Reduced H3K27me3 Expression is Common in Nodular Melanomas of Childhood Associated With Congenital Melanocytic Nevi But Not in Proliferative Nodules

    loading  Checking for direct PDF access through Ovid


In Reply:
We read with great interest the article “Reduced H3K27me3 expression is common in nodular melanomas of childhood associated with congenital melanocytic nevi but not in proliferative nodules” by Busam and colleagues, in the March 2017 issue of The American Journal of Surgical Pathology.
The pathologic distinction between melanoma and benign proliferative nodules developing within a large or giant congenital melanocytic nevus (CMN) can be extremely difficult. While such childhood melanomas are rare, they are often lethal. The authors reported diminished immunohistochemical expression of H3K27me3 in 4 of 5 such cancers arising in CMN, in contrast to proliferative nodules or adult-onset melanoma. Here, we report an additional case of bona fide lethal malignant transformation of a scalp CMN that was also characterized by loss of H3K27me3 immunoreactivity.
A child presented at birth with a medium-sized CMN (M1) of the scalp (Fig. 1A) measuring 10 cm in greatest dimension, heterogenously colored, with a rugose surface and displaying scattered dermal nodules (according to the classification of CMN by Krengel et al1). Incomplete resection was performed when the child was 18 months old. At 4 years old, he presented again following the rapid growth of a tumor within the remaining CMN (Fig. 1B), which was suspected to represent malignant transformation and was immediately resected. Sentinel lymph node biopsy was positive and in under a year, the melanoma metastasized to the parotid, lung, bone, and brain, leading to the patient’s death 8 months after diagnosis, despite combined Endoxan and Nivolumab treatment.
Histologically, the nevus displayed features consistent with CMN: superficial epithelioid pigmented melanocytes arranged in nests, with deeper maturation to a more spindle-like, diffuse architecture. Clinically and histologically, several proliferative nodules (Figs. 1C, E) were characterized by nondestructive, expansive dermal nodules with higher cell density than adjacent nevus, crowding, enlarged soma, and a more pronounced epithelioid or fusiform cytology. These proliferative nodules presented histologically reassuring features such as cellular blending with adjacent nevus, lack of high-grade cytonuclear atypia, absence of necrosis, no pagetoid spread, and a mitotic activity of <2 per mm2.
In contrast, the melanoma presented as a dense amelanotic dermal nodule measuring 15 mm in greatest diameter, with a 12 mm Breslow thickness (Fig. 1D). It displayed sharp demarcation from the adjacent nevus, thinning of the overlying epidermis without junctional activity, lymphovascular invasion, brisk mitotic activity (>50 mitoses/mm2) and isolated necrotic or apoptotic cells. The melanoma was composed of densely packed atypical melanocytes, with monomorphous basophilic small-cell cytology, scant cytoplasm, round vesicular nuclei, and variably sized eosinophilic nucleoli (Fig. 1F).
Immunohistochemically, the CMN and the dermal proliferative nodules displayed a mosaic pattern of staining for p16 (encoded by the CDKN2A gene) (Fig. 2A) and broadly expressed H3K27me3 (Fig. 2B, C, respectively). In contrast, the melanoma showed diffuse and intense staining with p16 (Fig. 2D), overexpression of Ki67 (30% to 80% of stained nuclei; Fig. 2E), as well as aberrant heterogenous expression of HMB45, strikingly widespread loss of Melan-A expression, and preserved nuclear expression of BAP1. On a molecular level, PCR-HRM followed by direct sequencing showed a c.37G>C (p.Gly13Arg) gain-of-function mutation of NRAS, without detectable mutations in BRAF or the TERT promoter. Consistent with the report by Busam and colleagues, >90% loss of H3K27me3 expression was noted in the melanoma (Fig. 2F), while retained in adjacent lymphocytes and in keratinocytes (which served as internal controls; Fig. 2G).
Epigenetic modifications are important events in the transformation of cells, as they can change gene transcription in a mitotically stable manner. Histones are methylated by EZH2, the catalytic core subunit of the Polycomb Repressive Complex (PRC2). The trimethylation of lysine 27 in histone H3 is associated with transcriptional silencing and sequestration to heterochromatin.
    loading  Loading Related Articles