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IHBDs are derived from hepatic progenitor cells, while EHBDs originate directly from the endoderm through a separate branching morphogenetic process. Traits that are important for cancer are often found to overlap in developmental and other processes. Therefore, it has been suggested that intrahepatic cholangiocarcinomas (iCCAs) and extrahepatic cholangiocarcinomas (eCCAs) have different developmental mechanisms. While much evidence is being gathered on the mechanism of iCCAs, the evidence for eCCA is still very limited. The main reason for this is that there are very few appropriate animal models for eCCA. We can gain important insights from these animal models, particularly genetically engineered mouse models (GEMMs). GEMMs are immunocompetent and mimic human CCA subtypes with a specific mutational pattern, allowing the development of precancerous lesions, that is, biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). This review provides a summary of the pathogenesis and mechanisms of eCCA that can be revealed by GEMMs. Furthermore, we discuss several clinical questions, such as whether BilIN and IPNB really become malignant, whether the peribiliary gland is the origin of eCCAs, and others.<\/jats:p>","DOI":"10.1111\/pin.13287","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T12:02:00Z","timestamp":1667995320000},"page":"589-605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Development of extrahepatic bile ducts and mechanisms of tumorigenesis: Lessons from mouse models"],"prefix":"10.1111","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3291-0274","authenticated-orcid":false,"given":"Hiroyuki","family":"Tomita","sequence":"first","affiliation":[{"name":"Department of Tumor Pathology Gifu University Graduate School of Medicine Gifu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Hara","sequence":"additional","affiliation":[{"name":"Department of Tumor Pathology Gifu University Graduate School of Medicine Gifu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.20710"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2010.06.020"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2012.23"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2009.07.020"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370213489926"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24590"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2011.01462.x"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28326"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012418-013013"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJGM.S186854"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14093"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-0310-z"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12253-018-0491-8"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.31083\/j.fbl2703085"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.857140"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14844"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.03.026"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21144993"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1957168"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2192"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606857"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000610"},{"key":"e_1_2_11_24_1","unstructured":"WHO Classification of Tumours Editorial Board. 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