Epidemiology of Malignant Melanoma in Central Europe: Risk Factors and Prognostic Predictors. Results of the Central Malignant Melanoma Registry of the German Dermatological Society

The Central Malignant Melanoma Registry (CMMR) of the German Dermatological Society was established in 1983, and 7789 cutaneous malignant melanomas (CMM) were registered by 35 dermatological departments in Germany, Austria and Switzerland until the end of 1989. Population-based incidence rates, risk factors for developing CMM and prognostic parameters for predicting the final outcome were investigated in separate multicenter studies performed by the CMMR. Among the 7789 CMM registered, there was a preponderance of females (57.7%) versus males (42.3%). The age distribution peaked in the 5th and 6th decade of life for both sexes with a mean age of 52 years. The mean detection age was 50 years for superficial spreading melanoma, 53 for nodular melanoma, and 65 for lentigo maligna melanoma. Mean tumor thickness decreased from 2 mm in 1983 to 1.5 mm in 1989, indicating better CMM-awareness of the population and the medical community in this area. 90% of the patients presented with clinical stage I CMM without detectable metastases at first diagnosis. The incidence of CMM in Berlin (West) was assessed based on 960 cases diagnosed between 1980 and 1986. The incidence increased by 49% between 1980-81 and 1985-86, and the age standardized-incidence rate (European standard population) was 9.8 for males and 7.8 for females per 100,000 inhabitants and year in 1985-86. Mortality rates decreased in this period from 3.5 to 2.6 for males and slightly increased for females from 1.2 to 1.6 per 100,000 inhabitants and year. A case control study on the relative risk (RR) for developing CMM revealed the total number of melanocytic nevi (MCN) to be the strongest risk predictor (15x - 50x increased RR), followed by the presence of dysplastic MCN (7x increased RR) and the skin type I (2x increased RR). Interestingly, no differences between CMM-cases and controls were found with respect to the history of sunburns or other parameters of sun exposure in this study. Multivariate analysis of 5093 stage I CMM-patients from four departments with long-term follow-up revealed that tumor thickness is the strongest predictor of survival with an almost linear correlation to the risk of death for tumor thickness up to 6 mm with no further increase in mortality for higher tumor thickness. The best classification of tumor thickness for survival prediction was 1 mm, 1.01 ?2 mm, 2.01 ?4 mm and > 4 mm in our data set on 5093 patients. Sex was found to be the second most important prognostic factor showing a significant advantage for females. Furthermore, a high risk was identified for tumors localized on the upper trunk, upper arm, neck and scalp on the upper trunk, upper arm, neck and scalp (=TANS); the anatomical site, therefore, should be taken into account for a prognostic classification of primary CMM.     

Immunohistochemical determination of HER-2/neu overexpression in malignant melanoma reveals no prognostic value, while c-Kit (CD117) overexpression exhibits potential therapeutic implications

BACKGROUND: HER-2/neu and c-kit (CD117) onco-protein are increasingly being recognized as targets for therapy in solid tumors, but data on their role in malignant melanoma is currently limited. We studied the prevalence of overexpression of HER-2/neu and c-Kit in 202 patients with malignant melanoma to evaluate a possible prognostic value of these molecular targets in malignant melanoma. METHODS: Overexpression of HER-2/neu and c-Kit was evaluated using immunohistochemical assays in 202 archival tissue specimens. RESULTS: Between 1991 and 2001, 202 subjects (109 males; 54% and 93 females; 46%) with malignant melanoma were studied with a mean age of 57 years (age range: 15-101 years). The most common histologic type was amelanotic melanoma (n = 62; 30.7%) followed by superficial spreading melanoma (n = 54; 26.7%). The depth of penetration of melanoma (Breslow thickness, pT Stage) ranged from 0.4 mm (stage pT1) to 8.0 mm (stage pT4A). Mean thickness was 2.6 mm (stage pT3A). The ECOG performance scores ranged from 0 to 3. Only 2 patients (0.9%) revealed HER-2/neu overexpression, whereas 46 (22.8%) revealed c-Kit overexpression. Multivariate analysis performed did not show a significant difference in survival between c-Kit positive and negative groups (p = 0.36). Interestingly, not only was c-Kit more likely to be overexpressed in the superficial spreading type, a preliminary association between the presence or absence of c-Kit overexpression and the existence of another second primary tumor was also observed. CONCLUSIONS: The results of our large study indicate that the HER-2/neu onco-protein neither has a role in melanogenesis nor is a potential target for clinical trials with monoclonal antibody therapy. This indicates there is no role for its testing in patients with malignant melanoma. Although c-Kit, expressed preferentially in the superficial spreading type, may not have prognostic value, it does have significant therapeutic implications as a molecular target warranting further investigation.     

