Zen Y, Quaglia A, Heaton N, Rela M & Portmann B
(2011) Histopathology 59, 1100–1110
Two distinct pathways of carcinogenesis in primary sclerosing cholangitis

Aims: To identify clinicopathological characteristics of cholangiocarcinoma and premalignant lesions arising in patients with primary sclerosing cholangitis (PSC).

Methods and results: This study consisted of 25 patients with PSC and bile duct neoplasia [16 with cholangiocarcinoma and nine with biliary intra-epithelial neoplasia (BilIN) equivalent to biliary dysplasia]. Tumour cell morphology, growth patterns, history of inflammatory bowel disease and postoperative survival were recorded. Immunohistochemistry for CK7, CK20, MUC1, MUC2, MUC5AC, MUC6 and CDX2 was performed to characterize cell phenotypes. Cholangiocarcinoma and BilIN were classified into intestinal (n = 14) and non-intestinal classical (n = 11) types. Intestinal-type lesions showed histological features resembling intestinal dysplasia or adenocarcinoma. Intestinal-type cholangiocarcinoma commonly showed intraductal papillary proliferation and mucinous nodule formation. Intestinal-type lesions often had an intestinal immunophenotype that was not detected in classical-type lesions: CK20, 50% versus 0% (P = 0.007); MUC2, 86% versus 0% (P < 0.001); CDX2, 54% versus 0% (P = 0.003). Less commonly, intestinal-type cholangiocarcinoma showed perineural invasion (P = 0.003). Patients with intestinal-type cholangiocarcinoma had a more favourable cancer-specific prognosis than those with classical-type cholangiocarcinoma (P = 0.043).

Conclusions: Bile ducts in PSC show two distinct dysplasia–carcinoma sequences as evidenced by differences in cell morphology, growth patterns, immunophenotypes and grade of malignancy.

