Cases Of Cutaneous Melanoma Research Articles

Trends in incidence, mortality, and survival of cutaneous malignant melanoma over three decades: a population-based study in Southern Spain.

Cutaneous malignant melanoma (CMM) represents a global public health problem. Epidemiological studies about CMM trends tend to focus on single indicators or lack information about tumor characteristics that can help gain a more thorough understanding of CMM epidemiology. To fill this gap, we studied CMM trends in incidence, mortality, and survival over three decades and considering sex, age, and tumor characteristics. Data were obtained for all new cases of CMM diagnosed 1985-2017 from the population-based cancer registry in Granada (Southern Spain) and for deaths due to CMM by the Ministry of Health of the Spanish government. Incidence, mortality, and survival estimates were obtained according to sex, age group, anatomical site, histological type, Breslow index, and Clark level. Observed and net survival were calculated for 1, 3, and 5 years using the Kaplan-Meier and Pohar-Perme methods, respectively. Log-linear jointpoint regression was used to assess temporal trends in age-standardized rates of incidence and mortality. Between 1985-2017, 2,446 patients aged 15 years and older were newly diagnosed with CMM. There was a significant increase in incidence, both in men and women (APC 4.4% and 3.7% respectively), mainly in superficial spreading and nodular melanomas, and more pronounced among those with <1mm Breslow index. Mortality rates increased, mainly driven by increases among men and individuals ≥65 years old. Nodular melanoma had the worst prognosis, with a 5-year observed survival of 67.1% compared to survival greater than 90% for the other subtypes. 5-year net survival improved from 78.3% in 1985-1997 to 88.6% in 2008-2017, with a clear trend by Breslow index. The incidence of melanoma in early stages in Southern Spain has increased over the past decades. This has been accompanied by noticeable improvements in mortality and survival, especially among younger age groups, suggesting the potential effectiveness of prevention strategies, and new treatment regimens.

Abstract A042: Desmosome mutations in the microenvironment regulate melanoma proliferation

Abstract Desmosomes are transmembrane protein complexes critical for cell-cell adhesion in epithelial tissues and other cell types. In skin cancers like melanoma, epithelial cells called keratinocytes are the predominant cells in the primary melanoma microenvironment, yet it remains largely unknown whether this cell type is subject to genetic alterations during melanoma development and its role in early melanoma progression. In this study, using an integrative analysis of tumor mutations and protein biophysical interactions, we identify a high frequency of genetic alterations in desmosome-related genes in human cancers, with the highest occurrences in cutaneous melanoma. Notably, over 70% of cutaneous melanoma cases exhibit mutations in desmosome genes and desmosome gene mutations are associated with lowered expression of the desmosome complex in melanoma. Using spatial transcriptomics and immunohistochemistry analyses, we find that the decrease in desmosome gene expression predominantly occurs in keratinocytes within the tumor microenvironment rather than in the melanoma cells themselves. To study the functional significance of this alteration in melanoma development, we used a human melanoma/keratinocyte co-culture system using primary melanoma cell lines. Our studies show that knockdown of desmosome genes in keratinocytes markedly increased proliferation of adjacent melanoma cells in melanoma/keratinocyte co-cultures. Additionally, melanoma cell proliferation is enhanced when exposed to media preconditioned by desmosome-deficient keratinocytes. These observations suggest that the gradual accumulation of mutations in desmosome genes within neighboring keratinocytes may create a conducive environment that primes melanoma cells for neoplastic transformation. This study underscores the critical role of genetic alterations in the tumor microenvironment in melanoma progression and highlights the potential for targeting desmosome-related pathways in therapeutic strategies against melanoma. Citation Format: Mohita Tagore. Desmosome mutations in the microenvironment regulate melanoma proliferation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A042.

Genetic Characteristics of Cutaneous, Acral, and Mucosal Melanoma in Japan.

