Multiple Primary Melanomas Research Articles

1216 Multiple primary melanomas are associated with increased risk of internal malignancy

1216 Multiple primary melanomas are associated with increased risk of internal malignancy

Concordance of somatic mutational profile in multiple primary melanomas.

This study aimed to determine the frequency and concordance of BRAF and NRAS mutation in tumours arising in patients with multiple primary melanoma (MPM). Patients with MPM managed at one of three tertiary referral centres in Melbourne, Australia, from 2010 to 2015 were included. Incident and subsequent melanomas underwent mutation testing. Cohen's kappa (κ) coefficient assessed agreement between incident and subsequent primary melanomas for both BRAF and NRAS mutation status (mutant versus wild-type). Mutation testing of at least two primary tumours from 64 patients was conducted. There was poor agreement for both BRAF and NRAS mutation status between incident and subsequent melanomas (κ=0.10, 95% CI -0.10 to 0.42; κ=0.06, 95% CI -0.10 to 0.57, respectively). In view of the low concordance in BRAF mutation status between incident and subsequent melanomas, mutational analysis of metastatic tissue, rather than of a primary melanoma, in patients with MPM should be used to guide targeted therapy.

Similar survival of patients with multiple versus single primary melanomas based on Utah Surveillance, Epidemiology, and End Results data (1973-2011)

Survival data are mixed comparing patients with multiple primary melanomas (MPM) to those with single primary melanomas (SPM). We compared MPM versus SPM patient survival using a matching method that avoids potential biases associated with other analytic approaches. Records of 14,138 individuals obtained from the Surveillance, Epidemiology, and End Results registry of all melanomas diagnosed or treated in Utah between 1973 and 2011 were reviewed. A single matched control patient was selected randomly from the SPM cohort for each MPM patient, with the restriction that they survived at least as long as the interval between the first and second diagnoses for the matched MPM patient. Survival curves (n=887 for both MPM and SPM groups) without covariates showed a significant survival disadvantage for MPM patients (chi-squared 39.29, P<.001). However, a multivariate Cox proportional hazards model showed no significant survival difference (hazard ratio 1.07, P=.55). Restricting the multivariate analysis to invasive melanomas also showed no significant survival difference (hazard ratio 0.99, P=.96). Breslow depth, ulceration status, and specific cause of death were not available for all patients. Patients with MPM had similar survival times as patients with SPM.

Dermoscopy and confocal microscopy for metachronous multiple melanomas: morphological, clinical, and molecular correlations.

Cutaneous melanoma is one of the most frequent malignancies of the skin in Caucasian populations. Patients who develop cutaneous melanoma are at increased risk of developing a second primary melanoma. The estimated incidence of multiple primary melanoma (MPM) ranges from 1.2% to 8.2% of cases, with a high preponderance of melanomas occurring metachronously. The aim of this study was to describe dermoscopic, microscopic, clinical, and molecular correlations between first and subsequent melanomas in patients with metachronous MPMs. Twenty-four paired melanomas from 12 MPM patients were evaluated for architectural characteristics based on dermoscopy and confocal microscopy, as well as for mutations in BRAF and NRAS genes by Sanger-based sequencing analysis. Specific scores used for classifying features of dermoscopy (global pattern; 7-point check list; ABCD Stolz score) and confocal microscopy (Segura and Pellacani) were compared with genetic and histological data. Consistency in dermoscopic patterns between the primary and subsequent cutaneous melanomas were observed in about two thirds of cases, whereas concordant features based on confocal microscopy were found in only about two fifths of cases. The majority of patients (7/12; 58%) presented consistent BRAF/NRAS mutation patterns between first and subsequent primary melanomas. A significant association between BRAF mutations and Pellacani score was evident. Similarities between the index melanoma and subsequent cutaneous melanomas were observed with regards to dermoscopic features and, to a much less extent, confocal microscopy findings. Our data further indicate that the Pellacani score may be used to predict BRAF mutations.

