Semin Liver Dis 2011; 31(1): 049-060
DOI: 10.1055/s-0031-1272839
© Thieme Medical Publishers

Intrahepatic Cholangiocarcinoma: New Insights in Pathology

Christine Sempoux1 , Ghalib Jibara2 , Stephen C. Ward3 , Cathy Fan3 , Lihui Qin3 , Sasan Roayaie2 , M. Isabel Fiel3 , Myron Schwartz2 , Swan N. Thung3
  • 1Department of Pathology, Cliniques Universitaires Saint Luc, Brussels, Belgium
  • 2Division of Surgical Oncology, Department of Surgery, The Mount Sinai Medical Center, New York, New York
  • 3The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, New York, New York
Further Information

Publication History

Publication Date:
22 February 2011 (online)

ABSTRACT

Cholangiocarcinomas are malignant tumors that derive from cholangiocytes of small intrahepatic bile ducts or bile ductules (intrahepatic cholangiocarcinoma; ICC), or of large hilar or extrahepatic bile ducts (extrahepatic cholangiocarcinoma; ECC). ICC and ECC differ in morphology, pathogenesis, risk factors, treatment, and prognosis. This review focuses on ICC, which is rising in incidence with the emergence of hepatitis C virus (HCV) infection as a risk factor. The authors examined 73 ICC, which were resected at The Mount Sinai Medical Center in New York City, and reviewed the literature. The tumors were categorized into classical and nonclassical ICCs based on histopathology. Classical ICCs (54.8%) were characterized by a tubular, glandular, or nested pattern of growth, were significantly associated with tumor size of more than 5 cm and the absence of underlying liver disease and/or advanced fibrosis. Nonclassical ICCs (45.2%) consisted of tumors with trabecular architecture, tumors that exhibited features of extrahepatic carcinomas, and carcinomas considered to be derived from hepatic progenitor cells, i.e., combined hepatocellular/cholangiocarcinomas and cholangiolocellular carcinomas (ductular type of ICC). They were smaller and often arose in chronic liver disease, mostly HCV infection, and/or with significant fibrosis. The role of immunohistochemistry in the diagnosis of ICC and the importance of the new American Joint Committee on Cancer Staging System for ICC are also discussed.