References

1 Weismüller TJ, Wedemeyer J, Kubicka S, Strassburg CP, Manns MP. The challenges in primary sclerosing cholangitis – aetiopathogenesis, autoimmunity, management and malignancy. J. Hepatol. 2008; 48; S38–S57.
10.1016/j.jhep.2008.01.020
CASPubMedWeb of Science®Google Scholar
2 Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am. J. Gastroenterol. 2004; 99; 523–526.
10.1111/j.1572-0241.2004.04067.x
PubMedWeb of Science®Google Scholar
3 Bergquist A, Ekbom A, Olsson R et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J. Hepatol. 2002; 36; 321–327.
10.1016/S0168-8278(01)00288-4
PubMedWeb of Science®Google Scholar
4 Boberg KM, Bergquist A, Mitchell S et al. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand. J. Gastroenterol. 2002; 37; 1205–1211.
10.1080/003655202760373434
CASPubMedWeb of Science®Google Scholar
5 Zen Y, Adsay NV, Bardadin K et al. Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod. Pathol. 2007; 20; 701–709.
10.1038/modpathol.3800788
PubMedWeb of Science®Google Scholar
6 Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Precancerous bile duct pathology in end-stage primary sclerosing cholangitis, with and without cholangiocarcinoma. Am. J. Surg. Pathol. 2010; 34; 27–34.
10.1097/PAS.0b013e3181bc96f9
PubMedWeb of Science®Google Scholar
7 Sobin LH, Gospodarowicz MK, Wittekind Ch. Digestive System Tumours. In LH Sobin, MK Gospodarowicz, Ch Wittekind eds. UICC International Union Against Cancer. TNM classification of malignant tumours, 7th edn. Oxford: Wiley-Blackwell, 2010; 63–135.
Google Scholar
8 Higashi M, Yonezawa S, Ho JJ et al. Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma. Hepatology 1999; 30; 1347–1355.
10.1002/hep.510300609
CASPubMedWeb of Science®Google Scholar
9 Van Klinken BJ, Dekker J, Büller HA, de Bolòs C, Einerhand AW. Biosynthesis of mucins (MUC2-6) along the longitudinal axis of the human gastrointestinal tract. Am. J. Physiol. 1997; 273; G296–G302.
CASPubMedWeb of Science®Google Scholar
10 Zen Y, Sasaki M, Fujii T et al. Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct – an immunohistochemical study of 110 cases of hepatolithiasis. J. Hepatol. 2006; 44; 350–358.
10.1016/j.jhep.2005.09.025
CASPubMedWeb of Science®Google Scholar
11 Zen Y, Fujii T, Itatsu K et al. Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas. Hepatology 2006; 44; 1333–1343.
10.1002/hep.21387
CASPubMedWeb of Science®Google Scholar
12 Chen TC, Nakanuma Y, Zen Y et al. Intraductal papillary neoplasia of the liver associated with hepatolithiasis. Hepatology 2001; 34; 651–658.
10.1053/jhep.2001.28199
CASPubMedWeb of Science®Google Scholar
13 Shimonishi T, Zen Y, Chen TC et al. Increasing expression of gastrointestinal phenotypes and p53 along with histologic progression of intraductal papillary neoplasia of the liver. Hum. Pathol. 2002; 33; 503–511.
10.1053/hupa.2002.124030
CASPubMedWeb of Science®Google Scholar
14 Shimonishi T, Miyazaki K, Nakanuma Y. Cytokeratin profile relates to histological subtypes and intrahepatic location of intrahepatic cholangiocarcinoma and primary sites of metastatic adenocarcinoma of liver. Histopathology 2000; 37; 55–63.
10.1046/j.1365-2559.2000.00932.x
CASPubMedWeb of Science®Google Scholar
15 Zen Y, Fujii T, Itatsu K et al. Biliary cystic tumors with bile duct communication: a cystic variant of intraductal papillary neoplasm of the bile duct. Mod. Pathol. 2006; 19; 1243–1254.
10.1038/modpathol.3800643
PubMedWeb of Science®Google Scholar
16 Bu-Ghanim M, Suriawinata A, Killackey M, Schwartz ME, Jaffe D, Fiel MI. Invasive colloid carcinoma arising from intraductal papillary neoplasm in a 50-year-old woman with primary sclerosing cholangitis. Semin. Liver Dis. 2004; 24; 209–213.
10.1055/s-2004-828897
PubMedWeb of Science®Google Scholar
17 Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008; 48; 1106–1117.
10.1002/hep.22441
CASPubMedWeb of Science®Google Scholar
18 Bangarulingam SY, Bjornsson E, Enders F et al. Long-term outcomes of positive fluorescence in situ hybridization tests in primary sclerosing cholangitis. Hepatology 2010; 51; 174–180.
10.1002/hep.23277
CASPubMedWeb of Science®Google Scholar
19 Jarnagin WR, Bowne W, Klimstra DS et al. Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann. Surg. 2005; 241; 703–712.
10.1097/01.sla.0000160817.94472.fd
PubMedWeb of Science®Google Scholar
20 Hoang MP, Murakata LA, Katabi N, Henson DE, Albores-Saavedra J. Invasive papillary carcinomas of the extrahepatic bile ducts: a clinicopathologic and immunohistochemical study of 13 cases. Mod. Pathol. 2002; 15; 1251–1258.
10.1097/01.MP.0000036450.61830.8E
PubMedWeb of Science®Google Scholar
21 Adsay NV, Merati K, Nassar H et al. Pathogenesis of colloid (pure mucinous) carcinoma of exocrine organs: coupling of gel-forming mucin (MUC2) production with altered cell polarity and abnormal cell–stroma interaction may be the key factor in the morphogenesis and indolent behavior of colloid carcinoma in the breast and pancreas. Am. J. Surg. Pathol. 2003; 27; 571–578.
10.1097/00000478-200305000-00002
PubMedWeb of Science®Google Scholar
22 Shibahara H, Tamada S, Goto M et al. Pathologic features of mucin-producing bile duct tumors: two histopathologic categories as counterparts of pancreatic intraductal papillary-mucinous neoplasms. Am. J. Surg. Pathol. 2004; 28; 327–338.
10.1097/00000478-200403000-00005
PubMedWeb of Science®Google Scholar

Citing Literature

Volume59, Issue6

December 2011

Pages 1100-1110

Two distinct pathways of carcinogenesis in primary sclerosing cholangitis

Abstract

References

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Two distinct pathways of carcinogenesis in primary sclerosing cholangitis

Abstract

References

Citing Literature

References

Related

Information