Primary Cutaneous Melanoma Research Articles

INNV-19. MULTIMODAL THERAPY FOR BRAF V600E MUTANT MELANOMA BRAIN METASTASES: CHARACTERIZATION OF CHRONOLOGICAL TREATMENT STRATEGIES AND ASSOCIATIONS WITH OVERALL SURVIVAL

Abstract BACKGROUND B-raf proto-oncogene (BRAF)-mutant melanoma brain metastases (BRAF MBM) are associated with poor prognosis. Amidst our large institutional experience treating patients with BRAF MBM with multimodality therapy, our aim was to identify disease and treatment-related prognostic features, accounting for longitudinal sequence of events, to inform clinical decision-making. METHODS We retrospectively reviewed electronic health records of 100 patients with primary cutaneous melanoma diagnosed with BRAF MBM. Demographic, disease, and clinical factors including treatment sequencing were tabulated. Descriptive statistics were used to summarize the study population and non-parametric tests were used to evaluate differences across groups. A multivariable Cox regression identified factors associated with overall survival (OS) following BRAF MBM diagnosis. RESULTS Median follow-up was 22 months and median OS was 33.5 months. Patients received an average [standard deviation (SD)] of 3.36 [1.06] unique therapies. After adjustment for covariates, greater number of brain metastases at initial diagnosis (hazard ratio (HR) 2.3 [1.14-4.62], p=0.01 for 3-10 metastases and HR 2.54 [1.01-6.36], p=0.04 for >10 metastases, respectively), receipt of combination IO and targeted therapy prior to BRAF MBM diagnosis (HR 2.91 [1.08-7.86], p=0.03), and receipt of no unique subsequent therapy after initial management strategy (HR 3.89 [1.48-10.16], p=0.005) were significantly associated with worse OS. CONCLUSIONS Despite heterogeneity in individual treatment sequences, patients with greater intracranial disease burden and those receiving combination targeted and immunotherapy prior to BRAF MBM diagnoses had the worst outcomes. Dynamic changes in therapy resistance may inform optimal treatment strategies for individuals with BRAF MBM.

Systematic review of risk prediction tools for primary cutaneous melanoma outcomes and validation of sentinel lymph node positivity prediction in a UK tertiary cohort.

It is difficult for clinicians to make predictions for cancer progression or outcomes based on AJCC staging for individual patients. Models individualising risk prediction for clinical outcomes are developed using patient level data, advanced statistical techniques, and artificial intelligence. A systematic search identified cutaneous melanoma prognostic prediction tools published between January 1985-March 2023. Population comparisons of key clinico-pathological variables, external prediction of receiver operating characteristics and calibration analysis are applied to an unselected group of patients undergoing sentinel lymph node biopsy in a UK University hospital setting (n = 1564). Twenty-nine models were identified which predicted survival, disease recurrence or sentinel lymph node positivity (Internal validation n = 19 and external validation n = 14). 3 out of 7 tools for sentinel node positivity were contemporaneous with available characteristics for external validation. External validation of models by Lo et al. Friedman et al. & Bertolli et al. highlighted good discriminative performance (AUC 68.1% (64.5-71.8%), 77.1% (66.8-85.7%) & 68.6% (63.3-74.1%) respectively) but were sub-optimally calibrated for the UK patient cohort (Calibration intercept & slope Friedman: -4.01 & 32.92, Lo: -1.17 & 0.44, Bertolli: -2.75 & 4.88). This work highlights the complexity of predictive modelling and the rigorous validation process necessary to ensure accurate predictions. Our search highlights a tendency to focus on discriminative performance over calibration, and the possibility for inconsistent predictions when tools are applied to populations with differing characteristics.

Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas

BackgroundWhile the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA)...

DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance.

Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival. InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets. Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both P = .002), Breslow thickness (CIMP P = .002; IM P = .006), and mitotic index (both P < .001) compared with LM, while IM had higher N stage than CIMP (P = .01) and LM (P = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM. Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.