REFERENCES

  • 1 Nakanuma Y, Curado M P, Franceschi S et al.. Intrahepatic cholangiocarcinoma. In: Bosman F T, Carneiro F, Hruban R H, Theise N D, eds. WHO Classification of Tumours of the Digestive System. Lyon: IARC Press; 2010: 217-224
  • 2 Anthony P P. Tumours and tumour-like lesions of the liver and the biliary tract: aetiology, epidemiology and pathology. In: MacSween R NM, Burt A D, Portmann B C, Ishak K G, Scheuer P J, Anthony P P, eds. Pathology of the Liver. London: Churchill Livingstone; 2002: 711-775
  • 3 Malhi H, Gores G J. Cholangiocarcinoma: modern advances in understanding a deadly old disease.  J Hepatol. 2006;  45 (6) 856-867
  • 4 Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 1: epidemiology and etiology.  J Gastroenterol Hepatol. 2002;  17 (10) 1049-1055
  • 5 Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcation within the port hepatis: an unusual tumor with distinctive clinical and pathological features.  Am J Med. 1965;  38 241-256
  • 6 Okuda K, Kubo Y, Okazaki N, Arishima T, Hashimoto M. Clinical aspects of intrahepatic bile duct carcinoma including hilar carcinoma: a study of 57 autopsy-proven cases.  Cancer. 1977;  39 (1) 232-246
  • 7 Aishima S, Kuroda Y, Nishihara Y et al.. Proposal of progression model for intrahepatic cholangiocarcinoma: clinicopathologic differences between hilar type and peripheral type.  Am J Surg Pathol. 2007;  31 (7) 1059-1067
  • 8 Khan S A, Thomas H C, Davidson B R, Taylor-Robinson S D. Cholangiocarcinoma.  Lancet. 2005;  366 (9493) 1303-1314
  • 9 Konstadoulakis M M, Roayaie S, Gomatos I P et al.. Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome.  Surgery. 2008;  143 (3) 366-374
  • 10 Endo I, Gonen M, Yopp A C et al.. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection.  Ann Surg. 2008;  248 (1) 84-96
  • 11 Blechacz B, Gores G J. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment.  Hepatology. 2008;  48 (1) 308-321
  • 12 Nathan H, Pawlik T M, Wolfgang C L, Choti M A, Cameron J L, Schulick R D. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis.  J Gastrointest Surg. 2007;  11 (11) 1488-1496, discussion 1496–1497
  • 13 Khan S A, Toledano M B, Taylor-Robinson S D. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma.  HPB (Oxford). 2008;  10 (2) 77-82
  • 14 Shaib Y, El-Serag H B. The epidemiology of cholangiocarcinoma.  Semin Liver Dis. 2004;  24 (2) 115-125
  • 15 Hammill C W, Wong L L. Intrahepatic cholangiocarcinoma: a malignancy of increasing importance.  J Am Coll Surg. 2008;  207 (4) 594-603
  • 16 Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States.  Hepatology. 2001;  33 (6) 1353-1357
  • 17 Shaib Y H, Davila J A, McGlynn K, El-Serag H B. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?.  J Hepatol. 2004;  40 (3) 472-477
  • 18 Gatto M, Bragazzi M C, Semeraro R et al.. Cholangiocarcinoma: update and future perspectives.  Dig Liver Dis. 2010;  42 (4) 253-260
  • 19 Welzel T M, McGlynn K A, Hsing A W, O'Brien T R, Pfeiffer R M. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States.  J Natl Cancer Inst. 2006;  98 (12) 873-875
  • 20 West J, Wood H, Logan R F, Quinn M, Aithal G P. Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971-2001.  Br J Cancer. 2006;  94 (11) 1751-1758
  • 21 Donato F, Gelatti U, Tagger A et al.. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy.  Cancer Causes Control. 2001;  12 (10) 959-964
  • 22 Yamamoto S, Kubo S, Hai S et al.. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma.  Cancer Sci. 2004;  95 (7) 592-595
  • 23 Tomimatsu M, Ishiguro N, Taniai M et al.. Hepatitis C virus antibody in patients with primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma) in Japan.  Cancer. 1993;  72 (3) 683-688
  • 24 Kobayashi M, Ikeda K, Saitoh S et al.. Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis.  Cancer. 2000;  88 (11) 2471-2477
  • 25 Shaib Y H, El-Serag H B, Nooka A K et al.. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study.  Am J Gastroenterol. 2007;  102 (5) 1016-1021