Survival According to BRAF-V600 Tumor Mutations – An Analysis of 437 Patients with Primary Melanoma

The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies.     

Patterns of initial recurrence and prognosis after sentinel lymph node biopsy and selective lymphadenectomy for melanoma

The histologic status of the sentinel lymph node is a highly significant prognostic factor for patients with clinically localized cutaneous melanoma. The patterns of initial treatment failure of patients with positive sentinel lymph node biopsy versus those with negative results have not been well described. The purpose of this study was to determine the relative prognostic importance of sentinel lymph node status and to compare patterns of initial treatment failure and prognosis of node-positive versus node-negative cutaneous melanoma patients staged by sentinel lymph node biopsy and selective lymphadenectomy. The authors reviewed the pertinent demographic and surgical data in a consecutive series of patients with cutaneous melanoma who underwent sentinel lymph node staging of nonpalpable regional nodes. Sentinel lymph node biopsy was performed using a combination of blue dye and radiolocalization. Patients with positive biopsy results underwent selective lymphadenectomy, whereas those with negative results were observed. Site(s) and date(s) of initial recurrence and death were determined, and disease-free and overall survival probabilities were compared between positive and negative groups using the log-rank test and multivariable Cox regression analysis. Between February of 1994 and August of 2000, 408 patients with melanoma underwent sentinel lymph node biopsy to stage 518 regional lymph node basins. Mean Breslow tumor thickness was 2.27 mm (range, 0.2 to 14.0 mm). Eighty-five patients (20.8 percent) had at least one histologically positive sentinel lymph node, and selective lymphadenectomy yielded additional positive lymph nodes in 18 of 84 patients (21.4 percent). Recurrences were noted in 70 patients (17 percent) at a median follow-up period of 31.4 months. Recurrences were more frequent in patients with positive biopsy results (36.5 percent) than in those with negative results (12.1 percent, p < 0.0001). Distant sites of initial recurrence were more likely in the positive group than in the negative group (71 percent versus 49 percent of recurrences, respectively; p = 0.06). The false-negative rate for sentinel lymph node staging was 4.5 percent and overall accuracy was 99 percent compared with clinical follow-up. Disease-free and overall survival correlated significantly with tumor thickness, ulceration, sentinel lymph node status, and the number of tumor-positive lymph nodes (two-sided p < 0.0001 for all comparisons). Multivariable analysis revealed that sentinel lymph node status (p = 0.003), tumor thickness (p = 0.016), ulceration (p = 0.006), and age (p = 0.003) were significant independent predictors of survival for the entire group. Tumor thickness and ulceration were significant predictors of recurrence and survival in sentinel node-negative patients but not in sentinel node-positive patients. Sentinel lymph node histology is possibly the most important negative predictor of early recurrence and survival in patients with American Joint Committee on Cancer stage I and II melanoma. The number of positive lymph nodes provides additional prognostic information. Although sentinel node-negative patients are a prognostically favorable group, various combinations of local and regional recurrences comprise the most common pattern of initial relapse after a negative sentinel lymph node biopsy result.     

