diagnostics Review Review of Dermoscopy and Reflectance Confocal Microscopy Features of the Mucosal Melanoma Andrea De Pascalis 1,* , Jean Luc Perrot 2, Linda Tognetti 1, Pietro Rubegni 1 and Elisa Cinotti 1 1 Department of Medical, Surgical and Neurological Science, Dermatology Section, University of Siena, S. Maria alle Scotte Hospital, 53100 Siena, Italy; [email protected] (L.T.); [email protected] (P.R.); [email protected] (E.C.) 2 Department of Dermatology, University Hospital of Saint-Etienne, 42000 Saint-Etienne, France; [email protected] * Correspondence: [email protected]; Tel.: +39-0577-585428; Fax: +39-0577-585484 Abstract: Mucosal melanoma is a rare tumor with aggressive biological behavior and poor prognosis. Diagnosis is often performed at an advanced stage when the lesions become symptomatic. Although dermoscopy and reflectance confocal microscopy (RCM) are widely used techniques for the diagnosis of cutaneous tumors, their use for mucosal lesions is not well established, probably because the latter are rarer. The objective of this study was to evaluate current literature on these imaging techniques for mucosal melanoma. We searched in PubMed and Cochrane databases all studies up to October 2020 dealing with dermoscopy, RCM, and mucosal melanoma. We found that the most relevant dermoscopic features were structureless pattern and/or the presence of multiple colors. RCM examination mainly showed numerous basal hyper-reflective dendritic cells and loss of normal architecture of the papillae of the lamina propria. Although diagnostic algorithms have been proposed for both techniques, the limit of these methods is the absence of large studies and of standardized and shared diagnostic criteria. Keywords: melanoma; mucosa; dermoscopy; reflectance confocal microscopy Citation: De Pascalis, A.; Perrot, J.L.; Tognetti, L.; Rubegni, P.; Cinotti, E. Review of Dermoscopy and Reflectance Confocal Microscopy 1. Introduction Features of the Mucosal Melanoma. Mucosal melanoma can affect the glabrous portion of the lips, oral, sinonasal, genital, Diagnostics 2021 11 , , 91. https:// urinary, gastrointestinal, anorectal, and conjunctival locations [1]. It is rare, with an inci- doi.org/10.3390/diagnostics11010091 dence rate around 1% of all melanomas [2]. However, because of its anatomic localization and lack of early visible signs and symptoms, it is usually diagnosed at an advanced stage Received: 3 December 2020 with poor prognosis [3]. Clinically, it most often is a solitary, brown to black macule that can Accepted: 7 January 2021 Published: 8 January 2021 be difficult to differentiate from melanosis that is the most common cause of pigmentation in which can be observed in the mucosa [4,5]. Moreover it is estimated, that about a fifth Publisher’s Note: MDPI stays neu- of mucosal melanomas are amelanotic, which makes the diagnosis even more difficult tral with regard to jurisdictional clai- (Figure1 )[1,6]. In the initial phase of growth, mucosal melanomas are indolent and asymp- ms in published maps and institutio- tomatic and most people do not seek medical attention until swelling or ulceration and nal affiliations. consequent bleeding occur (Figure1). The histopathological appearance of mucosal melanoma is similar to its cutaneous counterpart. Mucosal melanomas are heterogeneous and can show epitheloid, spindle- shaped, or mixed cytomorphology. This spindle tumor cell type, in particular, is more Copyright: © 2021 by the authors. Li- common in mucosal melanoma than in cutaneous melanoma [7]. The oncogenic drivers censee MDPI, Basel, Switzerland. of mucosal melanoma are quite different from cutaneous melanoma. The mutation rate This article is an open access article of KIT and SF3B1 is higher in mucosal melanoma as compared to cutaneous melanoma. distributed under the terms and con- While, the common drivers (BRAF and NRAS) found in cutaneous melanoma have lower ditions of the Creative Commons At- mutation rate in mucosal melanoma [1,8]. tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Diagnostics 2021, 11, 91. https://doi.org/10.3390/diagnostics11010091 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 91 2 of 10 Diagnostics 2021, 11, x FOR PEER REVIEW 2 of 10 (a) (b) (c) (d) FigureFigure 1. ClinicalClinical ( a),), dermoscopic dermoscopic (b) and RCMRCM ((cc,,dd)) aspectaspect ofof aa hypomelanotichypomelanotic mucosal mucosal melanoma. mela- noma.