Lower Breslow Thickness Research Articles

A comparison of isolated limb infusion/perfusion, immune checkpoint inhibitors, and intralesional therapy as first-line treatment for patients with melanoma in-transit metastases.

Isolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in-transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first-line ILI/ILP, ICI, and TVEC. Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first-line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM. A total of 551 patients were treated, with ILI/ILP (n=356), ICI (n=125), and TVEC (n=70) with median follow-up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p =.002). Breslow thickness was lowest with TVEC (p =.007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p =.01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p =.029) and a longer local progression-free survival (PFS) (hazard ratio [HR], 0.40; p =.003). ILI/ILP had shorter local PFS (HR, 1.72; p =.012), PFS (HR, 1.79; p <.001), distant metastasis-free survival (DMFS) (HR, 1.75; p =.014), overall survival (HR, 1.82; p =.009), and melanoma-specific survival (HR, 2.29; p =.004). Stage IIIB disease had longer DMFS (HR, 0.24; p <.001) compared to IIIC/D. TVEC as first-line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first-line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.

Median Breslow thickness during, post and pre-COVID-19 lockdown and correlation with socioeconomic factors.

e21574 Background: Access to routine cancer care during COVID-19 pandemic was greatly affected. The impact of this on melanoma care is unknown. Breslow thickness (BT) was seen to decrease and then increase during and post-COVID-19 lockdown in Italy. Here, we aim to study the impact of COVID-19 lockdown on melanoma care in the United States. Methods: Patients diagnosed with cutaneous melanoma (CM) pre (September 15th 2019-March 14th 2020), during (March 15th-June 14th 2020), and post-lockdown (June 15th-December 14th 2020) were retrospectively studied using Metropolitan Detroit Cancer Surveillance System (MDCSS) database. Patients without an identifiable primary lesion, or with ocular, mucosal, or acral melanoma were excluded. Demographic and clinical characteristics were reviewed. The primary endpoint was median BT during and post vs pre-lockdown. Fisher's exact and Kruskal-Wallis tests were performed for categorical and continuous variables, respectively, to compare groups. Interaction in subgroup analyses was assessed using likelihood ratio tests. Linear regression analyses were performed with Box-Cox transformed BT. Cox proportional hazards regression analyses were performed for overall survival. Covariates for multivariable analysis were selected using LASSO-based penalized regression models. Results: 802 patients were included (pre N = 347, during N = 87, post N = 368). Patients diagnosed with CM post-lockdown were younger (age &lt; 50 years pre = 14%, during = 13%, post = 23%). More patients diagnosed pre-lockdown carried government-issued insurance (pre = 48%, during = 39%, post = 38%). No difference (diff) in median BT was seen between periods (median = 0.6mm for pre, during, and pos). Married status was associated with a lower BT vs unmarried (diff = -0.19, 95% CI -0.36 to -0.014, p = 0.034) and higher census tract poverty level was associated with a higher BT (5%-10% diff = 0.17, 95% CI 0.004 to 0.33, p = 0.045; 10%-100% diff = 0.27, 95% CI 0.093 to 0.45, p = 0.003) vs 0-5% poverty on univariable analysis. Male gender was associated with a lower BT on multivariable analysis (diff = -0.12, 95% CI -0.20 to -0.04, p = 0.005) and lower risk of death on univariable analysis (HR = 0.50, 95% CI 0.31 to 0.82, p = 0.006). Conclusions: We found no difference in median BT during and post- vs pre-lockdown. We also identified at-risk populations (female, unmarried, and living in greater poverty areas) who could benefit from proactive melanoma care. Time to surgery from initial diagnosis during and post vs pre-lockdown would be of interest to study further.

