Melanoma Subtypes Research Articles

Mucosal Melanoma: Review from a Pathologist Point of View

Mucosal melanomas are rare malignant tumors arising from the epithelia lining the inner mucosal surfaces of the body. Unlike cutaneous melanoma, we have a limited understanding of mucosal melanomas is currently limited. Mucosal melanomas are characterized by genetic alterations quite distinct from cutaneous melanomas; however, their causative and promoting factors are unknown. These melanomas are characteristically diagnosed at a later stage due to their occult locations, leading to a worse prognosis. Dedicated staging systems for mucosal melanomas exist only for sinonasal and conjunctival melanomas. Therefore, risk stratification of patients with mucosal melanomas, particularly those arising from the anogenital area, is challenging. Recent studies have shown that minor modifications of the AJCC 8th Edition cutaneous melanoma staging system can group patients fairly robustly; however, the proposed T-categorization systems have yet to be validated in larger cohorts. We summarize the demographic, clinical, histopathologic, and molecular features of common subtypes of mucosal melanomas and highlight the outstanding needs in this field.

Beyond nest size: the clinicopathological spectrum of large nested melanocytic tumours and the value of comparative genomic hybridisation and mRNA expression analysis

Large nested melanomas (LNMs) are a rare subtype of naevoid melanoma consisting of large junctional melanocytic nests that are more common in older individuals and/or associated with sun damage. However, the presence of large melanocytic nests alone does not lead to a diagnosis of malignancy ​as they can also be found in melanocytic naevi. LNMs are challenging because they lack most classic histological features of malignancy and require thorough clinicopathological evaluation. This ambiguity calls for a critical reassessment of the current diagnostic criteria for the subclassification of benign or malignant within the spectrum of large nested melanocytic tumuors (LNMTs).18Eighteen LNMTs and six special-site control melanocytic naevi (SSMNs) ​were studied using different approaches: clinical features, dermoscopy, histopathology, immunohistochemistry, array comparative genomic hybridisation (aCGH) and mRNA sequencing analysis, with the aim of identifying novel and reproducible criteria for the recognition of LNMs.Careful clinicopathological evaluation of the 18 LNMTs led to the diagnosis of seven LNMs and 11 large nested melanocytic naevi (LNMNs). Lentiginous spread and nest bridging were significantly associated with LNMs after Holm–Bonferroni correction. Asymmetry, largest nest size, poor lateral demarcation, the number of colours and dermoscopic structures, and PRAME immunostaining were more common in LNMs but did not reach statistical significance. Four of seven LNMs and nine of 11 LNMNs lacked the BRAF V600E mutation. Regarding aCGH, no LNMN or SSMN cases had ≥3 copy number variations (CNVs), in contrast to 50% of LNM cases. Importantly, LNM and LNMN could be distinguished by differential mRNA expression of nine genes.Our study demonstrates that there is a spectrum of LNMTs and that the clinicopathologic diagnosis of LNM, for which we support the term “late-onset nested naevoid melanomas”, can be significantly strengthened by the presence of lentiginous pattern, nest bridging, gene CNV and differential mRNA expression.

Comparative Whole-Genome Sequencing Analysis of In-situ and Invasive Acral Lentiginous Melanoma: Markedly Increased Copy Number Gains of GAB2 , PAK1 , UCP2 , and CCND1 are Associated with Melanoma Invasion.

Acral lentiginous melanoma (ALM) is the most common subtype of acral melanoma. Even though recent genetic studies are reported in acral melanomas, the genetic differences between in-situ and invasive ALM remain unclear. We aimed to analyze specific genetic changes in ALM and compare genetic differences between in-situ and invasive lesions to identify genetic changes associated with the pathogenesis and progression of ALM. We performed whole genome sequencing of 71 tissue samples from 29 patients with ALM. Comparative analyses were performed, pairing in-situ ALMs with normal tissues and, furthermore, invasive ALMs with normal and in-situ tissues. Among 21 patients with in-situ ALMs, 3 patients (14.3%) had SMIM14 , SLC9B1 , FRG1 , FAM205A , ESRRA , and ESPN mutations, and copy number (CN) gains were identified in only 2 patients (9.5%). Comparing 13 invasive ALMs with in-situ tissues, CN gains were identified in GAB2 in 8 patients (61.5%), PAK1 in 6 patients (46.2%), and UCP2 and CCND1 in 5 patients (38.5%). Structural variants were frequent in in-situ and invasive ALM lesions. Both in-situ and invasive ALMs had very low frequencies of common driver mutations. Structural variants were common in both in-situ and invasive ALMs. Invasive ALMs had markedly increased CN gains, such as GAB2 , PAK1 , UCP2 , and CCND1 , compared with in-situ lesions. These results suggest that they are associated with melanoma invasion.

