Otsuka Hiroshi, Kohashi Kenichi, Yoshimoto Masato, Ishihara Shin, Toda Yu, Yamada Yuichi, Yamamoto Hidetaka, Nakashima Yasuharu, Oda Yoshinao
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Pathol Res Pract. 2018 Mar;214(3):417-425. doi: 10.1016/j.prp.2017.12.015. Epub 2018 Jan 31.
The histological definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is quite difficult because the morphological features are not specific and no useful immunohistochemical marker has been identified. Loss-of-function mutations in EED or SUZ12, which encode the core subunit of polycomb repressive complex 2 (PRC2), were reported in MPNSTs, and the mutations were shown to cause inactivation of PRC2, leading to loss of trimethylation of histone H3 at lysine 27 (H3K27me3). Immunohistochemistry of H3K27me3 is expected to be a specific marker for MPNSTs. We evaluated immunohistochemical expression of H3K27me3 in MPNSTs with heterologous components and metachronous cases of MPNSTs. Among 145 MPNST samples, 50 (34.5%) showed complete loss of staining, and 45 (31.0%) showed partial loss of staining. Regarding the backgrounds of MPNSTs, 43 patients of neurofibromatosis type 1 (NF-1)-associated MPNST demonstrated 19 (44.2%) complete and 12 (27.9%) partial loss of H3K27me3. Among MPNSTs with heterologous component, almost all of MPNSTs with epithelioid differentiation (8/9 samples, 88.9%) retained H3K27me3, and malignant Triton tumors without epithelioid component lacked H3K27me3 at high rate (91.7%). Five of 20 metachronous MPNST cases showed significantly reduced expression of H3K27me3 between primary and later-occurring tumors, but in some cases increased expression of H3K27me3 in the clinical course (such as complete loss to partial loss) was observed. If the tumors are recurrent or metastatic, H3K27me3 expression should be reduced or at least maintained because loss of H3K27me3 is due to genetic mutation of EED or SUZ12. MPNSTs, especially those associated with NF-1, can occur in heterochronous and multiple patterns, and the identification of increased expression of H3K27me3 during a patient's clinical course can be helpful for determining whether the tumors are heterochronous, multiple or not. As heterochronous and multiple tumors may show lower malignancy compared to recurrent or metastatic tumors, favorable prognosis may be expected when H3K27me3 expression is increased.
恶性外周神经鞘瘤（MPNST）的组织学确诊相当困难，因为其形态学特征不具特异性，且尚未发现有用的免疫组化标志物。据报道，MPNST中存在EED或SUZ12的功能丧失性突变，这两种基因编码多梳抑制复合物2（PRC2）的核心亚基，且这些突变会导致PRC2失活，进而导致组蛋白H3赖氨酸27位点（H3K27me3）的三甲基化缺失。H3K27me3的免疫组化有望成为MPNST的特异性标志物。我们评估了H3K27me3在伴有异源成分的MPNST以及MPNST异时性病例中的免疫组化表达情况。在145例MPNST样本中，50例（34.5%）显示染色完全缺失，45例（31.0%）显示染色部分缺失。关于MPNST的背景情况，43例1型神经纤维瘤病（NF-1）相关的MPNST中，19例（44.2%）显示H3K27me3完全缺失，12例（27.9%）显示部分缺失。在伴有异源成分的MPNST中，几乎所有具有上皮样分化的MPNST（8/9样本，88.9%）保留了H3K27me3，而无上皮样成分的恶性蝾螈瘤H3K27me3缺失率较高（91.7%）。20例MPNST异时性病例中有5例在原发肿瘤和后续发生的肿瘤之间显示H3K27me3表达显著降低，但在某些病例中也观察到临床病程中H3K27me3表达增加（如从完全缺失到部分缺失）。如果肿瘤是复发或转移的，H3K27me3表达应降低或至少维持不变，因为H3K27me3的缺失是由于EED或SUZ12的基因突变所致。MPNST，尤其是与NF-1相关的MPNST，可呈异时性和多发性模式，在患者临床病程中识别H3K27me3表达增加有助于确定肿瘤是否为异时性、多发性。由于异时性和多发性肿瘤相比复发或转移性肿瘤可能显示较低的恶性程度，当H3K27me3表达增加时可能预示预后良好。
