Pathology and molecular pathology of cholangiocarcinoma

Abstract

Biliary tract cancers are a wide group of heterogeneous neoplasms of the biliary tree, composed of intrahepatic cholangiocarcinoma perihilar bile duct cancer and distal bile duct cancer, according to location. The variability in location reflects the different morphologies and molecular alterations. In particular, intrahepatic peripheral mass forming cholangiocarcinoma is represented by the “small duct type” cholangiocarcinoma, which is different from the “large duct type” cholangiocarcinoma that, although intrahepatic, behaves similar to extrahepatic bile duct cancers, perihilar and distal ones. Recently, molecular targetable alterations, mainly FGFR2 fusions and IDH1 mutations, have been described, mostly in the intrahepatic “small duct type” subgroup and have opened the way, together with rarer targetable alterations, for personalisation of therapy also in these aggressive neoplasms.

Keywords

Biliary tract cancer / cholangiocarcinoma / molecular pathology / WHO classification / targetable alterations

References

[1] Nagtegaal ID,Klimstra D.WHO Classification of Tumours Editorial BoardThe 2019 WHO classification of tumours of the digestive system.Histopathology2020;76:182-8 PMCID:PMC7003895

[2] Cardinale V,Carpino G.Intrahepatic cholangiocarcinoma: review and update.Hepatoma Res2018;4:20

[3] Komuta M,Vandecaveye V.Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes.Hepatology2012;55:1876-88

[4] Nakanuma Y,Ikeda H.Intrahepatic cholangiocarcinoma with predominant "ductal plate malformation" pattern: a new subtype.Am J Surg Pathol2012;36:1629-35

[5] Chua D,Ang TL.Malignant transformation arising within unusual and rare hepatic lesions: fibropolycystic disease form of ductal plate malformation and biliary adenofibroma.Int J Surg Pathol2018;26:542-50

[6] Kaminsky P,Sasatomi E.Biliary adenofibroma: a rare hepatic lesion with malignant features.Hepatology2017;65:380-3

[7] Nakanuma Y,Kakuda Y.Intraductal papillary neoplasm of bile duct: updated clinicopathological characteristics and molecular and genetic alterations.J Clin Med2020;9:E3991 PMCID:PMC7763595

[8] Nakanishi Y,Ohara M.Intraductal papillary neoplasm arising from peribiliary glands connecting with the inferior branch of the bile duct of the anterior segment of the liver.Pathol Int2011;61:773-7

[9] Schlitter AM,Klöppel G.Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases.Mod Pathol2015;28:1249-64

[10] Quigley B,Pehlivanoglu B.Hepatobiliary mucinous cystic neoplasms with ovarian type stroma (so-called "hepatobiliary cystadenoma/cystadenocarcinoma"): clinicopathologic analysis of 36 cases illustrates rarity of carcinomatous change.Am J Surg Pathol2018;42:95-102

[11] Bosman FT,Hruban RH.WHO classification of tumours of the digestive system. 4th ed. Geneva: World Health Organization; 2010. PMCID:PMC7003895

[12] Taguchi J,Tanaka M,Takazawa T.A clinicopathological study on combined hepatocellular and cholangiocarcinoma.J Gastroenterol Hepatol1996;11:758-64

[13] Joseph NM,Umetsu SE.Genomic profiling of combined hepatocellular-cholangiocarcinoma reveals similar genetics to hepatocellular carcinoma.J Pathol2019;248:164-78

[14] Beaufrère A,Paradis V.Combined hepatocellular-cholangiocarcinoma: an update.J Hepatol2021;74:1212-24

[15] Geramizadeh B,Bahraini A.Synchronous hepatocellular carcinoma and cholangiocarcinoma in a patient transplanted for cryptogenic cirrhosis.Int J Org Transplant Med2014;5:125-8 PMCID:PMC4149740

[16] Jain R,Serra S.The use of Cytokeratin 19 (CK19) immunohistochemistry in lesions of the pancreas, gastrointestinal tract, and liver.Appl Immunohistochem Mol Morphol2010;18:9-15

[17] Akiba J,Hattori S.Clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification.Am J Surg Pathol2013;37:496-505

[18] Baumann U,Ramani P,Strain AJ.Expression of the stem cell factor receptor c-kit in normal and diseased pediatric liver: identification of a human hepatic progenitor cell?.Hepatology1999;30:112-7

[19] Nakamura H,Totoki Y.Genomic spectra of biliary tract cancer.Nat Genet2015;47:1003-10

[20] Israel MA,McGregor KA.Comparative genomic analysis of intrahepatic cholangiocarcinoma: biopsy type, ancestry, and testing patterns.Oncologist2021;25:1-10 PMCID:PMC8417854