CDK4 gene copy number increase and concurrent genetic changes in acral melanoma of a Chinese cohort

Acral melanoma (AM) is the most common subtype of melanoma in Asian population. Abnormalities in the p16-cyclin D1-CDK4 signalling pathway play a crucial role in the development and progression of AM. However, the alterations of CDK4 gene copy number in AM are underreported. In this study, we investigated CDK4 gene copy number and concurrent molecular changes in a Chinese cohort with AM, in aim of exploring CDK4 gene alterations and its significance in AM. We examined copy number alterations of CDK4 with fluorescence in situ hybridisation (FISH) in 31 patients with AM. Six patients with CDK4 high-level copy number increase were examined by next-generation sequencing to detect concurrent molecular changes. Using FISH, 12 (12/31, 38.7%) cases showed CDK4 copy number increase, with 6 (6/31, 19.4%) low-level copy number increase and 6 (6/31, 19.4%) high-level copy number increase. Five of six CDK4 low-level copy number increase cases were accompanied by polysomy of chromosome 12, while one case was not. Two of six CDK4 high-level copy number increase cases were accompanied by polysomy of chromosome 12, while four cases were not. CDK4 copy number increase was significantly correlated with younger patient age. In six CDK4 high-level copy number increase cases, one case was found to be accompanied by NRAS mutation, one case was accompanied by HER2 mutation, one case was accompanied by BCL2L11 mutation ​and one case was accompanied by BRAF, HER2 and BCL2L11 mutations. Our study confirmed the presence of CDK4 copy number increase in AM cases. Detecting CDK4 copy number increase by FISH can be reliable in the diagnosis of AM. Some CDK4 copy number increases are the results of polysomy of chromosome 12. CDK4 high-level copy number increase coexists with other pathogenic mutations in AM. CDK4 appears to be a promising target for AM treatment and is expected to be combined with other targeted therapies.

Classification of Cutaneous Melanoma and Melanocytic Nevi with MicroRNA Ratios Is Preserved in the Acral Melanoma Subtype

Classification of Cutaneous Melanoma and Melanocytic Nevi with MicroRNA Ratios Is Preserved in the Acral Melanoma Subtype

DNA methylation variations of DNA damage response correlate survival and local immune status in melanomas.

We aimed to explore the impact of DNA methylation alterations on the DNA damage response (DDR) in melanoma prognosis and immunity. MATERIAL &METHODS: Different melanoma cohorts with molecular and clinical data were included. Hierarchical clustering utilizing different combinations of DDR-relevant CpGs yielded distinct melanoma subtypes, which were characteristic of different prognoses, transcriptional function profiles of DDR, and immunity and immunotherapy responsesbut were associated with similar tumor mutation burdens. We then constructed and validated a clinically applicable 4-CpG risk-score signature for predicting survival and immunotherapy response. Our study describes the close interrelationship amongDNA methylation, DDR machinery, local tumor immune status, melanoma prognosis, and immunotherapy response.

BAUSSS biomarker improves melanoma survival risk assessment.

