Carmelo Urso

Melanocytes with clear vacuolated cytoplasm and scalloped nuclei, resembling mature sebocytes, can occur in congenital, acquired, and blue melanocytic nevi but are rare in malignant melanomas. A case of primary cutaneous melanoma with sebocyte-like cells is reported. The patient was a 75-year-old male patient with a large pigmented lesion located on his right forearm. Histopathologically, the tumor showed two distinctive types of neoplastic cells: atypical melanocytes with eosinophilic cytoplasm and scattered cells with scalloped nuclei, sometimes containing pseudoinclusions, and clear multivacuolated cytoplasm, closely mimicking sebaceous differentiation. Immunohistochemically, sebocyte-like cells were positive for SOX10, PRAME, EMA, and factor XIIIa. A literature review identified six additional cases, three metastatic and three primary melanomas with sebocytes-like cells. Histopathologically, two variants were recognized. In addition to conventional melanoma cells, most of lesions (three metastatic and two primary tumors) contained sebocyte-like melanocytes only; two primary tumors showed sebocyte-like cells mixed to other clear cells, such as intermediate and/or balloon melanocytes.

Melanocytic nevi can show a great number of morphological, cytoarchitectural, and stromal variations. Some of these histopathological patterns, infrequent or unusual, can occasionally produce diagnostic doubts or problems. A 22-year-old female patient presented a poorly pigmented cutaneous polypoid lesion of the scalp. Histopathological examination showed an intradermal melanocytic nevus composed of aggregates, nests, and cords of benign melanocytes, with collagenous stroma and large lipomatous areas. In the lipidized portion of the lesion, nevus cells, arranged in clusters, nests, and cords, were intimately associated with mature-appearing adipocytes, CD34-positive spindle cells, Alcian Blue–positive fibromyxoid stroma, and eosinophilic collagen bundles, findings resembling those typically seen in spindle cell lipoma. Spindle cell lipomatous metaplasia, rarely observed in some benign nonmelanocytic skin lesions, can be considered an additional unusual, not previously described, stromal variation occurring in melanocytic nevi.

After 25 years, “Ackerman’s conundrum”, namely, the distinction of benign from malignant Spitz neoplasms, remains challenging. Genomic studies have shown that most Spitz tumors harbor tyrosine and serine/threonine kinase fusions, including ALK, ROS1, NTRK1, NTRK2, NTRK3, BRAF and MAP3K8, or some mutations, such as HRAS and MAP3K8. These chromosomal abnormalities act as drivers, initiating the oncogenetic process and conferring basic bio-morphological features. Most Spitz tumors show no additional genomic alterations or few ones; others harbor a variable number of mutations, capable of conferring characteristics related to clinical behavior, including CDKN2A deletion and TERT-p mutation. Since the accumulation of mutations is gradual and progressive, tumors appear to form a bio-morphologic spectrum, in which they show a progressive increase of clinical risk and histological atypia. In this context, a binary classification Spitz nevus-melanoma appears as no longer adequate, not corresponding to the real genomic substrate of lesions. A ternary classification Spitz nevus-Spitz melanocytoma-Spitz melanoma is more adherent to the real neoplastic pathway, but some cases with intermediate ambiguous features remain difficult to diagnose. A prognostic stratification of Spitz tumors, based on the morphologic and genomic characteristics, as a complement to the diagnosis, may contribute to better treatment plans for patients.

Clear-cell dermal duct tumor is a benign adnexal neoplasm composed of dermal multiple solid islands of clear cells, displaying ductal differentiation. Histopathologically, lesions can be subdivided into 2 distinct subgroups: (1) “pure” clear-cell dermal duct tumors, entirely composed of clear cells, and (2) “mixed” clear-cell dermal duct tumors, showing an associated conventional poroid component. Such a subclassification may be significant for the differential diagnosis: the less frequent “mixed” variant may be more easily recognized because of the presence of poroid and cuticular cells and the more frequent “pure” variant is to be distinguished from many other benign and malignant dermal clear-cell epithelial tumors.

Folliculosebaceous cystic hamartoma is a cutaneous malformation composed of a cystic folliculosebaceous structure associated with mesenchymal elements, generally consisting of fibrous stroma, adipocytes and small vascular channels. We report the case of a 55-year-old female patient with a cutaneous nodule of the right nasal wing. Microscopically, the lesion showed a dilated hair follicle with multiple sebaceous glands, surrounded by a mesenchymal component composed of fibromyxoid stroma, spindle cells, mature-appearing adipocytes and collagen bundles, resembling spindle cell lipoma, associated with an additional neural component, consisting of small nerve bundles. In folliculosebaceous cystic hamartoma, the association of spindle cell lipomatous and neural components has not previously reported.

Over the past several decades, the study of Spitz neoplasms has flourished, with expanded conceptualization and refined terminology, providing a framework for the assessment and classification of Spitz nevi, atypical Spitz Tumors, and Spitz melanoma. Cancer genomics have generated concepts such as driver and passenger genes and clonal evolution, which can be applied to Spitz tumors. Herein, we provide a historical perspective, followed by a summary of current knowledge and clinical approaches for these challenging tumors.

Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.

Citation: Urso C. Melanocytic skin tumors: genetic aberrations and clinicopathological classification. Dermatol Pract Concept. 2020;10(1):e2020005. DOI: https://doi.org/10.5826/dpc.1001a05 Accepted: September 29, 2019; Published: December 31, 2019 Copyright: ©2019 Urso. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The author has no conflicts of interest to disclose. Authorship: The author takes responsibility for this publication. Corresponding author: Carmelo Urso, MD, Dermatopathology Study Center of Florence, Via Della Cernaia, 88, I-50129 Florence, Italy. Email: cylaur@libero.it

Studies on the genomic aberrations in melanocytic neoplasms have shown a complex genomic landscape. In nevi and melanomas, a MAP-kinase pathway activation was generally found, produced by different chromosomal aberrations, including BRAF, NRAS, HRAS, GNAQ, GNA11, BAP1, CTNNB1, MAP2K1, PRKAR1A, and NF1 mutations, and ALK, ROS1, NTRK1, RET, MET, BRAF, NTRK3, and PRKCA fusions. Melanomas also showed a variable number of additional mutations ablating tumor-suppression mechanisms and activating other oncogenic pathways, including CDKN2A loss, PTEN loss, as well as TP53 and TERT-promoter mutations. Moreover, borderline melanocytic tumors displayed the same chromosomal aberrations, but more mutations than nevi and fewer than melanomas. In this context, the notion that melanocytic neoplasms can be classified as benign/malignant is hardly supportable, because all neoplasms harbor a certain number of mutations and the progression risk, that is, the malignant potential, is related and proportional to the burden of pathogenic mutations. Moreover, from the genomic analysis, in parallel to the current diagnostic categories of “nevi,” “melanomas,” and “melanocytomas,” some aggregations or classes of tumors based on the characteristic types of driver mutations/fusions emerge as possible and more rationale, including Spitzoid neoplasms, blue neoplasms, BAP1-inactivated melanocytic neoplasms, deep penetrating melanocytic neoplasms, pigment-synthesizing melanocytic neoplasms, and “common” melanocytic neoplasms. Each of these classes, showing the same driver mutations/fusions, demonstrates to have the same pathogenesis and may be genetically considered as a single tumor, although with a variable amount of progression risk. Histologic features, being an expression of the mutational state, could be used to obtain an approximate risk assessment in each single tumor.