{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T23:29:01Z","timestamp":1769038141328,"version":"3.49.0"},"reference-count":111,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Intrahepatic cholangiocarcinomas (iCCAs) are histologically subdivided into small duct-type (SD-iCCA) and large duct-type (LD-iCCA). LD-iCCA versus SD-iCCA may differ in the molecular\/genetic profiles and oncogenesis, including precursor lesions. While several precursors, such as high-grade biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm of bile duct (IPNB), have been proposed for LD-iCCA, the potential SD-iCCA precursors remain to be identified. Amid growing interests in the precursors of SD-iCCA, benign \u201cbiliary lesions\/neoplasms developing in the hepatic parenchyma (BLNP)\u201d such as von Meyenburg complexes (VMCs), bile duct adenomas (BDAs), and biliary adenofibroma (BAF), have been noted to determine whether they have the potential for precursor of SD-iCCA. Herein, these BLNPs were reviewed. BLNP can be classified into three categories. First, traditional VMC and BDA in normal livers which lack atypical features are categorized as \u201ctraditional BLNP\u201d. Second, a constellation of several lesions such as VMC and BDA detectable in the background livers of SD-iCCA and in chronic liver disease (unusual VMC and BDA), VMC with dysplastic features, BDA located in the deep hepatic parenchyma, multiple BDA, BDA presenting the BRAF V600E mutation, and BAF harboring variable dysplasia or in situ carcinomas, which may include neoplastic lesions but do not show invasive growth, are categorized as \u201cunusual\/dysplastic BLNP\u201d. Third, tubulocystic carcinoma with BAF-like features (AI-TCC) and SD-iCCA with ductal plate malformation (DPMP) which share overlapping features and show relatively good post-operative outcomes and retained features of VMC or DPM, and BDA and BAF, are categorized as \u201clow-grade malignant BLNP\u201d. While the first category is benign and may not be related to SD-iCCA, some of the second category may be related to SD-iCCA, and the third category is malignant and shows invasive growth. The latter two categories may form a common biliary tumorigenic spectrum involving BLNP. Precursors of SD-iCCA, if they exist, may be included in the second category, and the third category may represent unique carcinomas possibly associated with or followed by conventional SD-iCCA. In conclusion, this novel approach to categorize BLNPs into three categories guarantees further studies of precursors of and their progression to conventional SD-iCCA.<\/jats:p>","DOI":"10.3390\/cancers18020328","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T08:48:08Z","timestamp":1768985288000},"page":"328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spectrum of Biliary Lesions\/Neoplasms in Hepatic Parenchyma with Reference to a Precursor of Small Duct-Type Intrahepatic Cholangiocarcinoma: Comprehensive Categorization into Three Groups"],"prefix":"10.3390","volume":"18","author":[{"given":"Yasuni","family":"Nakanuma","sequence":"first","affiliation":[{"name":"Division of Pathology, Shizuoka Cancer Center, Shizuoka 411-8777, Japan"},{"name":"Department of Diagnostic Pathology, Fukui Prefecture Saiseikai Hospital, Wadanakacho Funahashi 7-1, Fukui 918-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2514-760X","authenticated-orcid":false,"given":"Motoko","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Human Pathology, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9498-2886","authenticated-orcid":false,"given":"Yuko","family":"Kakuda","sequence":"additional","affiliation":[{"name":"Division of Pathology, Shizuoka Cancer Center, Shizuoka 411-8777, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuma","family":"Oishi","sequence":"additional","affiliation":[{"name":"Division of Pathology, Shizuoka Cancer Center, Shizuoka 411-8777, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"ref_1","unstructured":"WHO (2019). Classification of Tumours Editorial Board. Digestive System Tumours, International Agency for Research on Cancer. [5th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1002\/hep.30289","article-title":"Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances","volume":"69","author":"Sirica","year":"2019","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/s41571-023-00770-1","article-title":"Cholangiocarcinoma\u2014Novel biological insights and therapeutic strategies","volume":"20","author":"Ilyas","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bpg.2015.02.006","article-title":"Pathologic classification of