The American Joint Committee on Cancer (AJCC) method of staging melanoma is dated and inaccurate. It ignores important prognostic melanoma features, especially the patient's age. BAUSSS is more accurate in determining survival risk for primary cutaneous melanoma patients who have no clinical or imaging evidence of nodal or distant metastases. BAUSSS is an algorithm incorporating analysis of Breslow thickness, Age, Ulceration, Subtype of melanoma, Sex and Site. These are the six features from the patient history along with the details from the melanoma pathology report that are most predictive of mortality outcome. To develop a single-page document that allows the clinician to determine BAUSSS biomarker-predicted prognosis in consultation with the patient. From various data sources, we developed an algorithm to predict melanoma mortality using the BAUSSS biomarker system. The single-page algorithm was made available to download at https://globalmelanoma.net/bausss-survival-chart, thus being readily available without charge to all clinicians and their patients. BAUSSS method of determining melanoma prognosis is more accurate and less costly than the AJCC staging system. The only surgery the patient requires is wide local excision of the primary tumour. This method of ascertaining melanoma risk does not require added surgery, costs, hospitalization, tests and anaesthesia, such as would be required if sentinel lymph node biopsy was undertaken. BAUSSS can be a useful tool in determining which primary melanoma patients are at sufficiently high risk to be considered for adjuvant drug therapy. We encourage clinicians to download and print in colour this single-page BAUSSS mortality prediction tool, laminate it, and use it face to face with the patient in consultations. Not only will the patient be able to recognize his/her long-term prognosis but will also be able to see how their tumour severity compares with others.

Weakly supervised deep learning image analysis can differentiate melanoma from naevi on haematoxylin and eosin-stained histopathology slides.

The broad histomorphological spectrum of melanocytic pathologies requires large data sets to develop accurate and generalisable deep learning (DL)-based diagnostic pathology classifiers. Weakly supervised DL promotes utilisation of larger training data sets compared to fully supervised (patch annotation) approaches. To evaluate weakly supervised DL image classifiers for discriminating melanomas from naevi on haematoxylin and eosin (H&E)-stained pathology slides. A representative H&E slide for 260 naevi and 260 melanomas from mucocutaneous sites at one tertiary institution was digitized. Clinicopathological features were recorded for each case including thickness and histological subtype. Whole-slide or whole-tissue section labels were applied. The ground truth was established by consensus diagnosis from two pathologists. Multiple-instance learning models, Trans-MIL, CLAM and DTFD-MIL were evaluated at 10×, 20× and 40× magnifications using stratified fivefold Monte Carlo cross-validation, with 80/10/10 splits for training/validation/test groups, to predict melanoma from naevus. Heatmaps were generated to understand model performance. Naevi cases were younger (median age: 51 years; melanoma median age: 71.5 years), with more balanced sex distribution (males: 48.8%, melanoma male subgroup: 64.2%). The most frequent histological subtypes of naevi and melanomas were dysplastic compound (n = 99, 38.1%) and superficial spreading (n = 124, 47.7%), respectively. Average AUC (±1 SD) for Trans-MIL, CLAM and DTFD-MIL across test groups were 0.9952 ± 0.006, 0.9925 ± 0.0052 and 0.9708 ± 0.0328, at 20× magnification, respectively. Performance of the models varied according to the magnification used. Heatmaps from the two best performing models, Trans-MIL and CLAM, generally indicated attention on appropriate tissue regions for interpretation. Weakly supervised DL on pathological slides of common mucocutaneous melanocytic tumours provides highly accurate diagnostic value for discrimination of melanomas and naevi. External validation and further assessment on less frequently occurring histologic subtypes and borderline cases using this method is required.

Predominance of hyperprogression in mucosal melanoma during anti-PD-1 monotherapy treatment.

