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15 pages, 1776 KiB

Open AccessArticle

Mucosal Melanoma Clinical Management and Prognostic Implications: A Retrospective Cohort Study

by Laia Clavero-Rovira, Álvaro Gómez-Tomás, Patricia Bassas-Freixas, Domingo Bodet, Berta Ferrer, Javier Hernández-Losa, Eva Muñoz-Couselo, Assumpció Pérez-Benavente, Vicente García-Patos and Carla Ferrándiz-Pulido

Cancers 2024, 16(1), 227; https://doi.org/10.3390/cancers16010227 - 3 Jan 2024

Cited by 5 | Viewed by 2441

Abstract

Mucosal melanoma (MM) is an uncommon melanoma subtype affecting mucosal surfaces of the head and neck, anorectal region, and vulvovaginal area. We aimed to present our experience at a tertiary-level hospital regarding MM diagnosis, management, monitoring of progression, mutations, and outcome predictors. We [...] Read more.

Mucosal melanoma (MM) is an uncommon melanoma subtype affecting mucosal surfaces of the head and neck, anorectal region, and vulvovaginal area. We aimed to present our experience at a tertiary-level hospital regarding MM diagnosis, management, monitoring of progression, mutations, and outcome predictors. We performed a registry-based cohort study including MM cases diagnosed from 2012 to 2022 and retrospectively characterized somatic mutations on BRAF, NRAS and c-KIT. We employed Kaplan–Meier curves, log-rank tests, and Cox regression analysis to explore prognostic factors and survival outcomes in a cohort of 35 patients, mainly women (63%) with a median age of 70 years. Predominantly, MM occurred in the vulvovaginal region (48.6%). At diagnosis, 28.6% had lymph node involvement, and 31.4% also had distant metastasis. Mutations in BRAF and c-KIT were identified in 3/35 (9%) and 2/6 patients (33%), respectively. Surgery was performed in 71.4% of patients, and most received systemic treatment (65.7%). Lower disease stage, thinner Breslow depth, and surgical resection were associated with improved overall survival. Notably, age, sex, radiotherapy, and BRAF mutant status did not affect survival. Standard management typically involves immunotherapy. Cases with BRAF or c-KIT mutations may be considered for targeted therapies. Unfortunately, MM prognosis remains unfavorable, with a less than 50% survival rate at 2 years. Full article

(This article belongs to the Special Issue New Concepts and Recent Advances in the Management of Skin Cancer)

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8 pages, 4404 KiB

Open AccessCase Report

Successful Multidisciplinary Treatment with Laparoscopic Hepatectomy and Adjuvant Therapy for Metachronous Solitary Hepatic Metastasis after Excision of a Primary Anorectal Malignant Melanoma: A Case Report

by Ryotaro Shimazaki, Masahiro Hagiwara, Chikayoshi Tani, Hiroyoshi Iwata, Hiroyuki Takahashi, Marika Fukuyama, Taisuke Matsuya, Koji Imai, Sayaka Yuzawa, Mishie Tanino and Hideki Yokoo

Curr. Oncol. 2024, 31(1), 203-210; https://doi.org/10.3390/curroncol31010013 - 29 Dec 2023

Cited by 1 | Viewed by 1751

Abstract

Anorectal malignant melanoma (ARMM) is extremely rare and generally lethal, irrespective of the treatment administered. The disease is often diagnosed late, metastases being present in approximately two-thirds of patients at the time of initial diagnosis. Solitary metastasis of ARMM to a distant organ [...] Read more.

Anorectal malignant melanoma (ARMM) is extremely rare and generally lethal, irrespective of the treatment administered. The disease is often diagnosed late, metastases being present in approximately two-thirds of patients at the time of initial diagnosis. Solitary metastasis of ARMM to a distant organ is exceedingly rare. A 76-year-old woman with a history of laparoscopic abdominoperineal resection of an ARMM 13 months previously, was found to have a solitary liver metastasis in the follow-up computed tomography. A preoperative work-up showed no other distant metastases nor contraindication to surgery. It was therefore considered that resection was indicated. The metachronous solitary liver metastasis from an ARMM was treated by laparoscopic wedge hepatectomy of the eighth segment 18 months after excision of her primary ARMM. Adjuvant therapy with pembrolizumab was initiated and continued at 6-week intervals. The patient has not exhibited any immune related Adverse Effects (irAE) during or subsequent to treatment with pembrolizmab and has now completed 12 months of adjuvant pembrolizumab therapy, having survived 33 months from the initial operation for primary ARMM, and remaining recurrence-free 14 months after hepatectomy. ARMM is extremely rare and resection of a metachronous solitary metastasis followed by adjuvant therapy has not previously been reported. We hope this case will be useful for clinicians who might treat similar patients. Full article

