Variant Of Melanoma Research Articles

Desmoplastic Melanoma

Desmoplastic melanoma is a rare fibrosing variant of melanoma. It typically affects elderly patients but can occasionally affect young or middle-aged individuals. Desmoplastic melanoma is relevant as a diagnostic pitfall for pure tumor variants' distinct histopathologic and clinical features. The latter includes a lower regional lymph node involvement frequency and a more favorable prognosis among thick melanomas. Classic cases of desmoplastic melanoma tend to carry a high mutation burden. Patients with metastases from those tumors tend to respond favorably to novel immunotherapies.

Dermal melanoma with plasmacytoid differentiation in a dog.

A 10-y-old spayed female Staffordshire Terrier dog was evaluated because of a cutaneous left ear base mass. Cytology revealed sheets of cells with anisocytosis and anisokaryosis, round-to-oval or plasmacytoid cytoplasm, and round, central, or eccentric nuclei; binucleate cells were present. Cytologic findings were consistent with a round cell tumor (plasmacytoma or agranular mast cell tumor), amelanotic melanoma, or anaplastic carcinoma. Histologically, neoplastic cells were polygonal to elongate, with round-to-oval nuclei and prominent nucleoli and arranged in sheets and nests on a fibrovascular stroma. Neoplastic cells with plasmacytoid morphology (round, glassy, eosinophilic cytoplasm with eccentric nuclei) were present in ~30% of the neoplasm. There were 18 mitoses in 2.37 mm2 (10 FN22/40× fields). Neoplastic cells had cytoplasmic immunolabeling for melan A and PNL2 and no immunolabeling for AE3/1 and MUM1, consistent with a dermal melanoma with plasmacytoid differentiation. The patient was re-evaluated ~1 mo after the first biopsy because of local recurrence of the original mass and new masses on the interscapular area and right elbow; these neoplasms were histologically identical to the original submission, plus scattered neoplastic cells in the new masses contained brown cytoplasmic pigment. The dog was euthanized because of swelling and hemorrhage of the tumors and right pelvic limb lameness. Our findings were consistent with a dermal melanoma with plasmacytoid features that were similar to human plasmacytoid melanoma, a rare variant of human melanoma that is diagnostically challenging as it may mimic a plasmacytoma.

Clinical Characteristics and Special Considerations in the Management of Rare Melanoma Subtypes.

Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.

Giant conjunctival melanoma with rich vascularization causing persistent bleeding.

The present study reported a rare case of persistent bleeding caused by conjunctival melanoma containing abundant vascular channels. A 44-year-old Japanese woman presented with a left upper eyelid nodule in February 2023. A pigmented conjunctival mass was present in the upper palpebral conjunctiva. Enhanced computed tomography demonstrated marked enhancement in the left eyelid in the artery phase, indicating hemangioma. The patient suffered blunt trauma to the face in May 2023 and continuous bleeding occurred. Doctors in the emergency room attempted hemostasis by diathermy and suture, but the bleeding could not be stopped. The patient eventually underwent emergent orbital exenteration of the left eye. At high magnification of the histology sample of the bleeding site, small-to-large vascular channels with various vascular lumens made up of endothelial cells within the conjunctival melanoma tissue could be observed. The tumor cells were positive for SOX10, Melan A, S100 and HMB45. We herein propose a novel variant of conjunctival melanoma with rich vascularization, clinically causing persistent bleeding.

Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment.

Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis. Independent analysis of published genomic and transcriptomic sequencing identified that receptor tyrosine kinase (RTK) ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. To target these unique genetic changes, a zebrafish acral melanoma model was exposed to a panel of narrow and broad spectrum multi-RTK inhibitors, revealing that dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration. The potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM patient-derived xenograft (PDX) tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks. Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.

Somatic structural variants drive distinct modes of oncogenesis in melanoma.

The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histological and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the role of topologically associated domain (TAD) boundary altering SVs on cancer-related genes. Following our prior identification of double-stranded break repair deficiency in a subset of triple wild-type cutaneous melanoma, we identified MRE11 and NBN loss-of-function SVs in melanomas with this mutational signature. Experimental knockouts of MRE11 and NBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARPi in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact.

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

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

Multidisciplinary approach and treatment of acral and mucosal melanoma.