A minority subset of immunotherapy patients manifests hyperprogressive disease (HPD), with the disparity in melanoma subtypes yet to be reported. This study aimed to delineate the proportion and prognosis of HPD in patients receiving anti-PD-1 monotherapy and to identify patient with HPD clinical characteristics across melanoma subtypes to inform clinical decision making. Utilizing 4 established HPD definitions, the incidence of HPD in patients with advanced melanoma on anti-PD-1 monotherapy was determined. The incidence rates and prognostic abilities of various HPD definitions were compared to elect the most effective one. This facilitated a comparative analysis of subtypes and clinical features between patients with HPD and traditional progression. A total of 262 patients with advanced melanoma treated with anti-PD-1 monotherapy from 5 prospectively registered clinical trials were included in the study. The objective response rate (ORR) and disease control rate (DCR) was 21% and 58%, respectively, with 42% showcasing progression disease. The HPD incidences by 4 definitions were 13.2%, 16.8%, 10.8%, and 28.2%. All definitions effectively segregated HPD patients, with significantly poorer outcome than other progressive patients. The Delta TGR > 100 definition was the most indicative of a reduced overall survival, corroborated by the highest hazard ratio and statistical significance. The number of metastatic organs over 2 is a risk factor for HPD (OR = 4.18, P = .0103). Mucosal melanoma was the HPD prevalent subtype (OR = 3.13, P = .0489) in multivariable analysis, which is also indicated by RECIST criteria (P = .005). A delta TGR exceeding 100 best identified HPD patients in the advanced melanoma population treated with anti-PD-1 monotherapy. Hyperprogression was notably prevalent in mucosal melanoma patients with multiple metastatic organs. Caution against HPD is warranted when applying anti-PD-1 monotherapy in mucosal subtype.

Exploring the Germline Genetics of In Situ and Invasive Cutaneous Melanoma

It is unknown whether germline genetic factors influence in situ melanoma risk differently than invasive melanoma risk. To determine whether differences in risk of in situ melanoma and invasive melanoma are heritable. Three genome-wide association study meta-analyses were conducted of in situ melanoma vs controls, invasive melanoma vs controls, and in situ vs invasive melanoma (case-case) using 4 population-based genetic cohorts: the UK Biobank, the FinnGen cohort, the QSkin Sun and Health Study, and the Queensland Study of Melanoma: Environmental and Genetic Associations (Q-MEGA). Melanoma status was determined using International Statistical Classification of Diseases and Related Health Problems codes from cancer registry data. Data were collected from 1987 to 2022, and data were analyzed from September 2022 to June 2023. In situ and invasive cutaneous melanoma. To test whether in situ and invasive melanoma have independent heritable components, genetic effect estimates were calculated for single-nucleotide variants (SNV; formerly single-nucleotide polymorphisms) throughout the genome for each melanoma. Then, SNV-based heritability was estimated, the genetic correlation between melanoma subtypes was assessed, and polygenic risk scores (PRS) were generated for in situ vs invasive status in Q-MEGA participants. A total of 6 genome-wide significant loci associated with in situ melanoma and 18 loci with invasive melanoma were identified. A strong genetic correlation (genetic r = 0.96; 95% CI, 0.76-1.15) was observed between the 2 classifications. Notably, loci near IRF4, KLF4, and HULC had significantly larger effects for in situ melanoma compared with invasive melanoma, while MC1R had a significantly larger effect on invasive melanoma compared with in situ melanoma. Heritability estimates were consistent for both, with in situ melanoma heritability of 6.7% (95% CI, 4.1-9.3) and invasive melanoma heritability of 4.9% (95% CI, 2.8-7.2). Finally, a PRS, derived from comparing invasive melanoma with in situ melanoma genetic risk, was on average significantly higher in participants with invasive melanoma (odds ratio per 1-SD increase in PRS, 1.43; 95% CI, 1.16-1.77). There is much shared genetic architecture between in situ melanoma and invasive melanoma. Despite indistinguishable heritability estimates between the melanoma classifications, PRS suggest germline genetics may influence whether a person gets in situ melanoma or invasive melanoma. PRS could potentially help stratify populations based on invasive melanoma risk, informing future screening programs without exacerbating the current burden of melanoma overdiagnosis.

Comparison of Ophthalmologists versus Dermatologists for the Diagnosis and Management of Periorbital Atypical Pigmented Skin Lesions.

