Subtype Of Cutaneous Melanoma Research Articles

A Narrative Review of the Evolution of Diagnostic Techniques and Treatment Strategies for Acral Lentiginous Melanoma.

Acral melanoma (AM) is a subtype of cutaneous melanoma located on the palms, soles, and nails. The pathogenesis of AM involves mechanical stimulation and characteristic tumor-promoting mutations, such as those in the KIT proto-oncogene. Dermoscopy is useful for diagnosing AM, which is characterized by parallel ridge patterns and irregular diffuse pigmentation. Although histopathological confirmation is the gold standard for diagnosing AM, lesions showing minimal histopathological changes should be considered early-stage AM if they clinically resemble it. Recently, immunohistochemical staining of preferentially expressed antigen in melanoma has been recognized as a useful method to distinguish benign from malignant melanocytic tumors. Research reveals that AM is associated with an immunosuppressive microenvironment characterized by increased numbers of M2 macrophages and regulatory T cells, alongside a decreased number of tumor-infiltrating lymphocytes. Mohs micrographic surgery or digit-sparing wide local excision has been explored to improve quality of life and replace wide local excision or proximal amputation. AM has a worse prognosis than other subtypes, even in the early stages, indicating its inherent aggressiveness.

Detection of human papillomavirus (HPV) in malignant melanoma

The most common type of melanoma is cutaneous melanoma (CM). The predominant mutational signature is that of ultraviolet radiation (UVR) exposure. The Cancer Genome Atlas (TCGA) molecular classification includes four major subtypes of CM based on common genetic alterations involving the following genes: BRAF, NRAS, and NF1, with a small fraction being “triple” wild-type. The two main signaling pathway abnormalities in CM are the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositol-3-kinase (PI3K) pathway. Other less common types include mucosal melanomas (MM) and uveal melanoma (UM), which have a significantly different genomic landscape. Although few studies reported rare cases with HPV-positive (HPV+) melanoma, the clinicopathological and molecular characteristic of this entity has not been well-described. Among the 2084 melanoma cases queried at our institution, we identified seven patients diagnosed with HPV+ melanoma (prevalence 0.03 %), including five instances of CM and two of MM. The majority of cases were positive for HPV16 (n = 6). Most of the patients were elderly and with advanced disease (n = 6), although this finding may be attributed to the relative frequency of our institution testing advanced-stage tumors. Histologically, most cases showed high degree of pleomorphism and high mitotic count (5 or more mitoses/mm2) (n = 6). UVR signature was present in the CM, but not in the MM cases. Alterations in either MAPK and/or PI3K pathways were detected in the majority of cases (n = 6). The most common genetic abnormalities detected in this study occurred in the TERT promoter (TERTp) (n = 5), a finding that has been reported to be associated with aggressive disease. Our data shows that while HPV+ melanoma is rare, identifying this disease entity could help guide therapy given the demonstrated genomic alterations.

Abstract 4863: A retrospective study characterizing 1714 cases of epithelioid cell melanoma

Abstract Introduction: Epithelioid cell melanoma (ECM) is a variant of cutaneous melanoma (CM) typically characterized by large malignant cells with abundant, glassy cytoplasm and large nuclei. ECMs are aggressive neoplasms and tend to have worse prognosis than other subtypes of CM with a higher risk of metastasis1. Few studies have explored the demographic features of ECM and their effects on outcomes. Using data from the National Cancer Database (NCDB), we hope to fill this gap. Methods: This is a retrospective study of patients diagnosed with ECM(ICD-8771) between 2004 and 2020 in the National Cancer Database (NCDB) describing demographic features associated with and tumor characteristics of ECM (N = 1714). Descriptive statistics were collected for all patients with ECM and CM (N = 827623) and were compared using Pearson Chi-Square test. Overall survival was determined by the Kaplan-Meier test. Cox regression analysis was used to determine which factors led to decreased survival in ECM. All statistical tests were evaluated for a significance of P < 0.05. Exclusion criteria included missing data. Results: The cases of ECM were composed mainly of White (96%) males (58.9%), and most had private insurance as the primary payor at diagnosis (50.1%). Greater than half of ECM cases had a primary site of skin on the trunk, upper limbs, or shoulders. Cox regression analysis revealed that patients with ECM treated at integrated network cancer programs had a HR of 0.46 when compared to community centers (95% CI 0.257 - 0.831, P < 0.05). Those with ECM treated at academic programs and comprehensive community cancer programs had hazard ratios of 0.41 (95% CI 0.239 - 0.701, P < 0.05) and 0.49 (95% CI 0.288 - 0.845, P < 0.05) respectively when compared to community programs. Only patients with ECM who had private insurance as primary payor at diagnosis had better outcomes when compared to non-insured with an HR of 0.40 (95% CI 0.225 - 0.714, P < 0.05). In addition, patients with ECM were more likely to be treated at academic centers than patients with CM (55.48% vs 46.95%, P < 0.05). The mean survival of patients with ECM was 12.3 months less than those with CM (141.1 months versus 153.4 months.) Conclusion: Overall survival for patients was better at academic centers, integrated network cancer programs, and comprehensive community cancer programs when compared to community centers. In addition, only patients who had private insurance were found to have better outcomes than those who were uninsured. These findings help shed light on the effects of certain socioeconomic and factors on outcomes in ECM. We hope this study will be a launching point for further inquiry into the causal relationships these factors have on outcomes in this rare cancer. 1. (Russo A, Avitabile T et al. Iris Melanoma: Management and Prognosis. Appl Sci 2020; 10: 8766). Citation Format: Mohammed Al Kurnas, Xinxin Wu, Anusha Mubin, Peter T. Silberstein. A retrospective study characterizing 1714 cases of epithelioid cell melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4863.