Acral and mucosal melanomas are more prevalent in Asians than in Caucasians, unlike cutaneous melanomas, which are predominant in Caucasians. Recent studies have suggested that non-Caucasian cutaneous melanomas responded less to immune checkpoint inhibitors, highlighting the need for genetic profiling across ethnicities. This study aimed to elucidate the genetic characteristics of Japanese melanomas, which is an under-researched topic. Single-nucleotide variants, indels, and copy number alterations in 104 Japanese melanoma patients (37 cutaneous, 52 acral, and 15 mucosal) were analyzed using custom panel sequencing. Driver events were detected in 94% of the cases. Among cutaneous melanoma cases, 76% had BRAF mutations, and 8% had NRAS mutations. In acral melanoma, BRAF (9%), NRAS (17%), KRAS (8%), KIT (19%), and NF1 (7%) mutations were detected. Major driver mutations in mucosal melanoma were detected in NRAS, KRAS, NF1, PTEN, GNAQ, and KIT. The median tumor mutational burden across all melanoma types was 4.6 mutations/Mb, with no significant difference between the cutaneous and acral/mucosal types. Of the 21 patients with both primary and metastatic lesions, 11 showed distinct mutations in each. Potentially actionable mutations were detected in 58 patients in addition to BRAF V600E/K mutations in 31. This study highlights distinct genetic abnormalities and actionable alterations in Japanese melanoma patients. This suggests a lower tumor mutational burden in East Asian cutaneous melanoma, which may affect the efficacy of immune checkpoint inhibitors. The heterogeneity of driver mutations across and within individuals highlights the need for personalized treatment approaches.

The Utility of PRAME and Ki-67 as Prognostic Markers for Cutaneous Melanoma.

Cutaneous melanoma can lead to metastasis, and it is associated with high mortality. Currently, there are no widely accepted immunohistochemistry markers for melanoma prognosis in routine staging. Preferentially expressed antigen in melanoma (PRAME) is a possible biomarker for prognosis in several noncutaneous neoplasms. Ki-67 is a cell proliferation marker correlated with poor outcomes in many cancers. This study assessed PRAME and Ki-67 as potential prognostic markers for sentinel lymph node outcomes and survival among melanoma patients. This is a retrospective study analyzing cutaneous melanoma cases from a Brazilian cancer center (2005-2021). All cases were tested using immunohistochemistry to evaluate PRAME expression and Ki-67 index. Descriptive analysis, Spearman correlations, means comparison, Kaplan-Meier analysis, χ2, and Cox models were performed. In univariate analysis of 123 cutaneous melanoma cases, high extent (P = 0.0267) and elevated intensity (P = 0.043) of PRAME were associated with decreased overall survival. The Ki-67 index was associated with overall survival (P = 0.05) and sentinel lymph node status (P = 0.0403), with a positive correlation between the markers (P = 0.0004) and between Ki-67 and Breslow thickness (P = 0.0001). However, in multivariate analysis, only Breslow thickness significantly influenced overall survival (P = 0.0003). Then, the present results can suggest that elevated PRAME and Ki-67 expression are associated with poor overall survival in cutaneous melanoma; however, in multivariate analysis, only the Breslow thickness had a significant influence. These findings highlight the potential of PRAME and Ki-67 as prognostic markers, opening frontiers that could improve strategies for treating cutaneous melanoma.

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.

The Prognostic Significance of Tumoral Melanosis.

Tumoral melanosis (TM) is a histological term to describe a nodular aggregation of macrophages containing melanin pigment (melanophages) that is devoid of viable melanocytes. It is most often identified in skin, where it may be appreciated clinically as a pigmented lesion; however, it can also be found in other organs such as lymph nodes. The presence of TM is usually thought to signify the presence of a regressed melanoma or other pigmented tumor. Until recently, it was a relatively uncommon finding; however, with the use of effective systemic therapies against melanoma, its occurrence in histological specimens is more frequent. We identified and reviewed all histopathological diagnoses of TM at any organ site reported at a single institution from 2006 to 2018. TM cases were paired with non-TM cases of cutaneous melanoma through propensity score matching at a 1:2 ratio, and their survival outcomes were compared. The clinical outcomes examined included recurrence-free survival (RFS), distant disease-free survival (DDFS), melanoma-specific survival (MSS), and overall survival (OS). TM was reported in 79 patients. Their median age was 65 years (range 22-88), with a 2:1 male predominance (51 out of 79, 65%). The most common organ involved was the skin (67%), with a third of all cases localized to a lower limb (36%). TM had a strong association with the presence of melanoma (91%) and regression at other sites of melanoma (54%), suggesting that it is part of a systemic immune response against melanoma. Most patients with TM either previously or subsequently developed histologically confirmed melanoma in the same anatomical region as the TM (89%). Thirty-five TM patients were matched with 70 non-TM cases. Patients with melanoma who developed TM without prior regional or systemic therapy showed improved MSS (p = 0.03), whereas no statistically significant differences were observed in terms of RFS, DDFS, and OS. TM usually occurs in the context of a previous or subsequent cutaneous melanoma and is associated with improved MSS. It is important that TM is recognized by pathologists and documented in pathology reports.