(b) Dermoscopy (b) Dermoscopy shows shows structureless structureless grey and grey white and colorwhite andcolor remnants and remnants of pigmentation. of pigmentation. (c,d) Re- (c,d) Reflectance confocal microscopy features at the epidermal level (images acquired with Vi- flectance confocal microscopy features at the epidermal level (images acquired with VivaScope 3000, vaScope 3000, Caliber, New York, USA): atypical cells are indicated by red arrows. Caliber, New York, NY, USA): atypical cells are indicated by red arrows. TheThe histopathological biological behavior appearance of mucosal of melanomamucosal melanoma notoriously is similar differs to from its cutaneous counterpart.melanoma. TheMucosal greater melanomas blood and are lymphatic heterogeneous flow in and mucosa can show and the epitheloid, differences spindle- in the shaped,genetic profileor mixed of mucosal cytomorphology. melanoma This eases spindle its local tumor and remote cell type, spread. in particular, Therefore, mucosalis more commonmelanoma in hasmucosal a bad melanoma prognosis than with in a cutane five-yearous survivalmelanoma rate [7]. of The 10–25% oncogenic of cases drivers and ofaverage mucosal survival melanoma of two are years. quite different If lymphatic from glands cutaneous have melanoma. been affected, The prognosismutation rate drops of KITeven and further SF3B1 [9]. is higher in mucosal melanoma as compared to cutaneous melanoma. While,Up the to common date, the drivers only tool (BRAF available and NRAS) to improve found the in prognosis cutaneous of melanoma this tumor have is its lower early mutationdiagnosis. rate Dermoscopy in mucosal melanoma and reflectance [1,8]. confocal microscopy (RCM) are broadly used imagingThe proceduresbiological behavior for the non-invasive of mucosal diagnosismelanoma of notoriously skin melanoma, differs but from their cutaneous diagnostic melanoma.value for mucosal The greater melanoma blood is and not lymphatic adequately flo recognizedw in mucosa [10, 11and]. the differences in the geneticReflectance profile of confocalmucosal microscopymelanoma eases (RCM) its islocal a noninvasive and remote technique spread. Therefore, of skin imaging, muco- salwhich melanoma produces has high-resolution a bad prognosis images with a of five- theyear upper survival 250 µm rate of the of skin,10–25% and of is cases effective and averagein distinguishing survival of between two years. benign If lymphatic and malignant glands skinhave lesions been affected, [12]. Recently, prognosis the drops RCM evendevices further dedicated [9]. to the skin have been also applied to perform “virtual biopsies” of the mucosaUp [to13 date,]. In fact,the only mucosa tool isavailable particularly to improve suitable the for prognosis RCM because of this of tumor its thin is or its absent early diagnosis.cornified layer Dermoscopy and its thin and epitheliumreflectance thatconf allowsocal microscopy a deeper penetration(RCM) are broadly of the laser used with im- agingthe consequent procedures possibility for the non-invasive of exploring diagnosis deeper tissue of skin levels. melanoma, The images but offeredtheir diagnostic by RCM valuecorrelate for withmucosal histologic melanoma features, is not with adequately the difference recognized that RCM [10,11]. provides horizontal sections and conventionalReflectance confocal histology microscopy provides vertical(RCM) sectionsis a noninvasive of the tissue. technique Moreover, of skin the imaging, absence whichof the stratumproduces corneum high-resolution determines images a higher of the resolution upper 250 in theμm upper of the layers skin, thanand is in effective the skin inon distinguishing RCM, having abetween better-detailed benign visualizationand malignant of skin the cellularlesions [12]. morphology Recently, [12 the]. RCM de- vices dedicated to the skin have been also applied to perform “virtual biopsies” of the Diagnostics 2021, 11, 91 3 of 10 The mucosa is similar to the skin with an epithelium corresponding to the epidermis and a lamina propria corresponding to the dermis. Therefore, RCM shows in the epithelium the same honeycomb pattern of the epidermis, characterized by polygonal cells with a hyper-reflective outer part (mainly corresponding to the cellular membrane) and a hypo- reflective inner part (mainly corresponding to the cytoplasm); nuclei are easily visible as bright large round structures in the center of the cells. The lamina propria consists of bright collagen fibers arranged in bundles. Papillae are less evident than in the skin due to the flattened epithelium. When papillae are visible, they are edged and grouped in small clusters with a roundish or elongated shape, thus defining the “ringed” pattern and the “draped” pattern, respectively. Moreover, papillae are rimmed by monomorphous cells, corresponding to the basal epithelial cells that could be slightly more pigmented (and therefore brighter) than the suprabasal cells. Few dendritic bright cells corresponding to Langerhans cells can also be observed in healthy mucosa [14,15]. We realized