Analysis and prediction of 5-year survival in patients with cutaneous melanoma: a model-based period analysis.

The survival and prognosis of patients are significantly threatened by cutaneous melanoma (CM), which is a highly aggressive disease. It is therefore crucial to determine the most recent survival rate of CM. This study used population-based cancer registry data to examine the 5-year relative survival rate of CM in the US. Period analysis was used to assess the relative survival rate and trends of patients with CM in the Surveillance, Epidemiology, and End Results (SEER) database during 2004-2018. And based on the data stratified by age, gender, race and subtype in the SEER database, a generalized linear model was 12established to predict the 5-year relative survival rate of CM patients from 2019 to 2023. The 5-year relative survival increased to various degrees for both total CM and CM subtypes during the observation period. The improvement was greatest for amelanotic melanoma, increasing from 69.0% to 81.5%. The 5-year overall relative survival rates of CM were 92.9%, 93.5%, and 95.6% for 2004-2008, 2009-2013, and 2014-2018, respectively. Females had a marginally higher survival rate than males for almost all subtypes, older people had lower survival rates than younger people, white patients had higher survival rates than nonwhite ones, and urban locations had higher rates of survival from CM than rural locations did. The survival rate of CM was significantly lower for distant metastasis. The survival rate of patients with CM gradually improved overall during 2004-2018. With the predicted survival rate of 96.7% for 2019-2023, this trend will still be present. Assessing the changes experienced by patients with CM over the previous 15 years can help in predicting the future course of CM. It also provides a scientific foundation that associated departments can use to develop efficient tumor prevention and control strategies.

Clinical and Immunologic Features of Germline Pathogenic Variant-Positive Patients with Melanoma.

Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10% to 15% of all melanoma cases. No studies to date examine the immunologic features that may differentiate survival differences between germline pathogenic variant (gPV)-positive patients with melanoma from gPV-negative patients with melanoma. Adult patients with melanoma and clinical characteristics suggesting hereditary predisposition to cancer were prospectively recruited to undergo germline testing and flow cytometric analysis of peripheral immune suppressor cells. In this cohort, gPV-positive patients (n = 72) had a significantly improved melanoma-specific survival (MSS) compared with gPV-negative patients (n = 411; HRadj, 0.32; 95% CI, 0.13-0.82; P = 0.01). These survival improvements among gPV-positive patients were most apparent among cutaneous melanoma subtypes (HRadj, 0.12; 95% CI, 0.016-0.86; P = 0.03) and numerically improved in later-stage (IIB-IV) patients (HRadj, 0.34; 95% CI, 0.10-1.11; P = 0.06). Further, gPV-positive patients had a significantly lower level of total circulating PMN-MDSC compared with gPV-negative patients (P = 0.01), which was most apparent in those diagnosed with later stages (IIB-IV) of melanoma (P = 0.009). Finally, a significant upregulation of inflammatory transcriptome signatures in later-stage gPV-positive patients (n = 21) was observed in comparison with gPV-negative patients (n = 173) in the cutaneous melanoma cohort (SKCM) of The Cancer Genome Atlas (TCGA). gPV-positive patients with melanoma exhibit improved MSS in addition to reduced peripheral PMN-MDSC and an enhanced inflammatory microenvironment.