  • 26 El-Serag H B, Engels E A, Landgren O et al.. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population-based study of U.S. veterans.  Hepatology. 2009;  49 (1) 116-123
  • 27 Sirica A E. Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy.  Hepatology. 2005;  41 (1) 5-15
  • 28 Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 2: molecular pathology and treatment.  J Gastroenterol Hepatol. 2002;  17 (10) 1056-1063
  • 29 Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M. Anatomic and molecular pathology of intrahepatic cholangiocarcinoma.  J Hepatobiliary Pancreat Surg. 2003;  10 (4) 265-281
  • 30 Berthiaume E P, Wands J. The molecular pathogenesis of cholangiocarcinoma.  Semin Liver Dis. 2004;  24 (2) 127-137
  • 31 Sia D, Hoshida Y, Villanueva A et al.. Molecular classification of human intrahepatic cholangiocarcinoma defines two classes with distinct biology and outcome.  Hepatology. 2010;  52 374A (Abstract)
  • 32 Khan S A, Thomas H C, Toledano M B, Cox I J, Taylor-Robinson S D. p53 Mutations in human cholangiocarcinoma: a review.  Liver Int. 2005;  25 (4) 704-716
  • 33 Okabe H, Beppu T, Hayashi H et al.. Hepatic stellate cells may relate to progression of intrahepatic cholangiocarcinoma.  Ann Surg Oncol. 2009;  16 (9) 2555-2564
  • 34 Torbenson M, Yeh M M, Abraham S C. Bile duct dysplasia in the setting of chronic hepatitis C and alcohol cirrhosis.  Am J Surg Pathol. 2007;  31 (9) 1410-1413
  • 35 Wu T T, Levy M, Correa A M, Rosen C B, Abraham S C. Biliary intraepithelial neoplasia in patients without chronic biliary disease: analysis of liver explants with alcoholic cirrhosis, hepatitis C infection, and noncirrhotic liver diseases.  Cancer. 2009;  115 (19) 4564-4575
  • 36 Perumal V, Wang J, Thuluvath P, Choti M, Torbenson M. Hepatitis C and hepatitis B nucleic acids are present in intrahepatic cholangiocarcinomas from the United States.  Hum Pathol. 2006;  37 (9) 1211-1216
  • 37 Gerber M A. Histopathology of HCV infection.  Clin Liver Dis. 1997;  1 (3) 529-541, vi
  • 38 Redston M S, Wanless I R, Redston M S, Wanless I R. The hepatic von Meyenburg complex: prevalence and association with hepatic and renal cysts among 2843 autopsies [corrected].  Mod Pathol. 1996;  9 (3) 233-237
  • 39 Desmet V J. Congenital diseases of intrahepatic bile ducts: variations on the theme “ductal plate malformation”.  Hepatology. 1992;  16 (4) 1069-1083
  • 40 Colombari R, Tsui W M. Biliary tumors of the liver.  Semin Liver Dis. 1995;  15 (4) 402-413
  • 41 Ishak K G, Goodman Z D, Stocker J T. Tumors of the liver and intrahepatic bile ducts. In: Rosai J, Sobin L H, eds. Atlas of Tumor Pathology. Washington, DC: AFIP; 1999: 245-270
  • 42 Washington K. Liver neoplasms. In: Iacobuzio-Donahue C A, Montgomery E A, eds. Gastrointestinal and Liver Pathology. Philadelphia: Churchill Livingstone Elsevier; 2005: 582-632
  • 43 Goodman Z D. Neoplasms of the liver.  Mod Pathol. 2007;  20 (Suppl 1) S49-S60
  • 44 Ferrel L D. Benign and malignant tumors of the liver. In: Odze R D, Goldblum J R, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. Philadelphia: Saunders Elsevier; 2009: 1291-1325
  • 45 Jain D, Sarode V R, Abdul-Karim F W, Homer R, Robert M E. Evidence for the neoplastic transformation of Von-Meyenburg complexes.  Am J Surg Pathol. 2000;  24 (8) 1131-1139
  • 46 Jain D, Ahrens W, Finkelstein S. Molecular evidence for the neoplastic potential of hepatic Von-Meyenburg complexes.  Appl Immunohistochem Mol Morphol. 2010;  18 (2) 166-171
  • 47 Song J S, Lee Y J, Kim K W, Huh J, Jang S J, Yu E. Cholangiocarcinoma arising in von Meyenburg complexes: report of four cases.  Pathol Int. 2008;  58 (8) 503-512
  • 48 Xu A M, Xian Z H, Zhang S H, Chen X F. Intrahepatic cholangiocarcinoma arising in multiple bile duct hamartomas: report of two cases and review of the literature.  Eur J Gastroenterol Hepatol. 2009;  21 (5) 580-584
  • 49 Bhathal P S, Hughes N R, Goodman Z D. The so-called bile duct adenoma is a peribiliary gland hamartoma.  Am J Surg Pathol. 1996;  20 (7) 858-864
  • 50 Allaire G S, Rabin L, Ishak K G, Sesterhenn I A. Bile duct adenoma. A study of 152 cases.  Am J Surg Pathol. 1988;  12 (9) 708-715
