第5版WHO消化系统肿瘤分类解读：胆道系统肿瘤的更新及进展

doi:10.16139/j.1007-9610.2023.02.08

摘要/Abstract

摘要：

第5版WHO消化系统肿瘤分类中，胆道系统肿瘤更新后总体改变不多。在良性肿瘤及癌前病变部分，将胆管上皮内瘤变的3级分类系统改为高级别与低级别两个级别。同时新增胆囊与胆管导管乳头状肿瘤伴相关浸润性癌。肝内胆管肿瘤分类中，新增胆管腺瘤和胆管腺纤维瘤。这两类疾病在以往版本，常在与胆管癌鉴别诊断中提到。第5版WHO消化系统肿瘤分类的肝内胆管癌分为小胆管亚型和大胆管亚型，并不再推荐使用胆管细胞癌和细胆管细胞癌的名称。肝外胆管癌首次列为单独部分，除常见的组织学类型外，还包括鳞状细胞癌、腺鳞癌和未分化癌。另外，新版分类中增加了不少分子病理学相关的内容，为肿瘤的精准分类及诊断提供了依据。

关键词: 胆道系统肿瘤, 病理诊断, 肿瘤分类

Abstract:

Overall, there was little change in biliary system tumors of the 5th edition of WHO classification of digestive system tumors after update. The three-tiered classification of biliary intraepithelial neoplasia changed to two-tiered system: high-grade and low-grade, in the section of benign tumors and precancerous lesions. And both intracholecystic and intraductal papillary tumors associated with invasive carcinoma were added. The classification of intrahepatic bile duct tumors introduced parts of bile duct adenoma and bile duct adenofibroma, which were mentioned previously in the differential diagnosis with bile duct carcinoma. Intrahepatic cholangiocarcinoma was divided into small bile duct subtype and large bile duct subtype in the 5th edition of WHO classification, and the names of cholangiocellular carcinoma and cholangiole cell carcinoma were no longer recommended to use. Extrahepatic cholangiocarcinoma was listed as a separate part for the first time, including squamous cell carcinoma, adenosquamous carcinoma and undifferentiated carcinoma in addition to common histological types. Some new contents of molecular pathology in the 5th edition of WHO classification were added, which provided the basis for precise classification and diagnosis of tumors in biliary system.

Key words: Biliary system tumor, Pathological diagnosis, Tumor classification

中图分类号:

R735.8

罗方秀, 马乾宸, 袁菲. 第5版WHO消化系统肿瘤分类解读：胆道系统肿瘤的更新及进展[J]. 外科理论与实践, 2023, 28(02): 124-131.

LUO Fangxiu, MA Qianchen, YUAN Fei. The fifth edition of WHO classification of digestive system tumors: update and progress on biliary system tumors[J]. Journal of Surgery Concepts & Practice, 2023, 28(02): 124-131.