ERK mediates interferon gamma-induced melanoma cell death

BackgroundInterferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway.MethodsWe performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death.ResultsWe show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins.ConclusionsOur results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.

Genomic subtypes of cutaneous melanoma have distinct metabolic profiles: A single-cell transcriptomic analysis.

Genomic profiling previously classified melanoma into distinct subtypes based on the presence or absence of mutations in driver genes, but metabolic differences between and within these groups have yet to be thoroughly analyzed. Thus, the objective of the present study is to provide the first effort to holistically characterize the metabolic landscape of qualified melanoma genomic subtypes at single-cell resolution. Expression data for a total of 1145 malignant cells sourced from NRAS(Q61L), BRAF(V600E), and NRAS/BRAF WT melanomas were retrieved from the Broad Single Cell Portal. Metabolic activity was interrogated by pathway scoring and gene set enrichment analysis. A total of 53 metabolic pathways were differentially regulated in at least one melanoma genomic subtype. Some notable findings include: BRAF/NRAS WT cells were enriched for fatty acid biosynthesis and depleted for metabolism of alanine, aspartate, and glutamate; BRAF(V600E) melanoma cells were enriched for beta-alanine metabolism and depleted for phenylalanine metabolism; NRAS(Q61L) melanoma cells were enriched for steroid biosynthesis and depleted for linoleic acid metabolism. Primary limitations include the total quantity of single cells and breadth of available genomic subtypes plus inherent noisiness of the applied methodologies. Nonetheless, these findings nominate novel, testable therapeutic targets.

Molecular Subtypes Based on PANoptosis Genes and Characteristics of Immune Infiltration in Cutaneous Melanoma.

Cutaneous melanoma (CM) remains the most life-threatening form of skin cancer. Further risk stratification and search for new prognostic targets for CM are of positive clinical significance. PANoptosis is defined as an inflammatory programmed cell death mediated by the PANoptosome complex and cannot be characterized by pyroptosis, apoptosis or necroptosis alone. Although PANoptosis is closely associated with many diseases including cancer, it has not been reported in CM. Combined with GTEx and TCGA database, we extracted 14 PANoptosis-related genes (PAGs). The molecular subtypes of CM were then analyzed by PAGs and their associations with the immune microenvironment and immunotherapy reactivity were analyzed. LASSO and univariate Cox analysis was performed on PAGs-related differentially expressed genes to establish PAGs characteristics that could effectively predict the prognosis of CM patients. Immune infiltration, tumor mutation burden analysis, immunotherapy response and drug sensitivity analysis were used to further analyze the causes of prognostic differences. Our study provides a new perspective on the role of PANoptosis in CM.

Dissecting the relationship between ethnicity and response to checkpoint inhibitors in patients with acral melanoma.

e21597 Background: Aral lentiginous melanoma (ALM) constitutes the most common subtype of cutaneous melanoma (CM) among people with pigmented skin, accounting to up to 70% of cases. In a prior study of 44 patients with advanced, unresectable ALM treated with checkpoint inhibitors, we demonstrated differential response to checkpoint inhibitors by ethnicity with Hispanic patients having a higher response to therapy compared to non-Hispanic patients. Accumulating evidence suggests that tumor mutation burden (TMB) can predict the efficacy of immune checkpoint inhibitors (ICI) in solid malignancies, including cutaneous melanoma. ALM however has significantly lower TMB compared to cutaneous melanoma suggesting that there are other mechanisms outside of TMB driving this response. Here, expanding upon our prior work, we will examine outcomes in over 130 patients and report for the first time, the correlation between ethnicity and response to checkpoint inhibitors in the largest dataset to our knowledge of acral melanoma patients. Methods: This was a retrospective analysis of all advanced and metastatic ALM patients treated with anti-CTLA4 (ipilimumab) or anti-PD1 (pembrolizumab or nivolumab) ICI between March 2011 and January 2019 at the University of Texas MD Anderson Cancer Center, Texas. Clinical response, progression free and overall survival outcomes (PFS and OS) and their correlation to ethnicity and TMB will be evaluated. Objective response will be measured using RECIST 1.1. OS and PFS will be estimated using the Kaplan-Meier method, and differences between groups assessed using the log-rank test. Associations between OS and PFS and measures of interest will be determined using Cox proportional hazards regression models. Results: 132 patients with Stages III-IV ALM (III: 27% and IV: 73%) were included in the analysis. Median age was 66.6 years old (15.8-92.5) and 58% were men. 28 (21.2%) self-identified as Hispanic, 101 (76.5%) were non-Hispanic, and 3 (2.3%) did not provide their ethnicity. The best objective response rate (ORR) was 27 (20.4%), with 9 (6.8%) showing complete response (CR) and 18 (13.6%) showing partial response (PR). 48 (36.4%) patients received anti-PD1 based- therapy while 57 (43.2%) received anti-CTLA4 only. We will present immune phenotyping of both adaptive and innate immune arms to investigate further mechanisms of differential response. Conclusions: The data from our prior small retrospective study suggested that non-Hispanic patients with ALM had low response rates to CPI presumably due to low TMB while interestingly, Hispanic patients, despite relatively low TMB have high response rates paralleling those seen in the overall cutaneous melanoma population. This data will provide the rationale to design prospective studies to investigate further how tumor micro-environment varies with ethnicity.