Frequency and Clinicopathological Profile Associated with Braf Mutations in Patients with Advanced Melanoma in Spain

Real-world data on BRAF mutation frequency in advanced melanoma are lacking in Spain. Moreover, data available on clinicopathological profile of patients with advanced BRAF-mutant melanoma are currently limited. This study aimed to assess the frequency of BRAF V600 mutations in Spanish patients with advanced or metastatic melanoma and to identify clinical and histopathological features associated with BRAF-mutated tumors. A multicenter, cross-sectional epidemiological study was conducted in 33 Spanish hospitals in adult patients with stage IIIc/IV melanoma. A total of 264 patients were included. The median age was 68 years and 57% were male. Melanoma mainly involved skin with intermittent (40.4%) and low or no sun exposure (43.5%). Most patients (85.6%) had stage IV disease (M1a: 19.3%; M1b: 13.3%; M1c: 22.7%). Serum lactate dehydrogenase levels were elevated in 20% of patients. Superficial spreading melanoma was the most frequent histological type (29.9%). Samples were predominantly obtained from metastases (62.7%), mostly from skin and soft tissues (80%). BRAF mutation analysis was primarily performed using the Cobas 4800 BRAF V600 Mutation Test (92.8%) on formalin-fixed, paraffin-embedded tissue (95.8%). BRAF mutations were detected in 41.3% of samples. Multivariate analysis identified age (odd ratio [OR] 0.975) and stage IV M1a (OR 2.716) as independent factors associated with BRAF mutation. The frequency of BRAF mutations in tumor samples from patients with advanced or metastatic melanoma in Spain was 41.3%. BRAF mutations seem to be more frequent in younger patients and stage M1a patients.This study provides the basis for further investigation regarding BRAF-mutated advanced melanoma in larger cohorts.     

The characterization and potential impact of melanoma cases with unknown thickness in the United States’ Surveillance,Epidemiology, and End Results Program, 1989–2008

Background: In the United States, the Surveillance, Epidemiology, and End Results (SEER) Program is the authoritative source for population-based data on melanoma incidence and mortality. However, missing data on tumor thickness may lead to biased analyses in this frequently used database. We sought to characterize invasive melanomas with unknown thickness with emphasis on their association with melanoma survival, and to employ techniques to overcome the limitations of missing data on tumor thickness. Methods: We conducted a retrospective cohort analysis of non-occult invasive melanomas in the SEER database from 1989 to 2008. Results: Of 182 184 cases, 24 329 (13%) had unknown thickness. From 1989–1993 to 2004–2008, the proportion of unknown thickness cases decreased from 22% to 9% (P_trend < 0.001). Unknown thickness cases had a significantly increased risk of death due to melanoma (hazard ratio [HR] 3.09, 95% confidence interval [CI]: 2.99, 3.19) than known thickness cases with an increasing trend over time (P_trend < 0.001). In multivariate analysis, unknown thickness was found to be independently associated with poorer prognostic factors and lack of cancer-directed surgical treatment. Melanoma survival of cases with unknown thickness appeared most similar to 2.01–4.00 mm thickness cases. Multiple imputation demonstrated that imputed tumor thickness was significantly associated with melanoma survival (HR 1.31, 95% CI: 1.30, 1.32) and Clark level (odds ratio [OR] 1.85, 95% CI: 1.82, 1.89) though the strength of associations were not as strong as the associations of original SEER-coded known tumor thickness with melanoma survival (HR 1.46, 95% CI: 1.45, 1.47) and Clark level (OR 2.92, 95% CI 2.89, 2.95), respectively. Conclusions: Exclusion of missing data on melanoma thickness from SEER introduces a selection bias that leads to an underestimation in the prevalence of fatal and likely thicker melanomas. Multiple imputation appears to be an effective tool to predict missing tumor thickness data.     

