Journal of Clinical Medicine Review Cutaneous and Mucosal Melanomas of Uncommon Sites: Where Do We Stand Now? Emi Dika 1,2,* , Martina Lambertini 1,2, Cristina Pellegrini 3, Giulia Veronesi 1,2, Barbara Melotti 4, Mattia Riefolo 5, Francesca Sperandi 4, Annalisa Patrizi 1,2, Costantino Ricci 5,6 , Martina Mussi 1,2 and Maria Concetta Fargnoli 3 1 Dermatology, IRCCS Policlinico di Sant’Orsola, via Massarenti 9, 40138 Bologna, Italy; [email protected] (M.L.); [email protected] (G.V.); [email protected] (A.P.); [email protected] (M.M.) 2 Dermatology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy 3 Dermatology, Department of Biotechnological and Applied Clinical Science, University of L’Aquila, 67100 L’Aquila, Italy; [email protected] (C.P.); [email protected] (M.C.F.) 4 Division of Oncology, IRCCS di Policlinico Sant’Orsola, via Massarenti 9, 40138 Bologna, Italy; [email protected] (B.M.); [email protected] (F.S.) 5 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy; [email protected] (M.R.); [email protected] (C.R.) 6 Pathology Unit, Ospedale Maggiore, 40100 Bologna, Italy * Correspondence: [email protected]; Tel.: +39-0512144849 Abstract: Melanomas arising at uncommon sites include a group of lesions related to unusual localizations in specific ethnic groups. The rarity of the disease often represents a limit to the participation of patients in specific trials. However, this peculiar genetic scenario has important therapeutic implications regarding new oncologic therapies. The aim of this article is to review the Citation: Dika, E.; Lambertini, M.; clinical features, somatic alterations and therapeutic options for melanomas of uncommon sites. Pellegrini, C.; Veronesi, G.; Melotti, B.; They can be classified as cutaneous and mucosal lesions affecting the nail apparatus, palms/soles, Riefolo, M.; Sperandi, F.; Patrizi, A.; oral mucosa, genital area and scalp. The prognosis may be worse compared to melanomas of other Ricci, C.; Mussi, M.; et al. Cutaneous and Mucosal Melanomas of districts, and a prompt diagnosis may dramatically influence the outcome. Dermatologists and Uncommon Sites: Where Do We oncologists should therefore distinguish this melanoma subgroup in terms of surgical intervention Stand Now?. J. Clin. Med. 2021, 10, and medical treatment. Due to the lack of mutations in genes usually found in cutaneous melanomas, 478. https://doi.org/jcm10030478 the discovery of novel targets is required to develop new strategies and to change the prognosis of non-responders or wild-type patients. Academic Editor: Maria Teresa Fierro Received: 2 January 2021 Keywords: melanoma; nail; oral; scalp; genital; acral Accepted: 24 January 2021 Published: 28 January 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Melanomas of uncommon sites encompass both cutaneous and mucosal lesions related published maps and institutional affil- to an unusual localization in specific ethnic groups. The histopathological interpretation iations. may be challenging, and known site-related atypical features may sometimes increase diagnostic dilemmas for pathologists. They represent a separate subgroup with peculiar genetic alterations and, in some cases, may be associated with a worse prognosis compared to melanomas of other districts. The umbrella term “sun-protected melanomas” has been Copyright: © 2021 by the authors. considered inadequate to describe a heterogeneous pool of mucosal, acral and vulvovaginal Licensee MDPI, Basel, Switzerland. melanomas with distinct genetic profiles [1]. The treatment choice and outcome may This article is an open access article therefore be challenging. distributed under the terms and The aim of this article is to describe the clinical features of cutaneous and mucosal conditions of the Creative Commons melanomas of uncommon sites and review the reported somatic molecular alterations and Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ emerging treatment options for these aggressive variants. Dermatologists and oncologists 4.0/). should specifically consider this subgroup in terms of surgical intervention and medical J. Clin. Med. 2021, 10, 478. https://doi.org/10.3390/jcm10030478 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 478 2 of 15 J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 15 treatment. Here, we will focus on melanomas arising on acral body areas, including the nailtreatment. apparatus Here, and we palms/soles, will focus onoral melanomas mucosa, genital arising area on and acral scalp. body areas, including the nail apparatus and palms/soles, oral mucosa, genital area and scalp. 