Abstract 419: Elevated Akt/mTOR signaling drives therapy resistance in ALM

Abstract Metastatic acral lentiginous melanoma (ALM) is the most lethal subtype of cutaneous melanoma and effective therapies for patients have not been established. Studies revealed a link between the dysregulation of CDK4/6 and ALM mortality, however CDK4/6 inhibitors (CDK4i/6i) have proved ineffective in patients with advanced ALM. The tumor suppressor Rb was recently shown to have a novel suppressive role towards mTORC2. Here, we elucidate the role of a non-canonical tumor suppressor function of Rb in negative regulation of mTOR in CDK4i/6i-resistance. We hypothesize that the loss of Rb induced by CDK4i/6i triggers phosphorylation of Akt and downstream mTORC1 signaling pathways. We characterized baseline activity of the PI3K/AKT/mTOR pathway in a panel of ALM cell lines, finding heterogeneity across signaling. We immunoblotted for key proteins involved in the signal reprogramming hypothesized: pRb, pAkt, pS6 to define activation status and found the loss of Rb phosphorylation preceded the enrichment of pAKT, supporting the non-canonical role of Rb tumor suppression and the Rb-mTORC2 signaling axis as intrinsic CDK4i/6i mechanism. In parallel, we assessed the essential protein-protein interactions required for mechanistic mTORC1 activation—mTOR and Rheb GTPase. The enrichment of these interactions shortly after introducing CDK4i/6i supported our hypothesized mechanism. Translational utility of CDK4i/6i and mTORi dual inhibition was determined via long-term Colony Formation Assays (CFAs) using Palbociclib, rapamycin and sapanisertib (TAK228), a catalytic mTOR inhibitor. We generated Palbociclib (acquired)-resistant ALM cell lines and investigated the pharmacological inhibition of PI3K signaling pathways through immunoblot and colony-formation assays. Concurrent mTORi and CDK4i/6i inhibition showed effective reduction in pRb, pS6, Cyclin D and increases in Cleaved PARP protein, suggesting apoptotic cell death was elevated with combined CDK4i/6i+mTORi treatment. Similarly, CFAs revealed dual inhibition elicited superior antiproliferative effect over the monotherapy treatments. CFAs with acquired-resistance cell lines also showed that combination inhibition decreased colony formation, showing the potential utility of concurrent CDK4i/6i and mTORi as an approach against acquired resistance. Our results show the efficacy of combined inhibition as an anti-tumor strategy. Citation Format: Jeremy A. Bravo Narula, Vito W. Rebecca. Elevated Akt/mTOR signaling drives therapy resistance in ALM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 419.

Oncogenic signaling pathways and hallmarks of cancer in Korean patients with acral melanoma

Acral melanoma (AM), a rare subtype of cutaneous melanoma, shows higher incidence in Asians, including Koreans, than in Caucasians. However, the genetic modification associated with AM in Koreans is not well known and has not been comprehensively investigated in terms of oncogenic signaling, and hallmarks of cancer. We performed whole-exome and RNA sequencing for Korean patients with AM and acquired the genetic alterations and gene expression profiles. KIT alterations (previously known to be recurrent alterations in AM) and CDK4/CCND1 copy number amplifications were identified in the patients. Genetic and transcriptomic alterations in patients with AM were functionally converge to the hallmarks of cancer and oncogenic pathways, including 'proliferative signal persistence', 'apoptotic resistance', and 'activation of invasion and metastasis', despite the heterogeneous somatic mutation profiles of Korean patients with AM. This study may provide a molecular understanding for therapeutic strategy for AM.