Low educational attainment is still associated with late melanoma diagnosis: A cross-sectional study from a European setting with universal healthcare

BackgroundAn early diagnosis of cutaneous melanoma remains determinant for improved survival. Low educational attainment has been associated with a late-stage diagnosis in settings where access to healthcare is restricted. Little evidence is available from regions with universal healthcare. We aimed at analysing whether educational attainment was associated with Breslow thickness at diagnosis in a peripheral European region with universal healthcare (in the Canary Islands, Spain).MethodsWe conducted a cross-sectional study with prospectively collected data (2010–2017). Patients were recruited at diagnosis, and information about Breslow thickness, age at diagnosis, gender, highest educational attainment and site of melanoma were registered. Univariate and multivariate linear regression analyses were performed.ResultsLow educational attainment was associated with thicker tumours at diagnosis. The association remained true after adjustment for age, gender and site of melanoma. In the multivariate analysis, tumours diagnosed in patients with low educational attainment were on average 1.08 mm thicker (95% confidence interval: 0.36–1.81; p = 0.003) than those diagnosed in patients with high educational attainment.ConclusionPublic health strategies targeting this vulnerable group are currently needed in the Canary Islands (Spain).     

Histopathologic variables differentially affect melanoma survival by age at diagnosis

We evaluated clinical, phenotypic, behavioral, and histopathologic variables in relationship to melanoma‐specific survival by age at diagnosis among 650 population‐based melanoma patients in Connecticut, with 20 years of follow‐up. Only one variable, skin awareness, was significantly associated with melanoma mortality in both groups. The variables that differed between the age‐groups were anatomic site, Breslow thickness, histologic subtype, mitoses, tumor‐infiltrating lymphocytes (TILs), and solar elastosis. Head and neck melanoma, Breslow thickness, nodular melanoma, and solar elastosis were all significantly more likely to be associated with mortality among the older subjects; among the younger subjects, the presence of mitoses was associated with an increased probability of dying and TILs were associated with a reduced risk of mortality.     

Surgical considerations in the management of malignant melanoma of the ear

Malignant melanomas of the external ear are rare and are difficult lesions to treat because of the cosmetic importance and the reconstructive difficulty of their location. The literature suggests that these lesions have a worse prognosis than melanomas occurring elsewhere and that radical resection is the "correct" treatment. To clarify this issue, we examined 21 consecutive patients (19 male, 2 female) with malignant melanoma of the ear seen at the Yale-New Haven Hospital over the last 10 years. Nineteen patients had a diagnosis of primary malignant melanoma of the ear, one had a local recurrence, and one had an in-transit melanoma from an unknown primary site. The mean thickness of the lesions was 2.7 mm. Two patients had palpable nodes, which in both cases turned out to be histologically positive for tumor. All patients underwent local excision and reconstruction using chondrocutaneous or fasciocutaneous flaps or skin grafts. There was one local recurrence (0.5 mm original thickness); there were two patients with regional recurrences, both of whom died within a year with disseminated disease. Forty-three percent have been followed for 5 or more years and all are alive and free of disease. This suggests that malignant melanoma of the ear may be safely treated by conservative excision and reconstruction.     

Threshold values of high-risk echocardiographic epicardial fat thickness

Objective: Echocardiographic epicardial adipose tissue is a new index of cardiac and visceral adiposity with great potential as a diagnostic tool and therapeutic target. In this study, we sought to provide threshold values of echocardiographic epicardial fat thickness associated with metabolic and anthropometric risk factors. Methods and Procedures: Epicardial fat thickness was measured in 246 consecutive white subjects (120 women, 126 men, median age 46 years (30–65), median BMI 32 kg/m² (22–52), median waist circumference 100.5 cm (85–140)), who underwent routine transthoracic echocardiogram for standard clinical indications. Metabolic syndrome (MetS), Insulin resistance, BMI, and waist circumference categories were identified and epicardial fat was calculated. Results: Among 246 subjects, 58% had MetS. These subjects showed median values of epicardial fat thickness of 9.5 and 7.5 mm (in men and women, respectively), significantly higher than those found in subjects without MetS (no MetS) (P < 0.001). Receiver operating characteristics (ROC) analysis showed that epicardial fat thickness of 9.5 and 7.5 mm maximize the sensitivity and specificity to predict MetS, in men and women, respectively. In separate analyses, median epicardial fat thickness values of 9.5 and 7.5 mm were cutoff points associated with high abdominal fat in men and women, respectively. When insulin sensitivity was considered separately, epicardial fat thickness of 9.5 mm was associated with insulin resistance. Discussion: Median values of 9.5 and 7.5 mm should be considered the threshold values for high‐risk echocardiographic epicardial fat thickness in white men and women, respectively. Echocardiographic epicardial fat measurement may be of help for cardiometabolic risk stratification and therapeutic interventions targeting the fat.     