(This article belongs to the Section Surgical Oncology)

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27 pages, 2872 KiB

Open AccessReview

Intra-Abdominal Malignant Melanoma: Challenging Aspects of Epidemiology, Clinical and Paraclinical Diagnosis and Optimal Treatment—A Literature Review

by Sinziana Ionescu, Alin Codrut Nicolescu, Octavia-Luciana Madge, Laurentiu Simion, Marian Marincas and Mihai Ceausu

Diagnostics 2022, 12(9), 2054; https://doi.org/10.3390/diagnostics12092054 - 24 Aug 2022

Cited by 11 | Viewed by 5357

Abstract

According to European consensus-based interdisciplinary guidelines for melanoma, cutaneous melanoma (CM) is the most deadly form of dermatological malignancy, accounting for 90% of the deaths of skin cancer patients. In addition to cutaneous melanoma, mucosal melanoma occurs in four major anatomical sites, including [...] Read more.

According to European consensus-based interdisciplinary guidelines for melanoma, cutaneous melanoma (CM) is the most deadly form of dermatological malignancy, accounting for 90% of the deaths of skin cancer patients. In addition to cutaneous melanoma, mucosal melanoma occurs in four major anatomical sites, including the upper respiratory tract, the conjunctiva, the anorectal region, and the urogenital area. As this cancer type metastasizes, a classification used in the current medical literature is the distinction between secondary lesions and primary malignant melanoma of the abdominal cavity. Given that malignant melanoma is the most common cancer that spreads to the gastrointestinal tract, different imaging modalities compete to diagnose the phenomenon correctly and to measure its extension. Treatment is primarily surgery-based, supported by immunotherapy, and prolongs survival, even when performed at stage IV illness. In the end, special forms of malignant melanoma are discussed, such as melanoma of the genito-urinary tract and amelanotic/achromic melanoma. The importance of this present literature review relies on yielding and grouping consistent and relevant, updated information on the many aspects and challenges that a clinician might encounter during the diagnosis and treatment of a patient with intra-abdominal melanoma. Full article

(This article belongs to the Special Issue Advances in Image-Guided Diagnosis and Treatment of Abdominal Diseases)

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6 pages, 1907 KiB

Open AccessCase Report

Metastatic Anorectal Melanoma Presenting as Seizures: An Infrequent Culprit

by Joao Galante, Sola Adeleke, Rosemeen Parkar, Nipin Bagla, Albert Edwards, Stergios Boussios and Rakesh Raman

Diseases 2022, 10(2), 21; https://doi.org/10.3390/diseases10020021 - 8 Apr 2022

Cited by 1 | Viewed by 2989

Abstract

Anorectal malignant melanoma is a rare culprit of malignancies in the anorectal region. With a presentation that mimics the vastly more common colorectal tumours, clinical misdiagnosis and diagnostic delays often occur, contributing to a dismal prognosis. The authors report a case of metastatic [...] Read more.

Anorectal malignant melanoma is a rare culprit of malignancies in the anorectal region. With a presentation that mimics the vastly more common colorectal tumours, clinical misdiagnosis and diagnostic delays often occur, contributing to a dismal prognosis. The authors report a case of metastatic anorectal malignant melanoma presenting as seizures. Though our standard diagnostic pathway for suspected anorectal malignancies was followed, and despite the patient having computerized tomography (CT) of the head earlier, this presentation nonetheless led to a prolongation of time needed to reach histological diagnosis and delay in commencing definitive treatment. It also highlights the paucity of research into the pathophysiology and management of this infrequent but aggressive disease, and the need for raising awareness about this condition to the medical community so that it is considered as a plausible differential diagnosis from the outset and diagnostic pathways adjusted accordingly. Full article

(This article belongs to the Section Oncology)

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21 pages, 5262 KiB

Open AccessReview

Anorectal and Genital Mucosal Melanoma: Diagnostic Challenges, Current Knowledge and Therapeutic Opportunities of Rare Melanomas

by Margaret Ottaviano, Emilio Francesco Giunta, Laura Marandino, Marianna Tortora, Laura Attademo, Davide Bosso, Cinzia Cardalesi, Antonietta Fabbrocini, Mario Rosanova, Antonia Silvestri, Liliana Montella, Pasquale Tammaro, Ester Marra, Claudia Trojaniello, Maria Grazia Vitale, Ester Simeone, Teresa Troiani, Bruno Daniele and Paolo Antonio Ascierto

Biomedicines 2022, 10(1), 150; https://doi.org/10.3390/biomedicines10010150 - 11 Jan 2022

Cited by 21 | Viewed by 5366

Abstract

Mucosal melanomas (MM) are rare tumors, being less than 2% of all diagnosed melanomas, comprising a variegated group of malignancies arising from melanocytes in virtually all mucosal epithelia, even if more frequently found in oral and sino-nasal cavities, ano-rectum and female genitalia (vulva [...] Read more.