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参考文献 39

[1]	The WHO Classification of Tumors Editorial Board. WHO classification of tumours of digestive system tumors[M]. 5th ed. Lyon:IARC press: 2019.
[2]	GERAMIZADEH B. Precursor lesions of cholangiocarcinoma: a clinicopathologic review[J]. Clin Pathol, 2020, 13:2632010X20925045.
[3]	ETTEL M, EZE O, XU R. Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma[J]. World J Hepatol, 2015, 7(25):2563-2570. doi: 10.4254/wjh.v7.i25.2563 pmid: 26557948
[4]	HE C, FUKUMURA Y, TORIYAMA A, et al. Pyloric gland adenoma (PGA) of the gallbladder: a unique and distinct tumor from PGAs of the stomach, duodenum, and pancreas[J]. Am J Surg Pathol, 2018, 42(9):1237-1245. doi: 10.1097/PAS.0000000000001117 pmid: 29975247
[5]	ADSAY V, JANG K T, ROA J C, et al. Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases[J]. Am J Surg Pathol, 2012, 36(9):1279-1301. pmid: 22895264
[6]	ROCHA F G, LEE H, KATABI N, et al. Intraductal pa-pillary neoplasm of the bile duct: a biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas?[J]. Hepatology, 2012, 56(4):1352-1360. doi: 10.1002/hep.v56.4 URL
[7]	NAKANUMA Y, UESAKA K, KAKUDA Y, et al. Intraductal papillary neoplasm of bile duct: updated clinicopathological characteristics and molecular and genetic alterations[J]. J Clin Med, 2020, 9(12):3991. doi: 10.3390/jcm9123991 URL
[8]	ALBORES-SAAVEDRA J, ALCÁNTRA-VAZQUEZ A, CRUZ-ORTIZ H, et al. The precursor lesions of invasive gallbladder carcinoma. Hyperplasia, atypical hyperplasia and carcinoma in situ[J]. Cancer, 1980, 45(5):919-927. doi: 10.1002/(ISSN)1097-0142 URL
[9]	MAZER L M, LOSADA H F, CHAUDHRY R M, et al. Tumor characteristics and survival analysis of incidental versus suspected gallbladder carcinoma[J]. J Gastrointest Surg, 2012, 16(7):1311-1317. doi: 10.1007/s11605-012-1901-y URL
[10]	BAL M M, RAMADWAR M, DEODHAR K, et al. Patho-logy of gallbladder carcinoma: current understanding and new perspectives[J]. Pathol Oncol Res, 2015, 21(3):509-525. doi: 10.1007/s12253-014-9886-3 URL
[11]	ADSAY N V, KLIMSTRA D S. Benign and malignant tumors of the gallbladder and extrahepatic biliary tract - sciencedirect[M]//ODZE R D, GOLDBLUM J R. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 2nd ed. Philadelphia: W.B.Saunders, 2009:845-875.
[12]	DURSUN N, ESCALONA O T, ROA J C, et al. Mucinous carcinomas of the gallbladder: clinicopathologic analysis of 15 cases identified in 606 carcinomas[J]. Arch Pathol Lab Med, 2012, 136(11):1347-1358. doi: 10.5858/arpa.2011-0447-OA pmid: 23106580
[13]	VARDAMAN C, ALBORES-SAAVEDRA J. Clear cell carcinomas of the gallbladder and extrahepatic bile ducts[J]. Am J Surg Pathol, 1995, 19(1):91-99. pmid: 7802141
[14]	KONISHI E, NAKASHIMA Y, SMYRK TC, et al. Clear cell carcinoid tumor of the gallbladder - a case without von Hippel-Lindau disease[J]. Arch Pathol Lab Med, 2003, 127(6):745-747. doi: 10.5858/2003-127-745-CCCTOT URL
[15]	ROA J C, BASTURK O, ADSAY V. Dysplasia and carcinoma of the gallbladder: pathological evaluation, sampling, differential diagnosis and clinical implications[J]. Histopathology, 2021, 79(1):2-19. doi: 10.1111/his.v79.1 URL
[16]	ROA J C, TAPIA O, CAKIR A, et al. Squamous cell and adenosquamous carcinomas of the gallbladder: clinicopathological analysis of 34 cases identified in 606 carcinomas[J]. Modern Pathol, 2011, 24(8):1069-1078. doi: 10.1038/modpathol.2011.68 pmid: 21532545
[17]	TASKIN O C, AKKAS G, MEMIS B, et al. Sarcomatoid carcinomas of the gallbladder: clinicopathologic characteristics[J]. Virchows Arch, 2019, 475(1):59-66. doi: 10.1007/s00428-019-02583-z
[18]	RIZVI S, KHAN S A, HALLEMEIER C L, et al. Cholangiocarcinoma - evolving concepts and therapeutic strategies[J]. Nat Rev Clin Oncol, 2018, 15(2):95-111. doi: 10.1038/nrclinonc.2017.157 pmid: 28994423
[19]	ALBORES-SAAVEDRA J, CHABLÉ-MONTERO F, MÉNDEZ-SÁNCHEZ N, et al. Adenocarcinoma with pyloric gland phenotype of the extrahepatic bile ducts: a previously unrecognized and distinctive morphologic variant of extrahepatic bile duct carcinoma[J]. Hum Pathol, 2012, 43(12):2292-2298. doi: 10.1016/j.humpath.2012.04.003 URL
[20]	LENDVAI G, SZEKERCZÉS T, ILLYÉS I, et al. Cholangiocarcinoma: classification, histopathology and molecular carcinogenesis[J]. Pathol Oncol Res, 2020, 26(1):3-15. doi: 10.1007/s12253-018-0491-8 pmid: 30448973
[21]	NAKAMURA H, ARAI Y, TOTOKI Y, et al. Genomic spectra of biliary tract cancer[J]. Nat Genet, 2015, 47(9):1003-1010. doi: 10.1038/ng.3375 pmid: 26258846
[22]	KIM S J, AKITA M, SUNG Y N, et al. MDM2 amplification in intrahepatic cholangiocarcinomas: its relationship with large-duct type morphology and uncommon KRAS mutations[J]. Am J Surg Pathol, 2018, 42(4):512-521. doi: 10.1097/PAS.0000000000001006 URL
[23]	LOUIS C, PAPOUTSOGLOU P, COULOUARN C. Molecular classification of cholangiocarcinoma[J]. Curr Opin Gastroenterol, 2020, 36(2):57-62. doi: 10.1097/MOG.0000000000000611 URL
[24]	PUJALS A, AMADDEO G, CASTAIN C, et al. BRAF V600E mutations in bile duct adenomas[J]. Hepatology, 2015, 61(1):403-405. doi: 10.1002/hep.27133 URL
[25]	PUJALS A, BIOULAC-SAGE P, CASTAIN C, et al. BRAF V600E mutational status in bile duct adenomas and hamartomas[J]. Histopathology, 2015, 67(4):562-567. doi: 10.1111/his.2015.67.issue-4 URL
[26]	SASAKI M, SATO Y, NAKANUMA Y. Bile duct ade-noma may be a precursor lesion of small duct type intrahepatic cholangiocarcinoma[J]. Histopathology, 2021, 78(2):310-320. doi: 10.1111/his.v78.2 URL
[27]	ARNASON T, BORGER D R, CORLESS C, et al. Biliary adenofibroma of liver: morphology, tumor genetics, and outcomes in 6 cases[J]. Am J Surg Pathol, 2017, 41(4):499-505. doi: 10.1097/PAS.0000000000000773 pmid: 28266931
[28]	GUPTA A, DIXON E. Epidemiology and risk factors: intrahepatic cholangiocarcinoma[J]. Hepatobiliary Surg Nutr, 2017, 6(2):101-104. doi: 10.21037/hbsn URL
[29]	MOEINI A, HABER P K, SIA D. Cell of origin in biliary tract cancers and clinical implications[J]. JHEP Rep, 2021, 3(2):100226.
[30]	MATSUKUMA K E, YEH M M. Update on the pathology of liver neoplasms[J]. Ann Diagn Pathol, 2019, 38:126-137. doi: S1092-9134(18)30305-8 pmid: 30597357
[31]	NAKANUMA Y, MIYATA T, UCHIDA T. Latest advances in the pathological understanding of cholangiocarcinomas[J]. Expert Rev Gastroenterol Hepatol, 2016, 10(1):113-127. doi: 10.1586/17474124.2016.1104246 URL
[32]	MONDACA S, RAZAVI P, XU C, et al. Genomic characterization of ERBB2-driven biliary cancer and a case of response to ado-trastuzumab emtansine[J]. JCO Precis Oncol,3:PO.19.00223.
[33]	AISHIMA S, ODA Y. Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type[J]. J Hepatobiliary Pancreat Sci, 2015, 22(2):94-100. doi: 10.1002/jhbp.v22.2 URL
[34]	AKITA M, SAWADA R, KOMATSU M, et al. An immunostaining panel of C-reactive protein, N-cadherin, and S100 calcium binding protein P is useful for intrahepatic cholangiocarcinoma subtyping[J]. Hum Pathol, 2021, 109:45-52. doi: 10.1016/j.humpath.2020.12.005 pmid: 33321161
[35]	ROSS J S, WANG K, GAY L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing[J]. Oncologist, 2014, 19(3):235-242. doi: 10.1634/theoncologist.2013-0352 pmid: 24563076
[36]	LOWERY M A, PTASHKIN R, JORDAN E, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention[J]. Clin Cancer Res, 2018, 24(17):4154-4161. doi: 10.1158/1078-0432.CCR-18-0078 pmid: 29848569
[37]	STEINER P E, HIGGINSON J. Cholangiolocellular carcinoma of the liver[J]. Cancer, 1959, 12(4):753-759. pmid: 13663020
[38]	NAKANUMA Y, SATO Y, IKEDA H, et al. Intrahepatic cholangiocarcinoma with predominant "ductal plate malformation" pattern: a new subtype[J]. Am J Surg Pathol, 2012, 36(11):1629-1635. doi: 10.1097/PAS.0b013e31826e0249 pmid: 23073321
[39]	NAULT J C, VILLANUEVA A. Biomarkers for hepatobiliary cancers[J]. Hepatology, 2021, 73(Suppl 1):115-127. doi: 10.1002/hep.v73.s1 URL