口腔疣状癌和口腔鳞癌组织中E-cadherin表达的对比研究

目的:研究E-钙粘素(E-cadherin,E-cd)在口腔疣状癌和口腔鳞癌中的表达,探讨E-cd与口腔疣状癌,口腔鳞癌分化程度的关系。方法:采用免疫组织化学和免疫电镜方法检测18例口腔疣状癌、20例口腔鳞癌组织中的E-cd表达。结果:E-cd在正常口腔黏膜、口腔疣状癌、高分化鳞癌和低分化鳞癌中主要位于胞膜及胞浆上。电镜观察显示E-cd在胞膜主要定位于桥粒,胞浆主要定位于粗面内质网和线粒体上。定量检测显示:E-cd在正常口腔黏膜、口腔疣状癌、高分化鳞癌和低分化鳞癌中的阳性表达率分别100%(8/8)、61.1%(11/18)、50.0%(5/10)和30.0%(3/10)。口腔疣状癌E-cd蛋白的平均染色强度与高分化鳞癌间差异无显著性,但明显低于正常黏膜组(P<0.05)而高于低分化鳞癌(P<0.05)。结论:E-cd的表达水平随口腔肿瘤分化程度的降低而降低,且超微结构的表达部位与肿瘤的分化程度存在相关性。     

Angiogenesis and vascular growth factor receptor expression in malignant melanoma.

The growth and metastases of many solid tumors are dependent on the recruitment of new blood vessels. Tumor angiogenesis is most likely initiated by paracrine release of growth factors that bind to their corresponding endothelial cell surface receptors. To determine whether angiogenesis and growth factor receptor expression are consistent findings in malignant melanoma, primary human melanomas were examined for mRNA expression of receptors for fibroblast growth factors (FGFR-1, FGFR-2), vascular endothelial growth factor (VEGFR-1, VEGFR-2), and the receptors Tiel and Tie2. Charts were reviewed and archival formalin-fixed, paraffin-embedded primary tumors were obtained from patients with thin (<1 mm; n = 10), intermediate (1 to 4 mm; n = 10), or thick malignant melanoma (>4 mm; n = 8). Also examined was whether melanoma cell lines could induce endothelial growth factor receptor synthesis by metabolic labeling. It was found that tumor vascularity did not correlate with clinical stage, melanoma thickness, or clinical outcome. It was also found that melanoma cell lines were not capable of directly regulating endothelial cell synthesis of growth factor receptors. However, expression of Tiel and VEGFR-2 mRNA by the tumor vasculature in select stage IA-IIB patients, and FGFR-1 mRNA expression by the tumor cells in the same clinical stages was found. The expression of these growth factor receptors did not correlate with clinical outcome. These data suggest that angiogenesis is not a prominent characteristic of primary malignant melanoma lesions and that the endothelial cell expression of Tiel and VEGFR-2 in vivo is probably not directly induced by the tumor.     