Hereditary melanoma: a five-year study of Brazilian patients in a cancer referral center - phenotypic characteristics of probands and pathological features of primary tumors

Background:Approximately five to 10% of all melanomas occur in families with hereditary predisposition and the main high-risk melanoma susceptibility gene is the CDKN2A. Objectives:To describe, after a five-years study, the clinical data of patients (probands) from familial melanoma kindreds, and the pathological characteristics of their melanoma. Methods:The inclusion criteria were melanoma patients with a family history of melanoma or pancreatic cancer (first- or second-degree relatives) or patients with multiple primary melanomas (MPM). Results:A total of 124 probands were studied, where 64 were considered familial cases and 60 MPM. Mean age at diagnosis was 50 years. Our results show that the following characteristics were prevalent: skin phototype I/II (89.5%), sunburn during childhood (85.5%), total number of nevi ≥50 (56.5%), Breslow thickness ≤1.0mm (70.2%), tumors located on the trunk (53.2%) and superficial spreading melanomas (70.2%). Study limitations:Analyses of probands’ relatives will be demonstrated in future publication. Conclusions:Our findings are in agreement with previous familial melanomas reports. Fifteen new melanomas in 11 patients were diagnosed during follow up, all of which were ≤1.0 mm. This is the largest dataset of Brazilian melanoma prone kindreds to date, thus providing a complete database for future genetic studies.

Differences in the diagnosis of primary cutaneous melanoma in the public and private healthcare systems in Joinville, Santa Catarina State, Brazil

Background:Cutaneous melanoma accounts for up to 80% of deaths caused by skin cancer. Diagnostic suspicion and access to medical care and early intervention in suspected cases is vital to the patient’s prognosis. Objectives:To compare demographic and histopathological characteristics of primary cutaneous melanoma diagnosed in the public healthcare system (Sistema Único de Saúde SUS) and the private system in Joinville, Santa Catarina State, Brazil. Methods:This cross-sectional retrospective study analyzed primary cutaneous melanoma cases recorded from 2003 to 2014 in the resident population of Joinville. Ethical approval was obtained from the local Research Ethics Committee. Results:893 cases of primary cutaneous melanoma were identified. Patients in the private system were mostly younger, while there were more elderly patients in the public healthcare system (p <0.001). There was no statistically significant association between type of care (public/private) and gender or presence of multiple primary cutaneous melanomas. Histological diagnosis of superficial spreading melanoma was more common in patients treated in private healthcare, while nodular melanoma was more frequent in patients in the public healthcare system (p <0.001). Mean Breslow depth in patients treated in private healthcare was 1.35mm, compared to 2.72mm in the public system (p <0.001). Study limitations:This was a retrospective study using secondary databases. Conclusions:thin cutaneous melanoma (in situ cutaneous melanoma and Breslow T1) showed the strongest association with the private healthcare system, while thick cutaneous melanoma was more frequent in the public system (Breslow category T3 and T4) (p <0.001).

Multiple primary melanoma: a single centre retrospective review.

Prognosis has been shown to be worse for patients with multiple primary melanomas than those with a single melanoma. One recent retrospective study showed that older, white men were at higher risk of multiple primary melanomas. In our institution 2057 melanomas were diagnosed between January 1994 and March 2016. We identified 99 (4.8%) patients who had multiple primary melanomas. The average number of melanomas was 2.5 (range: 2-10). The site for first and second melanomas was similar in 30%. We found that subsequent melanomas were more likely to be in situ and thinner in terms of Breslow thickness and Clarks level. The commonest subtypes were superficial spreading and lentigo maligna. The commonest sites involved were the lower limbs. We found no significant difference in age between our total melanoma group and the multiple primary melanoma group (64 and 66 years, respectively). The average time of diagnosis between the first and second melanomas was 33.7 months. Additionally, 70% of second melanomas were diagnosed within 2 years of first diagnosis, highlighting the importance of ongoing skin surveillance in patients with a recent diagnosis of melanoma.

Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report

BackgroundMultiple Myeloma is a cancer of plasma cells associated with significantly reduced survival. Long term survivorship from myeloma is very rare and despite advances in its treatment the disease is generally considered incurable. We report a patient diagnosed with myeloma carrying a germline mutation of a tumour suppressor gene who has effectively been cured.Case presentationA 36-year-old woman was diagnosed with IgG lambda myeloma in 1985. She was treated with melphalan chemotherapy followed by high-dose melphalan and autologous stem cell rescue and since remained in complete remission despite not having received any additional therapy. After eliciting a prior history of multiple primary melanomas and breast cancer, she was tested for and shown to be a carrier for a germline mutation in CDKN2A.ConclusionsThis is the second case report of germline mutation of CDKN2A being associated with myeloma. CDKN2A is a stabiliser of p53. Long term survivorship after high dose DNA damaging chemotherapy with melphalan in this patient is compatible with an increased chemo-sensitivity due to impairment of the DNA repair pathway.

Heterogeneity of BRAF, NRAS, and TERT Promoter Mutational Status in Multiple Melanomas and Association with MC1R Genotype: Findings from Molecular and Immunohistochemical Analysis

Data on somatic heterogeneity and germline-somatic interaction in multiple primary melanoma (MPM) patients are limited. We investigated the mutational status of BRAF, NRAS, and TERT promoter genes in 97 melanomas of 44 MPM patients and compared molecular and immunohistochemical findings. We further evaluated the association of somatic alterations with the germline MC1R genotype. Mutations in BRAF gene were identified in 41.2% (40/97) of melanomas, in NRAS in 2.1% (2/97), and in TERT promoter in 19.6% (19/97). Distribution of BRAF mutations did not differ across multiple melanomas (P=0.85), whereas TERT promoter changes decreased from first to subsequent melanomas (P=0.04). Intrapatient discrepancy of BRAF mutations among multiple tumors was detected in 14 of 44 MPM patients (32%) and of BRAF/NRAS/TERT promoter genes in 20 of 44 (45%). We observed a high rate of agreement between allele-specific TaqMan assay and immunohistochemistry in BRAFV600E detection (κ=0.83, P<0.01) with 86 of 97 melanomas (88.7%) presenting similar BRAF status. Germline MC1R variants were identified in 81.4% (35/43) of MPM patients with no association of MC1R genotype with somatic mutations or with intrapatient concordance of somatic mutational profile. Our results support the genetic diversity of multiple melanomas and show that somatic heterogeneity is not influenced by inherited MC1R variants. Immunohistochemistry may be useful as an initial screening test.

Multiple Primary Acral Lentiginous Melanomas (MPALM).

We present a rare case of a patient with multiple primary acral lentiginous melanomas of the foot. We would like to highlight the importance of whole-skin examination in all patients, even by the general practitioners, aiming the maximal early detection of acral lentiginous melanomas, considering their rapid progression, early metastatic spread and extremely poor prognosis. It can be extrapolated from current literature; however, that appropriate management of these patients, including staging work and surgical intervention, is to be determined by the individual characteristics of the melanoma and the patient’s concomitant risk factors, if any.

592 Clinical, dermoscopic and confocal features of nevi and melanomas in a multiple primary melanoma patient with the MITF p.E318K homozygous mutation

592 Clinical, dermoscopic and confocal features of nevi and melanomas in a multiple primary melanoma patient with the MITF p.E318K homozygous mutation

Reduced disease‐specific survival following a diagnosis of multiple primary cutaneous malignant melanomas—a nationwide, population‐based study

Outcome data comparing patients with multiple primary invasive cutaneous malignant melanomas (MPMs) to single primary invasive cutaneous malignant melanomas (SPMs) show conflicting results. We have analyzed differences in disease-specific survival between these patients in a nationwide population-based setting. From the Swedish Melanoma Register, 27,235 patients were identified with a first invasive cutaneous malignant melanoma (CMM) between 1990 and 2007, followed-up through 2013. Of these, 700 patients developed MPMs. Cox proportional hazard regression was used for adjusted cause-specific hazard ratios (HRs). An interval of ≤5 years between CMM diagnoses was significantly correlated to a decreased CMM-specific survival in Stage I-II MPM- vs. SPM-patients (HR 1.32; 95% CI 1.04-1.67; p = 0.02). MPM-patients with longer time interval between diagnoses experienced similar risk of CMM-death as SPM-patients. The risk of CMM-death increased by almost 50% above the expected outcome according to stage of the index CMM by the diagnosis of a second CMM (HR 1.48; 95% CI 1.19-1.85; p < 0.001). MPM vs. SPM-patients had a worse outcome (HR 1.38; 95% CI 1.05-1.83; p = 0.001). This emphasizes the importance of prevention efforts in SPM-patients to decrease the risk of subsequent CMMs and has implications for more vigilant follow-up in MPM-patients.