分类	ICD-0 编码	分类	ICD-0编码
良性上皮性肿瘤及癌前病变		恶性上皮性肿瘤
胆囊幽门腺腺瘤	8140/0	胆囊癌
胆管上皮内瘤变，低级别	8148/0	腺癌，NOS	8140/3
胆管上皮内瘤变，高级别	8148/2	肠型腺癌	8144/3
胆囊内乳头状肿瘤伴低级别上皮内瘤变	8503/0	透明细胞癌，NOS	8310/3
胆囊内乳头状肿瘤伴低级别上皮内瘤变	8503/0	黏液腺癌	8480/3
胆囊内乳头状肿瘤伴高级别上皮内瘤变	8503/2	低黏附性癌伴或不伴印戒细胞	8490/3
胆管导管内乳头状肿瘤伴低级别上皮内瘤变	8503/0	胆囊内乳头状肿瘤伴相关浸润性癌	8503/3
胆管导管内乳头状肿瘤伴高级别上皮内瘤变	8503/2	黏液性囊性肿瘤伴相关浸润性癌	8470/3
		鳞状细胞癌，NOS	8070/3
		未分化癌，NOS	8020/3
		肝外胆管癌
		胆管癌	8160/3
		胆管导管内乳头状肿瘤伴相关浸润性癌	8503/3
		鳞状细胞癌，NOS	8070/3
		腺鳞癌	8560/3
		未分化癌，NOS	8020/3
		神经内分泌瘤，NOS	8240/3
		神经内分泌瘤，G1	8240/3
		神经内分泌瘤，G2	8249/3
		神经内分泌瘤，G3	8249/3
		神经内分泌癌，NOS	8246/3
		大细胞神经内分泌癌	8013/3
		小细胞神经内分泌癌	8041/3
		混合性神经内分泌-非神经内分泌肿瘤（MiNEN）	8154/3

