Sclerosing melanocytic tumors with MAP2K1 in-frame deletions and copy number gains in 15q: a distinctive pathway of nevogenesis

We read with great interest the recent publication entitled “MAP2K1-mutated melanocytic tumors have reproducible histopathologic features and share similarities with melanocytic tumors with BRAF V600E mutations,” which provides an in depth analysis of the histomorphologic, immunophenotypic and cytogenetic features of six atypical melanocytic tumors harboring MAP2K1 in frame deletions.¹ Alomari et al. 2023 points out that these lesions may be recognized by the presence of SPARK-like architecture superficially and/or a desmoplastic Spitz nevus-like appearance deeper in the dermis. The degree of junctional atypia and pagetoid growth was variable in these cases. By immunohistochemistry (IHC) patchy-weak p16 expression and incomplete HMB45 stratification were common findings. Interestingly, all 6 cases demonstrated chromosomal copy number changes, with 5/6 demonstrating a gain in chromosome 15. In 2/6 cases, gain in 15q and loss of X were the sole aberrations.

Recently, one of the current authors (BJF) was asked to review a shave biopsy taken from the leg of 75-year-old Caucasian female 13 years prior, at the request of the clinician who noted unusual recurrent pigmentation at the clinical site over time. The original interpretation was that of a “compound nevus, consistent with congenital type”. On retrospective re-examination, atypical features were identified which included moderate pagetoid growth, dermal sclerosis, and a population of enlarged Spitzoid-appearing melanocytes at various levels within the dermis. Rare mitotic activity was identified, and the lesion was transected at the base (Figure 1). Further IHC revealed patchy-to-weak p16 expression, incomplete HMB45 stratification, and no labeling with PRAME. SNP array demonstrated a gain of 15q and loss of X (with the latter felt to represent an age-related change), findings which made melanoma unlikely (Figure 2). Despite the reduction in p16 expression on IHC, there was no evidence of CDKN2A deletion on 9p, raising the possibility of a copy neutral mutation or epigenetic alteration. It was recommended that the clinically recurrent lesion be re-excised given these constellation of atypical features, with the ultimate excision specimen demonstrating residual/recurrent atypical nevus retaining similar features with no evidence of melanoma (Figure 3).

Figure 1.

Shave biopsy of a melanocytic lesion from the right leg of a then 62-year-old Caucasian female. At lower power (top panel), there is a broad junctional component which extends slightly beyond the dermal component. There is a suggestion of maturation with spindling of the cells lower in the dermis. However, on closer inspection (bottom panel, right) the melanocytes in the deeper portion of the biopsy are associated with sclerotic collagen and there are scattered enlarged- atypical appearing epithelioid cells, some with prominent nucleoli and some retaining cytoplasmic melanin. There is apparent cytomorphologic atypia and occasional pagetosis of heavily pigmented melanocytes within the epidermis (bottom panel, left).

Figure 2.

HMB 45 and p16 immunohistochemistry from the right leg lesion (top panel). SNP array copy number plot demonstrating a gain in 15q and loss of X (middle panel). Characteristics of the MAP2K1 mutation (lower panel).

Figure 3.

Re-excision specimen of the right leg lesion. At lower power (top panel), there is a melanocytic proliferation arising within a scar, with the the junctional component roughly approximating the dermal component. On closer inspection of the dermo-epidermal junction (bottom panel, right) there are heavily pigmented melanocytes with rare pagetosis. In the dermis (bottom panel, left) there are scattered enlarged, epithelioid and spindled melanocytes within a background of sclerotic collagen.

On further literature review, a similar gain in 15q was reported by Olson et al. 2021 in a cohort (n=8) of atypical melanocytic nevi. Olson et al. 2021 described their lesions to have consistent histomorphologic features of a wedge-shaped intradermal component accompanied by sclerosis and maturation partially impaired by the presence of enlarged epithelioid melanocytes at various levels within the dermis.² Upon reviewing the more recent analysis by Alomari et al. 2023, it is felt that the current lesion in question and those reported by Olson et al. 2021 may in fact all represent subtle variations of an otherwise distinctive melanocytic tumor.² Given these similarities, follow-up sequencing analysis in the current case was pursued and confirmed the presence of an underlying MAP2K1 driver mutation, strengthening the association of MAP2K1 in frame deletions with gains in 15q.

Given the similarities of the current lesion together with those reported by Alomari et al 2023 and Olsen et al 2021, we believe these represent subtle variations of an otherwise distinctive melanocytic tumor (Table 1)^1,2 As a reproducible entity, it remains to be seen how it may be best classified in the next edition of the World Health Organization (WHO) classification of cutaneous melanocytic neoplasms. We feel that the dermal sclerosis, impaired maturation/pseudomaturation with Spitz-epithelioid cytomorphology, aberrant p16 and HMB45 staining patterns, low mitotic activity and occasional pagetoid growth evident in these should probably be regarded as genuine atypia/dysplasia. With greater awareness, we believe that dermatopathologists should be able to distinguish it from the more common papular congenital-pattern nevi that demonstrate true maturation/ neurotization more indicative of senescence. The possibility that this constellation of features could implicate the potential for further progression and malignant degeneration over a variable period of time warrants further study.

Table 1.

Summary of reported cases of sclerosing melanocytic tumors with pseudomaturation, gain in 15q and/or confirmed MAP2K1 frame deletions

Report	No. Of Cases	Age Range	Gender	Anatomic Location	Epidermal or Dermal	Somatic Variant of MAP2K1	Gain in chromosome 15?
Olson et al. 2021	8	40-> 74	Female (6) Male (2)	Extremity (5) Trunk (3)	Compound (7) Dermal (1)	Not assessed	Yes
Alomari et al. 2023	5	30-> 66	Female (4) Male (1)	Extremity (5)	Compound (5)	p.I102_K104del (3) p.Q58_E62del (2)	Yes
Hamad et al. 2023 (current report)	1	61	Female	Extremity	Compound	c.171_185del	Yes

The vast majority of melanocytic tumors with MAP2K1 mutations and gains in 15q reported to date were recognized as atypical and re-excised at the time of diagnosis. Designation as a low grade melanocytoma might be considered on the basis of the histomorphologic atypia and the presence of two molecular alterations: pathogenic deletion in MAP2K1 and duplication of 15q. Based on prior reports describing the morphologic diversity of melanocytic tumors with MAP2K1 in frame deletions, it does not appear that gains in 15q are inevitable sequelae of this particular mutation and it may therefore be considered specific to the entity described herein.^3–5

In the current case, it was not entirely possible to rule out evolving melanoma in-situ, as the most atypical junctional portion of the lesion could have been diluted out on SNP array analysis. However, this is considered less likely given the considerably less junctional atypia evident on the years later re-excision specimen. We hypothesize that the most atypical portion of the tumor at the junction was removed via the initial saucerization accounting for the very slow, low-grade recurrence over time. Dermatopathologists should consider recommending complete excision of thick, partially sampled melanocytic tumors with these features to minimize the risk of further progression until its true biologic potential is better elucidated.