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A Comprehensive Review of a Rare Subclass of Mucosal Melanoma with Emphasis on Differential Diagnosis and Therapeutic Approaches

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A Comprehensive Review of a Rare Subclass of Mucosal Melanoma with Emphasis on Differential Diagnosis and Therapeutic Approaches cancers Review Urological Melanoma: A Comprehensive Review of a Rare Subclass of Mucosal Melanoma with Emphasis on Differential Diagnosis and Therapeutic Approaches Gerardo Cazzato 1,*,† , Anna Colagrande 1,†, Antonietta Cimmino 1, Concetta Caporusso 1, Pragnell Mary Victoria Candance 1, Senia Maria Rosaria Trabucco 1, Marcello Zingarelli 2, Alfonso Lorusso 2, Maricla Marrone 3 , Alessandra Stellacci 3 , Francesca Arezzo 4, Andrea Marzullo 1, Gabriella Serio 1, Angela Filoni 5, Domenico Bonamonte 5, Paolo Romita 5, Caterina Foti 5, Teresa Lettini 1 , Vera Loizzi 4, Gennaro Cormio 4 , Leonardo Resta 1 , Roberta Rossi 1,‡ and Giuseppe Ingravallo 1,‡ 1 Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, 70124 Bari, Italy; [email protected] (A.C.); [email protected] (A.C.); [email protected] (C.C.); [email protected] (P.M.V.C.); [email protected] (S.M.R.T.); [email protected] (A.M.); [email protected] (G.S.); [email protected] (T.L.); [email protected] (L.R.); [email protected] (R.R.); [email protected] (G.I.) 2 Section of Urology, Deparment of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, 70124 Bari, Italy; [email protected] (M.Z.); [email protected] (A.L.) 3 Section of Legal Medicine, Interdisciplinary Department of Medicine, Bari Policlinico Hospital, Citation: Cazzato, G.; Colagrande, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy; [email protected] (M.M.); A.; Cimmino, A.; Caporusso, C.; [email protected] (A.S.) Candance, P.M.V.; Trabucco, S.M.R.; 4 Section of Ginecology and Obstetrics, Department of Biomedical Sciences and Human Oncology, Zingarelli, M.; Lorusso, A.; Marrone, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy; [email protected] (F.A.); M.; Stellacci, A.; et al. Urological [email protected] (V.L.); [email protected] (G.C.) 5 Section of Dermatology, Department of Biomedical Sciences and Human Oncology, Melanoma: A Comprehensive University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy; angela.fi[email protected] (A.F.); Review of a Rare Subclass of Mucosal [email protected] (D.B.); [email protected] (P.R.); [email protected] (C.F.) Melanoma with Emphasis on * Correspondence: [email protected]; Tel.: +39-3405203641 Differential Diagnosis and † These authors contributed equally. Therapeutic Approaches. Cancers ‡ These authors contributed equally. 2021, 13, 4424. https://doi.org/ 10.3390/cancers13174424 Simple Summary: Mucosal melanoma accounts for only about 1% of all melanoma cases worldwide, but achieving the correct recognition, diagnosis and prognosis is of extreme importance for the Academic Editors: Suzie Chen and patient. Moreover, primary melanoma of the urinary tract is a rarity among rarities, accounting Cesare Massone for less than 4% of all the mucosal melanomas. The urethra is the most common location for this Received: 11 July 2021 type of melanoma, followed by the bladder and ureter with decreasing incidences. Patients with Accepted: 30 August 2021 this form of melanoma are usually elderly (over 60 years) and asymptomatic or have hematuria Published: 2 September 2021 symptoms. Compared to other mucosal melanomas, there is not much knowledge of the risk factors, etiology, and molecular characteristics of urological melanoma. In addition, there are no uniform Publisher’s Note: MDPI stays neutral staging systems or treatment protocols available for this disease. A thorough knowledge of the with regard to jurisdictional claims in existence and management of this disease entity is essential to allow research advances in this area published maps and institutional affil- and, in particular, to devise innovative therapies. In this paper, we focus in detail on melanoma iations. originating from the uropoietic apparatus, discuss the cases reported in literature of this very rare and still partially enigmatic melanoma subclass, and consider the scenario leading to metastasization to neighboring organs. Copyright: © 2021 by the authors. Abstract: Melanoma is reported as the 19th most common cancer worldwide, with estimated age- Licensee MDPI, Basel, Switzerland. standardized incidence rates of 2.8–3.1 per 100,000. Although the origin is most frequently cutaneous, This article is an open access article mucosal melanoma has been described several times in literature, and despite its rarity (only 1% of all distributed under the terms and melanomas), increasing attention is being paid to this disease form. Within this subgroup, melanomas conditions of the Creative Commons of