54814 Mitotic Rate is More Important than Breslow Thickness for Predicting Sentinel Lymph Node Biopsy Positivity and Melanoma-Associated Survival for T1 Cutaneous Malignant Melanoma Cases

54814 Mitotic Rate is More Important than Breslow Thickness for Predicting Sentinel Lymph Node Biopsy Positivity and Melanoma-Associated Survival for T1 Cutaneous Malignant Melanoma Cases

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.

Melanoma Deaths by Thickness: Most Melanoma Deaths Are Not Attributable to Thin Melanomas

IntroductionPrevious population-based studies have reported that the majority of melanoma mortality is related to patients with thin (≤1 mm Breslow thickness) melanomas. The aim of the present study was to evaluate the relative proportion of melanoma-specific deaths across all stages of melanoma at diagnosis over the past 20 y in the United States. MethodsA review of all cutaneous melanoma cases in the US Surveillance, Epidemiology, and End Results registry from 2004 to 2020 was performed. Breslow thickness was categorized as thin (≤1.0 mm), intermediate (>1-4 mm), or thick (>4 mm). All-cause deaths and melanoma-specific deaths were compared across tumor thickness and stage groups at diagnosis. Survival analysis was performed with nonmelanoma deaths considered as a competing risk to estimate the cumulative incidence of melanoma-specific death. ResultsMost melanoma deaths occurred in patients who initially presented with local disease (53%) compared to regional (36%) or distant (11%) disease (P < 0.001). However, most (66%) of the melanoma-specific deaths in patients who presented with localized disease were in those with intermediate or thick (i.e., Breslow thickness >1.0 mm) primary tumors compared to those with thin melanomas (34%). The cumulative incidence of melanoma-specific death at 10 y in patients with localized thin melanomas at the time of diagnosis was 2.6% (95% confidence intervals 2.5%-2.7%). ConclusionsThe public health burden in terms of melanoma-specific mortality is related to patients with tumors >1 mm Breslow thickness, many of whom have regional and distant metastatic disease at the time of diagnosis, not patients with thin melanomas.

Efficacy and safety of combined anti-angiogenic chemoradiotherapy with PD-1 monoclonal antibody in advanced melanoma: A retrospective study.

e21516 Background: Malignant melanoma, characterized by its aggressiveness and early metastasis, poses significant challenges in terms of treatment efficacy. This retrospective study aimed to assess the efficacy and safety of the integrated treatment regimen in patients (pts) with advanced melanoma. Methods: 42 pts with histologically confirmed inoperable stage III or IV melanoma and ECOG PS 0 or 1 were included in this retrospective study conducted from September 2020 to August 2023. Pts received combination therapy with albumin-bound paclitaxel, bevacizumab (bev), and toripalimab (tor) (Q3W). Maintenance therapy with bev and tor was given after 6-8 cycles without disease progression or intolerable adverse reactions. Personalized radiotherapy was delivered. Radiological evaluations were performed every 2 cycles during combination therapy and every 3 cycles during maintenance therapy using RECIST 1.1 criteria. Adverse events were graded according to NCI-CTCAE version 4.03. Results: All pts underwent at least one efficacy evaluation. The male-to-female ratio was 1:1, with a median age of 61.5 years (range: 34-80 years). Treatment-naïve pts accounted for 47.6% (n = 20), second-line pts for 35.7% (n = 15), third-line pts for 11.9% (n = 5), and fourth-line pts for 4.8% (n = 2). There were 25 cases (59.5%) of acral melanoma, 4 cases (9.5%) of cutaneous melanoma, 12 cases (28.6%) of mucosal melanoma, and 1 case (2.4%) with an unknown primary site. During the treatment period, 66.7% (n = 28) of pts received radiotherapy. As of December 2023, 26 out of 43 pts showed tumor shrinkage, including 2.4% (n = 1) achieving CR through conversion surgery following PR, maintaining it for 30 months. The ORR was 61.9%, with a confirmed ORR of 57.1%, and a DCR) of 92.9%. The median PFS was 14.4 months, and the median OS has not yet been attained. Common adverse events included alopecia (100%), hypertriglyceridemia (61.9%), elevated transaminases (59.5%), anemia (59.5%), leukopenia (52.4%), hypercholesterolemia (52.4%), peripheral neuropathy (50%). No treatment-related deaths were reported. Conclusions: This study demonstrates that PD-1 monoclonal antibody in combination with chemotherapy, anti-angiogenic therapy and radiotherapy offers a promising therapeutic option for advanced melanoma. Keywords:Malignant melanoma; Albumin-bound paclitaxel; Bevacizumab; PD-1 monoclonal antibody; Radiotherapy.