Histological regression in melanoma: impact on sentinel lymph node status and survival

Regression in melanoma is an immunological phenomenon that results in partial or complete replacement of the tumor with variably vascular fibrous tissue, often accompanied by pigment-laden macrophages and chronic inflammation. In some cases, tumor-infiltrating lymphocytes (TILs) may represent the earliest phase of this process. The prognostic significance of regression has long been a matter of debate, with inconsistent findings reported in the literature to date. This study sought to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes in a large cohort of patients managed at a single centre. Clinical and pathological parameters for 8,693 consecutive cases were retrieved. Associations between regression and SLN status, overall survival (OS), melanoma-specific survival (MSS) and recurrence-free survival (RFS) were investigated using logistic and Cox regression. Histological evidence of regression was present in 1958 cases (22.5%). Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p < 0.0001). Multivariable analysis showed that regression in combination with TILs independently predicted a negative SLN biopsy (OR 0.33; 95% C.I. 0.20–0.52; p < 0.0001). Patients whose tumors showed both regression and TILs had the highest 10-year OS (65%, 95% C.I. 59–71%), MSS (85%, 95% C.I. 81–89%), and RFS (60%, 95% C.I. 54–66%). On multivariable analyses, the concurrent presence of regression and TILs independently predicted the lowest risk of death from melanoma (HR 0.69; 95% C.I. 0.51–0.94; p = 0.0003) as well as the lowest rate of disease recurrence (HR 0.71; 95% C.I. 0.58–0.85; p < 0.0001). However, in contrast, in the subgroup analysis of Stage III patients, the presence of regression predicted the lowest OS and RFS, with MSS showing a similar trend. Overall, these findings indicate a prognostically favorable role of regression in primary cutaneous melanoma. However, in Stage III melanoma patients, regression may be a marker of more aggressive disease.

A Retrospective, Observational Analysis of Tumor Infiltrating Lymphocytes and Tumor Regression in Melanoma

Tumor infiltrating lymphocytes (TILs) and regression are thought to be distinct markers of the immune response to melanoma. This study sought to analyze the relationship of TIL grade and presence of regression to each other and to other prognostic histopathologic and clinical values in melanoma. A retrospective analysis was conducted using patients diagnosed with melanoma between 2013 and 2019 whose complete histopathologic reports were available. Regression was seen in 48.9%, 30.1% and 37.9% of patients with brisk, non-brisk, and absent TILs respectively (P=0.019). Melanoma tumors with brisk TILs were found to have a lower Breslow thickness than those with non-brisk or absent (P= 0.001). Tumors with regression were also found to have lower Breslow thickness (P<0.001). Neither TIL grade nor regression were protective of nodal metastasis or associated with improved survival. Brisk TILs have a positive association with thinner tumors and the presence of tumor regression relative to non-brisk or absent TILs. This may suggest a more robust immune response in tumors with brisk TILs. Further exploration of the interplay between TIL grade, lymphocyte cell subtype and lymphocyte density may help explain this finding.

The association between serum vitamin D level and risk and prognosis of melanoma: a systematic review and meta-analysis.

Vitamin D has antineoplastic effects, but the synthesis of vitamin D requires ultraviolet radiation, a known risk factor for melanoma. To investigate the correlations between serum vitamin D levels and risk and prognosis of melanoma. A systematic review and meta-analysis were conducted. Online databases were searched on 31 Oct 2018. Twenty-five studies with a total of 11166 patients with melanoma were included. There was no significant difference in serum vitamin D levels between patients with melanoma and controls [standardized mean difference (SMD), -0.185; 95% confidence interval (CI), -0.533 to 0.162]. However, the prevalence of vitamin D deficiency was significantly higher in patients with melanoma than that in controls (odds ratio, 2.115; 95% CI, 1.151-3.885). In terms of prognosis, serum vitamin D levels were significantly higher in melanoma patients with lower Breslow thickness (≦1 vs. >1mm: SMD, 0.243; 95% CI, 0.160-0.327). Moreover, melanoma patients with lower vitamin D levels had a significantly higher mortality rate (hazard ratio, 1.558; 95% CI, 1.258-1.931). Vitamin D deficiency is associated with higher Breslow thickness and mortality in melanoma patients.