Society of Surgical Oncology Consensus Statement: Assessing the Evidence for and Utility of Gene Expression Profiling of Primary Cutaneous Melanoma.

Gene expression profiling (GEP) of primary cutaneous melanoma aims to offer prognostic and predictive information to guide clinical care. Despite limited evidence of clinical utility, these tests are increasingly incorporated into clinical care. A panel of melanoma experts from the Society of Surgical Oncology convened to develop recommendations regarding the use of GEP to guide management of patients with melanoma. The use of currently available GEP tests were evaluated in three clinical scenarios: (1) the utility in patient selection for sentinel lymph node biopsy; (2) the utility to guide surveillance; and (3) the utility to inform adjuvant therapy. As a basis for these recommendations, the panel performed a systematic review of the literature, including articles published from January 2012 until August 2023. After review of 137 articles,50met the inclusion criteria. These articles included evidence related to three available GEP tests: 31-GEP, CP-GEP, and 11-GEP. The consensus recommendations were finalized using a modified Delphi process. The panel found that current evidence often fails to account for known clinicopathologic risk factors and lacks high-level data. The panel recognizes that thestudy of GEP tests is still evolving. The integration of GEP into routine clinical practice for predicting sentinel lymph node status and patient prognosis in melanoma is therefore not currently recommended. At present, GEP should be considered primarily an investigational tool, ideally used in the context of clinical trials or specialized research settings.

The Expression of miR-211-5p in Sentinel Lymph Node Metastases of Malignant Melanoma Is a Potential Marker for Poor Prognosis

Metastatic primary cutaneous melanoma is a frequently fatal disease despite recent therapeutic advances. Biomarkers to stratify patients’ prognosis are lacking. MicroRNAs (miRNAs) are small, non-coding RNAs. We aimed to determine the expression of miR-211-5p in primary tumors and metastases of malignant melanoma and its potential use as a prognostic biomarker. We performed in situ hybridization for miRNA-211-5p on 109 FFPE melanoma samples from 76 patients, including 31 paired primary tumor/metastasis samples. For validation, we performed in silico analyses of TCGA skin cutaneous melanoma (SKCM) cohort. High miR-211-5p expression was more frequent in primary tumors (70.8%) compared to metastases (39.3%). In metastases, it was associated with a significantly worse overall survival. Data from TCGA SKCM cohort confirmed that high miR-211-5p expression in melanoma metastases, but not primary tumors, is associated with worse overall survival. MiR-211-5p expression in metastases is associated with a shorter survival, emphasizing the potential of miR-211-5p as a risk predictor for a less favorable clinical outcome in metastatic disease. In situ hybridization could be implemented in a routine laboratory workflow and can be performed on diagnostic tissue.

Evaluation of Multiple Tissue Levels Frequently Upstages Patients With Clinically Localized Thin Primary Cutaneous Melanoma.

Breslow thickness (BT), ulceration, and microsatellitosis are critical prognostic parameters for cutaneous melanoma staging. These parameters can vary depending on the number of tissue levels examined from individual paraffin blocks. We sought to evaluate all prognostic histopathologic parameters in melanoma for their variations between levels, taken at regular intervals, in a single study. We analyzed 40 consecutive cases of primary cutaneous (nonacral) melanoma through five hematoxylin and eosin sections, taken at 100 μm intervals, for staging and prognostic parameters. Examination of additional levels resulted in (a) an increase in BT in 47.5% (19 out of 40) of cases and (b) detection of ulceration in a further 5% (2/40). This resulted in upstaging for 20% (8 out of 40) of patients (15% because of BT, 2.5% because of ulceration, and 2.5% because of BT and ulceration). The upstaging effect was incremental, with approximately 5% of patients upstaged with each additional 100 μm interval (up to 400 μm). Incipient ulceration and epidermal consumption were infrequent (10% of cases); however, when present, ulceration was subsequently observed in half of cases. We encountered no cases where microsatellitosis was detected at deeper levels. The performance of additional tissue levels is a simple and inexpensive procedure that can improve the accuracy of staging for patients with thin (pT1) primary cutaneous melanomas. It may be pertinent for pathologists to consider additional levels for thin melanomas when a BT measurement is close to a staging threshold (e.g., within 0.1-0.3 mm for pT1a vs. pT1b, or pT1b vs. pT2a), or when incipient ulceration is encountered.

