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We have previously shown that the functional melanoma risk variant rs12203592 in interferon regulatory factor-4 (IRF4) was associated with increased Breslow thickness, an important prognostic indicator for melanoma. In line with this, a recent study found evidence for an association between the minor T allele of this single nucleotide polymorphism (SNP) and melanoma-specific survival in patients from two European hospitals.

Background Demographic, clinical, and morphological characteristics of cutaneous melanoma are unknown for the Colombian population. We aim to provide these characteristics as well as population-based incidence and survival data. Methods All patients with an invasive cutaneous melanoma diagnosed in the period 2000-2009 registered in the population-based cancer registry of the metropolitan area of Bucaramanga were included for analysis (n = 169). Age-standardized incidence rates were calculated and melanoma-specific and overall survival estimated with follow-up until June 9, 2016, using Kaplan-Meier methodology, stratifying for gender, anatomical localization, and type of affiliation to the social security system. Results The age-standardized melanoma incidence rate was 1.7 per 100,000, with lower limbs being the most affected body sites (42.6% of all melanomas). A high proportion of melanomas presented on the plants or palms (16%) and under the nails (7.1%); at least 24.3% of melanomas were ulcerated, and 21.1% had a Breslow thickness more than 2 mm. Melanoma-specific 5-year survival was 79.3%, with worst survival for melanomas localized on the plants (64.6%) and subungual areas (55.6%). Affiliation to the subsidized type of affiliation to the social security system was statistically significantly (P = 0.003) associated with poorer survival (68.8%) compared to the special regimes (95.8%). Conclusions Melanoma is a relatively rare cancer in Colombia with mainly the acral sites, high proportion of thick and ulcerated melanomas, and relatively poor survival being distinct features, indicating the need for tailor-made primary and secondary prevention strategies. Better training of pathologists in the difficult field of melanoma would improve precision of available data.

Desmoplastic melanoma (DM) is an uncommon variant of melanoma that can be challenging to diagnose. Phenotypic variations in terms of the proportion of spindled cells and fibromucinous stroma have led to the subclassification of pure (90% spindled cells) and mixed (90% spindled cells admixed with epithelioid cells) histopathologic DM subtypes. This subclassification is not just semantic; several studies have underscored differences in clinical and prognostic behaviors of the subtypes. In this review, we parse the literature on DM subtypes with an emphasis on histopathologic, immunohistochemical, and genetic data to ascertain whether these factors influence and/or affect their differing biological behaviors. Demographics regarding age, location, and clinical behavior of the subtypes are detailed, as is the impact of dermoscopy as a diagnostic adjunct. Despite the plethora of markers used, our findings suggest that few differentiate between the DM subtypes. Differential expression of PD-L1 suggests that patients with the mixed subtype are likely better candidates for anti-PD/PD-L1 therapy. Significant differences between the subtypes in terms of neurofibromin expression and the frequency of TERT promoter mutations suggest that the subtypes have distinct genetic drivers. Thus, immunohistochemical and genetic analyses imply that these likely affect the biological behaviors of the DM subtypes.

Background: Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to support this timeframe.Aim: To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients.Methods: Between 1993 and 2008, 1080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors.Results: Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00 mm (IQR 1.90-4.80 mm), 442 (44%) were ulcerated. Median follow-up was 36 months (IQR 20-62 months). Median time interval was 47 days (IQR 32-63 days). Median Breslow thickness was equal for both = 47 days interval: 3.00 mm (1.90-5.00 mm) vs 3.00 mm (1.90-4.43 nom) (p = 0.402). Sentinel node tumor burden was significantly higher in patients operated >= 47 days (p = 0.005). Univariate survival was not significantly different for median time interval. Multivariable analysis confirmed that time interval was no independent prognostic factor for MSS.Conclusions: Time interval from primary melanoma excision until SNB was no prognostic factor for MSS in this SNB positive cohort. This information can be used to counsel patients. (C) 2016 Elsevier Ltd and British Association of Surgical Oncology/European Society of Surgical Oncology. All rights reserved.

Purpose Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. Patients and Methods On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. Results Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (Ptrend < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. Conclusion At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.

Aims In 1970, Breslow described his eponymously named thickness measurement. No-one has sought to enhance Breslow thickness (BT). This purpose of this study was to demonstrate proof of concept that the density of melanoma cells at the position where Breslow thickness is measured is a morphological prognostic biomarker, which we name Breslow density (BD). The hypothesis was that BD has prognostic value for overall survival (OS) and is independent of BT. Methods and results We analysed 100 cutaneous melanomas and followed REMARK guidelines. BD was the estimated percentage dermal area occupied by melanoma cells in a specified location. BT and BD had a strong correlation (p = 2.1 x 10-11) but despite this they were independent prognostic factors for OS in Cox regression (BD: HR 1.03, p=0.001849 and BT: HR 1.09, p=0.000146). This was corroborated by an independent effect on melanoma specific survival. We assessed whether BT and BD could be combined into a Breslow score. A prognostic index based on Cox regression coefficients was used and this showed a marginal improvement in predicted 5-year survival compared to BT alone (are under curve 94.8% v 96.7%). Conclusions We show proof of concept that BD represents a novel morphological prognostic biomarker that is independent of BT and that there is potential to combine these into a Breslow score. Larger studies are needed to validate BD, but the simplicity of this biomarker makes it a strong candidate for translation to clinical practice. This article is protected by copyright. All rights reserved.

9577 Background: Unlike other solid tumors, the impact of primary HS on melanoma survival and response to systemic therapy is not well studied. Nodular melanoma (NM) has a worse prognosis than superficial spreading melanoma (SSM), which is usually attributed to thicker primary tumors. Herein, we examine the hypothesis that HS might have an impact on MSS independent of thickness and that NM and SSM exhibit different mutational landscapes that associate with response to checkpoint inhibitor immunotherapy (IT) and BRAF targeted therapy (TT) in the metastatic setting. Methods: Primary NM and SSM patients prospectively enrolled at NYU (2002 - 2016) were compared to the most recent SEER cohort (1973 - 2012) and analyzed with respect to MSS. Next-Generation Sequencing (NGS) was performed on a subset of matched tumor-germline pairs, allowing a comparison of the mutational landscape between NM and SSM. In the metastatic setting, survival analyses were used to compare outcomes and responses to treatment across HS. Results: The NYU cohort of 1,621 patients with either NM (n = 510) or SSM (n = 1,111) was representative of the analogous SEER cohort (21,339 NM, 97,169 SSM), with NM presenting as thicker, more ulcerated, and later stage (all p < 0.001). Among the NYU cohort, NM was found to have lower rates of TIL (p = 0.047), higher mitotic index (p < 0.001), and higher rates of NRAS mutation (p < 0.001). In multivariate Cox models, NM was a significant predictor of worse MSS, independent of thickness and stage (p = 0.01). NM had a significantly lower mutational burden across the exome (p < 0.001). Some of the most under-mutated genes noted in NM were NOTCH4, BCL2L12 and RPS6KA6 (all p < 0.01). Among patients treated with TT (n = 56), NM remained a significant predictor of worse MSS (p = 0.004). However, there was no difference in response to IT. Conclusions: NM and SSM show divergent mutational patterns which may contribute to their different clinical behaviors and responses to BRAF targeted therapy. More studies are needed to better understand the key molecular and cellular processes driving such differences. Integration of HS data into prospective clinical trial reporting is needed to better assess its impact on response to treatment.

8563 Background: The significance of melanoma pigmentation is poorly studied despite being fundamental to melanocyte biology. We examined its pathological and clinical associations in primary melan...