Prioridad de derivación de los casos de melanoma desde atención primaria

IntroductionIn the Spanish health system, most patients are referred to the Dermatology Unit by their Primary Care physician, who establishes the referral priority. The purpose of the present study was to evaluate the proportion of cutaneous melanomas referred through priority routes compared to those referred through ordinary routes, and the differences between them. MethodsThis is an observational, cross-sectional, retrospective, and descriptive study. Data were collected from cutaneous melanoma patients referred by Primary Care physicians in the Health Department of Castellón between November 2016 and November 2018. The statistical analysis was carried out using SPSS®. ResultsA total of 43 cutaneous melanomas were referred from Primary Care in the study period. Of these, 51.2% were referred through ordinary routes, compared to 48.8% that were referred through priority routes. The average Breslow thickness of the cases referred by ordinary route (0.87mm) was significantly lower than that of those referred by priority route (2.52mm) (P=.013). ConclusionsReferral routes are being used improperly since more than half of patients with cutaneous melanoma are referred from Primary Care through the ordinary route. Melanomas with a lower Breslow thickness are more frequently referred in this way, which suggests that Primary Care physicians have a particular difficulty in identifying cases of melanoma in its earliest stages.

Oestrogen receptor expression in melanoma.

Sexual hormones share a common cholesterol-derived steroid backbone and comprise oestrogens, gestagens and androgens. They elicit numerous physiological and pathological functions; for example androgens are known to contribute to prostatic cancer development, whereas oestrogens are of major importance in the pathogenesis of breast cancer. In 1986, the presence of oestrogen receptors (ER) on breast cancer cells was described as one of the first biomarkers in oncology.1 ER expression is still routinely used both for predictive and therapeutic purposes with the selective ER modulator tamoxifen remaining an efficacious breast cancer treatment both in the adjuvant and palliative setting. The ‘classical’ ERs (ERα and ERβ) are found in many other tissues, such as lung, colorectal mucosa, thyroid tissue or lymphoid cells. Observations of darkening or sometimes growing melanocytic nevi in pregnancy as well as of prognostic differences between female and male melanoma patients suggested that sexual hormones may also impact on melanocyte function and melanoma development.2 Both ‘classical’ ERs have been detected in melanoma tissue, with ERβ being the predominant subtype 3 Already over 20 years ago, tamoxifen was tested in combination with chemotherapy in the treatment of metastatic melanoma and demonstrated improved response rates compared to chemotherapy alone.4 However, a meta-analysis of subsequent clinical trials with tamoxifen did not detect a positive influence of additional tamoxifen treatment on overall survival in advanced melanoma.5 The pathogenetic impact of ER expression differs between different cancer types. For example, ERβ proves to have an antiproliferative effect in prostate cancer, while, in contrast, its expression is associated with poor prognosis in ovarian cancer.6, 7 Besides ER α and β, also ‘nonclassical’ oestrogen receptors such as the G protein-coupled oestrogen receptor (GPER) are investigated with growing interest. In the present issue of this journal, Fabian et al.8 report on differential expression of GPER in a total of 81 primary melanomas, either pregnancy-associated melanoma (PAM) or nonpregnancy-associated melanoma (NPAM). GPER is thought to allow for alternative oestrogen-mediated signalling via the MAP-kinase and other intracellular pathways in cells lacking classical ERs. As for other ERs, its role in the pathogenesis of hormone-related cancer is ambiguous with both tumour-promoting and tumour-protective effects proposed in the literature.9 In melanoma, Fabian and colleagues found a significantly higher immunohistochemical and immunofluorescent cytoplasmatic expression of GPER in PAM compared with NPAM (78.4% vs. 27.9%; P = 0.0000), while similar frequencies of ER β expression were reported in both groups (81.6% vs. 60.5%). For immunohistochemical analyses, the authors used ER antibody clones that have recently been considered as specific.10 This is important, because a number of other available ER antibodies have been shown not to stain consistently or to have problems with cross-reactivity. Double receptor expression of ER β and GPER was detected in 73% and 28% of PAM and NPAM, respectively, and was associated with established positive prognostic markers such as lower Breslow thickness, lower mitotic rate and presence of peritumoural lymphocyte infiltration. Hence, the authors suggest that immunohistochemical double ER expression may serve as a novel prognostic indicator in melanoma. This hypothesis needs additional investigation. First, because double receptor expression was not associated with improved disease-free survival in multivariate analysis, which may be attributed to the small sample size of the study, but may also reflect that ERs are predominantly expressed on thinner, less proliferative primary melanomas for other, yet unknown reasons. Second, although ER expression was significantly more frequent in PAM, no survival difference was demonstrated for PAM compared to NPAM, which is in line with the literature on melanoma in pregnancy.11 In addition, the relevance of driver mutations such as BRAF or NRAS for ER expression is not understood. Taken together, the influence of oestrogen and associated receptor expression patterns on melanoma development remains unclear. Further research in this field is needed, especially as the superior prognosis of female melanoma patients continues to imply a role of sexual hormones in melanoma pathogenesis. Contrary parts of oestrogens (tumour-promoting) and progestins (protective) have been recently suggested in this context.12 Moreover, the role of antihormonal therapeutics such as tamoxifen may be worth rethinking in selected melanoma patients.13

