The WHO 2018 Classification of Cutaneous Melanocytic Neoplasms: Suggestions From Routine Practice

Abstract

The “multidimensional” World Health Organization (WHO) classification 2018 of melanocytic tumors encompasses nine melanoma pathways (seven of which for cutaneous melanoma) according to a progression model in which morphologically intermediate melanocytic tumors are cosidered as simulators and/or precursors to melanoma. These “intermediates” can be subclassified into: i) a “classical” subgroup (superficial/thin compound: dysplastic nevus), which is placed within the morphologic and molecular progression spectrum of classical (Clark’s and McGovern’s) melanoma subtypes (superficial spreading and, possibly, nodular); and ii) a “non-classical” subgroup (thick compound/dermal: “melanocytomas”) whose genetic pathways diverge from classical melanoma subtypes. Such a progression model is aimed at giving a conceptual framework for a histopathological classification; however, routine clinicopathological practice strongly suggests that most melanomas arise de novo and that the vast majority of nevi are clinically stable or even involuting over time. Clinicopathological correlation can help identify some severely atypical but benign tumors (e.g.: sclerosing nevus with pseudomelanomatous features) as well as some deceptively bland melanomas (e.g.: lentiginous melanoma; nested melanoma), thereby addressing some ambiguous cases to a correct clinical management. The recently available adjuvant therapy regimens for melanoma raise the problem of a careful distinction between severely atypical (high grade) melanocytoma and “classical” melanoma: conventional morphology can guide an algorithmic approach based on an antibody panel (anti-mutated BRAF, BAP1, PRAME, ALK, TRKA, MET, HRAS-WT, ROS; beta catenin; R1alpha; p16; HMB45; Ki67), a first-line molecular study (identification of hot spot mutations of BRAF and NRAS) and an advanced molecular study (sequencing of NF1, KIT, BRAF, MAP2K1, GNAQ, GNA11, PLCB4, CYSLTR2, HRAS; fusions studies of BRAF, RET, MAP3K8, PRKCA); as a final step, next-generation sequencing can identify melanocytic tumors with rare genetic signatures and melanocytic tumors with a high tumor mutation burden which should be definitely ascribed to the category of classical melanoma with the respective therapeutic options.

Comprehensive Analysis of Colorectal Cancer Immunity and Identification of Immune-Related Prognostic Targets

“…Overall, it has low expression in colon cancer as compared to adjacent normal tissues, suggesting it is a tumor suppressor gene. The expression of CYSLTR2 has also significantly been downregulated in multiple myeloma [ 38 ], melanoma [ 39 ], and colorectal cancer [ 34 ], which reveals its tumor suppressor function in other cancers also. In COAD, dysregulation of CYSLTR2 has been associated with the proliferation and migration of the cancer cells [ 40 ].…”

Molecular Markers and Targets in Melanoma

“…The World Health Organization (WHO) recognizes these challenges and incorporate the known molecular pathways in the latest WHO melanocytic tumor classification, introducing the concept of “intermediate” lesions. As stated in a recent review on the topic, this multidimensional classification showed that the view of melanocytic tumors as either benign or malignant might no longer be the proper approach [ 42 ]. Thus, WHO 2018 indicates nine categories/pathways leading to melanoma, each with specific genetic drivers ( Table 1 ).…”

“…Certainly, to reduce diagnostic uncertainties and maintain a diagnostic approach based on the WHO 2018 classification, histological assessment should be accompanied by basic immunohistochemistry (IHC) and molecular tests. Recent recommendations of the European Society of Pathology, the European Organization for Research and Treatment of Cancer, and the EURACAN for the diagnosis of intermediate melanocytic proliferations and melanoma variants indicate that most pathology laboratories should perform basic IHC tests, such as: HMB-45; SOX10; MITF, tyrosinase, MART-1; P16; Ki-67/MIB1; BAP1 (BRCA1-associated protein 1); β-catenin; PRAME; and at least one molecular method to detect BRAF codon 600 and NRAS mutations [ 42 ]. The most difficult cases that require complementary studies should be analyzed in specialized referral centers, where laboratories can determine a higher grade in a given lesion or the identification of molecular targets that can benefit from targeted therapy.…”

Dermoscopic Criteria, Histopathological Correlates and Genetic Findings of Thin Melanoma on Non-Volar Skin

“…A positive anti-PRAME immunostain can favour the diagnosis of a "traditional" melanoma from a nevus as well as loss of p16 by negative staining. Ki67 highlights mitotic figures [54].…”