Disparities by sex in Hispanic patients with cutaneous melanoma: A national database analysis.

e23045 Background: Melanoma is the fifth most common form of malignancy in the United States.1 Studies have established that Hispanic patients have worse melanoma-specific survival compared to non-Hispanic White individuals.2 However, there is a paucity of literature investigating sex differences in patient characteristics and outcomes within Hispanic melanoma patients. Thus, the aim of this study is to further examine sex differences in melanoma characteristics and disease-specific survival within Hispanic patients. Methods: Individuals of Hispanic descent diagnosed with microscopically confirmed cases of cutaneous melanoma (ICD-O-3 codes 8720/3-8780/3; Primary Site codes C44.0-C44.9) between 2000 and 2020 were identified through the Surveillance, Epidemiology, and End Results (SEER) database. Statistical analyses involved Chi-squared tests, Kaplan-Meier and log-rank methods, and multivariate Cox regression, with significance set at a p-value &lt; 0.05. Results: In a cohort of 12,328 Hispanic melanoma patients (43.3% male, 56.7% female), a significant association between sex and age was found (p &lt; 0.001). The greatest proportion of males were in the 60-79 age group (39.7%), while females were predominantly in the 40-59 age group (39.0%). Greater number of males had truncal melanomas (31.4%) compared to females having lower extremity melanomas (35.2%) (p &lt; 0.001). Females exhibited higher rates of localized disease (80.3% vs 70.2%) while males were more frequently diagnosed with regional (18.5% vs 13.8%) and distant disease (11.3% vs 5.9%) (p &lt; 0.001). Males demonstrated greater mean Breslow thickness (1.80 vs 1.44; p &lt; 0.001), elevated rates of lymph node positivity (37.2% vs 27.2%; p &lt; 0.001), and metastatic disease (2.8% vs 1.6%; p &lt; 0.001). On univariate Kaplan-Meier analysis, males demonstrated significantly reduced disease-specific survival (182.9 months) compared to females (214.2 months) (p &lt; 0.001). After adjusting for age, disease stage, annual income, rural vs urban residence, and primary tumor site, male sex independently increased disease-specific mortality compared to females (HR = 1.31; 95% CI 1.16-1.48; p &lt; 0.001). Conclusions: Our investigation reveals that Hispanic males tend to receive melanoma diagnoses at older ages, advanced-stage disease, and primarily on the trunk.3 Furthermore, our study is the first to highlight a significantly reduced disease-specific survival in males compared to females. The observed sex differences may arise from a complex interplay of behavioral factors and immunological, hormonal, or genetic influences.4 Men exhibit a lower likelihood of engaging in skin self-examinations and seeking medical assistance. Limitations to this study include use of data reported through a national database. Nonetheless, this study underscores the significance of sex-specific variations in presentation and disease-specific survival among Hispanic patients.

NRAS mutation in melanoma: Association of codon-specific changes on patient outcomes.

