卵巢高钙血症型小细胞癌的研究进展

doi:10.12280/gjfckx.20210203

摘要/Abstract

摘要：

卵巢高钙血症型小细胞癌（small cell carcinoma of the ovary-hypercalcemic type,SCCOHT）是一类原发于卵巢的高度恶性、预后极差的罕见妇科肿瘤,常见于年轻女性。尽管该肿瘤的确切起源目前尚不明确,组织形态学上也与其他发生于卵巢的小细胞肿瘤较难鉴别,由于其临床罕见性,目前也没有明确的治疗方案指南,但是近年其分子发病机制方面有了一些突破性的研究进展。SCCOHT的基因组为二倍体,以SMARCA4的突变和SMARCA2的表达缺失为特征。免疫组织化学染色中两者所编码的BRG1和BRM蛋白表达的缺失成为了病理诊断中鉴别该肿瘤的重要手段。此外还出现了一些针对致病分子的靶向药物等治疗方案的研究。现主要对该肿瘤的临床病理特征、鉴别诊断、发病机制及治疗等方面的研究进展进行分析总结,以期进一步加深对该类病变的认识,为更加精准的诊断治疗奠定基础。

关键词: 卵巢肿瘤, 癌,小细胞, 卵巢高钙血症型小细胞癌, 诊断, 治疗

Abstract:

Primary small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. Although the origin of SCCOHT is still obscure, it is difficult to differentiate from other ovarian small cell tumors in histomorphology, and there are no definite treatment guidelines as the rarity, some breakthrough progress has been made in the molecular pathogenesis recent years. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression. The lack of expression of BRG1 and BRM proteins encoded by these two genes in immunohistochemical staining has become an important means to identify the tumor in pathological diagnosis. In addition, there are also some studies on treatment, such as targeted drugs for pathogenic molecules. In this review, the clinicopathological characteristics, differential diagnosis, pathogenesis and treatment of SCCOHT were analyzed and summarized, in order to further deepen the understanding of this disease and lay the foundation for more accurate diagnosis and treatment.

Key words: Ovarian neoplasms, Carcinoma,small cell, Small cell carcinoma of the ovary-hypercalcemic type, Diagnosis, Therapy

徐燕宁, 刘易欣, 陈凌. 卵巢高钙血症型小细胞癌的研究进展[J]. 国际妇产科学杂志, 2021, 48(5): 548-552.

XU Yan-ning, LIU Yi-xin, CHEN Ling. Advances in Small Cell Carcinoma of the Ovary-Hypercalcemic Type[J]. Journal of International Obstetrics and Gynecology, 2021, 48(5): 548-552.