Trends in three major histological subtypes of cutaneous melanoma in the Netherlands between 1989 and 2016.

Time trend analysis of cutaneous melanoma (CM) mortality in fair skin populations shows both a gradual decrease and/or an increase. To explain these differences, we analyzed long-term time trends in the incidence of the most common histological subtypes of CM: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma (NM). Using data from the Netherlands Cancer Registry and Statistics Netherlands, the number and rates of cases diagnosed with SSM, LLM, and NM from 1989 to 2016 were analyzed by age, calendar period, and birth cohort of people born in successive periods from 1925 to 1973. Primary CM was diagnosed in 52,000 men and 66,588 women in the study period. The annual age-standardized incidence rate increased three-fold from 14 to 42 per 100,000 person-years. The most common subtype was SSM (50%), followed by LMM (23%) and NM (14%). Age-specific subtype rates showed an upward trend over time for both men and women. Younger birth cohorts had higher rates of SSM and LMM diagnosis than older birth cohorts. This birth cohort pattern was not observed for NM. We observed a strong increase in the melanoma epidemic curves in the light-skinned Dutch population over the last three decades. This increase is explained by younger generations having higher rates of SSM and LMM than older generations.

Crosstalk of four kinds of cell deaths defines subtypes of cutaneous melanoma for precise immunotherapy and chemotherapy.

Cell death patterns can give therapeutic and biological clues that facilitate the development of individualized treatments for this lethal form of skin cancer. We employed unsupervised clustering to establish robust classifications based on the four kinds of cell death-associated gene expression of 462 melanoma patients in the Cancer Genome Atlas (TCGA) and tested their reproducibility in two independent melanoma cohorts of 558 patients. We then used dimensionality reduction of graph learning to display the different characteristics of cell death patterns and immune microenvironments. We examined 570 cell death-associated gene expression data of melanoma patients for exploration, independent verification, and comprehensive classification of five reproducible melanoma subtypes (CS1 to CS5) with different genomic and clinical features. Patients in death-inactive subtypes (CS1, CS2, and CS5) had the least immune and stromal cell infiltration, and their prognosis was the poorest. A death-active subtype (CS4), on the other hand, had the highest infiltrated immune and stromal cells and elevated immune-checkpoints. As a result, these patients had the highest response to immunotherapy and the best prognosis. An additional subtype (CS3) had more diversified cell death and immune characteristics with moderate prognoses. Based on graph learning, we successfully divided the CS3 subtype into two subgroups (group A and group B) with distinct survival outcomes and immune features. Finally, we identified eight potential chemical drugs that were specifically targeted for the therapy of melanoma subtypes. This research defines the intrinsic subtypes of melanoma based on the crosstalk of four kinds of cell deaths, which affords a blueprint for clinical strategies and guiding precise immunotherapy and chemotherapy for melanoma patients.

495 Clinicopathologic Characteristics of Trauma-Related Nail Apparatus Melanoma: A Comparative Study According to the Presence of Trauma Prior to Melanoma Development

Nail apparatus melanoma (NAM) is a subtype of cutaneous melanoma occurring at nail units and belongs to the acral lentiginous melanoma subgroup. Due to its unique anatomical structure to protect acral site, mechanical trauma may have a clinicoprognostic impact on NAM. Therefore, we investigated the clinicoprognostic and histopathological characteristics of NAM according to the presence of trauma history prior to melanoma development. Clinicopathological and follow-up data of patients with NAM according to trauma history were obtained.

A large superficial spreading melanoma with a secondary growth of fast-growing nodular melanoma: a case report from Syria

Introduction: Cutaneous melanoma (CM) is a cancer of melanocytes that has a poor prognosis and can metastasize to any organ. Presentation of case: Here, we report a unique case of a 59-year-old Syrian male with a nodular melanoma (NM) that grew and varied rapidly on a large superficial spreading melanoma (SSM), which was a pigmented lesion that lasted for 24 years on his trunk. The lesion developed on a part of his body that had not been exposed to the sun or any artificial sources of ultraviolet radiation. His personal and family history of melanoma and nonmelanoma skin cancer were negative. The histopathologic evaluation, along with the immunohistochemistry examination, confirmed the diagnosis. Clinical discussion: SSM and NM are the most common subtypes of CM. NM has a more rapid growth rate and more aggression compared to SSM, and it tends to be more invasive, ulcerated, and fatal than SSM. Conclusion: Despite the advanced stage of the NM and the large size of the lesion, no metastasis or lymphadenopathy had been found during the patient’s follow-up.