Cancer risks and survival in patients with multiple primary melanomas: Association with family history of melanoma and germline CDKN2A mutation status

Worse outcomes have been noted in patients with multiple primary melanomas (MPMs) than in patients with single primary melanomas. We investigated how family history of melanoma and germline CDKN2A mutation status of MPM patients affects risks of developing subsequent melanomas and other cancers and survival outcomes. Comprehensive data on cancer diagnoses and deaths of MPM patients, their first-degree relatives, and matched controls were obtained through Swedish national health care and population registries. Familial MPM cases with germline CDKN2A mutations were youngest at the diagnosis of their second melanoma (median age 42 years) and had among the MPM cohorts the highest relative risks (RR) compared to controls of developing >2 melanomas (RR 238.4, 95% CI 74.8-759.9). CDKN2A mutated MPM cases and their first-degree relatives were the only cohorts with increased risks of nonskin cancers compared to controls (RR 3.6, 95% CI 1.9-147.1 and RR 3.2, 95% CI 1.9-5.6, respectively). In addition, CDKN2A mutated MPM cases had worse survival compared with both cases with familial (HR 3.0, 95% CI 1.3-8.1) and sporadic wild-type MPM (HR 2.63, 95% CI 1.3-5.4). Our study examined outcomes in subgroups of MPM patients, which affected the sample size of the study groups. This study demonstrates that CDKN2A mutation status and family history of melanoma significantly affects outcomes of MPM patients.

Characterization of melanoma susceptibility genes in high-risk patients from Central Italy

Genetic susceptibility to cutaneous melanoma has been investigated in Italian high-risk melanoma patients from different geographical regions. CDKN2A, CDK4, and MC1R genes have been screened in most studies, MITF and POT1 were screened in only one study, and none analyzed the TERT promoter. We carried out a mutational analysis of CDKN2A, CDK4 exon 2, POT1 p.S270N, MITF exon 10, MC1R, and the TERT promoter in 106 high-risk patients with familial melanoma (FM) and sporadic multiple primary melanoma (spMPM) from Central Italy and evaluated mutations according to the clinicopathological characteristics of patients and lesions. In FM, CDKN2A mutations were detected in 8.3% of the families, including one undescribed exon 1β mutation (p.T31M), and their prevalence increased with the number of affected relatives within the family. MC1R variants were identified in 65% of the patients and the TERT rs2853669 promoter polymorphism was identified in 58% of the patients. A novel synonymous mutation detected in MITF exon 10 (c.861A>G, p.E287E), although predicted as a splice site mutation by computational tools, could not functionally be confirmed to alter splicing. For spMPM, 3% carried CDKN2A mutations, 79% carried MC1R variants, and 47% carried the TERT rs2853669 promoter polymorphism. MC1R variants were associated with fair skin type and light hair color both in FM and in spMPM, and with a reduction of age at diagnosis in FM patients. Mutations in CDK4 exon 2 and the POT1 p.S270N mutation were not detected. A low frequency of CDKN2A mutations and a high prevalence of MC1R variants characterize high-risk melanoma patients from Central Italy.

Novel germline risk loci in familial melanoma (FM).

