Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
Department of Pathology, La Timone Hospital, Marseille, France.
Mod Pathol. 2017 Dec;30(12):1677-1687. doi: 10.1038/modpathol.2017.91. Epub 2017 Jul 28.
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.
恶性外周神经鞘瘤的诊断仍然具有挑战性，尤其是在散发情况下。恶性外周神经鞘瘤是一种罕见的恶性肿瘤，由于缺乏特定的组织学标准、免疫组织化学和分子诊断标志物，必须考虑几个鉴别诊断，特别是黑色素瘤。最近，两个关键成分 SUZ12 和 EED 的失活突变导致多梳抑制复合物 2 (PRC2) 的失活，在很大一部分恶性外周神经鞘瘤中被报道。PRC2 的纯合失活诱导组蛋白 3 (H3) 赖氨酸 27 三甲基化 (H3K27me3) 的完全丧失。最近的研究表明，H3K27me3 的完全丧失对恶性外周神经鞘瘤具有高度特异性，可能是一种有用的免疫组织化学诊断标志物。因此，为了确定在黑色素瘤（其主要潜在模拟物）的鉴别诊断中，H3K27me3 完全缺失表达的特异性，我们在一组具有良好病理和遗传特征的原发性（神经纤维瘤病 1 (NF1)、放射相关和散发情况下）恶性外周神经鞘瘤（n=122）和一组原发性（促结缔组织增生性）和转移性黑色素瘤（n=265）中进行了 H3K27me3 免疫组织化学检测。总共 88 (72%) 例恶性外周神经鞘瘤，包括 46 (71%) NF1 相关、4 (100%) 放射相关和 38 (72%) 散发肿瘤，显示 H3K27me3 完全缺失。我们观察到组织学分级越高，H3K27me3 的丢失越多。有趣的是，我们在所有黑色素瘤中发现了 37%（n=98）的 H3K27me3 完全缺失，包括 25%（n=9）的原发性促结缔组织增生性黑色素瘤。此外，在所有恶性外周神经鞘瘤中观察到部分缺失（“镶嵌”模式）23 例（19%），所有黑色素瘤中观察到 136 例（51%）。免疫组织化学检测到的 H3K27me3 的完全缺失对恶性外周神经鞘瘤并不特异，在鉴别恶性外周神经鞘瘤与黑色素瘤时不能安全使用。