e21545 Background: NRAS mutant melanoma is an aggressive subtype making up 20-30% of cutaneous melanoma cases without specific treatment options beyond immune checkpoint inhibition (ICI). Previous studies have suggested specific NRAS codon mutations are associated with unique signaling pathways. To test the hypothesis that NRAS codon mutations in cutaneous melanoma may drive a preferential response to ICI, we evaluated specific genetic subsets of NRAS mutant melanoma based on the Q61 and G12/G13 codons. Methods: Cutaneous melanoma samples (n = 4091) were analyzed by NGS at Caris Life Sciences. Samples were stratified by NRAS status and subdivided into NRASQ61, NRASG12/13, and NRAS-wildtype. PD-L1 expression was assessed using IHC (positive ≥ 1%). TMB-high was defined as ≥ 10 mutations/Mb. Transcriptomic signatures of MAPK pathway activation and T-cell signatures were calculated. Real-world overall survival (rwOS) information was obtained from insurance claims data, with Kaplan-Meier estimates calculated from time on ICI until last date of contact. Mann-Whitney U, Chi-square, and Fisher exact tests were applied as appropriate, with p-values adjusted for multiple comparisons. Results: Cutaneous melanoma samples were comprised of 22% NRASQ61 (n = 902), 3.1% NRASG12/13 (n = 125) and 74.8% NRASWT (n = 3064), with the most common NRAS mutation being Q61R. Patients harboring NRASG12/13 codon changes were associated with concurrent mutations in BRAF (21.0 vs 6.4%, p&lt; 0.0001), NF1 (50.5% vs 8.7%, p&lt; 0.0001), KIT (3.2% vs 0.2%, p&lt; 0.001), ARID2 (22.1% vs 11.3%, p&lt; 0.01), MAP2K1 (7.2% vs 2.6%, p = 0.022) compared to NRASQ61. NRASG12/13 tumors were more frequently TMB-high compared to NRASQ61 or NRASWT (83.1% vs 62.1% vs 55.1%, p = 0.0001), but no difference was observed in the prevalence of dMMR/MSI-H or PD-L1 expression. Transcriptomic analysis showed that NRASQ61 mutants had a significantly higher MPAS compared to NRASG12/13 or NRASWT cohorts (Median: 1.16 vs 0.67 vs 0.46, p = 0.0147), while T-cell-inflamed scores were significantly higher in NRASWT compared to NRASQ61 (Median: 4 vs -40, p = 0.00492) but not to NRASG12/13 (Median: 4 vs -13.5, p = 0.674). No difference in rwOS was identified in NRASG12/13 and NRASQ61 melanoma treated with ICI (HR: 0.753, [95% CI: 0.43 – 1.31], p = 0.316). Conclusions: Patients with NRAS-mutated cutaneous melanoma exhibit codon-specific ( NRASQ61 vs NRASG12/13) signaling and prevalence of immunotherapy-related biomarkers. Our findings indicate that melanoma samples with NRASG12/13 mutation tend to exhibit immune richness suggesting they could be viewed as a distinct group that might potentially benefit from immune therapies. This observation offers valuable insight into codon-specific tumor subsets, differential response to therapy, resistance mechanisms, and the potential development of combination therapies to enhance survival outcomes of patients with NRAS mutant melanoma.

[Translated article] Melanoma Registry of the Spanish Academy of Dermatology and Venereology (REGESMEL): Description and Data in its First Year of Operation

IntroductionThe incidence of melanoma is rising in Spain. The prognostic stages of patients with melanoma are determined by various biological factors, such as tumor thickness, ulceration, or the presence of regional or distant metastases. The Spanish Academy of Dermatology and Venereology (AEDV) has encouraged the creation of a Spanish Melanoma Registry (REGESMEL) to evaluate other individual and health system-related factors that may impact the prognosis of patients with melanoma. The aim of this article is to introduce REGESMEL and provide basic descriptive data for its first year of operation. MethodsREGESMEL is a prospective, multicentre cohort of consecutive patients with invasive cutaneous melanoma that collects demographic and staging data as well as individual and healthcare-related baseline data. It also records the medical and surgical treatment received by patients. ResultsA total of 450 cases of invasive cutaneous melanoma from 19 participant centres were included, with a predominance of thin melanomas≤1mm thick (54.7%), mainly located on the posterior trunk (35.2%). Selective sentinel lymph node biopsy was performed in 40.7% of cases. Most cases of melanoma were suspected by the patient (30.4%), or his/her dermatologist (29.6%). Patients received care mainly in public health centers (85.2%), with tele-dermatology resources being used in 21.6% of the cases. ConclusionsThe distribution of the pathological and demographic variables of melanoma cases is consistent with data from former studies. REGESMEL has already recruited patients from 15 Spanish provinces and given its potential representativeness, it renders the Registry as an important tool to address a wide range of research questions.

The potential impact of dietary choices on melanoma risk: an anti-inflammatory diet

The role of inflammation in the aetiology of cancer is recognized. However, no study yet examined the association between an anti-inflammatory diet and cutaneous melanoma and explored whether it could be modified by genetic variations in cyclooxygenase-2 (COX-2), a key enzyme in inflammation. A case-control study was conducted in the IDI-IRCCS hospital in Rome, Italy with 273 cases of primary cutaneous melanoma and 269 controls frequency matched to cases. Information on socio-demographic and pigmentary characteristics, medical history, sun exposure and dietary habits were collected for all subjects. The − 765G > C polymorphism was identified in DNA extracted from blood samples. An anti-inflammatory diet score was created. Logistic regression models were fitted to obtain odds ratios (ORs) and 95% confidence intervals (CIs). A high anti-inflammatory diet score (≥ 8 anti-inflammatory dietary items) was associated with a decreased risk of cutaneous melanoma (OR: 0.29; 95%CI: 0.17–0.49, Ptrend < 0.0001) after adjusting for sex, age, education, number of common nevi, skin photo-type, solar lentigines and sunburns in childhood. COX-2 -765 G > C polymorphism was not an independent risk factor for cutaneous melanoma. Although interaction between − 765G > C genotypes and anti-inflammatory diet score was not statistically significant (p = 0.25), when stratified by -765 G > C genotypes the effect of the anti-inflammatory diet was slightly more pronounced for participants carrying – 765GG (OR: 0.17; 95%CI: 0.06–0.47, Ptrend < 0.001). Our study findings suggest that adherence to an anti-inflammatory diet is associated with a decreased risk of developing cutaneous melanoma. These results suggest the potential impact of dietary choices on melanoma risk.

