Intrahepatic Cholangiocarcinoma: New Insights in Pathology

Christine Sempoux; Ghalib Jibara; Stephen C Ward; Cathy Fan; Lihui Qin; Sasan Roayaie; M. Isabel Fiel; Myron Schwartz; Swan N Thung

doi:10.1055/s-0031-1272839

Seminars in Liver Disease, Inhaltsverzeichnis

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

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

Abstract

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.

KEYWORDS

Intrahepatic cholangiocarcinoma - cholangiolocarcinoma - histopathology - immunohistochemistry - HCV infection - hepatic progenitor cells

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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