Abstract 3289: Cutaneous melanocytic nevi and risk of melanoma deaths in women and men: a prospective study

Abstract Background: Increased number of common acquired melanocytic nevi (moles) has been associated with an increased risk of melanoma. It is unclear whether melanocytic nevi may predict melanoma deaths. We prospectively examined the association between number of melanocytic nevi and risk of melanoma deaths based on 77316 women from the Nurses’ Health Study (NHS) and 32454 men from the Health Professionals Follow-up Study (HPFS). Methods: In both cohorts, diagnosis of melanoma was reported biennially and pathologically confirmed. Deaths were confirmed by next of kin or the National Death Index. Information on the number of moles with ≥3 mm diameter on the upper extremity was collected in 1986. We used Cox regression models to evaluate the associations between number of melanocytic nevi and risk of melanoma deaths in the overall cohorts as well as only among melanoma cases. Results: A total of 2450 cases of melanoma were documented (1545 in NHS and 905 in HPFS), out of which we identified 192 incident deaths due to melanoma (87 in NHS and 105 in HPFS) during the follow-up (1986-2012). Increased number of melanocytic nevi was associated with melanoma deaths; the multivariate-adjusted hazard ratio (HR) for 3 or more melanocytic nevi compared with no nevi on the upper extremity was 2.55 (95% confidence interval (CI): 1.52-4.28) for women and 3.97 (95% CI: 2.54-6.22) for men. A secondary analysis further found that increased number of melanocytic nevi was associated with both lethal melanoma (melanoma cases that died of melanoma) and non-lethal melanoma. Among melanoma cases, increased number of melanocytic nevi was independently associated with risk of melanoma deaths in men, with a HR of 1.89 (95% CI: 1.17-3.05) for 3 or more melanocytic nevi. The association persisted even after adjusting for Breslow thickness of melanoma and appeared particularly stronger among those with lower Breslow thickness (P for interaction=0.03). However, number of melanocytic nevi was not significantly associated with risk of melanoma deaths among melanoma cases in women (HR=1.03, 95% CI: 0.61-1.76 for 3 or more nevi). Conclusion: Increased number of melanocytic nevi was significantly associated with risk of melanoma deaths in our cohorts of women and men. A high number of melanocytic nevi may independently predict the risk of melanoma deaths among men with melanoma. Citation Format: Wen-Qing Li, Hao Geng, Eunyoung Cho, Abrar Qureshi. Cutaneous melanocytic nevi and risk of melanoma deaths in women and men: a prospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3289. doi:10.1158/1538-7445.AM2017-3289