1535 Background: While about 10% of cutaneous melanoma (CM) clusters in families, known high-risk loci explain not more than 40% of expected inherited risk. Besides the most frequently mutated genes in FM (e.g. CDKN2A), it is estimated that the remaining 60% of FM susceptibility is due to the interaction of environment with specific pools of rare known loci and yet unknown high-risk genes. In our study, we report the discoveries of novel germline genetic risk factors in FM in a recently developed FM cohort at New York University Langone Medical Center (NYULMC) consisting of CM and multiple primary melanomas (MPM) of Ashkenazi Jewish (AJ) and non-AJ European ancestries. Methods: As part of an ongoing ascertainment of FM at NYULMC, we assessed the status of CDKN2A mutations using Sanger sequencing, examining the coding regions of 47 AJ FM families and 81 non-AJ FM kindreds. In high-risk mutation-negative families, we applied whole-exome sequencing (WXS) and an innovative hot-spot mutational analysis of non-coding regions to identify novel high-risk loci associated with FM susceptibility. Results: We found that frequencies of CDKN2A deleterious mutations in our FM cohort (13%) are comparable with observations from previous studies. We have also identified a specific CDKN2A coding mutation in FM kindreds of AJ ancestry, which is particularly interesting as CDKN2A mutations in AJ cohorts have been sparsely reported in prior studies. The WXS/targeted non-coding sequencing of mutation-negative families identified putatively deleterious mutations in regulatory regions in the vicinity of several novel loci, including SMAD4 and PAX8, co-segregating in FM kindreds. Conclusions: Our unique FM ascertainment, including &gt; 50% AJ kindreds, provides an excellent platform for mapping high-risk genetic susceptibility in FM. Novel deleterious mutations identified in non-coding regulatory regions of SMAD4 and PAX8 genes, some with increased frequency in AJ families, suggest a need for a more thorough investigation of the non-coding genome using a founder FM population, as we propose here. As our ongoing ascertainment expands, we are pursuing validation of our observations through comprehensive sequencing efforts.

Elevated Blood Neutrophil-to-Lymphocyte Ratio: A Readily Available Biomarker Associated with Death due to Disease in High Risk Nonmetastatic Melanoma.

Elevated peripheral blood neutrophil-to-lymphocyte ratio (NLR) is associated with poor oncologic outcomes in patients with stage IV melanoma and other solid tumors, but its impact has not been characterized for patients with high-risk, nonmetastatic melanoma. Retrospective review of a melanoma database identified patients with high-risk melanoma who underwent operation with curative intent at a single institution. NLR was calculated from blood samples obtained within 2weeks before operation. Multiple primary melanomas and concurrent hematologic or other metastatic malignancies were excluded. Cumulative incidence of death due to disease was estimated, and Gray's test was used to examine the effect of NLR on melanoma disease-specific death (DOD). Multivariable competing risks regression models assessed associated factors. Data on 1431 patients with high-risk, nonmetastatic melanoma were analyzed. Median follow-up for survivors was 4years. High NLR (≥3 or as continuous variable) was associated with older age, male sex, thicker primaries, higher mitotic index, and more advanced nodal status. On multivariate analysis, high NLR (≥3 or as a continuous variable), older age, male sex, ulcerated primary, lymphovascular invasion, and positive nodal status were all independently associated with worse DOD. NLR is a readily available blood test that was independently associated with DOD in patients with high-risk, nonmetastatic melanoma. It is unclear whether high NLR is a passive indicator of poor prognosis or a potential therapeutic target. Further studies to evaluate the prognostic role of NLR to potentially identify those more likely to benefit from adjuvant immunotherapy may prove informative.

Correlations of EGF G1380A, bFGF C754G and VEGF T460C polymorphisms with malignant melanoma susceptibility and prognosis: A case-control study

This case-control study aims to investigate the correlations of EGF G1380A, bFGF C754G and VEGF T460C polymorphisms with the susceptibility and prognosis of malignant melanoma. A total of 153 patients with multiple primary melanomas were collected as the case group and another 170 healthy individuals were selected as the control group. ELISA and PCR-RFLP were performed to test the serum level of VEGF and to analyze the genotype as well as allele frequencies of VEGF T460C, EGF G1380A, and bFGF C754G, respectively. The patients were assigned into complete remission (CR), partial remission (PR) and non-remission groups after treatment. HE and CD34 staining were conducted in tissue samples of CR and PR patients. Event-free survival (EFS) and overall survival (OS) were measured. AA genotype of EGF G1380A and GG genotype of bFGF C754G had higher frequency distribution in the case group than the control group. Patients with AA genotype of EGF G1380 and GG genotype of bFGF C754G had an elevated VEGF level in comparison to other genotypes. Patients with GA+GG genotypes of EGF G1380A and CG+CC genotypes of bFGF C754G had higher EFS and OS than those with AA genotype and those with GG genotype, respectively. According to the haplotype analysis, the case group had a notably higher frequency of TAG and CAG along with while lower frequency of TGG and CGC compared with the control group. Logistic regression analysis revealed that the polymorphisms of EGF G1380A and bFGF C754G as well as the haploid TAG increased the susceptibility of malignant melanoma. The results indicated that EGF G1380A and bFGF C754G gene polymorphisms were associated with the susceptibility and prognosis of malignant melanoma, and that the polymorphisms of EGF G1380A and bFGF C754G as well as the haploid TAG increased the susceptibility of malignant melanoma.