Background/Objectives: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) are significant subtypes of melanoma, with an annual incidence of 1.37 per 100,000 people in the U.S. These skin tumors, often found in photo-exposed areas such as the face, are frequently misdiagnosed, leading to delayed treatment or unnecessary excisions, especially in the elderly. Facial melanocytic skin tumors (lentigo maligna-LM/lentigo maligna melanoma-LMM) and their simulators (solar lentigo, pigmented actinic keratosis, seborrheic keratosis and lichen planus-like keratosis) often affect the periocular region. Thus, their diagnosis and management can involve different medical figures, mainly dermatologists and ophthalmologists. This study aimed to evaluate the ability of ophthalmologists to diagnose and manage pigmented skin lesions of the periorbital area. Methods: A multicentric, retrospective, cross-sectional study on a dataset of 79 periorbital pigmented skin lesions with both clinical and dermoscopic images was selected. The images were reviewed by six ophthalmologists and two dermatologists. Descriptive statistics were carried out, and the accuracy, sensitivity, and specificity, with their 95% confidence interval (95% CI), were estimated. Results: Ophthalmologists achieved a diagnostic accuracy of 63.50% (95% CI: 58.99-67.85%), while dermatologists achieved 66.50% (95% CI: 58.5-73.8). The sensitivity was lower for ophthalmologists in respect to dermatologists, 33.3% vs. 46.9%, respectively. Concerning the case difficulty rating, ophthalmologists rated as "difficult" 84% of cases, while for dermatologists, it was about 30%. Management was also consistently different, with a "biopsy" decision being suggested in 25.5% of malignant lesions by ophthalmologists compared with 50% of dermatologists. Conclusions: Ophthalmologists revealed a good diagnostic potential in the identification of periorbital LMs/LMMs. Given progressive population ageing and the parallel increase in facial/periorbital skin tumors, the opportunity to train new generations of ophthalmologists in the early diagnosis of these neoformations should be considered in the next future, also taking into account the surgical difficulty/complexity of this peculiar facial area.

Acral Melanoma Incidence and Survival Trends in 1990-2020: A Nationwide, Population-based Study.

Acral melanoma is a clinical subtype of melanoma with high mortality, on which research is limited in scope. This study aimed to assess incidence trends and melanoma-specific survival rates for acral melanoma in the Swedish population from 1990 to 2020.This cross-sectional study included patients with an acral melanoma diagnosis from 1990 to 2020 from the nationwide, population-based Swedish Melanoma Registry. Analyses on acral melanoma melanoma-specific survival rates were adjusted for age, sex, histopathological subtype, and tumour thickness. Clinicopathological features and melanoma-specific survival rates were compared between diagnostic periods: 1990-1999, 2000-2009, and 2010-2020, respectively. Changes in standardized incidence rates in 1996-2020 were evaluated separately for males and females. In total, 1,000 acral melanomas in 999 patients were included in the study. No significant yearly change in standardized incidence rates for either males or females was observed, even though the absolute number of cases increased. Factors such as male sex, age ≥ 70 years, and Breslow thickness > 1.0 were independently linked to lower melanoma-specific survival. The 5-year melanoma-specific survival across the studied period ranged from 75.8% to 77.9% for females, and from 62.4% to 71.7% for males.

Using Nomograms Wisely: Predicting Sentinel Node Positivity in Melanoma.

Four externally validated sentinel node biopsy (SNB) prediction nomograms exist for malignant melanoma that each incorporate different clinical and histopathologic variables, which can result in substantially different risk estimations for the same patient. We demonstrate this variability by using hypothetical melanoma cases. We compared the MSKCC and MIA calculators. Using a random number generator, 300 hypothetical thin melanoma "patients" were created with varying age, tumor thickness, Clark level, location on the body, ulceration, melanoma subtype, mitosis, and lymphovascular invasion (LVI). The chi-square test was used to detect statistically significant differences in risk estimations between nomograms. Multivariate linear regression was used to determine the most relevant contributing pathologic features in cases where the predictions diverged by > 10%. Of 300 randomly generated cases, 164 were deleted as their clinical scenarios were unlikely. The MSKCC nomogram generally calculated a lower risk than the MIA (p < 0.001). The highest risk score attained for any "patient" using MSKCC calculator was 15% achieved in one of 136 patients (0.7%), whereas using the MIA nomogram, 58 of 136 patients (43%, p < 0.001) had predicted risk >15%. Regression analysis on patients with >10% difference between nomograms revealed LVI (26, p < 0.001), mitosis (14, p < 0.001), and melanoma subtype (8, p < 0.001) were the factors with high coefficients within MIA that were not present in MSKCC. Nomograms are useful tools when predicting SNB risk but provide risk outputs that are quite sensitive to included predictors.