cholangiocarcinoma: New concepts","volume":"29","author":"Nakanuma","year":"2015","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s12253-018-0491-8","article-title":"Cholangiocarcinoma: Classification, histopathology and molecular carcinogenesis","volume":"26","author":"Lendvai","year":"2020","journal-title":"Pathol. Oncol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"805973","DOI":"10.1155\/2014\/805973","article-title":"What are the precursor and early lesions of peripheral intrahepatic cholangiocarcinoma?","volume":"2014","author":"Nakanuma","year":"2014","journal-title":"Int. J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1002\/jhbp.1308","article-title":"Pathological survey of precursor lesions in cholangiocarcinoma","volume":"30","author":"Nakanuma","year":"2023","journal-title":"J. Hepato-Biliary-Pancreat. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nakanuma, Y., Kakuda, Y., Sugino, T., Sato, Y., and Fukumura, Y. (2022). Pathologies of precursor lesions of biliary tract carcinoma. Cancers, 14.","DOI":"10.3390\/cancers14215358"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3350\/cmh.2016.0105","article-title":"Histopathology of a benign bile duct lesion in the liver: Morphologic mimicker or precursor of intrahepatic cholangiocarcinoma","volume":"22","author":"Lee","year":"2016","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_10","unstructured":"Burt, A.D., Ferrel, L.D., and Hubscher, S.G. (2023). Bile duct diseases. MacSween\u2019s Pathology of the Liver, Elsevier. [8th ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.proghi.2007.02.001","article-title":"Expression profiles of MUC mucins and trefoil factor family (TFF) peptides in the intrahepatic biliary system: Physiological distribution and pathological significance","volume":"42","author":"Sasaki","year":"2007","journal-title":"Prog. Histochem. Cytochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1111\/his.15162","article-title":"Heterogeneity of small duct- and large duct-type intrahepatic cholangiocarcinoma","volume":"84","author":"Kinzler","year":"2024","journal-title":"Histopathology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/liv.14093","article-title":"Anatomical, histomorphological and molecular classification of cholangiocarcinoma","volume":"39","author":"Kendall","year":"2019","journal-title":"Liver Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/hep.32624","article-title":"Proteogenomic characterization of cholangiocarcinoma","volume":"77","author":"Deng","year":"2023","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.humpath.2012.08.004","article-title":"Hilar cholangiocarcinoma and pancreatic ductal adenocarcinoma share similar histopathologies, immunophenotypes, and development-related molecules","volume":"44","author":"Gandou","year":"2013","journal-title":"Hum. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.hpb.2018.07.021","article-title":"Histological and molecular characterization of intrahepatic bile duct cancers suggests an expanded definition of perihilar cholangiocarcinoma","volume":"21","author":"Akita","year":"2019","journal-title":"HPB"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1111\/j.1440-1827.2010.02543.x","article-title":"A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: Is the biliary tract an incomplete pancreas?","volume":"60","author":"Nakanuma","year":"2010","journal-title":"Pathol. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1053\/j.semdp.2016.12.013","article-title":"Biliary tumors with pancreatic counterparts","volume":"34","author":"Nakanuma","year":"2017","journal-title":"Semin. Diagn. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"613","DOI":"10.5009\/gnl210174","article-title":"Genetic, clinicopathological, and radiological features of intrahepatic cholangiocarcinoma with ductal plate malformation pattern","volume":"16","author":"Chung","year":"2022","journal-title":"Gut Liver"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"652","DOI":"10.21037\/jgo.2018.08.18","article-title":"Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets","volume":"10","author":"Weinberg","year":"2019","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.humpath.2022.06.001","article-title":"Intrahepatic cholangiocarcinoma: Typical features, uncommon variants, and controversial related entities","volume":"132","author":"Zen","year":"2023","journal-title":"Hum. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1136\/jcp-2024-209708","article-title":"Cholangiocarcinoma classification: Current approach, relevance and challenges","volume":"78","author":"Goeppert","year":"2025","journal-title":"J. Clin. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"147","DOI":"10.32074\/1591-951X-251","article-title":"Benign biliary neoplasms and biliary tumor precursors","volume":"113","author":"Sarcognato","year":"2021","journal-title":"Pathologica"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.jhep.2005.09.025","article-title":"Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct\u2014An immunohistochemical study of 110 cases of hepatolithiasis","volume":"44","author":"Zen","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1136\/jcp-2024-209572","article-title":"von Meyenburg complexes are more frequently associated with cholangiocarcinoma","volume":"78","author":"Jain","year":"2025","journal-title":"J. Clin. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.humpath.2017.08.004","article-title":"Histopathological evidence of neoplastic progression of von Meyenburg complex to intrahepatic cholangiocarcinoma","volume":"67","author":"Bhalla","year":"2017","journal-title":"Hum. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ferrel, L.D., Kakar, S., Terracciano, L.M., and Wee, A. (2023). Tumours and tumour-like lesions of the liver. MacSween\u2019s Pathology of the Liver, Elsevier. [8th ed.].","DOI":"10.1016\/B978-0-7020-8228-3.00013-2"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.humpath.2005.11.008","article-title":"Multicystic biliary hamartoma: A hitherto undescribed lesion","volume":"37","author":"Zen","year":"2006","journal-title":"Hum. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1097\/PAS.0000000000001930","article-title":"Hepatic cysts: Reappraisal of the classification, terminology, differential diagnosis, and clinicopathologic characteristics in 258 cases","volume":"46","author":"Armutlu","year":"2022","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"105865","DOI":"10.1016\/j.humpath.2025.105865","article-title":"Neoplastic ductal plate malformation pattern rather than von Meyenburg complexes may be an early neoplastic lesion of small duct-type intrahepatic cholangiocarcinoma","volume":"161","author":"Nakanuma","year":"2025","journal-title":"Hum. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1097\/PAI.0000000000000132","article-title":"Malignant transformation in von-Meyenburg complexes: Histologic and immunohistochemical clues with illustrative cases","volume":"23","author":"Parekh","year":"2015","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1097\/00000478-199302000-00010","article-title":"Biliary adenofibroma. A heretofore unrecognized benign biliary tumor of the liver","volume":"17","author":"Tsui","year":"1993","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_33","first-page":"163","article-title":"Hepatic biliary adenofibroma: Histological characteristics, diagnostic challenges, and its role as a precursor to intrahepatic cholangiocarcinoma","volume":"4","author":"Liao","year":"2024","journal-title":"Clin. Transl. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1136\/jcp-2025-210126","article-title":"Biliary adenofibroma: Is it truly a benign neoplasm or benign-looking cholangiocarcinoma?","volume":"78","author":"Zen","year":"2025","journal-title":"J. Clin. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1097\/PAS.0000000000002278","article-title":"Tubulocystic carcinoma of bile ducts: A distinct type of cholangiocarcinoma associated with adenofibroma-type lesions","volume":"48","author":"Masetto","year":"2024","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s12328-014-0523-1","article-title":"Biliary adenofibroma with ominous features of imminent malignant changes","volume":"7","author":"Tsutsui","year":"2014","journal-title":"Clin. J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1097\/00000478-200008000-00011","article-title":"Evidence for the neoplastic transformation of Von-Meyenburg complexes","volume":"24","author":"Jain","year":"2000","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100815","DOI":"10.1016\/j.modpat.2025.100815","article-title":"Characterization of cholangiocarcinomas with tubulocystic morphology associated with biliary adenofibroma or iliary adenofibroma-like lesions","volume":"38","author":"Liao","year":"2025","journal-title":"Mod. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1097\/PAS.0b013e31826e0249","article-title":"Intrahepatic cholangiocarcinoma with predominant \u201cductal plate malformation\u201d pattern: A new subtype","volume":"36","author":"Nakanuma","year":"2012","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"214","DOI":"10.3350\/cmh.2014.20.2.214","article-title":"Intrahepatic cholangiocarcinoma with predominant ductal plate malformation pattern","volume":"2","author":"Choe","year":"2014","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1097\/PAS.0000000000001201","article-title":"Cholangiolocellular carcinoma with \u201cductal plate malformation\u201d pattern may be characterized by ARID1A genetic alterations","volume":"43","author":"Sasaki","year":"2019","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1002\/hep.1840160434","article-title":"Congenital diseases of intrahepatic bile ducts: Variations on the theme \u201cductal plate malformation\u201d","volume":"16","author":"Desmet","year":"1992","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/j.1600-0676.1982.tb00833.x","article-title":"Caroli\u2019s disease in congenital hepatic fibrosis and infantile polycystic disease","volume":"2","author":"Nakanuma","year":"1982","journal-title":"Liver"},{"key":"ref_44","first-page":"233","article-title":"The hepatic von Meyenburg complex: Prevalence and association with hepatic and renal cysts among 2843 autopsies [corrected]","volume":"9","author":"Redstone","year":"1996","journal-title":"Mod. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S0046-8177(79)80048-9","article-title":"Meyenburg complexes of the liver and bile cysts as a consequence of hepatic ischemia","volume":"10","author":"Popovsky","year":"1979","journal-title":"Hum. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1177\/10668969231168966","article-title":"Combined hepatocellular-cholangiocarcinoma with ductal platem malformation pattern: A case report with molecular analysis","volume":"32","author":"Moon","year":"2024","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.hpb.2021.06.423","article-title":"The rate of cholangiocarcinoma in Caroli Disease. A German multicenter study","volume":"24","author":"Makridis","year":"2022","journal-title":"HPB"},{"key":"ref_48","first-page":"592","article-title":"Cholangiocarcinoma arising in congenital hepatic fibrosis. A case report","volume":"99","author":"Daroca","year":"1975","journal-title":"Arch. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6354","DOI":"10.3748\/wjg.v11.i40.6354","article-title":"Imaging findings of biliary hamartomas","volume":"11","author":"Zheng","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s002619900469","article-title":"Bile duct hamartomas (von Meyenburg complexes): Value of MR imaging in diagnosis","volume":"24","author":"Maher","year":"1999","journal-title":"Abdom. Imaging"},{"key":"ref_51","first-page":"162","article-title":"Polycystic liver; Analysis of seventy cases","volume":"59","author":"Melnick","year":"1955","journal-title":"AMA Arch. Pathol."},{"key":"ref_52","unstructured":"Burt, A.D., Ferrel, L.D., and Hubscher, S.G. (2023). Developmental and inherited liver disease. MacSween\u2019s Pathology of the Liver, Elsevier. [8th ed.]."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"296","DOI":"10.12998\/wjcc.v6.i9.296","article-title":"Polycystic kidney and hepatic disease 1 gene mutations in von Meyenburg complexes: Case report","volume":"6","author":"Lin","year":"2018","journal-title":"World J. Clin. Cases"},{"key":"ref_54","unstructured":"Burt, A.D., Ferrel, L.D., and Hubscher, S.G. (2023). Vascular disorders. MacSween\u2019s Pathology of the Liver, Elsevier. [8th ed.]."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-0676.1987.tb00308.x","article-title":"Glandular elements around the intrahepatic bile ducts in man; their morphology and distribution in normal livers","volume":"7","author":"Terada","year":"1987","journal-title":"Liver"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.humpath.2016.06.019","article-title":"Proliferative index facilitates distinction between benign biliary lesions and intrahepatic cholangiocarcinoma","volume":"57","author":"Tsokos","year":"2016","journal-title":"Hum. Pathol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.humpath.2023.02.001","article-title":"Ancillary tests for hepatobiliary neoplasms: What we know and what we need to know","volume":"141","author":"Zhang","year":"2023","journal-title":"Hum. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/pin.12209","article-title":"Bile duct adenoma and von Meyenburg complex-like duct arising in hepatitis and cirrhosis: Pathogenesis and histological characteristics","volume":"64","author":"Aishima","year":"2014","journal-title":"Pathol. Int."