参考文献 26

[1]	Patibandla JR, Fehniger JE, Levine DA, et al. Small cell cancers of the female genital tract: Molecular and clinical aspects[J]. Gynecol Oncol, 2018,149(2):420-427. doi: 10.1016/j.ygyno.2018.02.004. doi: S0090-8258(18)30123-9 pmid: 29458976
[2]	刘磊, 杨长俊. 卵巢高钙血症型小细胞癌临床病理分析[J]. 诊断病理学杂志, 2020,27(3):192-194. doi: 10.3969/j.issn.1007-8096.2020.03.012. doi: 10.3969/j.issn.1007-8096.2020.03.012
[3]	Fahiminiya S, Sabbaghian N, Albrecht S, et al. Ovarian small cell carcinoma in one of a pair of monozygous twins[J]. Fam Cancer, 2019,18(2):161-163. doi: 10.1007/s10689-018-0108-0. doi: 10.1007/s10689-018-0108-0 pmid: 30284660
[4]	王遥, 杨佳欣, 俞梅, 等. 卵巢高钙血症型小细胞癌7例临床分析[J]. 国际妇产科学杂志, 2018,45(5):531-536. doi: 10.3969/j.issn.1674-1870.2018.05.010. doi: 10.3969/j.issn.1674-1870.2018.05.010
[5]	贾静, 刘从容, 张璐芳, 等. 卵巢高钙血症型小细胞癌1例并文献复习[J]. 临床与实验病理学杂志, 2013,29(8):911-913. doi: 10.3969/j.issn.1001-7399.2013.08.024. doi: 10.3969/j.issn.1001-7399.2013.08.024
[6]	Scully RE. Tumors of the ovary and maldeveloped gonads[M]. Atlas of tumor pathology. Washington DC: AFIP, 1979:316-317.
[7]	Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases[J]. Am J Surg Pathol, 1994,18(11):1102-1116. doi: 10.1097/00000478-199411000-00004. doi: 10.1097/00000478-199411000-00004 pmid: 7943531
[8]	Wang Y, Hoang L, Ji JX, et al. SWI/SNF Complex Mutations in Gynecologic Cancers: Molecular Mechanisms and Models[J]. Annu Rev Pathol, 2020,15:467-492. doi: 10.1146/annurev-pathmechdis-012418-012917. doi: 10.1146/annurev-pathmechdis-012418-012917
[9]	Aggarwal D, Gupta P, Chhabra P, et al. Small Cell Carcinoma of Ovary, Hypercalcemic Type: Cytologic, Histopathologic, and Immunohistochemical Landscapes of a Rare Case[J]. J Pediatr Adolesc Gynecol, 2021,34(1):98-102. doi: 10.1016/j.jpag.2020.07.017. doi: 10.1016/j.jpag.2020.07.017
[10]	Pressey JG, Dandoy CE, Pater LE, et al. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT): Comprehensive management of a newly diagnosed young adult[J]. Gynecol Oncol, 2020,158(3):538-546. doi: 10.1016/j.ygyno.2020.06.160. doi: S0090-8258(20)31975-2 pmid: 32654763
[11]	Gupta P, Kapatia G, Gupta N, et al. Small Cell Carcinoma of the Ovary: Clinicopathologic and Immunohistochemical Analysis of 7 New Cases of a Rare Malignancy[J]. Int J Surg Pathol, 2021,29(3):236-245. doi: 10.1177/1066896920947788. doi: 10.1177/1066896920947788
[12]	Tischkowitz M, Huang S, Banerjee S, et al. Small-Cell Carcinoma of the Ovary, Hypercalcemic Type-Genetics, New Treatment Targets, and Current Management Guidelines[J]. Clin Cancer Res, 2020,26(15):3908-3917. doi: 10.1158/1078-0432.CCR-19-3797. doi: 10.1158/1078-0432.CCR-19-3797 pmid: 32156746
[13]	Witkowski L, Carrot-Zhang J, Albrecht S, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type[J]. Nat Genet, 2014,46(5):438-443. doi: 10.1038/ng.2931. doi: 10.1038/ng.2931 pmid: 24658002
[14]	Ramos P, Karnezis AN, Craig DW, et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4[J]. Nat Genet, 2014,46(5):427-429. doi: 10.1038/ng.2928. doi: 10.1038/ng.2928
[15]	Witkowski L, Goudie C, Ramos P, et al. The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type[J]. Gynecol Oncol, 2016,141(3):454-460. doi: 10.1016/j.ygyno.2016.03.013. doi: S0090-8258(16)30071-3 pmid: 26975901
[16]	Karnezis AN, Wang Y, Ramos P, et al. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type[J]. J Pathol, 2016,238(3):389-400. doi: 10.1002/path.4633. doi: 10.1002/path.4633
[17]	Wang Y, Chen SY, Colborne S, et al. Histone Deacetylase Inhibitors Synergize with Catalytic Inhibitors of EZH2 to Exhibit Antitumor Activity in Small Cell Carcinoma of the Ovary, Hypercalcemic Type[J]. Mol Cancer Ther, 2018,17(12):2767-2779. doi: 10.1158/1535-7163.MCT-18-0348. doi: 10.1158/1535-7163.MCT-18-0348
[18]	Holdhof D, Johann PD, Spohn M, et al. Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases[J]. Acta Neuropathol, 2021,141(2):291-301. doi: 10.1007/s00401-020-02250-7. doi: 10.1007/s00401-020-02250-7
[19]	McCluggage WG, Witkowski L, Clarke BA, et al. Clinical, morphological and immunohistochemical evidence that small-cell carcinoma of the ovary of hypercalcaemic type (SCCOHT) may be a primitive germ-cell neoplasm[J]. Histopathology, 2017,70(7):1147-1154. doi: 10.1111/his.13177. doi: 10.1111/his.13177 pmid: 28130795
[20]	Schaefer IM, Agaimy A, Fletcher CD, et al. Claudin-4 expression distinguishes SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas[J]. Mod Pathol, 2017,30(4):539-548. doi: 10.1038/modpathol.2016.230. doi: 10.1038/modpathol.2016.230
[21]	Shorstova T, Marques M, Su J, et al. SWI/SNF-Compromised Cancers Are Susceptible to Bromodomain Inhibitors[J]. Cancer Res, 2019,79(10):2761-2774. doi: 10.1158/0008-5472.CAN-18-1545. doi: 10.1158/0008-5472.CAN-18-1545 pmid: 30877105
[22]	Shah RR. Safety and Tolerability of Histone Deacetylase (HDAC) Inhibitors in Oncology[J]. Drug Saf, 2019,42(2):235-245. doi: 10.1007/s40264-018-0773-9. doi: 10.1007/s40264-018-0773-9
[23]	Jelinic P, Ricca J, Van Oudenhove E, et al. Immune-Active Microenvironment in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Rationale for Immune Checkpoint Blockade[J]. J Natl Cancer Inst, 2018,110(7):787-790. doi: 10.1093/jnci/djx277. doi: 10.1093/jnci/djx277 pmid: 29365144
[24]	Zhou L, Mudianto T, Ma X, et al. Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer[J]. Clin Cancer Res, 2020,26(1):290-300. doi: 10.1158/1078-0432.CCR-19-1351. doi: 10.1158/1078-0432.CCR-19-1351
[25]	Lang JD, Hendricks W, Orlando KA, et al. Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition[J]. Clin Cancer Res, 2018,24(8):1932-1943. doi: 10.1158/1078-0432.CCR-17-1928. doi: 10.1158/1078-0432.CCR-17-1928
[26]	Xue Y, Meehan B, Macdonald E, et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary[J]. Nat Commun, 2019,10(1):558. doi: 10.1038/s41467-018-06958-9. doi: 10.1038/s41467-018-06958-9