Liu Zijian, Xiao Yin, Liu Xinxiu, Li Qiuhui, Liu Tao, Zhu Fang, Wu Gang, Zhang Liling
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Oncol. 2021 Dec 6;11:755893. doi: 10.3389/fonc.2021.755893. eCollection 2021.
Histiocytic sarcoma (HS) is a rare hematopoietic malignancy with an aggressive clinical presentation associated with a poor overall survival. To date, surgical resection, radiation therapy, and chemotherapy were often utilized for HS, but curative effects are rather disappointing.
A 19-year-old female was referred to our hospital with a pathologic diagnosis of HS in December 2017. The patient had a severe airway obstruction resulting from a large mass (6.0 cm × 4.4 cm) arising from the left parapharyngeal space. She did not respond to cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOEP) chemotherapy, then she was switched to radiotherapy and crizotinib according to next-generation sequencing (NGS) results (mutations in MET and MAP2K1). The patient got a partial response after radiotherapy and crizotinib, then she switched to imatinib combined with thalidomide treatment. The patient got a long-term complete response from the treatment and is alive 44 months after initial diagnosis without disease progression. Further KEGG pathway enrichment analysis of NGS results from patient's tissue revealed that phosphatidylinositol 3' kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways were activated in this HS patient. We further performed experiments in a canine histiocytic sarcoma cell line DH82, in order to explore the possible mechanism of imatinib plus thalidomide in HS. Results of cell counting kit-8 (CCK8) assays showed that the proliferation activity of DH82 was significantly inhibited by imatinib but not thalidomide. Combined thalidomide and imatinib treatment did not improve the inhibitory effects of imatinib to DH82. Results of Western blot confirmed the inhibitory effects of imatinib on DH82 by targeting activation of MAPK and PI3K/AKT pathways.
Radiotherapy combined with targeted therapy guided by NGS may be promising, and further perspective clinical trial is warranted for the localized HS.
组织细胞肉瘤（HS）是一种罕见的造血系统恶性肿瘤，临床表现具有侵袭性，总体生存率较低。迄今为止，手术切除、放射治疗和化疗常用于HS，但疗效相当令人失望。
一名19岁女性于2017年12月因病理诊断为HS转诊至我院。患者因左侧咽旁间隙出现一个大肿块（6.0 cm×4.4 cm）导致严重气道阻塞。她对环磷酰胺、阿霉素、长春新碱、泼尼松和依托泊苷（CHOEP）化疗无反应，随后根据下一代测序（NGS）结果（MET和MAP2K1突变）改为放疗和克唑替尼治疗。患者在放疗和克唑替尼治疗后获得部分缓解，然后改为伊马替尼联合沙利度胺治疗。患者从治疗中获得长期完全缓解，初始诊断后44个月仍存活且无疾病进展。对患者组织的NGS结果进行进一步的KEGG通路富集分析显示，该HS患者的磷脂酰肌醇3'激酶（PI3K）/AKT和丝裂原活化蛋白激酶（MAPK）通路被激活。我们进一步在犬组织细胞肉瘤细胞系DH82中进行实验，以探索伊马替尼加沙利度胺治疗HS的可能机制。细胞计数试剂盒-8（CCK8）检测结果显示，伊马替尼可显著抑制DH82的增殖活性，而沙利度胺无此作用。沙利度胺和伊马替尼联合治疗并未增强伊马替尼对DH82的抑制作用。蛋白质免疫印迹结果证实伊马替尼通过靶向MAPK和PI3K/AKT通路的激活对DH82具有抑制作用。
NGS指导下的放疗联合靶向治疗可能具有前景，对于局限性HS有必要开展进一步的前瞻性临床试验。