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/his.14222","article-title":"Bile duct adenoma may be a precursor lesion of small duct type intrahepatic cholangiocarcinoma","volume":"78","author":"Sasaki","year":"2021","journal-title":"Histopathology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/his.14932","article-title":"Bile duct adenoma and small-sized small duct type intrahepatic cholangiocarcinoma show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components","volume":"83","author":"Sasaki","year":"2023","journal-title":"Histopathology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1111\/his.12674","article-title":"BRAF V600E mutational status in bile duct adenomas and hamartomas","volume":"67","author":"Pujals","year":"2015","journal-title":"Histopathology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/PAI.0b013e3181b94fd8","article-title":"Molecular evidence for the neoplastic potential of hepatic Von-Meyenburg complexes","volume":"18","author":"Jain","year":"2010","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1097\/PAS.0000000000001148","article-title":"Cancerization of the pancreatic ducts: Demonstration of a common and under-recognized process using immunolabeling of paired duct lesions and invasive pancreatic ductal adenocarcinoma for p53 and Smad4 expression","volume":"42","author":"Hutchings","year":"2018","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00428-022-03333-4","article-title":"Cancerization of ducts in hilar cholangiocarcinoma","volume":"481","author":"Lee","year":"2022","journal-title":"Virchows Arch."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"151828","DOI":"10.1016\/j.anndiagpath.2021.151828","article-title":"Histopathological evidence of intrahepatic cholangiocarcinoma occurring in ductal plate malformation: A clinicopathologic study of 5 cases","volume":"55","author":"Wang","year":"2021","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_66","first-page":"737","article-title":"Combined hepatocellular-cholangiocarcinoma with stem cell features, ductal plate malformation subtype: A case report and proposal of a new subtype","volume":"6","author":"Terada","year":"2013","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_67","first-page":"e52992","article-title":"Mixed plate ductal intrahepatic cholangiocarcinoma mimicking hepatocellular carcinoma","volume":"16","author":"Ajmal","year":"2024","journal-title":"Cureus"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1097\/00000478-198809000-00007","article-title":"Bile duct adenoma. A study of 152 cases","volume":"12","author":"Allaire","year":"1988","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/hep.27133","article-title":"BRAF V600E mutations in bile duct adenomas","volume":"61","author":"Pujals","year":"2015","journal-title":"Hepatology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/modpathol.2013.206","article-title":"BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma","volume":"27","author":"Goeppert","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ijscr.2012.01.002","article-title":"Adenoma-carcinoma sequence in intrahepatic cholangiocarcinoma","volume":"3","author":"Pinho","year":"2012","journal-title":"Int. J. Surg. Case Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1097\/MEG.0b013e3282fc73b1","article-title":"Intrahepatic cholangiocarcinoma arising in multiple bile duct hamartomas: Report of two cases and review of the literature","volume":"21","author":"Xu","year":"2009","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1590\/s0004-2803.23032023-107","article-title":"Intrahepatic biliary proliferations: Histopathology and potential immunohistochemical markers","volume":"60","author":"Hirayama","year":"2023","journal-title":"Arq. Gastroenterol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1111\/his.13083","article-title":"BRAF V600E mutation in biliary proliferations associated with \u03b11-antitrypsin deficiency","volume":"70","author":"Angkathunyakul","year":"2017","journal-title":"Histopathology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1097\/PAS.0000000000000125","article-title":"Immunostaining for polycomb group protein EZH2 and senescent marker p16INK4a may be useful to differentiate cholangiolocellular carcinoma from ductular reaction and bile duct adenoma","volume":"38","author":"Sasaki","year":"2014","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1097\/00000478-199607000-00009","article-title":"The so-called bile duct adenoma is a peribiliary gland hamartoma","volume":"20","author":"Bhathal","year":"1996","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_77","first-page":"e71656","article-title":"A Case of Resectable Single-Nodule Intrahepatic Bile Duct Adenoma","volume":"16","author":"Okano","year":"2024","journal-title":"Cureus"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.humpath.2022.06.012","article-title":"Bile duct dysplasia and associated invasive carcinoma: Clinicopathological features, diagnosis, and practical challenges","volume":"132","author":"Liu","year":"2023","journal-title":"Hum. Pathol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s00428-020-02812-w","article-title":"Utility of DNA flow cytometry in distinguishing between malignant and benign intrahepatic biliary lesions","volume":"477","author":"Wen","year":"2020","journal-title":"Virchows Arch."