the uropoetic apparatus are a rarity among rarities. Indeed, less than 50 cases of primary melanoma Attribution (CC BY) license (https:// originating from the urinary bladder have been described, and even less originating from the kidney, creativecommons.org/licenses/by/ renal pelvis and urethra. In this work, we present a detailed review of the literature related to this 4.0/). Cancers 2021, 13, 4424. https://doi.org/10.3390/cancers13174424 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 16 mary melanoma originating from the urinary bladder have been described, and even less originat- Cancers 2021, 13, 4424 ing from the kidney, renal pelvis and urethra. In this work, we present a detailed review2 of of 15the literature related to this subclass of mucosal melanoma, delve into the biological landscape of this neoplasm and discuss current approaches, future perspectives and potential therapeutic ap- proaches. subclass of mucosal melanoma, delve into the biological landscape of this neoplasm and discuss current approaches, future perspectives and potential therapeutic approaches. Keywords: melanoma; mucosal melanoma; urology Keywords: melanoma; mucosal melanoma; urology 1. Introduction 1. IntroductionMucosal melanoma (MML) accounts for only 0.03% of all cancer diagnoses and 1.3% of allMucosal melanomas melanoma [1]. Typically, (MML) accountsthe median for age only at 0.03% diagnosis of all is cancer older: diagnoses 67 years compared and 1.3% ofto all 55 melanomasyears for cutaneous [1]. Typically, melanoma the median [1]; abou aget 65% at diagnosis of MML occurs is older: in 67women. years comparedThere does tonot 55 seem years to for be cutaneousa clear etiological melanoma association [1]; about with 65% ultraviolet of MML (UV) occurs rays, in women.although Thereno de- doesfinitive not results seem to are be ayet clear available; etiological trauma association has been with suggested ultraviolet as (UV)the possible rays, although etiological no definitiveagent [2,3]. results Among are the yet different available; localizations, trauma has beenMML suggested most frequently as the possiblearises from etiological mucous agentmembranes [2,3]. Among of the thehead different and neck localizations, (45–55%), MMLanorectal most region frequently (25%), arises and fromgenitourinary mucous membranestract (15–20%) of the [4,5]. head In andboth neck males (45–55%), and females, anorectal 5% regionof cases (25%), present and in genitourinary the distal urethra tract (15–20%)[6]. Primary [4,5 urinary]. In both system males melanomas and females, are the 5% least of cases common present among in the mucosal distal urethra melanomas [6]. Primaryand account urinary for systemless than melanomas 4% of all mucosal are the least melanomas common [1,6]. among The mucosal urethra melanomasis the most com- and accountmon site for for less this than type 4% of ofmelanoma, all mucosal followed melanomas by the [1 bladder,6]. The and urethra ureter is the(Figure most 1) common. Patients sitewith for this this form type of of melanoma melanoma, are followed usually by elderly the bladder (over and 60) ureterand asymptomatic (Figure1). Patients or have with he- thismaturia form symptoms of melanoma [6,7]. are The usually general elderly approach (over 60)for andmucosal asymptomatic melanomas or is have wide hematuria resection symptomssurgery with [6,7 lymph]. The generalnode dissection, approach followed for mucosal by melanomaschemotherapy is wideor immunotherapy resection surgery [7]. withHowever, lymph the node rarity dissection, of this neoplasm followed byand chemotherapy difficulties in orcollecting immunotherapy large case [7 series]. However, for ob- theservational rarity of thisand neoplasmtherapeutic and studies difficulties have hamp in collectingered the large possibility case series of devising for observational innovative andtherapies, therapeutic including studies targeted have hamperedtherapies. theMolecular possibility studies of devising of urinary innovative tract melanoma therapies, are includinglimited [7] targeted although therapies. it has been Molecular shown studies that a ofsmall urinary subgroup tract melanoma of primary are urinary limited tract [7] althoughmelanomas it has (about been 14%) shown are characterized that a small subgroup by the c-kit of mutation, primary urinary while the tract BRAF melanomas mutation (aboutis rare, 14%) being are infrequently characterized observed, by the c-kit unlike mutation, in cutaneous while the melanoma BRAF mutation [7]. is rare, being infrequently observed, unlike in cutaneous melanoma [7]. FigureFigure 1. 1.Primary Primary melanomamelanoma ofof thethe urinaryurinary tracttract isis aa rarityrarity among rarities (<4% of of all all the the mucosal mucosal melanoma).melanoma).
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