Mucosal melanomas (MM) are rare tumors, being less than 2% of all diagnosed melanomas, comprising a variegated group of malignancies arising from melanocytes in virtually all mucosal epithelia, even if more frequently found in oral and sino-nasal cavities, ano-rectum and female genitalia (vulva and vagina). To date, there is no consensus about the optimal management strategy of MM. Furthermore, the clinical rationale of molecular tumor characterization regarding BRAF, KIT or NRAS, as well as the therapeutic value of immunotherapy, chemotherapy and targeted therapy, has not yet been deeply explored and clearly established in MM. In this overview, focused on anorectal and genital MM as models of rare melanomas deserving of a multidisciplinary approach, we highlight the need of referring these patients to centers with experts in melanoma, anorectal and uro-genital cancers treatments. Taking into account the rarity, the poor outcomes and the lack of effective treatment options for MM, tailored research needs to be promptly promoted. Full article

(This article belongs to the Special Issue Diagnostics and Therapeutics of Melanoma)

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13 pages, 1807 KiB

Open AccessArticle

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

by Joanna P. Wróblewska, Dora Dias-Santagata, Adam Ustaszewski, Cheng-Lin Wu, Masakazu Fujimoto, M. Angelica Selim, Wojciech Biernat, Janusz Ryś, Andrzej Marszalek and Mai P. Hoang

Cells 2021, 10(9), 2216; https://doi.org/10.3390/cells10092216 - 27 Aug 2021

Cited by 20 | Viewed by 3478

Abstract

Background: The prognostic value of commonly recurrent mutations remains unclear in mucosal melanomas. Methods: Clinicopathologic parameters of 214 cases of mucosal melanomas diagnosed in 1989–2020 in several clinical institutions were analyzed. NRAS, KIT, BRAF, IGF2R and SF3B1 mutational analyses by [...] Read more.

Background: The prognostic value of commonly recurrent mutations remains unclear in mucosal melanomas. Methods: Clinicopathologic parameters of 214 cases of mucosal melanomas diagnosed in 1989–2020 in several clinical institutions were analyzed. NRAS, KIT, BRAF, IGF2R and SF3B1 mutational analyses by Sanger sequencing and next generation sequencing-based assay were performed in a subset of cases. Results: Of the triple (BRAF, NRAS, NF1)-negative cases, APC, KIT and KRAS are detected mainly in sinonasal, vulvovaginal and anorectal melanomas, respectively. NRAS, KIT, BRAF, IGF2R and SF3B1 mutations are detected in 19% (37/198), 22% (44/197), 12% (25/201), 16% (22/138) and 15% (20/133) of cases, respectively. In univariate analyses, advanced stage (p = 0.016), 65 years or older (p = 0.048) and presence of ulceration (p = 0.027) are significantly correlated with worse overall survival (OS), respectively. NRAS mutation significantly correlates with worse OS (p = 0.028) and worse melanoma-specific survival (MSS) (p = 0.03) for all cases of mucosal melanomas. In multivariate analyses, NRAS mutation remains as an independent predictor of worse OS (p = 0.036) and worse MSS (p = 0.024). Conclusion: NRAS mutation is a predictor of worse survival, independent of stage in mucosal melanomas. The significance of frequently mutated IGF2R in mucosal melanomas remains unclear. Full article

(This article belongs to the Special Issue Advances in Cellular and Molecular Research in Melanoma)

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Graphical abstract

11 pages, 2392 KiB

Open AccessArticle

Definition of Biologically Distinct Groups of Conjunctival Melanomas According to Etiological Factors and Implications for Precision Medicine

by Sophie Gardrat, Alexandre Houy, Kelly Brooks, Nathalie Cassoux, Raymond Barnhill, Stéphane Dayot, Ivan Bièche, Virginie Raynal, Sylvain Baulande, Richard Marais, Sergio Roman-Roman, Marc-Henri Stern and Manuel Rodrigues

Cancers 2021, 13(15), 3836; https://doi.org/10.3390/cancers13153836 - 30 Jul 2021

Cited by 15 | Viewed by 2635

Abstract

Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations [...] Read more.

Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations in BRAF, NRAS, HRAS, and KIT were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with BRAF and CDKN2A-mutated ConjMel tended to be younger while the NF1-mutated one tended to be older. The eight tumors arising from nevi were enriched in CTNNB1 mutations (63% vs. 8%; Fisher’s exact p-test = 0.001) compared to non-nevi ConjMel and five were devoid of BRAF, RAS, NF1, or KIT mutations, suggesting a specific oncogenic process in these tumors. The two KIT-mutated cases carried SF3B1 mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in ERBB2, IDH1, MET, and MAP2K1 (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. CTNNB1 mutations were associated with nevus-derived ConjMel. Concomitant KIT/SF3B1 mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas. Full article

(This article belongs to the Section Molecular Cancer Biology)

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12 pages, 3084 KiB

Open AccessArticle

Up-Regulation of PARP1 Expression Significantly Correlated with Poor Survival in Mucosal Melanomas

by Piotr Donizy, Cheng-Lin Wu, Jason Mull, Masakazu Fujimoto, Agata Chłopik, Yan Peng, Sara C. Shalin, M. Angelica Selim, Susana Puig, Maria-Teresa Fernandez-Figueras, Christopher R. Shea, Wojciech Biernat, Janusz Ryś, Andrzej Marszalek and Mai P. Hoang

Cells 2020, 9(5), 1135; https://doi.org/10.3390/cells9051135 - 5 May 2020

Cited by 26 | Viewed by 4877

Abstract

Introduction: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma. Methods: PARP1, PD-L1 and IDO1 immunostains were [...] Read more.

Introduction: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma. Methods: PARP1, PD-L1 and IDO1 immunostains were performed on 192 mucosal melanomas including 86 vulvar, 89 sinonasal, and 17 anorectal melanomas. Results: By Kaplan–Meier analyses, high PARP1 expression correlated with worse overall and melanoma-specific survival (log-rank p values = 0.026 and 0.047, respectively). Tumors with combined PARP1 and IDO1 high expression correlated with worse overall and melanoma-specific survival (p = 0.015, 0.0034 respectively). By multivariate analyses, high PARP1 expression remained a predictor of worse survival independent of stage. By Fisher’s exact test, high PARP1 expression correlated with highly mitogenic tumors (p = 0.02). High tumoral PD-L1 and IDO1 expression were associated with ulcerated primary tumors (p = 0.019, 0.0019, respectively). By linear regression analyses, correlations between PARP1 expression versus IDO1 expression (p = 0.0001) and mitotic index (p = 0.0052) were observed. Conclusion: Increased expression of PARP1 is an independent negative prognostic marker in mucosal melanomas. The association between PARP1 and IDO1 and their combined adverse prognostic role raise the potential of combined therapy in mucosal melanoma. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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16 pages, 1166 KiB

Open AccessArticle

MDM2, MDM4 and EGFR Amplifications and Hyperprogression in Metastatic Acral and Mucosal Melanoma

by Andrea Forschner, Franz-Joachim Hilke, Irina Bonzheim, Axel Gschwind, German Demidov, Teresa Amaral, Stephan Ossowski, Olaf Riess, Christopher Schroeder, Peter Martus, Bernhard Klumpp, Irene Gonzalez-Menendez, Claus Garbe, Heike Niessner and Tobias Sinnberg

Cancers 2020, 12(3), 540; https://doi.org/10.3390/cancers12030540 - 26 Feb 2020

Cited by 58 | Viewed by 6293

Abstract

Background: Mucosal and acral melanoma respond worse to immune checkpoint inhibitors (ICI) than cutaneous melanoma. MDM2/4 as well as EGFR amplifications are supposed to be associated with hyperprogression on ICI in diverse cancers. We therefore investigated the response of metastatic acral and mucosal [...] Read more.

Background: Mucosal and acral melanoma respond worse to immune checkpoint inhibitors (ICI) than cutaneous melanoma. MDM2/4 as well as EGFR amplifications are supposed to be associated with hyperprogression on ICI in diverse cancers. We therefore investigated the response of metastatic acral and mucosal melanoma to ICI in regard to MDM2/4 or EGFR amplifications and melanoma type. Methods: We conducted a query of our melanoma registry, looking for patients with metastatic acral or mucosal melanoma treated by ICI. Whole exome sequencing, FISH and immunohistochemistry on melanoma tissue could be performed on 45 of the total cohort of 51 patients. Data were correlated with patients’ responses to ICI and survival. Results: 22 out of 51 patients had hyperprogressive disease (an increase in tumor load of >50% at the first staging). Hyperprogression occurred more often in case of MDM2/4 or EGFR amplification or <1% PD-L1 positive tumor cells. Nevertheless, this association was not significant. Interestingly, the anorectal melanoma type and the presence of liver metastases were significantly associated with worse survival. Conclusions: So far, we found no reliable predictive marker for patients who develop hyperprogression on ICI, specifically with regard to MDM2/4 or EGFR amplifications. Nevertheless, patients with anorectal melanoma, liver metastases or melanoma with amplified MYC seem to have an increased risk of not benefitting from ICI. Full article

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