Variation in initial biopsy technique for primary melanoma diagnosis: A population-based cohort study in New South Wales, Australia

BackgroundFactors associated with non-adherence to guideline-recommended complete excision of suspicious cutaneous lesions are unclear. ObjectiveTo analyse patient, melanoma and clinician factors associated with initial diagnostic biopsy type; and determine whether unwarranted variation from guidelines occurred. MethodsThis population-based, cohort study involved analysis of data from questionnaires completed by clinicians who managed patients with newly-diagnosed, histopathologically-confirmed primary invasive cutaneous melanomas reported to the NSW Cancer Registry between 2006-2007. ResultsOf 2267 biopsies, complete excision was attempted in 69.1% of cases, but histologically incomplete in 14.0%. Multivariable regression analyses showed complete excision was more likely than: incision biopsy in patients <70years (p=0.016); shave biopsy in patients <80years (p=0.034); shave biopsy in melanomas of Breslow thickness 0.8-1.0mm or 2.1-4.0mm (p=0.039); than either punch (p<0.001) or shave biopsy (p<0.003) in melanomas on trunk or limbs; and punch biopsy when treated by a surgeon (p<0.001). Complete excision was less likely than: punch biopsies in females (p<0.003); with LMM or unknown histopathology (p=0.004); shave biopsy in patients with LMM, or other melanoma subtype (p=0.003); punch, shave or incision biopsy when treated by a dermatologist (p<0.001). LimitationsGeneralisability of these findings may be limited to the time of data collection. ConclusionGuideline adherence for biopsy type undertaken for clinically suspected melanoma appeared to be sub-optimal.

Lentigo Maligna and Lentigo Maligna Melanoma of the External Ear: Clinical and Dermoscopic Features of 19 Patients.

External ear lentigo maligna/lentigo melanoma (LM/LMM) represents approximately 1%-4% of all primary cutaneous melanomas. Over the past 20 years, dermoscopy has proven highly effective in early detection of LM/LMM, with recent studies identifying perifollicular linear projections (PLP) as a specific diagnostic criterion for early LM. However, in clinical practice, LM and LMM turn out to be very difficult to distinguish based on dermoscopic findings. Therefore, our retrospective monocentric study aimed to investigate dermoscopic characteristics, as well as the epidemiological and clinical data of 19 patients diagnosed with the external ear (EE) LM/LMM at the Oncologic Dermatology Unit in Bologna. Dermoscopic images were obtained using the FotoFinder Medicam 800HD, and specific criteria validated by the International Dermoscopy Society (IDS) for atypical pigmented facial lesions were assessed. Fisher's exact test was primarily used for statistical comparisons. As results, most of the patients were male (74%) with an average age (± SD) at diagnosis of 69.8 (± 15.1) years old. LMM appeared more commonly observed in elderly patients as compared to LM (mean 71.6 vs. 66.7, p = 0.514), presenting as pigmented macule (89.5%) of the ear lobule (23.9%). A statistically significant difference (p = 0.01) of tumour' diameter between LMM and LM was reported with the first resulting more than twice the size of the latter. Concerning dermoscopic findings, asymmetric pigmented follicles, obliteration of the follicular openings and grey circles were more frequently observed in LMM compared to LM (63.2% vs. 31.6%; 63.2% vs. 26.3%; 47.4% vs. 15.8%, respectively).

Exploring Patients' Perceptions of One-step Surgery for Primary Cutaneous Melanoma: A Qualitative Study.