T Cell-Engaging Bispecific Antibodies Targeting gp100 and PRAME: Expanding Application from Uveal Melanoma to Cutaneous Melanoma.

Uveal melanoma represents a rare and aggressive subtype of melanoma with limited treatment options and poor prognosis, especially in the metastatic setting. Tebentafusp, a bispecific fusion protein, offers a promising therapeutic approach by targeting gp100, an antigen highly expressed in uveal melanoma cells, and redirecting T cell-mediated cytotoxicity towards tumor cells. This review provides an overview of the preclinical and clinical data on tebentafusp in the management of metastatic uveal melanoma. We summarize the mechanism of action, clinical efficacy, safety profile, and ongoing research efforts surrounding this innovative immunotherapy. Preclinical studies have demonstrated the ability of tebentafusp to induce potent and specific anti-tumor immune responses against gp100-expressing uveal melanoma cells. Clinical trials have shown encouraging results, with tebentafusp exhibiting meaningful clinical activity in a subset of patients with metastatic uveal melanoma. Importantly, tebentafusp has also demonstrated a manageable safety profile. By specifically targeting tumor cells expressing gp100, tebentafusp offers a promising therapeutic avenue for individuals with metastatic uveal melanoma, meeting a significant clinical need in this context. Continued clinical trials will provide additional insights into the impact of tebentafusp on treatment-resistant metastatic cutaneous melanoma. Furthermore, we are exploring the potential of T cell engagers directed against the cancer testis antigen PRAME, which could have widespread utility in the treatment of cutaneous melanoma as well as other PRAME-expressing malignancies.

Lentigo maligna: a comprehensive review on diagnosis and treatment.

Lentigo maligna (LM), a form of melanoma in situ, and LM melanoma (LMM), its invasive counterpart, exhibit distinctive epidemiology, risk factors, and clinical features compared to other melanoma subtypes. Notably, LM occurs on chronically sun-damaged skin presenting as a slow-growing, ill-defined patch which makes it difficult to diagnose and to treat. Additionally, while LM generally presents a favourable prognosis, it can also lead to dermal invasion and behave similarly to other melanomas with the same Breslow thickness. Hence, surgery continues to be the cornerstone treatment. Wide excisions are often necessary, but challenges arise when these lesions manifest in cosmetically sensitive regions, limiting the feasibility and desirability of large excisions. Specialized approaches, including margin-controlled surgery and image-guided treatment with reflectance confocal microscopy, have been developed to address these issues. Other non-surgical treatments such as cryosurgery, imiquimod, radiotherapy, or photodynamic therapy, may also be used but commonly present with recurrent/persistent disease. Herein we comprehensively review the existing literature on the management of LM/LMM, and discus the potential new advances on managing this challenging skin cancer.

Proteogenomic insights into the biology and treatment of pan-melanoma

Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.

The genetic evolution of acral melanoma

Acral melanoma is an aggressive type of melanoma with unknown origins. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. We examine exome sequencing data of 139 tissue samples, spanning different progression stages, from 37 patients. We find that 78.4% of the melanomas display clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These complex genomic aberrations are typically shared across all progression stages of individual patients. TERT activating alterations also arise early, whereas MAP-kinase pathway mutations appear later, an inverted order compared to the canonical evolution. The punctuated formation of complex aberrations and early TERT activation suggest a unique mutational mechanism that initiates acral melanoma. The marked intratumoral heterogeneity, especially concerning MAP-kinase pathway mutations, may partly explain the limited success of therapies for this melanoma subtype.

Prognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma.

Macrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) have been implicated as drivers of tumor progression across a variety of cancers. Recent evidence suggests MIF as a therapeutic target in immune checkpoint inhibition (ICI) resistant melanomas, however clinical evidence of MIF and particularly of DDT remain limited. This retrospective study analyzed 97 patients treated at Yale for melanoma between 2002-2020. Bulk-RNA sequencing of patient tumor samples from the Skin Cancer SPORE Biorepository was used to evaluate for differential gene expression of MIF, DDT, CD74, and selected inflammatory markers, and gene expression was correlated with patient survival outcomes. Our findings revealed a strong correlation between MIF and DDT levels, with no statistically significant difference across common melanoma mutations and subtypes. Improved survival was associated with lower MIF and DDT levels and higher CD74:MIF and CD74:DDT levels. High CD74:DDT and CD74:MIF levels were also associated with enrichment of infiltrating inflammatory cell markers. These data suggest DDT as a novel target in immune therapy. Dual MIF and DDT blockade may provide synergistic responses in patients with melanoma, irrespective of common mutations, and may overcome ICI resistance. These markers may also provide prognostic value for further biomarker development.