Expression of G protein‐coupled oestrogen receptor in melanoma and in pregnancy‐associated melanoma

The hormone sensitivity of melanoma and the role of 'classical' oestrogen receptor (ER) α and β in tumour progression have been intensively studied with rather contradictory results. The presence of 'non-classical' G protein-coupled oestrogen receptor (GPER) has not been investigated on human melanoma tissues. To analyse the expression of GPER, ERα and ERβ in pregnancy-associated (PAM) and in non-pregnancy-associated (NPAM) melanomas in correlation with traditional prognostic markers and disease-free survival (DFS). Receptor protein levels were tested using immunohistochemistry in 81 formalin-fixed paraffin-embedded melanoma tissues. PAMs (n = 38) were compared with age- and Breslow thickness-matched cases (n = 43) including non-pregnant women (NPAM-W) (n = 22) and men (NPAM-M) (n = 21). The association between receptor expression and DFS was analysed by uni- and multivariate Cox proportional hazards regression. G protein-coupled oestrogen receptor was detected both in PAMs and NPAMs. In 39 of the 41 (95.1%) GPER-positive melanomas, GPER and ERβ were co-expressed. GPER/ERβ-positive melanomas were significantly more common in PAM compared to NPAM (P = 0.0001) with no significant difference between genders (P = 0.4383). In PAMs, the distribution of GPER and ERβ was similar (78.4% vs. 81.6%; P = 0.8504), while in NPAM, ERβ was the representative ER (60.5% vs. 27.9%; P = 0.0010) without gender difference (59.1% vs. 61.9%). GPER-/ERβ-positive melanomas were associated with lower Breslow thickness, lower mitotic rate and higher presence of peritumoral lymphocyte infiltration (PLI) compared to GPER-/ERβ-negative cases (P = 0.0156, P = 0.0036 and P = 0.0001) predicting a better DFS (HR = 0.785, 95% CI 0.582-1.058). Despite the significantly higher frequency of GPER and ERβ expression in PAM, no significant difference was found in DFS between PAM and NPAM. All but one case failed to show ERα expression. The presence of GPER and its simultaneous expression with ERβ can serve as a new prognostic indicator in a significant subpopulation of melanoma patients.

Poor Adherence to National Clinical Management Guidelines: A Population-Based, Cross-Sectional Study of the Surgical Management of Melanoma in New South Wales, Australia.

Standardization of the clinical management of melanoma through the formulation of national guidelines, based on interpretation of the existing evidence and consensus expert opinion, seeks to improve quality of care; however, adherence to national guidelines has not been well studied. A population-based, cross-sectional study of the clinical management of all patients with newly notified primary melanomas in the state of New South Wales, Australia, during 2006/2007 was conducted using cancer registry identification and questionnaires completed by treating physicians. Surgical margin guidelines were adhered to in 35% of cases; 45% were over treated and 21% were undertreated. Factors independently associated with non-concordance on multivariate analysis were lower Breslow thickness, lower socio-economic status of the physician's practice location, older physician age, lower physician caseload, and physicians who biopsied the lesion and then referred for definitive management. Complications were not related to over- or under-treatment on multivariate analysis (p=0.72). Sentinel lymph node biopsy was performed in 17% of patients with invasive melanoma, with the main determinant for selection being a Breslow thickness>0.75mm. The low level of concordance with national guidelines for surgical management of melanoma resulted in overtreatment of many patients. However, a fifth of patients were undertreated, which is likely to have resulted in increased locoregional recurrence rates. The better concordance achieved by physicians treating>30 melanomas per year suggests that a minimum caseload threshold for physicians treating melanoma patients would be desirable. High guideline concordance will ensure patients receive optimal care and minimize morbidity and health service costs.