High-frequency ultrasonography (> 20 MHz) has allowed for preoperative measurement of melanoma thickness and thus a one-step surgery strategy. The potential benefits of one-step surgery to patients remain unexplored. From June 2022 to August 2023, 2 dermatologists conducted semi-structured individual interviews with patients who had undergone HFUS examination allowing the choice for one-step surgery (group A) and with patients who had had standard two-step surgery (group B). Analysis of interviews with 21 patients (age range 31-81 years) revealed 5 main themes: (a) understanding the diagnosis, highlighting the significance of clear and comprehensive medical explanations; (b) personal factors considered in treatment decisions, including preferences for minimizing surgical procedures; (c) making choices, bearing responsibility, thus showcasing different levels of patient involvement in decision-making; (d) high- frequency ultrasonography reassurance emphasizing the role of medical reassurance, and (e) patient satisfaction, discussing surgical outcomes and the decision-making process. The majority of participants expressed a clear preference for one-step surgery, perceived as a pragmatic and fast surgical strategy while minimizing interventions. In conclusion, the results emphasize the importance of patient-centred care. These insights can guide improved preoperative consultations and enhance shared decision-making between healthcare professionals and patients regarding melanoma treatment strategies.

Multiple primary cutaneous melanoma in the amazon region of Peru

Reportamos el caso de un hombre de 82 años residente de Iquitos, región amazónica del Perú, con una historia de tres meses de lesiones cutáneas dolorosas de leves a moderadas en la extremidad inferior derecha. El examen clínico reveló cuatro tumores en la tibia derecha, que exhibían crecimiento exofítico, apariencia verrugosa y ulceración. Se observaron dos nódulos subcutáneos. Se observó linfadenopatía inguinal agrandada. El examen histopatológico reveló un diagnóstico de melanoma. Este caso enfatiza la necesidad de una vigilancia integral y multidisciplinaria en regiones con datos limitados sobre melanoma que conducen a un subdiagnóstico de esta malignidad. Además, destaca la importancia de la prevención primaria como la protección solar en zonas tropicales para prevenir el melanoma cutáneo, abogando por aumentar la concienciación y las medidas preventivas.

Long-Term survival across breslow thickness categories: Findings from a Population-Based study of 210,042 Australian melanoma patients.

The prognosis of a patient with a primary cutaneous melanoma is known to be related to the Breslow thickness of their tumor. This study sought to determine long-term (30-year) survival rates for the four AJCC 8th Edition T-categories by analyzing Australian registry data for 210,042 melanoma patients diagnosed from 1982-2014. The 30-year incidence rates of death due to melanoma and non-melanoma causes (with 95% confidence intervals) were 7.1% (CI 6.9-7.3%) and 32.8% (CI 32.3-33.3%), respectively. For T2 melanomas, the corresponding rates were 21.6% (CI 21.0-22.3%) and 35.6% (CI 34.7-36.6%), for T3 melanomas 34.2% (CI 33.4-35.1%) and 39.6% (CI 38.5-40.8%), and for T4 melanomas 44.3% (CI 43.2-45.3%) and 39.6% (CI 38.3-41.0%). A plateau in melanoma-related deaths occurred in T4 patients after 20 years but there were ongoing melanoma-related deaths for the other T-categories beyond 30 years. A progressive rise in the risk of death from other causes occurred across all T-categories.

Melanoma Incidence and Mortality Trends in Sweden.

Over the past decades, many global regions have experienced a steady increase in the incidence of cutaneous melanoma. However, more recently, a downward trend has been observed in the younger age groups in Australia and the US. Yet, in Europe, none of the countries have reported any significant decline in melanoma incidence for any age group. To assess melanoma incidence and mortality trends in Sweden, with a focus on individuals younger than the average age of melanoma onset. This cohort study used data on the national population from the Swedish Melanoma Registry and the Swedish Cancer Registry, which cover more than 99% of all primary invasive cutaneous melanomas diagnosed in the country. All patients diagnosed from 1990 to 2022 were included. Incidence and mortality rates per 100 000 inhabitants were calculated for each year and shown as average annual rates for every 5-year period from 1990 to 2022. Joinpoint regression models were used to evaluate statistical significance of temporal trends and points of change. There were 34 800 primary invasive cutaneous melanomas (19 582 [56.3%] in females and 15 218 [43.7%] in males) reported in 33 324 individuals younger than 60 years (median [IQR] age, 48 [36-58] years) from 1990 to 2022. A consistent rise in melanoma incidence was observed among those 50 to 59 years old. The age groups from 20 to 29 years, 30 to 39 years, and 40 to 49 years showed an incidence peak in 2013 to 2015 followed by stable or significantly declining rates until 2022. In patients younger than 20 years, melanoma incidence remained low with no significant trends. There was also a significant decline in melanoma mortality among 30- to 59-year-old individuals, but not in those 60 years and older. The findings of this cohort study showed a significant recent downward trend in both melanoma incidence and melanoma mortality in the age group 30 to 49 years in Sweden. The reasons for these declines are unclear but may include UV protection, public health campaigns, changing population demographics, and the introduction of effective melanoma treatment. None of these possibilities were evaluated; further study is needed.

