The diagnosis of
malignant peripheral nerve sheath tumor remains challenging, especially in the sporadic setting.
Malignant peripheral nerve sheath tumor is a rare
malignancy, and owing to the lack of specific histological criteria, immunohistochemical and molecular diagnostic markers, several differential diagnoses must be considered, in particular
melanoma. Recently, inactivation of the
polycomb repressive complex 2 (PRC2), induced by inactivating mutations in two of its critical constituents SUZ12 and EED, was reported in a large subset of
malignant peripheral nerve sheath tumors. Homozygous PRC2 inactivation induces complete loss of trimethylation at
lysine 27 of
histone 3 (H3K27me3). Recent studies suggest that complete loss of H3K27me3 is highly specific for
malignant peripheral nerve sheath tumor and may be a useful immunohistochemical diagnostic marker. Therefore, to determine the specificity of the complete loss of H3K27me3 expression in the context of the differential diagnosis of
malignant peripheral nerve sheath tumor from
melanoma (its major potential mimic), we performed H3K27me3 immunohistochemistry in a pathologically and genetically well-characterized cohort of primary (
neurofibromatosis type 1 (NF1), radiation-associated and sporadic context)
malignant peripheral nerve sheath tumors (n=122) and in a cohort or primary (desmoplastic) and metastatic
melanomas (n=265). In total, 88 (72%)
malignant peripheral nerve sheath tumors, including 46 (71%) NF1-associated, 4 (100%) radiation-associated, and 38 (72%) sporadic
tumors, showed complete loss of H3K27me3. We observed increased loss of H3K27me3 with increasing histological grade. Interestingly, we found complete loss of H3K27me3 in 37% (n=98) of all
melanomas, including 25% (n=9) of primary desmoplastic
melanomas. Moreover, partial loss ('mosaic' pattern) was observed in 23 (19%) of all
malignant peripheral nerve sheath tumors and in 136 (51%) of all
melanomas. Complete loss of H3K27me3 detected by immunohistochemistry is not specific for
malignant peripheral nerve sheath tumor and cannot be used safely when distinguishing
malignant peripheral nerve sheath tumor from
melanoma.