Invasive Scalp Melanoma: Role for Enhanced Detection Through Professional Training.

Scalp and neck melanomas (SNMs) have a relatively poor prognosis compared to other sites, and represent an anatomically challenging area for detection. The aim of this study was to identify the role of the hairdresser in detection of SNMs. A tertiary surgical oncology institutional database was retrospectively reviewed for all patients undergoing resection of a scalp, posterior neck, or retro auricular invasive primary melanoma between 2008 and 2014. SNMs accounted for 128 melanoma patients during the study period, with median age 66years, 88% male, and median Breslow thickness 1.55mm. Hairdressers detected 10% of all SNMs, with hairdresser-detected SNMs presenting 13years younger (53 vs. 66years, P=0.015), and with a trend towards lower Breslow depth (1.15 vs. 1.63) and more frequent discovery in AJCC Stage Ia or Ib (66.7% vs. 44.8%) than otherwise-detected SNMs. Women with SNMs were 1.8-fold more likely than men to have their SNMs detected by a hairdresser (P=0.001), and presented at higher AJCC clinical stage than men and required wider surgical resection margins (P=0.011). Women with hairdresser-detected SNMs were younger, with lower Breslow thickness and lower AJCC Clinical Stage than women with otherwise-detected SNM. This study suggests that hairdressers play a critical role in detection of invasive primary scalp and neck melanoma, accounting for 10% of all melanomas referred to a tertiary surgical oncology center. Quality improvement initiatives aimed at increasing early detection of scalp and neck melanoma should include members of the cosmetology community.

High nevus counts confer a favorable prognosis in melanoma patients.

A high number of nevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of nevi decreases from middle age onward but this senescence can be delayed in patients with melanoma. We investigated the effects of nevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2,184 melanoma cases, 684 (31.3%) had a high nevus count (>50). High nevus counts were associated with favorable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Nevus count was not predictive of sentinel node status. The crude 5‐ and 10‐year melanoma‐specific survival rate was higher in melanomas cases with a high nevus count compared to those with a low nevus count (91.2 vs. 86.4% and 87.2 vs. 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (hazard ratio [HR] = 0.43, confidence interval [CI] = 0.21–0.89). The favorable prognostic value of a high nevus count was also seen within the positive sentinel node subgroup of patients (HR = 0.22, CI = 0.08–0.60). High nevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behavior of melanoma tumors in patients with an excess of nevi.

Nevus-associated melanomas: clinicopathologic features.

The clinical significance of nevus-associated melanoma compared with de novo melanomas remains controversial. It has been suggested that nevus-associated melanomas have a higher Breslow thickness and therefore worse prognosis. Over a 10-year period, this study evaluated the incidence of nevus-associated melanoma and its prognostic significance related to clinicopathologic features. Cross-sectional study from 1995 through 2004 in a dermatopathology referral center. With available data, we evaluated sex, primary location, histologic subtype, Breslow thickness, Clark level, presence of ulceration, associated lesion, and histologic subtype of the associated lesion. Of 135,653 pathologic records from skin biopsy specimens over a 10-year period, 1,190 melanoma records were selected. Nevus-associated melanomas corresponded to 390 (32.8%) melanomas, with thin melanomas having a nevus 1.52 times the association observed with thick melanomas (>1.01 mm; 95% confidence interval, 1.16-1.99; P < .001). Superficial spreading melanoma was the most frequent, while no lentigo maligna melanoma was associated with nevi. The median Breslow thickness of nevus-associated melanomas was lower than that of de novo melanomas. Nevus-associated melanomas, which represent one-third of the melanomas in southeast Brazil, are associated with intermittent sun exposure, superficial spreading melanomas, and lower Breslow thickness. This is one of the largest series describing nevus-associated melanomas in Latin America.