[21] Valle JW,Nervi B,Zhu AX.Biliary tract cancer.Lancet2021;397:428-44

[22] Farshidfar F,Gingras MC.Cancer Genome Atlas NetworkIntegrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles.Cell Rep2017;19:2878-80 PMCID:PMC6141445

[23] Saborowski A,Vogel A.FGFR inhibitors in cholangiocarcinoma: what's now and what's next?.Ther Adv Med Oncol2020;12:1758835920953293 PMCID:PMC7498964

[24] Silverman IM,Friboulet L.Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib.Cancer Discov2021;11:326-39

[25] Wu YM,Kalyana-Sundaram S.Identification of targetable FGFR gene fusions in diverse cancers.Cancer Discov2013;3:636-47 PMCID:PMC3694764

[26] Cleary JM,Wu Q.FGFR2 extracellular domain in-frame deletions are therapeutically targetable genomic alterations that function as oncogenic drivers in cholangiocarcinoma.Cancer Discov2021;11:2488-505

[27] Lee K,Shin Y.Intrahepatic cholangiocarcinomas with IDH1/2 mutation-associated hypermethylation at selective genes and their clinicopathological features.Sci Rep2020;10:15820 PMCID:PMC7519101

[28] Goyal L,Sheth RA.Prognosis and clinicopathologic features of patients with advanced stage isocitrate dehydrogenase (IDH) mutant and IDH wild-type intrahepatic cholangiocarcinoma.Oncologist2015;20:1019-27 PMCID:PMC4571807

[29] Borger DR,Fan KC.Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.Oncologist2012;17:72-9 PMCID:PMC3267826

[30] Brat DJ,Aldape KD.Cancer Genome Atlas Research NetworkComprehensive, integrative genomic analysis of diffuse lower-grade gliomas.N Engl J Med2015;372:2481-98 PMCID:PMC4530011

[31] Demols A,Charry M.NTRK gene fusions in biliary tract cancers.J Clin Oncol2020;38:574

[32] Kheder ES.Emerging targeted therapy for tumors with NTRK fusion proteins.Clin Cancer Res2018;24:5807-14

[33] Marchiò C,Ladanyi M.ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research.Ann Oncol2019;30:1417-27

[34] Ju JY,Mahadevan MS,Kunk PR.Mismatch repair protein deficiency/microsatellite instability is rare in cholangiocarcinomas and associated with distinctive morphologies.Am J Clin Pathol2020;153:598-604

[35] Goeppert B,Renner M.Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma.Br J Cancer2019;120:109-14 PMCID:PMC6325153

[36] Marin JJG,Lamarca A.working group 6 of the COST-action 18122 (Euro-Cholangio-NET) as part of the European Network for the study of Cholangiocarcinoma (ENSCCA)Current and novel therapeutic opportunities for systemic therapy in biliary cancer.Br J Cancer2020;123:1047-59 PMCID:PMC7525457

[37] Loeuillard E,Buckarma E.Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma.J Clin Invest2020;130:5380-96 PMCID:PMC7524481

[38] Spizzo G,Xiu J.Frequency of BRCA mutation in biliary tract cancer and its correlation with tumor mutational burden (TMB) and microsatellite instability (MSI).J Clin Oncol2019;37:4085

[39] Spizzo G,Xiu J.Molecular profile of BRCA-mutated biliary tract cancers.ESMO Open2020;5:e000682 PMCID:PMC7312328

[40] Goeppert B,Renner M.BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma.Mod Pathol2014;27:1028-34

[41] Javle M,Shroff RT.Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.J Clin Oncol2018;36:276-82 PMCID:PMC6075847

[42] Albrecht T,Rössler S.HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis.BMC Cancer2019;19:1191 PMCID:PMC6896712

[43] Rüschoff J,Bilous M.HER2 testing in gastric cancer: a practical approach.Mod Pathol2012;25:637-50

[44] Montal R,Montironi C.Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.J Hepatol2020;73:315-27 PMCID:PMC8418904

[45] Cadamuro M,Lamarca A.Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic.Expert Opin Investig Drugs2021;30:377-88 PMCID:PMC8194059

[46] 33rd European congress of pathology - abstracts.Virchows Arch2021;479:1-320

[47] Chang TT,Tsai HW,Hsieh SY.Plasma proteome plus site-specific N-glycoprofiling for hepatobiliary carcinomas.J Pathol Clin Res2019;5:199-212 PMCID:PMC6648390

[48] Francaviglia I,Lazzari C.Identification and monitoring of somatic mutations in circulating cell-free tumor DNA in lung cancer patients.Lung Cancer2019;134:225-32

[49] Fabris L,Cagnin S,Gores GJ.Liver matrix in benign and malignant biliary tract disease.Semin Liver Dis2020;40:282-97

[50] Park DD,Xu G.Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans.Proc Natl Acad Sci U S A2020;117:7633-44 PMCID:PMC7148571