Sentinel lymph node biopsy for melanoma: experience with 234 consecutive procedures

Sentinel lymph node biopsy is increasingly used to identify occult metastases in regional lymph nodes of patients with melanoma. Selection of patients for sentinel lymph node biopsy and subsequent lymphadenectomy is an area of debate. The purpose of this study was to describe a large clinical series of these biopsies for cutaneous melanoma and to identify patients most likely to gain useful clinical information from sentinel lymph node biopsy. The Indiana University Melanoma Program computerized database was queried to identify all patients who underwent this procedure for clinically localized cutaneous melanoma. It was performed using preoperative technetium Tc 99m lymphoscintigraphy and isosulfan blue dye. Pertinent demographic, surgical, and histopathologic data were recorded. Univariate and multivariate logistic regression and classification table analyses were performed to identify clinical variables associated with sentinel node and nonsentinel node positivity. In total, 234 biopsy procedures were performed to stage 291 nonpalpable regional lymph node basins. Mean Breslow's thickness was 2.30 mm (2.08 mm for negative sentinel lymph node biopsy, 3.18 mm for positive). The mean number of sentinel nodes removed was 2.17 nodes per basin (range, 1 to 8). Forty-seven of 234 melanomas (20.1 percent) and 50 of 291 basins (17.2 percent) had a positive biopsy. Positivity correlated with AJCC tumor stage: T1, 3.6 percent; T2, 8.1 percent; T3, 27.4 percent; T4, 44 percent. By univariate logistic regression, Breslow's thickness (p = 0.003, continuous variable), ulceration (p = 0.003), mitotic index > or = 6 mitoses per high power field (p = 0.008), and Clark's level (p = 0.04) were significantly associated with sentinel lymph node biopsy result. By multivariate analysis, only Breslow's thickness (p = 0.02), tumor ulceration (p = 0.02), and mitotic index (p = 0.02) were significant predictors of biopsy positivity. Classification table analysis showed the Breslow cutpoint of 1.2 mm to be the most efficient cutpoint for sentinel lymph node biopsy result (p = 0.0004). Completion lymphadenectomy was performed in 46 sentinel node-positive patients; 12 (26.1 percent) had at least one additional positive nonsentinel node. Nonsentinel node positivity was marginally associated with the presence of multiple positive sentinel nodes (p = 0.07). At mean follow-up of 13.8 months, four of 241 sentinel node-negative basins demonstrated same-basin recurrence (1.7 percent). Sentinel lymph node biopsy is highly reliable in experienced hands but is a low-yield procedure in most thin melanomas. Patients with melanomas thicker than 1.2 mm or with ulcerated or high mitotic index lesions are most likely to have occult lymph node metastases by sentinel lymph node biopsy. Completion therapeutic lymphadenectomy is recommended after positive biopsy because it is difficult to predict the presence of positive nonsentinel nodes.     

Evaluation of nodal patterns for melanoma of the ear

Treatment of malignant melanoma of the external ear presents unique challenges. Because of the significant debate regarding the efficacy and validity of using sentinel lymph node mapping for the treatment of ear melanomas, data for a population of patients with melanomas of the ear who underwent surgical excision and reconstruction were reviewed to determine the efficacy of sentinel node mapping. A retrospective chart review of cases treated by a single surgical oncologist was performed. All patients who were treated for malignant melanomas and required reconstruction of the external ear by the plastic surgical service between 1995 and 2001 were identified. Nineteen patients were selected, of whom nine underwent sentinel node mapping. The average age of the patients was 65.2 years. Evaluation of melanoma depth, medical history, surgical margins, lymph node metastasis, and recurrence was performed. Lymphoscintigraphy with technetium-99-sulfur colloid and 1% Lymphazurin (isosulfan blue; Zenith Parenterals, Rosemont, Ill.) demonstrated widely variable lymphatic drainage patterns. The lower tail of the parotid gland and the upper cervical area were the two most common locations. The average number of sentinel nodes identified and removed was 3.7. The average Breslow thickness for these patients was 2.3 mm. None of these patients demonstrated micrometastatic disease in their sentinel nodes. The most common reconstructive procedure after surgical resection was the use of rotational advancement flaps. Localization of radioactivity, as detected with external technetium-99 scanning, was the most reliable method for detection of the sentinel lymph node basins and the individual nodes. The average value for the primary injection site was 8375 counts per second, and the average value for the nodes removed was 973.5 counts per second. Of the nine patients who underwent sentinel lymph node mapping, only one, with an initial lesion depth of 5 mm, developed a local recurrence. The average follow-up period in this study was 21 months (range, 12 to 79 months). All patients in this study were evaluated at least 1 year after the initial surgical resection. Patients were monitored by the same surgical oncologist every 3 months for the first 2 years. Little can be found in the literature regarding the efficacy of sentinel node biopsies for ear melanomas. Larger studies are indicated; however, it seems that this method is practical for designing therapeutic methods for patients with melanoma of the ear.     