Primary Dermal Melanoma

Primary dermal melanoma (PDM) is a rare subtype of melanoma with an estimated incidence of less than 1%. PDM presents entirely in the dermis or subcutis and histopathologically mimics cutaneous metastases of melanoma due to its lack of connection to the overlying epidermis. A thorough history and examination, including imaging evaluation for metastatic disease, will reveal no prior history or concurrent lesion of primary cutaneous or metastatic melanoma. Despite its histopathologic similarities to melanoma metastasis, PDM is associated with an unexpectedly favorable prognosis. This review discusses the clinical and histopathologic features of PDM as a distinct subtype of melanoma, as well as the current approach to clinical staging and management.

Congenital melanocytic nevi and risk of melanoma

The presence of congenital melanocytic nevi (CMN) is determined in utero. The location, size, and number of CMN may be of cosmetic concern with significant psychosocial implications. They may also be associated with symptoms such as pruritus, eczema/xerosis, and skin fragilit; however, the most medically concerning issue is the association of CMN with the risk of developing cutaneous melanoma, extracutaneous melanoma, and neurocutaneous melanocytosis (NCM). Patients with CMN are currently risk-stratified based on the projected adult maximum diameter of the largest CMN and the number of CMN (satellites) present. In small and medium CMN the absolute risk of developing cutaneous melanoma is estimated to be approximately 0.3% with a relative risk of 9.5. While patients with large CMN are at increased risk for developing primary cutaneous melanoma within the CMN, they are also at increased risk for developing primary melanoma within the central nervous system (CNS) in association with CNS melanocytic deposits, an entity known as NCM. The absolute risk for developing melanoma in patients with large CMN is estimated to be between 1.25-10% with a relative risk between 52-1046. Regarding the risk for the presence of NCM, the risk correlates with the number of CMN, with the lowest risk in those with a single CMN and with risk escalation as the number of CMN increase. We have provided an overview of the existing evidence about the risk of melanoma and NCM in patients with CMN. The role of the clinical examination, dermatoscopy, MRI scanning of the CNS, and the role of surgery in the management of CMN of varying sizes is discussed.

53106 Primary cutaneous melanoma patients stratified by the Merlin assay (CP-GEP): risk of nodal metastasis and long-term survival outcome in a U.S. cohort

53106 Primary cutaneous melanoma patients stratified by the Merlin assay (CP-GEP): risk of nodal metastasis and long-term survival outcome in a U.S. cohort

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.

G protein-coupled estrogen receptor 1 and collagen XVII endodomain expression in human cutaneous melanomas: can they serve as prognostic factors?

Melanoma incidence is increasing globally. Although novel therapies have improved the survival of primary melanoma patients over the past decade, the overall survival rate for metastatic melanoma remains low. In addition to traditional prognostic factors such as Breslow thickness, ulceration, and mitotic rate, novel genetic and molecular markers have been investigated. In our study, we analyzed the expression of G-protein coupled estrogen receptor 1 (GPER1) and the endodomain of collagen XVII (COL17) in relation to clinicopathological factors in primary cutaneous melanomas with known lymph node status in both sexes, using immunohistochemistry. We found, that GPER1 expression correlated with favorable clinicopathological factors, including lower Breslow thickness, lower mitotic rate and absence of ulceration. In contrast, COL17 expression was associated with poor prognostic features, such as higher tumor thickness, higher mitotic rate, presence of ulceration and presence of regression. Melanomas positive for both GPER1 and COL17 had significantly lower mean Breslow thickness and mitotic rate compared to cases positive for COL17 only. Our data indicate that GPER1 and COL17 proteins may be of potential prognostic value in primary cutaneous melanomas.