Prospective associations of leucocyte subtypes and obesity with the risk of developing cutaneous malignant melanoma in the UK Biobank cohort

BackgroundObesity is associated with chronic low-grade inflammation, which is linked to cancer development. Abdominal obesity (a body mass index, ABSI), however, has unusually been associated inversely with cutaneous malignant melanoma (CMM), while general obesity (body mass index, BMI) is associated positively. Leucocytes participate in inflammation and are higher in obesity, but prospective associations of leucocytes with cutaneous malignant melanoma are unclear.MethodsWe examined the prospective associations of neutrophil, lymphocyte, and monocyte counts (each individually), as well as the prospective associations of ABSI and BMI, with cutaneous malignant melanoma in UK Biobank. We used multivariable Cox proportional hazards models and explored heterogeneity according to sex, menopausal status, age (≥ 50 years at recruitment), smoking status, ABSI (dichotomised at the median: ≥73.5 women; ≥79.8 men), BMI (normal weight, overweight, obese), and time to diagnosis.ResultsDuring a mean follow-up of 10.2 years, 2174 CMM cases were ascertained in 398,450 participants. There was little evidence for associations with neutrophil or lymphocyte counts. Monocyte count, however, was associated inversely in participants overall (HR = 0.928; 95%CI: 0.888–0.971; per one standard deviation increase; SD = 0.144*109/L women; SD = 0.169*109/L men), specifically in older participants (HR = 0.906; 95%CI: 0.862–0.951), and more clearly in participants with low ABSI (HR = 0.880; 95%CI: 0.824–0.939), or with BMI ≥ 25 kg/m2 (HR = 0.895; 95%CI: 0.837–0.958 for overweight; HR = 0.923; 95%CI: 0.848–1.005 for obese). ABSI was associated inversely in pre-menopausal women (HR = 0.810; 95%CI: 0.702–0.935; SD = 4.95) and men (HR = 0.925; 95%CI: 0.867–0.986; SD = 4.11). BMI was associated positively in men (HR = 1.148; 95%CI: 1.078–1.222; SD = 4.04 kg/m2). There was little evidence for heterogeneity according to smoking status. The associations with monocyte count and BMI were retained to at least 8 years prior to diagnosis, but the association with ABSI was observed up to 4 years prior to diagnosis and not for longer follow-up time.ConclusionsMonocyte count is associated prospectively inversely with the risk of developing CMM in older individuals, while BMI is associated positively in men, suggesting a mechanistic involvement of factors related to monocytes and subcutaneous adipose tissue in melanoma development. An inverse association with ABSI closer to diagnosis may reflect reverse causality or glucocorticoid resistance.

Pathogenic mechanisms and etiologic aspects of Mycobacterium avium subspecies paratuberculosis as an infectious cause of cutaneous melanoma.

Infectious etiologies have previously been proposed as causes of both melanoma and non-melanoma skin cancer. This exploratory overview explains and presents the evidence for the hypothesis that a microorganism excreted in infected ruminant animal feces, Mycobacterium avium subspecies paratuberculosis (MAP), is the cause of some cases of cutaneous melanoma (CM). Occupational, residential, and recreational contact with MAP-contaminated feces, soil, sand, and natural bodies of water may confer a higher rate of CM. Included in our hypothesis are possible reasons for the differing rates and locations of CM in persons with white versus nonwhite skin, why CM develops underneath nails and in vulvar skin, why canine melanoma is an excellent model for human melanoma, and why the Bacille Calmette-Guérin (BCG) vaccine has demonstrated efficacy in the prevention and treatment of CM. The pathogenic mechanisms and etiologic aspects of MAP, as a transmittable agent underlying CM risk, are carefully deliberated in this paper. Imbalances in gut and skin bacteria, genetic risk factors, and vaccine prevention/therapy are also discussed, while acknowledging that the evidence for a causal association between MAP exposure and CM remains circumstantial.

Could the mitotic count improve personalized prognosis in melanoma patients?