  • 51 Tsui WMS, Loo K T, Chow LTC, Tse CCH. Biliary adenofibroma. A heretofore unrecognized benign biliary tumor of the liver.  Am J Surg Pathol. 1993;  17 (2) 186-192
  • 52 Varnholt H, Vauthey J N, Dal Cin P et al.. Biliary adenofibroma: a rare neoplasm of bile duct origin with an indolent behavior.  Am J Surg Pathol. 2003;  27 (5) 693-698
  • 53 Roskams T, van den Oord J J, De Vos R, Desmet V J. Neuroendocrine features of reactive bile ductules in cholestatic liver disease.  Am J Pathol. 1990;  137 (5) 1019-1025
  • 54 Gütgemann I, Haas S, Berg J P, Zhou H, Büttner R, Fischer H P. CD56 expression aids in the differential diagnosis of cholangiocarcinomas and benign cholangiocellular lesions.  Virchows Arch. 2006;  448 (4) 407-411
  • 55 Guglielmi A, Ruzzenente A, Campagnaro T et al.. Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.  World J Surg. 2009;  33 (6) 1247-1254
  • 56 Nakanuma Y, Sasaki M, Ikeda H et al.. Pathology of peripheral intrahepatic cholangiocarcinoma with reference to tumorigenesis.  Hepatol Res. 2008;  38 (4) 325-334
  • 57 Shiota K, Taguchi J, Nakashima O, Nakashima M, Kojiro M. Clinicopathologic study on cholangiolocellular carcinoma.  Oncol Rep. 2001;  8 (2) 263-268
  • 58 Komuta M, Spee B, Vander Borght S et al.. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin.  Hepatology. 2008;  47 (5) 1544-1556
  • 59 Kanamoto M, Yoshizumi T, Ikegami T et al.. Cholangiolocellular carcinoma containing hepatocellular carcinoma and cholangiocellular carcinoma, extremely rare tumor of the liver: a case report.  J Med Invest. 2008;  55 (1-2) 161-165
  • 60 Steiner P E, Higginson J. Cholangiolocellular carcinoma of the liver.  Cancer. 1959;  12 (4) 753-759
  • 61 Theise N D, Saxena R, Portmann B C et al.. The canals of Hering and hepatic stem cells in humans.  Hepatology. 1999;  30 (6) 1425-1433
  • 62 Sempoux C, Fan C, Singh P et al.. Cholangiolocellular carcinoma: an innocent-looking malignant liver tumor mimicking ductular reaction.  Semin Liver Dis. 2011;  31 (1) 92-98
  • 63 Kozaka K, Sasaki M, Fujii T et al.. A subgroup of intrahepatic cholangiocarcinoma with an infiltrating replacement growth pattern and a resemblance to reactive proliferating bile ductules: ‘bile ductular carcinoma’.  Histopathology. 2007;  51 (3) 390-400
  • 64 Theise N D, Nakashima O, Park Y N, Nakanuma Y. Combined hepatocellular-cholangiocarcinoma. In: Bosman F T, Carneiro F, Hruban R H, Theise N D, eds. WHO Classification of Tumours of the Digestive System. Lyon: IARC Press; 2010: 225-227
  • 65 Allen R A, Lisa J R. Combined liver cell and bile duct carcinoma.  Am J Pathol. 1949;  25 (4) 647-655
  • 66 Goodman Z D, Ishak K G, Langloss J M, Sesterhenn I A, Rabin L. Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study.  Cancer. 1985;  55 (1) 124-135
  • 67 Ward S C, Huang J, Tickoo S K, Thung S N, Ladanyi M, Klimstra D S. Fibrolamellar carcinoma of the liver exhibits immunohistochemical evidence of both hepatocyte and bile duct differentiation.  Mod Pathol. 2010;  23 (9) 1180-1190
  • 68 Capurro M, Wanless I R, Sherman M et al.. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma.  Gastroenterology. 2003;  125 (1) 89-97
  • 69 Shafizadeh N, Ferrell L D, Kakar S. Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum.  Mod Pathol. 2008;  21 (8) 1011-1018
  • 70 Aoki K, Takayasu K, Kawano T et al.. Combined hepatocellular carcinoma and cholangiocarcinoma: clinical features and computed tomographic findings.  Hepatology. 1993;  18 (5) 1090-1095
  • 71 Maeda T, Adachi E, Kajiyama K, Sugimachi K, Tsuneyoshi M. Combined hepatocellular and cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of clinicopathologic features.  Hum Pathol. 1995;  26 (9) 956-964
  • 72 Cazals-Hatem D, Rebouissou S, Bioulac-Sage P et al.. Clinical and molecular analysis of combined hepatocellular-cholangiocarcinomas.  J Hepatol. 2004;  41 (2) 292-298
  • 73 Theise N D, Yao J L, Harada K et al.. Hepatic ‘stem cell’ malignancies in adults: four cases.  Histopathology. 2003;  43 (3) 263-271