Uncovering molecular mechanisms for amelanotic/hypopigmented primary cutaneous melanoma.

A portion of approximately 2-20% of cutaneous melanoma (CM) are diagnosed as amelanotic/hypopigmented melanoma (AHM) and represent a challenge for early diagnosis. Since the degree to which somatic mutations and copy number aberrations (CNA) in genes associated with skin-lightening or albinism may contribute to the loss of tumour pigmentation in AHM samples has not yet been addressed, we have investigated loss of function mutations of key pigmentation genes in matched germline and AHM as well as pigmented melanoma (PM) tumour DNA samples. An analysis of clinical and histopathological characteristics together with whole exome sequencing data of 34 fresh frozen primary CM, graded according to the amount of pigmentation present was performed. Together with germline and somatic variant analysis, 30 samples were previously analysed for CNA changes. This study focussed on germline and somatic variants in the coding region of 16 genes known to be associated with albinism/hypopigmentation or variation in human pigmentation in all samples. Chromosomal regions encompassing these 16 genes were examined for DNA copy loss or gain. The finding that red hair related MC1R and TYR R402Q loss of activity gene variant alleles and genotypes are associated with AHM was validated in this study. Germline AHM-related gene variants were enriched in 70% (n=7 of 10) of AHM patients vs 8.3% (n=2 of 24) of PM patients. This surprisingly high frequency of rare germline variants in AHM patients constitutes the "first hit" and confirms that AHM patients are more likely to be albinism allele carriers than patients with PM. Next, in CNA analysis of each tumour sample, 50% (n=4 of 8) AHM samples with a pigmentation gene variant had LOH in the region containing the corresponding gene, and 25% (=2 of 8) had loss-of-heterozygosity (LOH) in chromosomal regions of two AHM-related genes. This study proposes that the likely molecular mechanism for development of amelanogenesis in AHM is carriage of an albinism/hypopigmentation allele followed by LOH of the corresponding gene in the tumour.

Proof of concept that melanoma nuclear count compares favourably with the benchmark histological prognostic feature, Breslow thickness.

Breslow thickness (BT) is the most important histological prognostic feature for melanoma prognosis, but it only captures tumour size in one dimension. Adding a further measurement in a different axis has been shown to improve prognostic value. It seems reasonable that further prognostic value could be obtained by estimating the number of invasive melanoma cells using nuclear count. The aim of this study was to show proof of concept that nuclear count has prognostic value independent of BT. Melanoma cell nuclei were labelled with SRY-related HMG-box 10 (SOX10) protein, the sections scanned and StarDist machine-learning algorithm used to count nuclei in 102 cases of primary cutaneous melanoma. Prognostic value was assessed using survival analyses. Nuclear count correlated strongly with T category, BT and calculated tumour area (each P < 0.001), suggesting that it was a valid marker of melanoma burden. Nuclear count was a predictor for overall survival in univariable analysis [hazard ratio (HR) = 2.25, confidence interval (CI) = 1.66-3.06, P < 0.001] and multivariable analysis (HR = 2.60, CI = 1.59-4.24, P < 0.001). BT and ulceration were significant in univariable analyses, but not in multivariable models with nuclear count. Models containing nuclear count showed the best fit. Similar results were seen for melanoma-specific and metastasis-free survival. Nuclear count was able to stratify melanomas within a given T stage. This study demonstrated proof of concept that counting melanoma nuclei may be an improved measure of invasive tumour burden compared to BT. Future studies will need to refine methods of nuclear detection and also to confirm its prognostic value.