Correction: Sunny Holidays before and after Melanoma Diagnosis Are Respectively Associated with Lower Breslow Thickness and Lower Relapse Rates in Italy

Correction: Sunny Holidays before and after Melanoma Diagnosis Are Respectively Associated with Lower Breslow Thickness and Lower Relapse Rates in Italy

Clinical and Histopathological Characteristics between Familial and Sporadic Melanoma in Barcelona, Spain.

BackgroundAbout 6 to 14% of melanoma cases occur in a familial setting. Germline mutations in CDKN2A are detected in 20 to 40% of melanoma families.ObjectiveTo characterise the clinical and histopathological characteristics of familial melanoma thus providing more information to clinicians and contribute to the understanding of the genetic-environment interplay in the pathogenesis of melanoma.MethodsClinical, histological and immunohistochemical characteristics of 62 familial melanomas were compared with 127 sporadic melanomas.Resultsvariables associated with familial melanoma were earlier age at diagnosis (OR 1.036; 95% CI 1.017–1.055), lower Breslow thickness (OR 1.288; 95% CI 1.013–1.683) and in situ melanomas (OR 2.645; 95% CI 1.211–5.778). Variables associated with CDKN2A mutation carriers were earlier age at diagnosis (OR 1.060; 95% CI 1.016–1.105), in situ melanomas (OR 6.961; 95% CI 1.895–25.567), the presence of multiple melanomas (OR 8.920; 95% CI 2.399–33.166) and the immunopositivity of the tumours for cytoplasmic survivin (OR 9.072; 95% CI 1.025–85.010).ConclusionsFamilial melanoma was significantly associated with the earlier age of onset, lower Breslow thickness and with a higher number of in situ melanomas; and also carriers of CDKN2A mutations were associated with a higher risk of multiple melanomas and cytoplasmic survivin immunostaining.

UV exposure and melanoma prognostic factors : results from Clinical National Melanoma Registry (CNMR)

Results From December 2010, we retrieved information from 3299 melanoma patients from 39 IMI (Intergruppo Melanoma Italiano) sites geographically representative. 40% of the patients are over 60 years old, 52% are men, 49% live in the north of Italy and 56% are at high educational level (at least high school). 8% of the patients have melanoma familiarity and 55% have fair phenotype (Fitzpatrick skintype I or II). 2% have metastases and 11% lymph-node involvement. 8% have very thick melanoma (Breslow>4 mm) and 21% ulcerated melanoma. Holidays in the sun five years before CM diagnosis, among non-metastatic patients, were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment including socio-demographic status, degree of doctor making the diagnosis and residence. Sunbed exposure is not significantly associated with Breslow thickness.

Conditional survival of malignant melanoma in The Netherlands: 1994–2008

BackgroundCutaneous malignant melanoma causes the majority of skin cancer related deaths and features increasing incidence and mortality rates in the Netherlands. Conditional survival analysis is performed on patients who survived the preceding year(s). MethodsPatients with invasive melanoma, as recorded in the population-based Netherlands Cancer Registry, were included. To assess prognosis of melanoma survivors according to gender and Breslow thickness, conditional five-year relative survival was calculated for lymph node negative melanoma patients and conditional one-year relative survival was analysed for melanoma patients with and without nodal involvement. FindingsBetween 1994 and 2008, 40,050 patients developed a melanoma (stage I–III, of whom 6% with nodal involvement). Six to 8years after diagnosis, survival of patients with a 1–2mm (T2) thick melanoma equalised the general population. Conditional five-year relative survival for patients with >4mm thick (T4) melanomas increased from about 60% at diagnosis to 90% at 7years after diagnosis. Largest improvements were found in patients with thick melanomas and female patients with nodal involvement. InterpretationThe prognosis for melanoma survivors improved with each additional year of survival after diagnosis, except for patients with a ⩽1mm thick melanoma, who never had any excess mortality during follow-up. Conditional survival of melanoma was better amongst females, amongst those with lower Breslow thickness and nodal stage.