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/j.1365-2559.2007.02735.x","article-title":"A subgroup of intrahepatic cholangiocarcinoma with an infiltrating replacement growth pattern and a resemblance to reactive proliferating bile ductules: \u2018bile ductular carcinoma\u2019","volume":"51","author":"Kozaka","year":"2007","journal-title":"Histopathology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1097\/01.pas.0000149710.01559.fe","article-title":"Immunohistochemistry can help distinguish metastatic pancreatic adenocarcinomas from bile duct adenomas and hamartomas of the liver","volume":"29","author":"Hornick","year":"2005","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1369\/00221554211035730","article-title":"Apical membrane expression of distinct sulfated glycans is a characteristic feature of ductules and their teactive and neoplastic counterparts","volume":"69","author":"Hoshino","year":"2021","journal-title":"J. Histochem. Cytochem."},{"key":"ref_83","first-page":"5908","article-title":"Intrahepatic bile duct adenoma (peribiliary gland hamartoma): A case report and review of literature","volume":"8","author":"Wei","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1097\/PAS.0b013e3181ead722","article-title":"An immunohistochemical profile of the so-called bile duct adenoma: Clues to pathogenesis","volume":"34","author":"Hughes","year":"2010","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/his.14125","article-title":"BRAF-associated bile duct adenomatosis: A new entity?","volume":"77","author":"Augustin","year":"2020","journal-title":"Histopathology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1158\/1078-0432.CCR-14-3296","article-title":"Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma","volume":"22","author":"Moeini","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.jhep.2018.01.009","article-title":"Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations","volume":"68","author":"Wardell","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1002\/hep.31829","article-title":"Genetic determinants of outcome in intrahepatic cholangiocarcinoma","volume":"74","author":"Boerner","year":"2021","journal-title":"Hepatology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e231476","DOI":"10.1001\/jamanetworkopen.2023.1476","article-title":"Association of BRAF Variants With Disease Characteristics, Prognosis, and Targeted Therapy Response in Intrahepatic Cholangiocarcinoma","volume":"6","author":"Xin","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"63","DOI":"10.5306\/wjco.v3.i4.63","article-title":"A case of very large intrahepatic bile duct adenoma followed for 7 years","volume":"3","author":"Koga","year":"2012","journal-title":"World J. Clin. Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/BF00192644","article-title":"Cholangiocarcinoma arising in bile duct adenoma with focal area of bile duct hamartoma","volume":"426","author":"Hasebe","year":"1995","journal-title":"Virchows Arch."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5249","DOI":"10.21873\/anticanres.15344","article-title":"Intrahepatic cholangiocarcinoma coexisting with multiple bile duct adenoma treated as liver metastasis from a pancreatic neuroendocrine tumor","volume":"41","author":"Oda","year":"2021","journal-title":"Anticancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1001\/archsurg.1978.01370150044007","article-title":"Bile duct adenomas as liver nodules. Bile duct adenoma and von Meyenburg complex-like duct arising in hepatitis and cirrhosis: Pathogenesis and histological characteristics","volume":"113","author":"Cho","year":"1978","journal-title":"Arch. Surg."