High-frequency ultrasound accuracy in preoperative cutaneous melanoma assessment: A meta-analysis.

High-frequency ultrasound (HFUS) can safely and efficiently visualize cutaneous tumour characteristics including depth. We aimed to evaluate its accuracy in measuring melanoma depth against the gold standard, histopathology, for treatment planning. A review of publications was conducted in March 2023 through five electronic databases. Thirty-six included articles studied patients who received HFUS (≥10 MHz) measurements, melanoma biopsy or excision, and reported a tumour depth correlation coefficient between HFUS and histopathology. We analysed correlation coefficients between HFUS and histopathology, measured tumour depths and shed light on reasons for mismeasurements. Additionally, we identified the reporting of critical metrics including, lesion characteristics, melanoma subtype, type of correlation coefficient, 95% confidence intervals for Pearson coefficients and sample size. The most common tumour imaged was superficial spreading melanoma on the trunk and extremities, followed by head/face. Maximum ultrasound frequencies ranged from 13 MHz to 100 MHz with participants ranging from 5 to 264. Histopathology and HFUS correlation coefficients ranged from 0.417 to 0.997 (median: 0.94, mean: 0.89 and SD: 0.13). Lower frequency probes (10-20 MHz) were less accurate in assessing melanoma thickness, with a cumulative mean correlation coefficient of 0.87 compared to 0.94 (20-25 MHz) and 0.98 (≥70 MHz). Studies demonstrated higher sonographic accuracy in melanomas >0.75 mm. Additionally, ultrasound may report increased melanoma depth compared to histopathology for reasons including lymphocytic infiltration, presence of a nevus and shrinkage during specimen processing. Furthermore, we found a gap in the reporting of details such as fundamental characteristics of lesion populations. Specifically, 86% (31 out of 36) of the studies failed to report one or more critical metrics, such as mean, median or range of lesion depths. HFUS may serve as a supplementary tool for preoperative melanoma assessment, with increased accuracy in thicker tumours. Frequencies <20 MHz are less reliable in assessing depth. Frequencies ≥70 MHz demonstrate stronger correlations to histopathology. Higher ultrasound accuracy was seen for melanomas with Breslow depth >0.75 mm.

National assessment of social vulnerabilities on head-neck melanoma care: A retrospective cohort study

BackgroundStudies addressing social determinants of health (SDH) in head-neck melanomas (HNM) have only assessed socioeconomic factor impact but not a wider scope of SDH. ObjectiveUtilizing the Social Vulnerability Index (SVI), to assess the influence of specific SDH and their quantifiable associations with HNM-management disparities across the varied community contexts in the US. MethodsThis retrospective cohort study analyzed adults diagnosed with head-neck melanomas between 1975-2017 from the Surveillance, Epidemiology, and End Results Program (SEER) database. Results374,138 HNM in adults between 1975-2017 were assessed for disparities affiliated with increasing overall vulnerability/SVI scores and SDH-themes. For several melanoma subtypes, higher social vulnerability significantly decreased odds (lowest for amelanotic, OR 0.74; 95% CI 0.63-0.86) for indicated surgery, increased odds of indicated radiation (highest for epithelioid cell, 1.44; 1.08-1.96) and advanced staging on first-presentation (highest for acral-lentiginous, 1.13; 1.01-1.27). Household composition, followed by socioeconomic status and minority-language status contributed significantly within the overall trend. LimitationsLimitations include unknown cause of death and SVI score calculation based on county of residency. ConclusionsThis investigation highlights significant detrimental trends in HNM management with overall social vulnerability while showcasing the quantifiable associations of specific SDH-themes on HNM-disparities.