特征	1型	2型
好发部位	肝内胆管	肝外胆管
胆管大体特征	囊性或圆柱状扩张	圆柱形或纺锤状扩张
黏液分泌	常见	罕见
组织学特征
被覆上皮	上皮规则、单一，乳头形态>管状形态	上皮不规则、复杂，以乳头状形态为主，呈筛状或实性生长模式
纤维轴心	纤细的纤维血管轴心	纤细血管，灶性纤维性间质
组织学亚型	胃型、肠型	肠型、胰胆管型
分级	多为高级别，伴局灶低级别区域	始终是高级别，时有灶性低级别区域
间质浸润	不常见（<50%），多为微小浸润，偶尔呈结节状	常见（>80%），呈轻、中程度浸润
与IPMN相似程度	相似	形态多样
进展可能性	较低	较高
预后	较好	比1型差

分类	ICD-0 编码	分类	ICD-0 编码
良性胆管肿瘤及癌前病变		胆管恶性上皮性肿瘤
胆管腺瘤	8160/0	肝内胆管癌	8160/3
胆管腺纤维瘤	9013/0	大胆管型胆管癌
胆管上皮内瘤变，低级别	8148/0	小胆管型胆管癌
胆管上皮内瘤变，高级别	8148/2	胆管导管内乳头状肿瘤伴相关浸润性癌	8503/3
胆管导管内乳头状肿瘤伴低级别上皮内瘤变	8503/0	黏液性囊性肿瘤伴相关浸润性癌	8470/3
胆管导管内乳头状肿瘤伴高级别上皮内瘤变	8503/2	未分化癌，NOS	8020/3
胆管导管内乳头状肿瘤伴高级别上皮内瘤变	8503/2	混合性肝细胞-胆管癌	8180/3
黏液性囊性肿瘤伴低级别上皮内瘤变	8470/0	神经内分泌瘤，NOS	8240/3
黏液性囊性肿瘤伴低级别上皮内瘤变	8470/0	神经内分泌瘤，G1	8240/3
黏液性囊性肿瘤伴高级别上皮内瘤变	8470/2	神经内分泌瘤，G2	8249/3
黏液性囊性肿瘤伴高级别上皮内瘤变	8470/2	神经内分泌瘤，G3	8249/3
		神经内分泌癌，NOS	8246/3
		大细胞神经内分泌癌	8013/3
		小细胞神经内分泌癌	8041/3
		混合性神经内分泌-非神经内分泌肿瘤（MiNEN）	8154/3

特征	iCCA		肝外胆管癌
特征	小胆管型	大胆管型	肝外胆管癌
细胞起源	肝内小胆管；可能与肝祖细胞有关	肝内大胆管或胆管周腺体	肝外胆管或胆管周腺体
形态学	被覆立方上皮的小导管状；罕见黏液分泌	分泌黏液的柱状细胞形成大导管状或乳头状	与大胆管型iCCA类似
免疫组织化学表型	共同表达CK7、CK19、EMA（MUC1）
免疫组织化学表型	表达C反应蛋白、N钙黏着素、CD56	表达S100、MUC5AC、MUC6、TFF1	与大胆管型iCCA类似
侵袭性	可形成卫星结节神经、脉管侵犯少见淋巴结转移少见	较少形成卫星结节神经、脉管侵犯多见肝内浸润性生长	与大胆管型iCCA类似
分子特征	IDH1/2、BRCA1/2、BAP1突变，FGFR2融合	KRAS、TP53突变	与大胆管型iCCA类似，KRAS突变频率更高