Familial melanoma and multiple primary melanoma.

Cutaneous melanoma (CM) has the highest mortality rates among the most common skin cancers, and its incidence is rising worldwide, thus representing a significant health care burden. CM is considered the most lethal skin cancer if not detected and treated during its early stages. Susceptibility to CM is also associated with an increased presence of atypical nevi and the occurrence of multiple primary melanoma. Personal history of CM increases the risk of developing a second melanoma by 5-8%. A family history of melanoma has also been strongly associated with an increased risk of melanoma. Approximately 5-10% of melanoma cases occur in a familial context. The main genes involved are CDKN2A, CDK4 and MC1R. The recent technological advances have allowed the identification of new genes involved in melanoma susceptibility: breast cancer 1 (BRCA1), BRCA1-associated protein 1 (BAP1), and telomerase reverse transcriptase (TERT).Tests on these genes allow to identify a larger number of high-risk individuals with a potential of developing familial melanoma and primary multiple melanomas. These patients also have a high risk of developing internal organ malignancies, especially pancreatic cancer. It is essential that these individuals receive adequate management along with frequent dermatological examinations, dermoscopic evaluation, genetic counselling and instrumental examinations aimed at the early identification of other tumors associated with CM.

MultiplePrimary Melanomas: A Common Occurrencein Western Sweden.

Patients diagnosed with a single primary cutaneous melanoma are at increased risk of developing multiple primary melanomas. The aim of this study is to describe the epidemiology of multiple primary melanomas (invasive and in situ) in Western Sweden. Data from the Swedish Melanoma Registry from 1990 to 2013 revealed that 898 patients (7.4%) developed 2,037 multiple primary lesions and 11,254 patients developed single lesions. The proportion of subsequent lesions that were melanoma in situ was 47%, compared with 26% of first melanomas (p < 0.0001).The median and mean time to diagnosis of a subsequent melanoma was 38 and 58 months (95% confidence interval (CI), 53-62 months). In total, 49% of subsequent melanomas were detected within 3 years. Patients and physicians should be aware of the high proportion of multiple primary melanomas in Western Sweden, especially during the first years of follow-up.

Chemosaturation with Percutaneous Hepatic Perfusion in Unresectable Hepatic Metastases

In patients with hepatic metastases from solid-organ malignancies, surgical resection may be a potentially curative option, but it is not possible in most cases. Chemosaturation with percutaneous hepatic perfusion was developed for the management of unresectable metastases to the liver. Relevant medical literature was summarized with regard to the outcomes and limitations of chemosaturation with percutaneous hepatic perfusion. Six articles were identified that contained data on 91 individuals who received chemosaturation with percutaneous hepatic perfusion. More than 60% of these study patients were diagnosed with ocular melanoma. The overall response rate was 48% and the rate of disease control was 90%. Chemosaturation with percutaneous hepatic perfusion improved the rates of overall and hepatic progression-free survival (PFS). The data are limited but suggest that the rate of PFS was improved in study patients with isolated melanoma hepatic metastases who received chemosaturation with percutaneous hepatic perfusion compared with those assigned to standard care. Our results suggest that chemosaturation with percutaneous hepatic perfusion produces favorable tumor response rates in select individuals with unresectable hepatic metastases from multiple primary cancers, particularly ocular and cutaneous melanomas. Data from a single randomized clinical trial have also shown that chemosaturation with percutaneous hepatic perfusion can affect hepatic PFS in certain patients.