Objective: To investigate the clinicopathological, immunophenotypic, and genetic features of malignant peripheral nerve sheath tumor (MPNST). Methods: Twenty-three cases of MPNST were diagnosed at the Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University), China, between January 2012 and December 2022 and thus included in the study. EnVision immunostaining and next-generation sequencing (NGS) were used to examine their immunophenotypical characteristics and genomic aberrations, respectively. Results: There were 10 males and 13 females, with an age range of 11 to 79 years (median 36 years), including 14 cases of neurofibromatosis type I-associated MPNST and 9 cases of sporadic MPNST. The tumors were located in extremities (7 cases), trunk (4 cases), neck and shoulder (3 cases), chest cavity (3 cases), paraspinal area (2 cases), abdominal cavity (2 cases), retroperitoneum (1 case), and pelvic cavity (1 case). Morphologically, the tumors were composed of dense spindle cells arranged in fascicles. Periphery neurofibroma-like pattern was found in 73.9% (17/23) of the cases. Under low magnification, alternating hypercellular and hypocellular areas resembled marbled appearance. Under high power, the tumor cell nuclei were irregular, presenting with oval, conical, comma-like, bullet-like or wavy contour. In 7 cases, the tumor cells demonstrated marked cytological pleomorphism and rare giant tumor cells. The mitotic figures were commonly not less than 3/10 HPF, and geographic necrosis was often noted. Immunohistochemically, tumor cells were positive for S-100 (14/23, 60.9%) and SOX10 (11/23, 47.8%). The loss of the CD34-positive fibroblastic network encountered in neurofibromas was observed in 14/17 of the MPNST cases. The loss of H3K27me3 expression was observed in 82.6% (19/23) of the cases. Moreover, SDHA and SDHB losses were presented in one case. NGS revealed that NF1 gene loss of function (germline or somatic) were found in all 5 cases tested. Furthermore, four cases accompanied with somatic mutations of SUZ12 gene and half of them had somatic mutations of TP53 gene, while one case with germline mutation in SDHA gene and somatic mutations in FAT1, BRAF, and KRAS genes. Available clinical follow-up was obtained in 19 cases and ranged from 1 to 67 months. Four patients died of the disease, all of whom had the clinical history of neurofibromatosis type Ⅰ. Conclusions: MPNST is difficult to be differentiated from a variety of spindle cell tumors due to its wide spectrum of histological morphology and complex genetic changes. H3K27me3 is a useful diagnostic marker, while the loss of CD34 positive fibroblastic network can also be a diagnostic feature of MPNST. NF1 gene inactivation mutations and complete loss of PRC2 activity are the common molecular diagnostic features, but other less commonly recurred genomic aberrations might also contribute to the MPNST pathogenesis.
目的： 探讨恶性外周神经鞘膜瘤（malignant peripheral nerve sheath tumor，MPNST）的临床病理学特征、免疫表型及分子遗传学特征。 方法： 收集江苏省人民医院（南京医科大学第一附属医院）2012年1月至2022年12月诊治的23例MPNST，观察其临床及组织病理学、免疫组织化学及分子病理特点，并复习相关文献。 结果： 患者中男性10例，女性13例，年龄11~79岁（中位年龄36岁），其中Ⅰ型神经纤维瘤病（neurofibromatosis type 1，NF-1）相关MPNST患者14例，散发性MPNST患者9例。发生于四肢7例、躯干4例、颈肩部3例、胸腔3例、脊柱旁2例、腹腔2例、腹膜后1例、盆腔1例。组织学上肿瘤主要由条束状增生、紧密排列的梭形细胞组成，17例（17/23，73.9%）肿瘤边缘可见神经纤维瘤样区域。低倍镜下可见肿瘤细胞丰富区与稀疏区交替镶嵌分布，形成大理石样外观。高倍镜下肿瘤细胞核形不规则，呈卵圆形或锥形、子弹头样或细长波浪样，7例肿瘤细胞明显多形性，可见瘤巨细胞；核分裂象活跃（≥3个/10 HPF），常可见地图样坏死。免疫组织化学：肿瘤细胞阳性表达S-100蛋白（14/23，60.9%）、SOX10（11/23，47.8%）；CD34纤维网格缺失（14/17），H3K27me3表达缺失（19/23，82.6%），1例出现SDHA及SDHB表达缺失。5例行二代测序患者中均发生NF1基因胚系或体系功能缺失性变异；4例有SUZ12基因体系突变，其中2例伴有TP53突变；1例伴有SDHA基因胚系突变及FAT1、BRAF、KRAS基因体系突变。随访19例，随访时间1~67个月；4例死亡，且均有NF-1病史。 结论： MPNST的形态学谱系广泛，基因改变复杂，需与多种梭形细胞肿瘤鉴别。H3K27me3完全缺失是诊断MPNST的重要免疫标记，CD34纤维网格不完整常提示神经纤维瘤恶性转化，NF1基因功能缺失性变异及PRC2基因复合物功能失活是较常见的分子诊断辅助依据，可能还伴有其他基因改变。.