2. Cutaneous Melanomas at Uncommon Sites 2.1.2. Cutaneous Acral Melanomas Melanomas at Uncommon Sites 2.1. Acral Melanomas The term acral melanoma includes a subset of melanomas affecting the nail unit, palmsThe and term soles. acral The melanoma pathogenetic includes mechanisms a subset of acral melanomas melanoma affecting have the not nail yet unit,beenpalms com- pletelyand soles. clarified The pathogenetic [2]. A role for mechanisms the trauma ha ofs acral been melanoma proposed, havealthough, not yet according been completely to some authors,clarified the [2]. trauma A role for may the simply trauma represent has been the proposed, reason although,inducing accordingpatients to to seek some a prompt authors, medicalthe trauma evaluation, may simply with representthe consequent the reason unex inducingpected recognition patients to of seek the disease a prompt [2–4]. medical The roleevaluation, of UV exposure with the is consequent not fully applicable unexpected to acral recognition melanomas, of the but disease it seems [2– more4]. The relevant role of inUV cutaneous, exposure as is compared not fully applicable to nail unit, to lesions. acral melanomas, UV signature but mutations it seems more(tandem relevant CC>TT in transitionscutaneous, and as comparedC>T transitions to nail at unit, dipyrimidine lesions. UVsites) signature are not commonly mutations detected (tandem in CC>TT acral melanomatransitions [1,5,6]. and C>T However, transitions in at1987, dipyrimidine Baran and sites)Juhlin are reported not commonly that the detected nail plate in acralmay representmelanoma a convex [1,5,6]. lens However, favoring in 1987,UV exposure Baran and to nail Juhlin matrix reported melanocytes that the [7]. nail In plate addition, may solarrepresent elastosis a convex has been lens favoringdetected UVin nail exposure melanoma to nail samples, matrix melanocytesalthough this [7 feature]. In addition, is not routinelysolar elastosis reported has by been pathologists. detected in nail melanoma samples, although this feature is not routinely reported by pathologists. Nail melanoma is uncommon in White patients, accounting for only 2% of all mela- Nail melanoma is uncommon in White patients, accounting for only 2% of all melanomas nomas but for almost one-fifth of the total cases in non-White subjects, including Asians but for almost one-fifth of the total cases in non-White subjects, including Asians and Afro- and Afro-Americans [8,9]. It usually presents as a brownish/black/grayish irregular lon- Americans [8,9]. It usually presents as a brownish/black/grayish irregular longitudinal gitudinal band of pigmentation (nail melanonychia) that may be associated with nail plate band of pigmentation (nail melanonychia) that may be associated with nail plate dystrophy dystrophy and abnormalities (Figure 1). The pigmentation can extend to the nail folds or and abnormalities (Figure1). The pigmentation can extend to the nail folds or to the sur- to the surrounding skin with the so-called Hutchinson’s sign [10–12] (Figures 1 and 2). rounding skin with the so-called Hutchinson’s sign [10–12] (Figures1 and2). Amelanotic Amelanotic lesions clinically present as a band of erythronychia or as eroded nodules with lesions clinically present as a band of erythronychia or as eroded nodules with nail plate nail plate abnormalities showing polymorphous vessels and milky-red areas on der- abnormalities showing polymorphous vessels and milky-red areas on dermatoscopy [13,14]. matoscopy [13,14]. Nail melanoma mainly arises in the great toenail, the thumb and the Nail melanoma mainly arises in the great toenail, the thumb and the second digit. Possible second digit. Possible differential diagnoses include tinea unguium, warts, hemorrhages differential diagnoses include tinea unguium, warts, hemorrhages or pyogenic granulomas, oroften pyogenic determining granulomas, a delay inoften the determining diagnosis and, a thus,delay a in worse the diagnosis prognosis [and,15]. thus, a worse prognosis [15]. Figure 1. Nail melanoma of the great toenail clinically presenting as a longitudinal melanonychia (a). At onychoscopy, (b) Figure 1. Nail melanoma of the great toenail clinically presenting as a longitudinal melanonychia (a). At onychoscopy, heterogeneous irregular longitudinal bands of pigment with nail plate dystrophy; pigmentation extends to the hyponych- (b) heterogeneous irregular longitudinal bands of pigment with nail plate dystrophy; pigmentation extends to the hypony- ium (Hutchinson’s sign). chium (Hutchinson’s sign). Cutaneous acral melanoma clinically appears as a pigmented brown-to-black macule (Figure3) or nodule, sometimes ulcerated, although amelanotic lesions can