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.

Keywords: clinicopathological correlation; dysplastic nevus; histopathology; immunohistochemistry; melanocytoma; melanoma; molecular biology.

Figure 1

Man, 54 years; a severely atypical melanocytic tumor of the abdomen characterized by a flat pigmented area with an eccentric nodule (A). On dermoscopy, the flat area is typified by a prominent and focally irregular pigment network, whereas the nodular area is characterized by an atypical vascular pattern (B). Histopathologically, the tumor is strikingly asymmetric (C; hematoxylin–eosin, ×25), with a broad highly cellular “shoulder” composed by junctional melanocytes arranged in irregular nests and in single unit (D; hematoxylin–eosin, ×400); the severely atypical junctional component spans above the dermal nodule, the latter being characterized by a lymphoid cell infiltrate (E; hematoxylin–eosin, ×250) and nests of nevocytes intermingled with moderately pleomorphic epithelioid melanocytes with “inclusion-like” cytoplasms (F; hematoxylin–eosin, ×400); all the melanocytic components of this tumor were BRAFv600e mutated protein positive (not shown) and only the dermal epithelioid cell component disclosed loss of the nuclear expression of BAP1 (G; ×250). The tumor was interpreted as an early melanoma developing as a neoplastic progression of a common nevus and not as a progression of a BIN.

Figure 2

Woman, 44 years; a reddish nodule of the thigh (A). Histopathology shows an expansile dermal nodule (B hematoxylin–eosin, ×25) composed by nests of epithelioid cells (C hematoxylin–eosin, ×250) and fascicles of spingle cells separated by thin fibrotic bands (D hematoxylin–eosin, ×250); the proliferation rate (Ki67-positive cells) is 5%, with no clusters of proliferating cells (E; ×250); the tumor cells are diffusely positive for TRKA (F; ×400). Molecular studies allowed to exclude the possibility of a dermal clear cell sarcoma and to establish a diagnosis of CRTC1-TRIM1 fused melanocytoma. Courtesy of Dr. Arnaud de la Fouchardière, Lyon, F.

Figure 3

(A–D) man, 53 years; a pigmented lesion of the back with a slightly irregular pigment network (A); after six months, the tumor appears as uniformly enlarged, with increasingly irregular pigment network (B). Histopathologically, the tumor is strikingly asymmetric (C; hematoxylin–eosin, ×25), with a lichenoid infiltrate at the base of its more severely atypical half (D; hematoxylin–eosin, ×100). Even if the histopathological picture might be interpreted as a melanoma in situ developing in the background of a dysplastic nevus, the homogeneous remodeling of the tumor documented with dermoscopic digital monitoring favored the diagnosis of melanoma de novo. E-H: Woman, 35 years; a pigmented lesion of the back with a thin and regular pigment network at the baseline (E); after eight months, a raised bluish areas is evident at the periphery (“dermoscopic island”) (F). Histopathologically the tumor shares with the previous case the striking asymmetry (G) hematoxylin-eosin, ×25) and the presence of a lichenoid infiltrate at the base of its more severely atypical half (H) hematoxylin-eosin, ×100). However, dermoscopic digital follow up data clarify that this case likely represents an early melanoma in situ over a junctional dysplastic nevus.

Figure 4

Man, 38 years at the time of the surgical excision of a pigmented lesion of the scapular area; at the baseline, the tumor shows a a relatively regular peripheral pigment network associated with slightly eccentric globules and a central bluish area (A) the tumor shows a progressive and relatively symmetric fading after 1 year (B), four years (C), and 6 years (D). The tumor discloses a “trizonal” histopathological pattern (E; hematoxylin–eosin, ×25), with an atypical junctional component, a scar-like dermal thickening (F; hematoxylin–eosin, ×100) and a very bland-appearing deep dermal component (G; hematoxylin–eosin, ×100); the proliferation rate (Ki67-positive dermal melanocytes, evaluated with a KI67/MART1 double stain) is very low (H; ×250). These histopathological features are consistent with the so-called “sclerosing nevus with pseudomelanomatus features”. Such a histopathological diagnosis is in keeping with the slowly progressive and relatively symmetrical involution of the tumor, as documented with dermoscopic digital monitoring. Clinical images provided by Dr. Luigi Ligrone, Salerno, I.

Figure 5

(A–E) Man 52 years. Dermoscopy of a large pigmented lesion of the back with an irregular pigment network at the baseline (A) after one year, the lesion shows an increase in size with a homogeneous remodeling and a more prominent pigment network (B) such a slow clinical evolution is akin to a lentigo maligna of chronically sun-exposed skin and virtually excludes a diagnosis of nevus. Histopathologically, the tumor has a dysplastic nevus-like silhouette (C; hematoxylin–eosin, ×25) but is severely atypical because of the striking predominance of tightly packed single melanocytes at the junction (D; hematoxylin–eosin, ×100). PRAME immunostain shows a strong and diffuse nuclear positivity in intraepidermal melanocytes (E) ×250), as expected in melanoma. Clinicopathological features of the lesion are diagnostic for lentiginous melanoma in situ. (F–I) Man, 59 years. A large pigmented lesion of the abdomen, dermoscopically characterized by tiny eccentically grouped globules and structureless peripheral areas (F) after seven months the peripheral strucureless areas show a clear-cut increase in size (G). Histopathologically there are some areas with a dysplastic nevus-like silhouette, but the epidermis is largely atrophic (H; hematoxylin–eosin, ×25) and junctional nests are very large and irregular (I; hematoxylin–eosin, ×250). These features suggest a diagnosis of melanoma in situ with a focally “nested” architecture.

Figure 6

Woman, 22 years. An ulcerated nodule of the right flank (A) dermoscopically characterized by keratoacanthoma-like features with vessels surrounded by a white halo (B). Histopathologically, the tumor has an irregularly nodular, exophytic silhouette with an epidermal “collarette”, a superficial crust, and a “brisk” inflammatory infiltrate in the dermis (C; hematoxylin–eosin, ×25); the superficial nests are very irregularly confluent with no sharp circumscription from the overlying epidermis (D; hematoxylin–eosin, ×250); dermal melanocytes show a “spitzoid” morphology, with spindle (E; hematoxylin–eosin, ×400) and epthelioid (F; hematoxylin–eosin, ×400) cells, both with reatively abundant and eosinophilic cytoplasms. In spite of the severe architectural atypia, the proliferation rate of the tumor (Ki67-positive dermal melanocytes) is low (G) ×250); however, the tumor is not an atypical Spitz tumor, but a classical nodular melanoma because it is positive to the antibody anti-BRAFv600e-mutated protein (H) ×250).

Figure 7

A flow chart illustrating a therapy-oriented morphomolecular approach to atypical dermal-based tumorigenic melanocytic neoplasms. Of paramount importance are: i) the distinction between melanocytomas (recognized as such by specific genetic signatures) and melanocytic tumors of uncertain malignant potential (MEL.T.U.M.P.; provisionally defined as tumors with unknown driver mutations); ii) among melanocytomas, the distinction between low-grade and high-grade tumors; iii) among MELTUMP, the distinction between tumors with a low tumor mutation burden and tumors with a a high tumor mutation burden, the latter being best managed as per “classical” melanoma.