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Original Investigation |

Association Between Confocal Morphologic Classification and Clinical Phenotypes of Multiple Primary and Familial Melanomas ONLINE FIRST

Thaís Corsetti Grazziotin, MD, PhD1,2,3; Ivette Alarcon, MD1; Renan Rangel Bonamigo, MD, PhD2; Cristina Carrera, MD, PhD1,4; Miriam Potrony, PhD1; Paula Aguilera, MD, PhD1,4; Joan-Anton Puig-Butillé, PhD1,4; Johanna Brito, MD1; Celia Badenas, PhD1,4; Llúcia Alós, MD1; Josep Malvehy, MD, PhD1,4; Susana Puig, MD, PhD1,4
[+] Author Affiliations
1Hospital Clinic I Provincial de Barcelona, Universitat de Barcelona and Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
2Department of Dermatology, Post-Graduation Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
3Pontifícia Universidade Católica do Rio Grande do Sul, School of Medicine, Porto Alegre, Brazil
4Centro de Investigación Biomédica en Red en Enfermedades Raras, Barcelona, Spain
JAMA Dermatol. Published online August 31, 2016. doi:10.1001/jamadermatol.2016.1189
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Importance  The improved knowledge of clinical, morphologic, and epidemiologic heterogeneity of melanoma in the context of multiple primary and familial melanomas may improve prevention, diagnosis, and prognosis of melanoma.

Objective  To characterize reflectance confocal microscopy (RCM) morphologic patterns of melanomas in multiple primary and familial melanomas.

Design, Setting, and Participants  In this cross-sectional, retrospective study, patients in a hospital-based referral center were recruited from March 1, 2010, through August 31, 2013; data analysis was conducted from September 1, 2013, through May 31, 2014. Consecutive primary melanomas, documented by dermoscopic and confocal examination, from multiple primary and familial melanomas with known CDKN2A mutational status were studied.

Main Outcomes and Measures  Epidemiologic, genetic, dermoscopic, and histologic data were evaluated according to an RCM morphologic classification: dendritic cell, round cell, dermal nest, combined, and nonclassifiable types.

Results  Fifty-seven melanomas from 50 patients (28 women [56%] and 49 white patients [98%]) were included: 23 dendritic cell (40%), 21 round cell (37%), 2 dermal nests (4%), 2 combined (4%), and 9 nonclassifiable (16%). The median (SD) age of the participants was 53.0 (16.9) years (interquartile range, 41.8-71.2 years), and the median (SD) age at the first melanoma was 46.0 (17.1) years (interquartile range, 35.8-61.5 years). Dendritic cell melanoma was characterized by older age at diagnosis, phototypes 2 and 3, more intense solar exposure, and moderate to severe solar lentigines; it was the most prevalent confocal type in facial lesions and was associated with the lentigo maligna histologic subtype. Round cell melanomas were identified more often in the familial context and in individuals with phototype 1 skin types; RCM features, such as junctional thickening, dense dermal nests, and nucleated cells within papillary dermis, were more frequently found in this subtype. Dermal nest and combined melanoma were associated with the absence of pigmented network on dermoscopy and thicker tumors on histologic analysis. Nonclassifiable type was associated, by RCM, with the absence of pagetoid cells on confocal examination and lower frequency of marked atypia on melanocytes in the basal cell layer; it presented with lower ABCD Total Dermoscopy Scores and RCM scores compared with the other types. CDKN2A mutation carriers may develop any RCM type of melanoma.

Conclusions and Relevance  Different routes to develop melanoma can be identified according to RCM morphologic classification, with dendritic cell melanomas being associated with chronic sun damage and round cell melanoma with early age at onset and phototype 1 in the context of multiple primary and familial melanomas. The morphologic expression of melanomas via dermoscopy and confocal examination varies according to differences in tumor stage and biological behavior.

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Figure 1.
Reflectance Confocal Microscopy Morphologic Presentation According to Confocal Microscopy Classification

A, Reflectance confocal microscopy reveals dendritic cells with large projections and nucleus within upper epidermis layers seen as an atypical cobblestone pattern; B, small round nucleated cells with refractive cytoplasm and dark nucleus in an atypical honeycomb epidermal pattern; C, large cerebriform nests formed by confluent aggregates of low reflecting cells, brainlike in appearance; D, pleomorphic cellular population with dendritic and round cells within a disarranged epidermis; and E, dermoepidermal junction with ringed pattern, edged and nonedged papillae with irregular junctional nests, and mild cytologic atypia in the basal layer.

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Figure 2.
Clinical and Dermoscopic Presentation According to Confocal Microscopy Classification

A (top), Dermoscopy reveals a melanocytic macular lesion on the left lateral trunk; A (bottom), reticular global pattern with atypical pigment network; B (top) melanoma on the right arm; B (bottom) globular pattern with irregular dots and globules and focal atypical network; C (top) slightly erythematous papular lesion on the frontal region; C (bottom) unspecific pattern with sparse atypical globules and vessels; D (top) palpable tumor on the infraescapular region; D (bottom) multicomponent pattern with atypical globules, blue whitish veil, blue regression, and short white streaks; E (top) flat melanocytic lesion on the forearm; and E (bottom) reticular pattern with atypical pigment network, structureless areas, and segmental streaks.

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Figure 3.
Histopathologic Presentation According to Confocal Microscopy Classification

A, Histopathologic presentation of an in situ superficial spreading melanoma; B, an in situ nevus-associated superficial spreading melanoma; C, a 1.1-mm-thick nevoid melanoma; D, an ulcerated 3.0-mm-thick superficial spreading melanoma; and E, a 0.2-mm-thick superficial spreading melanoma with more than 50% regression. Hematoxylin-eosin, original magnification ×100 (A), ×100 (B), ×40 (C), ×40 (D), and ×100 (E).

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