Low Serum 25-Hydroxyvitamin D Concentrations Are Associated with Increased Risk for Melanoma and Unfavourable Prognosis

Background

Low vitamin D status (serum 25(OH)D concentration) is associated with increased incidence and unfavourable outcome of various types of cancer. However, there are limited data on influence of serum 25(OH)D on risk and prognosis of malignant melanoma.

Methods

Basal serum 25(OH)D concentrations were retrospectively analyzed in a cohort of melanoma patients (n = 324) and healthy controls (n = 141). We tested the hypothesis that serum 25(OH)D concentrations are predictive of melanoma risk, thickness of primary melanomas, and overall survival (OS).

Results

Median serum 25(OH)D concentrations were significantly lower (p = 0.004) in melanoma patients (median = 13.6 ng/ml) as compared to controls (median = 15.6 ng/ml). Primary tumors of patients with low serum 25(OH)D concentrations (<10 ng/ml) had significantly (p = 0.006) greater Breslow thickness (median: 1.9 mm) as compared to patients with higher levels (>20 ng/ml; median: 1.00 mm). Patients with 25(OH)D serum concentrations in the lowest quartile had inferior overall survival (median: 80 months) comparing with the highest quartile (median: 195 months; p = 0.049).

Conclusions

Our data support the concept that serum 25(OH)D concentrations are associated with risk and prognosis of melanoma. Whether normalizing serum 25(OH)D concentrations in these patients improves outcomes will require testing in future clinical trials.     

Vitamin D Deficiency at Melanoma Diagnosis Is Associated with Higher Breslow Thickness

BackgroundEpidemiological evidence shows that people with thicker, or higher stage, melanomas have lower vitamin D status compared to those with thinner tumours. Evidence from experimental studies is inconsistent, but some suggest that administration of vitamin D metabolites can decrease tumour aggressiveness.ObjectivesDetermine the relationship between vitamin D status at diagnosis and melanoma thickness (as an indicator of prognosis), in a subtropical setting with high melanoma incidence.MethodsWe recruited 100 melanoma patients in Brisbane, Australia within days of their diagnosis. Data on factors previously associated with melanoma risk or prognosis were collected by questionnaire and physical examination. Serum for 25-hydroxyvitamin D3 [25(OH)D] levels was collected prior to wider excision biopsy; histological indicators of prognosis were obtained from pathology reports. We used multivariable logistic regression models to analyse the association between Breslow thickness (≥0.75 mm compared to <0.75 mm), Clark level (2–5 compared to 1) and presence of mitoses, and vitamin D status.ResultsSerum 25(OH)D <50 nmol/L (versus ≥50 nmol/L) was associated with a nearly four-fold increase in risk of having a thicker tumour (Adjusted OR = 3.82, 95% CI: 1.03, 14.14; p = 0.04, adjusted for age, sex, skin phototype, body mass index and season at diagnosis). There was no significant association with Clark level or presence of mitosis. Serum 25(OH)D levels in the highest quartile (≥69.8 nmol/L) were not associated with a more favourable prognosis.ConclusionsVitamin D deficiency at the time of melanoma diagnosis is associated with thicker tumours that are likely to have a poorer prognosis. Ensuring vitamin D levels of 50 nmol/L or higher in this population could potentially result in 18% of melanomas having Breslow thickness of <0.75 mm rather than ≥0.75 mm.     