Two subtypes of cutaneous melanoma with distinct mutational signatures and clinico-genomic characteristics.

Background: To decipher mutational signatures and their associations with biological implications in cutaneous melanomas (CMs), including those with a low ultraviolet (UV) signature. Materials and Methods: We applied non-negative matrix factorization (NMF) and unsupervised clustering to the 96-class mutational context of The Cancer Genome Atlas (TCGA) cohort (N = 466) as well as other publicly available datasets (N = 527). To explore the feasibility of mutational signature-based classification using panel sequencing data, independent panel sequencing data were analyzed. Results: NMF decomposition of the TCGA cohort and other publicly available datasets consistently found two mutational signatures: UV (SBS7a/7b dominant) and non-UV (SBS1/5 dominant) signatures. Based on mutational signatures, TCGA CMs were classified into two clusters: UV-high and UV-low. CMs belonging to the UV-low cluster showed significantly worse overall survival and landmark survival at 1-year than those in the UV-high cluster; low or high UV signature remained the most significant prognostic factor in multivariate analysis. The UV-low cluster showed distinct genomic and functional characteristic patterns: low mutation counts, increased proportion of triple wild-type and KIT mutations, high burden of copy number alteration, expression of genes related to keratinocyte differentiation, and low activation of tumor immunity. We verified that UV-high and UV-low clusters can be distinguished by panel sequencing. Conclusion: Our study revealed two mutational signatures of CMs that divide CMs into two clusters with distinct clinico-genomic characteristics. Our results will be helpful for the clinical application of mutational signature-based classification of CMs.

Does the morphology of cutaneous melanoma help to explain the international differences in survival? Results from 1 578 482 adults diagnosed during 2000–2014 in 59 countries (CONCORD-3)

BackgroundCONCORD‐3 highlighted wide disparities in population‐based 5‐year net survival for cutaneous melanoma during 2000–2014. Clinical evidence suggests marked international differences in the proportion of lethal acral and nodular subtypes of cutaneous melanoma.ObjectivesWe aimed to assess whether the differences in morphology may explain global variation in survival.MethodsPatients with melanoma were grouped into the following seven morphological categories: malignant melanoma, not otherwise specified (International Classification of Diseases for Oncology, third revision morphology code 8720), superficial spreading melanoma (8743), lentigo maligna melanoma (8742), nodular melanoma (8721), acral lentiginous melanoma (8744), desmoplastic melanoma (8745) and other morphologies (8722–8723, 8726–8727, 8730, 8740–8741, 8746, 8761, 8770–8774, 8780). We estimated net survival using the nonparametric Pohar Perme estimator, correcting for background mortality by single year of age, sex and calendar year in each country or region. All‐ages survival estimates were standardized using the International Cancer Survival Standard weights. We fitted a flexible parametric model to estimate the effect of morphology on the hazard of death.ResultsWorldwide, the proportion of nodular melanoma ranged between 7% and 13%. Acral lentiginous melanoma accounted for less than 2% of all registrations but was more common in Asia (6%) and Central and South America (7%). Overall, 36% of tumours were classified as superficial spreading melanoma. During 2010–2014, age‐standardized 5‐year net survival for superficial spreading melanoma was 95% or higher in Oceania, North America and most European countries, but was only 71% in Taiwan. Survival for acral lentiginous melanoma ranged between 66% and 95%. Nodular melanoma had the poorest prognosis in all countries. The multivariable analysis of data from registries with complete information on stage and morphology found that sex, age and stage at diagnosis only partially explain the higher risk of death for nodular and acral lentiginous subtypes.ConclusionsThis study provides the broadest picture of distribution and population‐based survival trends for the main morphological subtypes of cutaneous melanoma in 59 countries. The poorer prognosis for nodular and acral lentiginous melanomas, more frequent in Asia and Latin America, suggests the need for health policies aimed at specific populations to improve awareness, early diagnosis and access to treatment. What is already known about this topic? The histopathological features of cutaneous melanoma vary markedly worldwide.The proportion of melanomas with the more aggressive acral lentiginous or nodular histological subtypes is higher in populations with predominantly dark skin than in populations with predominantly fair skin. What does this study add? We aimed to assess the extent to which these differences in morphology may explain international variation in survival when all histological subtypes are combined.This study provides, for the first time, international comparisons of population‐based survival at 5 years for the main histological subtypes of melanoma for over 1.5 million adults diagnosed during 2000–2014.This study highlights the less favourable distribution of histological subtypes in Asia and Central and South America, and the poorer prognosis for nodular and acral lentiginous melanomas.We found that later stage at diagnosis does not fully explain the higher excess risk of death for nodular and acral lentiginous melanoma compared with superficial spreading melanoma.