Sunny Holidays before and after Melanoma Diagnosis Are Respectively Associated with Lower Breslow Thickness and Lower Relapse Rates in Italy

BackgroundPrevious studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort.MethodsA questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival.ResultsHolidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results.

BRAF mutation as a pejorative marker in metastatic melanoma.

8555 Background: BRAF mutation in melanoma has been shown to be associated with a trend in favour of a spontaneous worse outcome after metastases in a series of 197 patients in Australia. Objective: To correlate BRAF status in metastatic melanoma with clinicopathologic features and outcome. Methods: In our department in France 182 patients with metastatic melanoma have been tested for BRAF mutation between September 2009 and September 2011. Survival was assessed by log-rank test. Multivariate analysis was performed with Cox model. Results: From 182 patients, 88 (48.3%) were B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other mutation subtypes. BRAF-mutant patients were younger than BRAF wild-type patients at diagnosis of primary melanoma (median age 52.3 vs 60.7 years, respectively, p=0.003), and at diagnosis of distant metastasis (median age 53.6 vs 64.1 years respectively, p=0.002). 34 patients were treated by B-RAF inhibitors. There was no significant difference in other demographic features of patients with metastatic melanoma by mutation status. Features of the primary melanoma significantly associated with a BRAF mutation (p&lt;0.05) were histopathologic subtype (SSM), high mitotic rate (≥1/mm2), lower Breslow thickness (median Breslow: 2.2 vs 3.5 mm for BRAF mutant and BRAF-wild-type patients respectively, p=0.016), truncal location and location on occasionally exposed at sun site.The interval from diagnosis of first ever melanoma to first distant metastasis was not significantly different in BRAF-mutant and wild-type patients. The median overall survival (OS) from diagnosis of primary melanoma was 6.5 years for BRAF wild-type patients. Median OS was not reached in BRAF-mutant patients treated (34 of 88) with a BRAF inhibitor, but also in those not treated (p=0.24, and p=0.06 for treated BRAF-mutant vs BRAF wild-type). The overall survival from diagnosis of first distant metastasis was not significantly different (p=0.75). These results remained unchanged in a multivariate analysis. Conclusions: Our results confirm the characteristics of BRAF-mutant metastatic patients, and the efficacy of B-RAF inhibitors, but not that the presence of mutant-BRAF is per se a pejorative predictive marker.

Melanoma patients receive more follow‐up care than current guideline recommendations: a study of 546 patients from the general Dutch population

Follow-up of melanoma patients has been a continuing issue for discussion in the past years partly due to ever increasing incidence of this disease, as well as the lack of agreement regarding the reasons for, and the frequency of follow-up. Patients' perspectives are often not included in this continuing discussion on follow-up of melanoma patients. To examine to what extent follow-up was experienced, according to the guideline of 2005, by physicians and melanoma patients in a Dutch population from the south-east area of the Netherlands. The patient's perspective and satisfaction over said follow-up shall also be taken into account. Follow-up among melanoma survivors was investigated and compared with the recommendations of the current Dutch national guideline. All 699 melanoma patients registered at the Eindhoven Cancer Registry (between 1998 and 2008), and treated in 3 regional hospitals, were contacted via postal mail. The survey questioned about treatment, symptoms, impact on daily life and follow-up. Patients with multiple melanomas (n = 16) were excluded. Response rate was 80%, 418 patients were still under surveillance for their melanoma. The average time since diagnoses was 4 years, 71% had stage I melanoma. Almost 80% of patients with a Breslow thickness <1 mm, reported more frequent follow-up visits than the guideline recommends. Only 5% of the patients wanted to reduce their follow-up frequency. Eighty percent of patients were under supervision of a dermatologist: physical examination (25%), lymph node palpation (11%) and/or scar inspection (20%) did not regularly occur. These proportions were significantly higher among other specialism. Follow-up frequency was higher than recommended by the current melanoma guideline in a large group of patients, mainly those with lower Breslow thickness.