Dermatoscopy and High Frequency Sonography: Two Useful Non-Invasive Methods to Increase Preoperative Diagnostic Accuracy in Pigmented Skin Lesions

Dermatoscopy and high frequency sonography have recently been combined to increase diagnostic preoperative accuracy in the treatment of pigmented skin lesions. In this monocentric study 80 patients with pigmented skin lesions were evaluated clinically, by dermatoscopy, and 20 MHz-sonography followed by dermatohistopathological evaluation; 39 malignant melanomas, 37 common nevi, 3 dysplastic nevi, and 1 nevus Spitz were diagnosed histologically. In 72 of the 80 cases (91.3%) dermatoscopical diagnoses were confirmed by histopathology, compared to only 79% correct clinical diagnoses. For the mere clinical diagnosis of melanoma sensitivity was 79%, specificity was 78% and diagnostic accuracy was 65%. All diagnostic values increased by dermatoscopy: sensitivity reached 90%, specificity was 93%, and diagnostic accuracy was 83%. In order to determine tumor thickness preoperatively tumor thickness was measured by 20 MHz sonography. The correlation of tumor thickness between histometric and sonographic results was determined for nevi (r = 0.93) and melanoma (r = 0.95); 74.3% of melanomas were diagnosed correctly within an 0.2 mm range. Regarding the clinical important limit of 1 mm tumor thickness, 87.2% were diagnosed in accordance with histometric evaluation. An increase of 18% in diagnostic accuracy by dermatoscopy and 87.2% of correctly diagnosed cases of tumor thickness of malignant melanoma by high frequency sonography clearly demonstrate that these methods should be considered standard procedures in the diagnosis of pigmented skin lesions and will facilitate the decision on necessary surgical treatment.     

Adiposity in Childhood Is Related to C‐Reactive Protein and Adiponectin in Young Adulthood: From the Bogalusa Heart Study

To determine the association between cardiovascular (CV) risk factors in childhood and high‐sensitivity C‐reactive protein (hsCRP) and adiponectin in adulthood, 835 eligible white and African‐American young adult subjects (age range 24–42 years, average 34 years, 43% men, 31% African Americans) who had CV risk‐factor variable data from their childhood (20 years earlier, age range 5–18 years, average 14 years) were selected. Stepwise linear regression models revealed that mean logarithmic hsCRP level in adulthood was 0.02 greater with every increase of 1 mm in skinfold thickness in childhood, 0.25 greater for African Americans than whites, 0.36 greater for girls than boys, and 0.15 greater for every unit increase in BMI z score. Mean logarithmic adiponectin level in adulthood was 0.36 greater for girls than boys, 0.22 greater for whites than African Americans, and 0.01 less with every increase of 1 mm of childhood skinfold thickness. Seventy participants (8%) were overweight or obese in their childhood, and 64 of these (91%) remained obese in their young adulthood. In conclusion, childhood adiposity and African‐American race were associated with higher hsCRP and lower adiponectin levels in their adulthood. Skinfold thickness and BMI z score in childhood were the main obesity determinants for higher hsCRP and lower adiponectin levels in young adulthood.     

Evaluation of prognosis in Stage I cutaneous melanoma

A review of the literature on melanoma indicates that age, sex, size, ulceration, presence of satellites, absence of melanin, and whether or not the tumor is markedly raised above the surface of the surrounding skin are all useful criteria in evaluating the prognosis in Stage I cutaneous melanoma. Histological factors include the tumor type, the mitotic rate, and the maximum thickness of the tumor. The last is accurate for prognosis--objective, reproducible, and directly proportional to the mortality rate. Tumors less than 0.76 mm thick rarely, if ever, metastasize--and it appears that the size of the resection margin can safely be reduced for such thin tumors. The level of invasion (Clark) is less accurate in predicting the mortality.