UV-Induced Somatic Mutations Driving Clonal Evolution in Healthy Skin, Nevus, and Cutaneous Melanoma.

Introduction: Due to its aggressiveness, cutaneous melanoma (CM) is responsible for most skin cancer-related deaths worldwide. The origin of CM is closely linked to the appearance of UV-induced somatic mutations in melanocytes present in normal skin or in CM precursor lesions (nevi or dysplastic nevi). In recent years, new NGS studies performed on CM tissue have increased the understanding of the genetic somatic changes underlying melanomagenesis and CM tumor progression. Methods: We reviewed the literature using all important scientific databases. All articles related to genomic mutations in CM as well as normal skin and nevi were included, in particular those related to somatic mutations produced by UV radiation. Conclusions: CM development and progression are strongly associated with exposure to UV radiation, although each melanoma subtype has different characteristic genetic alterations and evolutionary trajectories. While BRAF and NRAS mutations are common in the early stages of tumor development for most CM subtypes, changes in CDKN2A, TP53 and PTEN, together with TERT promoter mutations, are especially common in advanced stages. Additionally, large genome duplications, loss of heterozygosity, and copy number variations are hallmarks of metastatic disease. Finally, the mutations driving melanoma targeted-therapy drug resistance are also summarized. The complete sequential stages of clonal evolution leading to CM onset from normal skin or nevi are still unknown, so further studies are needed in this field to shed light on the molecular pathways involved in CM malignant transformation and in melanoma acquired drug resistance.

Clinicopathologic Characteristics of Trauma-Related Nail Apparatus Melanoma: A Comparative Study according to the Presence of Trauma prior to Melanoma Development

Background: Nail apparatus melanoma (NAM) is a subtype of cutaneous melanoma occurring at nail units and belongs to the acral lentiginous melanoma subgroup. Due to its unique anatomical structure to protect the acral site, mechanical trauma may have a clinicoprognostic impact on NAM. Therefore, we investigated the clinicoprognostic and histopathological characteristics of NAM according to the presence of trauma history prior to melanoma development. Methods: Clinicopathological and follow-up data of patients with NAM according to trauma history were obtained. Results: We included 87 patients with NAM, 21.8% of whom had a previous trauma history. Trauma-related NAMs were more likely to involve the toenail (p = 0.040), include a high proportion of amelanotic melanomas (p = 0.038) as well as nail bed tumor (p = 0.013), and have a longer time interval between the onset of nail change and confirmed diagnosis (p = 0.012). Moreover, survival analysis revealed that trauma-related NAMs more frequently showed progression in general (p = 0.034) and nodal metastasis (p = 0.047) and had worse prognosis in terms of progression-free survival (p = 0.004). Conclusion: In conclusion, NAMs with previous trauma have unique clinicoprognostic characteristics. The specific clinicopathological features of NAMs according to trauma indicate that trauma may play a role in melanoma development.

197 Second primary cancer risk after diagnosis of melanoma by subtype

Background: Survivors of cutaneous melanoma (CM) have an increased risk for developing multiple cancers, including melanoma, breast cancer, prostate cancer, and non-Hodgkin lymphoma (NHL). Limited data exists comparing differences in second primary cancer (SPC) risk between CM subtypes. Purpose: To compare the spectrum of SPC risk between CM subtypes (superficial spreading, SSM; lentigo maligna, LMM; acral lentiginous, ALM; nodular, NM; desmoplastic, DM; amelanotic, AM). Methods: Using Surveillance, Epidemiology, and End Results (SEER) 18 cancer data (2000-2018), we calculated SPC risk by CM subtype.