A number of studies have indicated that the mitotic rate may be a predictive factor for poor prognosis in melanoma patients. The aim of this study was to investigate whether the mitotic rate is associated with other prognostic clinical and anatomopathological characteristics. After adjusting for other anatomopathological characteristics, we then verified the prognostic value of the number of mitoses, determining in which population subgroup this variable may have greater prognostic significance on 3-year mortality. The Veneto Cancer Registry (Registro Tumori del Veneto-RTV), a high-resolution population-based dataset covering the regional population of approximately 4.9 million residents, served as the clinical data source for the analysis. Inclusion criteria included all incident cases of invasive cutaneous malignant melanoma recorded in the RTV in 2015 (1,050 cases) and 2017 (1,205 cases) for which the number of mitoses was available. Mitotic classes were represented by Kaplan-Meier curves for short-term overall survival. Cox regression calculated hazard ratios in multivariable models to evaluate the independent prognostic role of different mitotic rate cut-offs. The results indicate that the mitotic rate is associated with other survival prognostic factors: the variables comprising the TNM stage (e.g., tumor thickness, ulceration, lymph node status and presence of metastasis) and the characteristics that are not included in the TNM stage (e.g., age, site of tumor, type of morphology, growth pattern and TIL). Moreover, this study demonstrated that, even after adjusting for these prognostic factors, mitoses per mm2 are associated with higher mortality, particularly in T2 patients. In conclusion, these findings revealed the need to include the mitotic rate in the histological diagnosis because it correlates with the prognosis as an independent factor. The mitotic rate can be used to develop a personalized medicine approach in the treatment and follow-up monitoring of melanoma patients.

SOX-10 and TRP-1 expression in feline ocular and nonocular melanomas.

In felines, ocular and nonocular melanomas are uncommon tumors that represent a diagnostic challenge for pathologists, especially when amelanotic. To date, the immunohistochemical diagnostic panel in cats is based on specific melanocytic markers (Melan-A and PNL2) and a nonspecific but sensitive marker (S100). In human medicine, SOX-10 is reported to be a sensitive antibody for the detection of melanoma micrometastasis in the lymph node. TRP-1, an enzyme involved in melanogenesis, has recently been used in humans and dogs as a specific melanocyte marker. The aim of this study was to evaluate the cross-reactivity and the expression of SOX-10 and TRP-1 antibodies in feline normal tissue and melanocytic tumors. Thirty-one cases of ocular, cutaneous, and oral melanomas were retrospectively evaluated and confirmed by histopathological examination and by immunolabeling with Melan-A and/or PNL2. SOX-10 nuclear expression in normal tissues was localized in epidermal, subepidermal, hair bulb, and iridal stromal melanocytes and dermal nerves. In melanomas, nuclear expression of SOX-10 was detected in ocular (11/12; 92%), oral (6/7; 86%), and cutaneous sites (12/12; 100%). TRP-1 cytoplasmic immunolabeling in normal tissue was observed in epidermal and bulbar melanocytes and in the lining pigmented epithelium of the iris and in its stroma. Its expression was positively correlated to the degree of pigmentation in the tumor and was observed in 75% of ocular (9/12), 43% of oral (3/7), and 33% of cutaneous melanomas (4/12). This study demonstrated the cross-reactivity of SOX-10 and TRP-1 antibodies in feline non-neoplastic melanocytes and their expression in ocular and nonocular melanomas.

Abstract 806: Rural residence as a protective factor in melanoma mortality: Insights from a comprehensive analysis of 3,979 New Mexico cases (2010-2017)