Acral and mucosal melanoma are uncommon variants of melanoma. Acral melanoma has an age-adjusted incidence of approximately 1.8 cases per million individuals per year, accounting for about 2% to 3% of all melanoma cases. On the other hand, mucosal melanoma, with an incidence of 2.2 cases per million per year, makes up around 1.3% of all melanoma cases. These melanomas, in addition to being biologically and clinically distinct from cutaneous melanoma, share certain clinical and pathologic characteristics. These include a more aggressive nature and a less favorable prognosis. Furthermore, they exhibit a different mutational pattern, with KIT mutations being more prevalent in acral and mucosal melanomas. This divergence in mutational patterns may partially account for the relatively poorer prognosis, particularly to immune checkpoint inhibitors. This review explores various aspects of acral and mucosal melanoma, including their clinical presentation, pathologic features, mutational profiles, current therapeutic approaches, outcomes associated with systemic therapy, and potential strategies to address resistance to existing treatments.

Functional analysis of recurrent CDC20 promoter variants in human melanoma

Small nucleotide variants in non-coding regions of the genome can alter transcriptional regulation, leading to changes in gene expression which can activate oncogenic gene regulatory networks. Melanoma is heavily burdened by non-coding variants, representing over 99% of total genetic variation, including the well-characterized TERT promoter mutation. However, the compendium of regulatory non-coding variants is likely still functionally under-characterized. We developed a pipeline to identify hotspots, i.e. recurrently mutated regions, in melanoma containing putatively functional non-coding somatic variants that are located within predicted melanoma-specific regulatory regions. We identified hundreds of statistically significant hotspots, including the hotspot containing the TERT promoter variants, and focused on a hotspot in the promoter of CDC20. We found that variants in the promoter of CDC20, which putatively disrupt an ETS motif, lead to lower transcriptional activity in reporter assays. Using CRISPR/Cas9, we generated an indel in the CDC20 promoter in human A375 melanoma cell lines and observed decreased expression of CDC20, changes in migration capabilities, increased growth of xenografts, and an altered transcriptional state previously associated with a more proliferative and less migratory state. Overall, our analysis prioritized several recurrent functional non-coding variants that, through downregulation of CDC20, led to perturbation of key melanoma phenotypes.

Pure and Mixed Variants of Desmoplastic Melanoma: A Single-Center, Retrospective, Clinicopathologic Review.

Desmoplastic melanoma (DM) is a rare melanoma variant. Prognostic indicators and survival vary widely and are further confounded by the histopathologic distinction between pure DM (pDM) and mixed DM (mDM) subtypes. The utility of current treatment guidelines is limited by the lack of evidence-based recommendations. To compare the clinicopathologic characteristics of pure and mixed subtypes of DMs. All cases of DM were identified from the Washington University in St Louis institutional pathology database between January 2000 and September 2022. Fifty-two cases were identified and subsequently categorized as pure ( n = 26) or mixed ( n = 26). Clinical and histopathologic data were collected and compared. There were no differences in demographics or tumor location between pure and mixed subtypes. Patients with mDM were more likely to have mitoses present ( p = .03). There were no differences in Breslow depth, tumor diameter, level of invasion, ulceration, and lymphovascular or perineural invasion. The utilization of sentinel lymph node biopsy ( p = .17) and sentinel lymph node positivity ( p = .67) were also similar. Despite histopathologic distinction between pDM and mDM, these subtypes were found to have similar clinicopathologic characteristics, including similar rates of sentinel lymph node metastasis.