  • 74 Ward S C, Thung S N, Lim K H et al.. Hepatic progenitor cells in liver cancers from Asian children.  Liver Int. 2010;  30 (1) 102-111
  • 75 Kim H, Park C, Han K H et al.. Primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype.  J Hepatol. 2004;  40 (2) 298-304
  • 76 Nakanuma Y, Sripa B, Vatanasapt V, Leong A SY, Ponchon T, Ishak K G. Intrahepatic cholangiocarcinoma. In: Hamilton S R, Aaltonen L A, eds. WHO Classification of Tumours, Pathology and Genetics. Tumours of the Digestive System. Lyon: IARC Press; 2000: 173-180
  • 77 Roskams T. Liver stem cells and their implication in hepatocellular and cholangiocarcinoma.  Oncogene. 2006;  25 (27) 3818-3822
  • 78 Lee C H, Chang C J, Lin Y J, Yeh C N, Chen M F, Hsieh S Y. Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma.  Br J Cancer. 2009;  100 (11) 1765-1770
  • 79 Rullier A, Le Bail B, Fawaz R, Blanc J F, Saric J, Bioulac-Sage P. Cytokeratin 7 and 20 expression in cholangiocarcinomas varies along the biliary tract but still differs from that in colorectal carcinoma metastasis.  Am J Surg Pathol. 2000;  24 (6) 870-876
  • 80 Mosnier J F, Kandel C, Cazals-Hatem D et al.. N-cadherin serves as diagnostic biomarker in intrahepatic and perihilar cholangiocarcinomas.  Mod Pathol. 2009;  22 (2) 182-190
  • 81 Lamps L W, Folpe A L. The diagnostic value of hepatocyte paraffin antibody 1 in differentiating hepatocellular neoplasms from nonhepatic tumors: a review.  Adv Anat Pathol. 2003;  10 (1) 39-43
  • 82 Stroescu C, Herlea V, Dragnea A, Popescu I. The diagnostic value of cytokeratins and carcinoembryonic antigen immunostaining in differentiating hepatocellular carcinomas from intrahepatic cholangiocarcinomas.  J Gastrointestin Liver Dis. 2006;  15 (1) 9-14
  • 83 Pan C C, Chen P C, Tsay S H, Chiang H. Cytoplasmic immunoreactivity for thyroid transcription factor-1 in hepatocellular carcinoma: a comparative immunohistochemical analysis of four commercial antibodies using a tissue array technique.  Am J Clin Pathol. 2004;  121 (3) 343-349
  • 84 Lai Y S, Thung S N, Gerber M A, Chen M L, Schaffner F. Expression of cytokeratins in normal and diseased livers and in primary liver carcinomas.  Arch Pathol Lab Med. 1989;  113 (2) 134-138
  • 85 Leong A S, Sormunen R T, Tsui W M, Liew C T. Hep Par 1 and selected antibodies in the immunohistological distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumours and metastatic carcinoma.  Histopathology. 1998;  33 (4) 318-324
  • 86 Lau S K, Prakash S, Geller S A, Alsabeh R. Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma.  Hum Pathol. 2002;  33 (12) 1175-1181
  • 87 Durnez A, Verslype C, Nevens F et al.. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin.  Histopathology. 2006;  49 (2) 138-151
  • 88 Uenishi T, Kubo S, Yamamoto T et al.. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence.  Cancer Sci. 2003;  94 (10) 851-857
  • 89 Zhuang P Y, Zhang J B, Zhu X D et al.. Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor.  Cancer. 2008;  112 (12) 2740-2748
  • 90 Edge S B. Intrahepatic bile ducts. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2009: 247-254
  • 91 Nathan H, Pawlik T M. Staging of intrahepatic cholangiocarcinoma.  Curr Opin Gastroenterol. 2010;  26 (3) 269-273
  • 92 Nathan H, Aloia T A, Vauthey J N et al.. A proposed staging system for intrahepatic cholangiocarcinoma.  Ann Surg Oncol. 2009;  16 (1) 14-22
  • 93 Yedibela S, Demir R, Zhang W, Meyer T, Hohenberger W, Schönleben F. Surgical treatment of mass-forming intrahepatic cholangiocarcinoma: an 11-year Western single-center experience in 107 patients.  Ann Surg Oncol. 2009;  16 (2) 404-412
  • 94 Nuzzo G, Giuliante F, Ardito F et al.. Intrahepatic cholangiocarcinoma: prognostic factors after liver resection.  Updates Surg. 2010;  62 (1) 11-19
  • 95 Scheuer P J. Classification of chronic viral hepatitis: a need for reassessment.  J Hepatol. 1991;  13 (3) 372-374

Swan N ThungM.D. 

Department of Pathology, Box 1194, The Mount Sinai Medical Center

One Gustave L. Levy Place, New York, NY 10029

Email: swan.thung@mountsinai.org

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