had a higher level of knowledge and a lower proportion requested further information as compared with the Control group. No differences were found on the psychological and psychosomatic variables.

Six-month follow-up of effects of an information programme for patients with malignant melanoma.

Using a randomized design, the effects of an information programme for melanoma patients were studied. The programme consisted of a group meeting and a brochure. The present study reports on the six-month follow-up of the effects of the programme. A total of 128 patients participated in the programme, 55 before and 73 after the first medical control visit. Questionnaires regarding knowledge about melanoma, psychological and psychosomatic variables were completed at the first medical control visit and six months later by mail. A questionnaire concerning patients attitudes to the programme was included after six months. Knowledge about melanoma increased and a majority of patients were satisfied with the information brochure, the group meeting and the group leader, but 40% considered that too few participants attended in their group meeting. No effects on psychological or psychosomatic variables were found. Men and women participated to the same extent.

Low level of education is associated with later stage at diagnosis and reduced survival in cutaneous malignant melanoma: a nationwide population-based study in Sweden.

BACKGROUND: A worse outcome has been reported for cutaneous malignant melanoma (CMM) patients with low socioeconomic status. We have investigated the association between level of education, clinical stage at diagnosis (stage at diagnosis) and CMM-specific survival in Sweden. METHODS: We identified 27,235 patients from the Swedish Melanoma Register diagnosed with a primary invasive CMM between 1990 and 2007 and linked data to nationwide, population-based, health and census registers with a follow-up to 2010. RESULTS: The odds ratio (OR) of higher disease stage at diagnosis was significantly increased in lower education groups (OR stage II versus I=1.6; 95% confidence interval (CI)=1.5-1.7. OR stage III-IV versus I=2.3; 95% CI=1.8-2.9). The risk of dying of CMM, was significantly increased in patients with low (hazard ratio (HR) low versus high=2.02; 95% CI=1.80-2.26; p<0.0001) and intermediate (HR intermediate versus high=1.35; 95% CI=1.20-1.51; p<0.0001) level of education. After adjustment for age, gender, stage at diagnosis and other known prognostic factors, the HRs remained significant for low versus high (HR=1.13; 95% CI=1.01-1.27; p=0.04) but not for intermediate versus high (HR=1.11; 95% CI=0.99-1.24; p=0.08) education. The HR associated with low level of education was significantly higher among female patients, patients <55 years, patients with truncal tumours and during the first 5 years after diagnosis. CONCLUSION: Lower level of education is associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. These results emphasise the need for improved early detection strategies.