Prognosis of naevoid melanomas

IntroductionThere appear to be several variants of naevoid melanoma suspected as having different outcomes, but follow-up studies have been few. We aimed to assess the prognosis of naevoid melanomas in a multi-centre study. Material and methodsFrom histopathology records we ascertained patients in the UK, Australia and Italy diagnosed with maturing naevoid melanoma (n = 65; 14; 7 respectively) and nodular/papillomatous naevoid melanoma (12; 6; 0), and patients with superficial spreading melanoma (SSM) from UK (73) and Australia (26). Melanoma deaths in UK patients were obtained from NHS Digital; in Australia, via the National Death Index and cancer registry; and in Italy, through clinical records. For maturing naevoid vs. SSM, we used Cox-proportional hazard regression models to compare survival adjusted for age, sex, tumour thickness, and ulceration, and additionally Fine-Gray regression analysis, to calculate sub-hazard ratios (SHR) in the UK cohort, accounting for competing causes of death. ResultsAmong UK patients, there was a non-significantly lower risk of melanoma death in maturing naevoid vs SSM, including after accounting for competing causes of death (SHR 0.40, 95% confidence interval (CI) 0.12–1.31), while among nodular/papillomatous naevoid melanoma patients, there were no melanoma deaths on follow-up. Two melanoma deaths occurred in Australian SSM patients, and none in maturing or nodular/papillomatous naevoid melanoma patients, after 5 years’ minimum follow-up. None of the 7 Italian patients with maturing naevoid melanoma died of melanoma after nearly 12 years’ average follow-up. ConclusionsThere was no significant difference in risk of death from melanomas with naevoid features, and SSM. Nodular/ papillomatous naevoid melanoma patients did not carry higher risk of death than SSM patients though the very few cases of the papillomatous naevoid variant limited our assessment.

A Subungual Nevoid Melanoma of the Right Hallux from a 65-Year-Old Man: A Case Report.

Nevoid melanoma (NeM) is a rare variant of malignant melanoma characterized by slight cellular atypia, polymorphism, and incomplete maturation. It most frequently occurs on the trunk and arms but rarely on the foot. Here, we report a subungual NeM of the right hallux. A 65-year-old man presented with severe pain of 6 months' duration to his right great toe following self-treatment for an ingrown nail. He was evaluated and treated with debridement of the toenail at an urgent medical center 3 months prior. However, this had not relieved his pain. The patient also noticed discoloration of his distal great toe over the past 3 months. Removal of part of the ingrown nail revealed a pigmented mass extending distally from the matrix. Surgical excision of the mass was performed because of the concern for malignancy. The diagnosis of NeM was based on histologic analysis along with enhanced diagnostic modalities. The patient was further treated with surgical amputation of the great toe and anti-programmed cell death-1 therapy. The patient had no relapse at 1-year follow-up. Nevoid melanoma is a rare variant of malignant melanoma on the toes, which needs to be differentiated from a nevus with atypia, with a variety of modalities including cellular and molecular profiling. The optimal treatment is amputation.

Prognosis of polypoid melanoma: a comparative study with non-polypoid melanomas.

Polypoid melanoma is considered an exophytic and frequently non-pigmented variant of nodular melanoma with an adverse prognosis; however, very few studies have been published about it with contradictory results. Therefore, our objective was to determine the prognostic value of this configuration in melanomas. A transversal retrospective study of 724 cases was analyzed according to the main configuration (polypoid vs. non-polypoid) regarding their clinicopathologic characteristics and survival analysis. Of the 724 cases, 35 (4.8%) met the definition of polypoid melanoma; such cases, compared with non-polypoid melanomas, were associated with a high Breslow thickness (7 mm vs. 3 mm), 68.6% had a Breslow >4 mm; showed different clinical stages of presentation, and presented more ulceration (77.1 vs. 51.4%). In the 5-year overall survival (OS) analysis, polypoid melanoma is associated with a lower 5-year OS, together with lymph node metastasis, Breslow thickness, clinical stage, mitoses per mm 2 , vertical growth phase, ulceration, and state of the surgical margins; however, in the multivariate analysis, the factors that remained independent predictors of death were the Breslow thickness groups, the clinical stage, the presence of ulceration, and the state of the surgical margins. Polypoid melanoma was not an independent predictor of OS. We found a prevalence of 4.8% of polypoid melanomas, which showed a worse prognosis than non-polypoid melanomas, explained by a higher proportion of ulcerated cases, greater Breslow thickness, and ulceration. However, polypoid melanoma was not an independent predictor of death.

Germline Variants in Childhood Cutaneous Melanoma

Germline Variants in Childhood Cutaneous Melanoma

Dermoscopic Findings of Clonal Seborrheic Keratosis and Pigmented Basal Cell Carcinoma in the Skin of Color Patients - A Comparison.

Dermoscopic Findings of Clonal Seborrheic Keratosis and Pigmented Basal Cell Carcinoma in the Skin of Color Patients - A Comparison.