Abstract Purpose: Cutaneous melanoma is a significant public health concern with increasing incidence rates over the past three decades. While survival rates have improved, disparities exist among racial/ethnic groups and socioeconomic factors. Our objective was to explore the connection between survival rates of cutaneous melanoma and demographic/socioeconomic factors in New Mexico's varied population, particularly in rural vs. urban settings. Methods: This retrospective study utilized data from the New Mexico Tumor Registry (NMTR) within the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. A total of 3,979 cases of cutaneous melanoma diagnosed between 2010 and 2017 among New Mexico residents were analyzed based on specific ICDO-3 criteria. The impact of demographic characteristics, socioeconomic factors, and stage at diagnosis on melanoma-specific mortality was investigated. Cases with incomplete data or where melanoma was not the primary cancer were excluded. Survival differences were assessed using Kaplan-Meier methods and the Cox Proportional Hazards Model, with analyses conducted with a significance threshold set at P=0.05. Only histologically confirmed melanoma cases were included in the study. Results: In our analysis of 3,979 melanoma cases spanning 2010 to 2017, non-Hispanic whites (NHW) displayed the highest incidence (n = 3,617, P &amp;lt; 0.001). Conversely, Hispanic Whites (HW) and American Indians (AI) exhibited a higher likelihood of later-stage diagnoses, with 19.2% of American Indians diagnosed at stage 3, in contrast to 3.9% of NHW and 10.3% of Hispanic Whites (P &amp;lt; 0.001). Rural areas showed a propensity for advanced-stage diagnoses (P &amp;lt; 0.001), and diagnosis stage exhibited an inverse relationship with per capita income (P &amp;lt; 0.001). Increased mortality was observed among males, individuals over 50, and American Indians (all P &amp;lt;0.05). Rural American Indian or Hispanic patients had a hazard ratio of mortality at 0.37 (95% CI, 0.15-0.89). An overall decline in melanoma mortality post-2012, with a notable reduction after mid-2015 (P &amp;lt; 0.001), despite a slight increase in diagnoses from 529 in 2010 to 569 in 2017 (P = 0.034) was observed. Sensitivity analyses revealed that rural residence among AI/Hispanic individuals was associated with a lower risk of melanoma-specific mortality (HR 0.37, p = 0.026 in the inclusive analysis; HR 0.36, p = 0.025 in the exclusion of in-situ cases). Conclusions: Our study indicates rural residency is associated with more advanced melanoma diagnoses and lower income correlates with later-stage diagnoses. However, rural living may offer a protective effect against mortality for American Indian/Hispanic populations. Overall mortality has declined since 2012, contrasting with a slight rise in diagnoses. Citation Format: Yeojin Park, Aaron Segura, Lynn Midani, Barbara Gutierrez, Larimar I. Rodriguez, Charles Wiggins, Vernon S. Pankratz, John R. Durkin. Rural residence as a protective factor in melanoma mortality: Insights from a comprehensive analysis of 3,979 New Mexico cases (2010-2017) [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 806.

Abstract 6979: Uncovering the BRAF interactome to identify novel therapeutic targets for BRAF driven melanoma and lung cancer

Abstract BRAF protein kinases act downstream of RAS-GTP and upstream of MEK&amp;gt;ERK MAP Kinase signaling. Notably, mutational activation of BRAF is a driver of approximately 8% of all cancers, with a particular prevalence in lung cancer, thyroid cancer, and melanoma. Importantly, melanoma is responsible for the largest number of skin cancer deaths per year. Patients whose melanoma is driven by mutationally-activated BRAF account for ~50% of cutaneous melanoma cases. The most common mutational alteration is BRAFT1799A, which encodes the BRAFV600E oncoprotein kinase. Combined inhibition of BRAFV600E plus MEK1/2 has been approved for the treatment of BRAFV600E-driven melanoma and lung cancer. Although patients with mutationally-activated BRAF often have a significant response to BRAFV600E-targeted therapeutics, many patients develop lethal drug-resistant disease. The BRAFV600E oncoprotein kinase is proposed to be a monomer, yet many questions remain regarding the biochemistry of these signaling interactions. Thus, we aim to better understand the molecular mechanisms driving BRAFV600E-mediated melanoma and lung cancer cell growth. Preliminary data using gel filtration chromatography and immunoblotting analysis indicates that BRAFV600E is detected in a large multiprotein complex. Interestingly, the addition of a BRAFV600E inhibitor, vemurafenib, shifted the elution of complexes with BRAFV600E into lower molecular weight fractions. Based on these preliminary results, we characterized the components of these complexes to advance our understanding of how mutationally activated BRAF exists in melanoma cells; and thus, provide future insight into how we can better therapeutically target BRAFV600E. Moreover, in order to further elucidate BRAF interactions, we employed a novel form of proximity labeling, TurboID, to unbiasedly identify novel BRAF interactors and better understand how drug treatments change the BRAF interactome. The top ten statistically significant interactors are being investigated to understand how BRAF complexes are formed within the cell, how the complexes are influenced by drug treatments, and how important the individual components are in the formation of complexes with BRAF. Here, we investigate an interaction between BRAFV600E and the tumor suppressor, TP53. Moreover, elucidating the molecular architecture of BRAFV600E signaling complexes could highlight new therapeutic options for patients who display either primary or acquired resistance to inhibitors of BRAFV600E signaling. Citation Format: Kayla T. OToole. Uncovering the BRAF interactome to identify novel therapeutic targets for BRAF driven melanoma and lung cancer [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 6979.