},{"key":"ref_94","first-page":"945","article-title":"Bile duct adenomas in heterozygous (MZ) deficiency of alpha 1-protease inhibitor","volume":"112","author":"Scheele","year":"1988","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_95","first-page":"282010","article-title":"Bile duct adenoma with oncocytic features","volume":"2014","author":"Johannesen","year":"2014","journal-title":"Case Rep. Pathol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1097\/00000478-200107000-00016","article-title":"Atypical bile duct adenoma, clear cell type: A previously undescribed tumor of the liver","volume":"25","author":"Hoang","year":"2001","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"154531","DOI":"10.1016\/j.prp.2023.154531","article-title":"NRAS-mutated oncocytic benign liver lesion in an organ donor: Pitfalls and troubles in frozen section diagnosis and risk assessment","volume":"246","author":"Simoncini","year":"2023","journal-title":"Pathol. Res. Pract."},{"key":"ref_98","first-page":"874826","article-title":"Cytopathologic, histopathologic, and immunohistochemical features of intrahepatic clear cell bile duct adenoma: A case report and review of the literature","volume":"2014","author":"Wu","year":"2014","journal-title":"Case Rep. Pathol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1177\/1066896907306968","article-title":"Alpha-1-antitrypsin-positive \u201csignet-ring\u201d bile duct adenoma in a patient with MMALTON mutation","volume":"16","author":"Gambarotti","year":"2008","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1097\/00000478-199201000-00003","article-title":"Bile duct adenomas with endocrine component. Immunohistochemical study and comparison with conventional bile duct adenomas","volume":"16","author":"McCue","year":"1992","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1097\/PAS.0000000000000773","article-title":"Biliary adenofibroma of liver: Morphology, tumor genetics, and outcomes in 6 cases","volume":"41","author":"Arnason","year":"2017","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"105872","DOI":"10.1016\/j.humpath.2025.105872","article-title":"Biliary adenofibroma and cholangiocarcinoma: Neighbors or relatives? A systematic and critical review","volume":"165","author":"Mattiolo","year":"2025","journal-title":"Hum. Pathol."},{"key":"ref_103","first-page":"5280884","article-title":"Biliary adenofibroma: A rare liver tumor with transition to invasive carcinoma","volume":"2022","author":"Alshbib","year":"2022","journal-title":"Case Rep. Surg."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.prp.2015.12.015","article-title":"A case of biliary adenofibroma with malignant transformation","volume":"212","author":"Thai","year":"2016","journal-title":"Pathol. Res. Pract."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/hep.28818","article-title":"Biliary adenofibroma: A rare hepatic lesion with malignant features","volume":"65","author":"Kaminsky","year":"2017","journal-title":"Hepatology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s40792-019-0661-2","article-title":"A case of biliary adenofibroma of the liver with malignant transformation: A morphomolecular case report and review of the literature","volume":"5","author":"Sturm","year":"2019","journal-title":"Surg. Case Rep."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"504584","DOI":"10.4061\/2010\/504584","article-title":"Biliary adenofibroma of the liver: Report of a case and review of the literature","volume":"2010","author":"Gurrera","year":"2010","journal-title":"Pathol. Res. Int."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1097\/00000478-200305000-00014","article-title":"Biliary adenofibroma: A rare neoplasm of bile duct origin with an indolent behavior","volume":"27","author":"Varnholt","year":"2003","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1177\/1066896918758172","article-title":"Malignant transformation arising within unusual and rare hepatic lesions: Fibropolycystic disease form of ductal plate malformation and biliary adenofibroma","volume":"26","author":"Chua","year":"2018","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"E107","DOI":"10.21037\/jgo.2016.09.14","article-title":"Malignant transformation of biliary adenofibroma: A liary cystic tumor","volume":"7","author":"Thompson","year":"2016","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"531","DOI":"10.4132\/jptm.2015.06.19","article-title":"Intrahepatic Cholangiocarcinoma with Ductal Plate Malformation-like Feature Associated with Bile Duct Adenoma","volume":"49","author":"Kwon","year":"2015","journal-title":"J. Pathol. Transl. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/2\/328\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T08:56:03Z","timestamp":1768985763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/2\/328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":111,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cancers18020328"],"URL":"https:\/\/doi.org\/10.3390\/cancers18020328","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]}}}