Dedifferentiated primary melanoma with rhabdoid features: a case report and literature review

Rhabdoid melanoma is an aggressive, rare variant of melanoma. Herein, we describe a case of rhabdoid melanoma and review the clinicopathological features of this neoplasm. A 59-year-old Caucasian female presented with a large cavitary wound located on her right posteromedial upper torso. Light microscopy of the lesion revealed patternless sheeting of neoplastic cells with cytoplasm containing eosinophilic inclusions and peripherally located large round-to-oval nuclei. Tumor cells stained positive for S100, Sox10, myoD1, desmin, and vimentin. CT imaging of the abdomen, chest, and pelvis demonstrated bilateral cannonball lung tumors, bilateral axillary and mediastinal lymphadenopathy, and a soft tissue mass involving the left upper back. These findings were consistent with a diagnosis of metastatic rhabdoid melanoma, which ultimately resulted in the patient’s demise. Increased awareness of this rare entity is crucial to the practicing physician in order to enhance recognition and provide the best possible healthcare to affected individuals.

Unusual Variant of Cutaneous Amelanotic Melanoma of the Cheek

Amelanotic melanoma is a type of cutaneous melanoma characterized by the absence of pigment. The rhabdoid features are an uncommon histological variant of malignant melanoma. Only a handful of primary rhabdoid melanoma cases have been reported in the literature.

Gene Expression Patterns of Osteopontin Isoforms and Integrins in Malignant Melanoma.

Osteopontin (OPN) is a multifunctional glycoprotein that physiologically interacts with different types of integrins. It is considered to be a possible prognostic biomarker in certain tumor types; however, various splicing isoforms exist, which have not been investigated in melanoma. We aimed to define the relative expression pattern of five OPN isoforms and clarify the prognostic significance of the splice variants in melanoma. We also aimed to investigate the expression pattern of eight integrins in the same tumors. Gene expression analyses revealed that the relative expression of OPNa, OPNb, and OPNc is significantly higher in metastatic tumors compared to primary lesions (p < 0.01), whereas the expression of OPN4 and OPN5 was low in both. The more aggressive nodular melanomas had higher expression levels compared to the superficial spreading subtype (p ≤ 0.05). The relative expression of the eight tested integrins was low, with only the expression of ITGB3 being detectable in nodular melanoma (Medianlog2 = 1.274). A positive correlation was found between Breslow thickness and the expression of OPNc variant, whereby thicker tumors (>4 mm) had significantly higher expression (p ≤ 0.05). The Breslow thickness was negatively correlated with the expression of OPN4, and similarly with ITGA2. OPNc also exhibited significant positive correlation with the presence of metastasis. Our data show that high expression of OPNa, OPNb, and especially OPNc and low expression of OPN4 and ITGA2 are associated with an advanced stage of tumor progression and poor prognosis in melanoma.

Iris Ring Melanoma Presenting as Scleral Pigmentation

To report a patient with a very rare variant of iris melanoma that grows in the shape of a ring (ring melanoma). A 65-year-old patient was examined because of a pigmented lesion on the sclera. After a complete ophthalmic and ultrasound examination, a ring melanoma was diagnosed. Enucleation of the affected eye was performed, and histology report confirmed iris ring melanoma. This type of malignancy represents an exceedingly rare variant of uveal melanoma, and because of atypical clinical picture, it can be easily overlooked or misdiagnosed, which often delays adequate treatment. Gonioscopy, transillumination, and ultrasound help us to recognize and diagnose ring melanoma. Suspicion should be raised with a clinical picture that shows unilateral pigmentary glaucoma. The objective of this presentation is to describe and outline the challenging diagnosis and management of this rare disease entity.

Immunohistochemistry in melanocytic lesions: Updates with a practical review for pathologists.

This review provides a summary of the immunohistochemical markers pertinent to the diagnosis of melanocytic lesions. There is considerable morphologic overlap between benign and malignant melanocytic lesions, and given the significant differences in clinical management, the diagnostic workup becomes crucial. Immunohistochemistry aids in the distinction between various melanocytic proliferations and recent contributions to the literature have furthered our optimization of panels in the diagnostic workup. In recent years, SOX10 has been considered as the optimal marker for melanocytic lesions given the similar sensitivity but higher specificity than S100. HMB-45 is less sensitive than S100 but demonstrates utility in confirmation of deceptively banal small cell and nevoid melanoma variants where deep nests of melanocytes are highlighted. Melan-A (MART-1) and MiTF show similar sensitivity to S100 however there is a lack of expression in spindle cell and desmoplastic melanomas.