Molecular Mechanisms of Cholangiocarcinogenesis: Are Biliary Intraepithelial Neoplasia and Intraductal Papillary Neoplasms of the Bile Duct Precursors to Cholangiocarcinoma?
Section snippets
Biliary intraepithelial neoplasia
BilIN is characterized by a flat or micropapillary growth of atypical biliary epithelium. It previously was called “atypical biliary epithelia” and “biliary dysplasia.” BilIN is characteristically a microscopic lesion that can progress to tubular adenocarcinoma. These premalignant lesions are classified commonly into three grades based on the degree of cellular and structural atypia: BilIN-1, BilIN-2, and BilIN-3.7, 8
BilIN typically is found in large intrahepatic biliary ducts and rarely is
Intraductal papillary neoplasm of the bile duct
IPNB is a macroscopic lesion characterized by prominent papillary growth of atypical biliary epithelium with a fibrovascular core and overproduction of mucin.9 IPNB, like BilIN, occurs in bile ducts associated with chronic inflammatory conditions such as hepatolithiasis or choledochocysts. IPNB can transform into two types of invasive cancers, each with different biologic behavior and prognosis: mucinous carcinoma or tubular adenocarcinoma.10 The histologic subtype of the invasive cancers
Cell-cycle proteins
Cyclin D1 is a proto-oncogene that is an important regulator of cell-cycle progression from the G1 to S phase. The cyclin D1 protein forms a complex with cyclin-dependent kinase-4 and -6 (CDK4 and CDK6) that allows cells to progress into S phase by phosphorylation and inactivation of the retinoblastoma protein.13 Cyclin D1 is overexpressed in many cancers, including intrahepatic CC, a consequence of gene amplification or defective regulation at the posttranscriptional level.14, 15, 16 Cyclin D1
Tumor suppressor genes
DPC4 (Smad4) is a tumor suppressor gene located on chromosome 18q and is a member of a highly conserved family of proteins involved in the transduction of signals from the transforming growth factor beta (TGF-β) family.21 DPC4 has been implicated in carcinogenesis through transmission of TGF-β epithelial growth inhibition signals.21 DPC4 mutations have been demonstrated in several reports of CC. Hahn and colleagues22 showed that 16% of resected biliary tract cancers had a mutation in the DPC4
Mucinous proteins
Mucin core proteins (MUC) are members of the mucin protein family that encode organ-specific glycoproteins produced by many epithelial tissues.33 MUC are anti-adhesion molecules that, when altered, may facilitate cancer cell invasion through the basement membranes.34, 35 These proteins disrupt the normal adhesive interactions between cellular integrins and the extracellular matrix.36, 37 Abnormal levels of sialylated MUC1 protein have been demonstrated in many adenocarcinomas, including
Cell-adhesion proteins
Alterations in normal cell-adhesion molecules may be an important determinant of cancer invasion and metastatic potential. E-cadherin is a tumor suppressor gene that produces a transmembrane protein involved in epithelial cell adhesion.41 The extracellular domain functions through calcium-dependent, homophilic interactions with the extracellular matrix. The intracellular portion is a catenin-like protein that transmits signals related to cell adhesion. Reduced expression of E-cadherin and/or
Matrix proteins
MMPs are critical proteins that metabolize extracellular matrix. Their physiologic activity is a complex dynamic between MMP activity, MMP inhibitors (ie, TIMP-1, TIMP-2), and the extracellular milieu (ie, electrolytes, stroma, and other chemical mediators). Overexpression of MMP may promote epithelial cancer invasion and metastasis. Several studies have demonstrated an increased expression of membrane-type metalloproteinase-1 (MT1)-MMP and MMP-7 in resected CC.47, 48 MT1-MMP degrades type 1
Summary
Two key premalignant lesions, BilIN and IPNB, have been implicated in the development of CC. These tumors share similarities with their pancreatic analogues, PanIN and IPMN. Each of these lesions follows different tumorigenic pathways with distinct genetic alterations (Table 1). Lesions of the BilIN and PanIN lineage develop a gradual progression of mutations in cyclin D1, p21, and p53 with greater loss of DPC4 and molecular cell adhesion expression. BilIN lesions have significantly higher
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Cited by (34)
Imaging in Gastroenterology
2018, Imaging in GastroenterologySurveillance in cholangiocellular carcinoma
2016, Best Practice and Research: Clinical GastroenterologyCitation Excerpt :Similar to colorectal adenoma and pancreatic intrapapillary mucinous neoplasia, a possible role of premalignant lesions for CCA is debated. Among these, biliary intraepithelial neoplasm and intraductal papillary neoplasms are most frequently found in perihilar and distal CCA, while bile duct adenoma, biliary adenofibroma and von Meyenburg complexes are more prominent in intrahepatic CCA [30,31], although this distinction is by no means absolute [32]. In Japan, the contrast agent Thorotrast was shown to elevate the risk for CCA development approximately 300-fold, leading to a ban of this agent in radiology practice [33].
Clinical and pathological features of intraductal papillary neoplasm of the biliary tract and gallbladder
2015, HPBCitation Excerpt :For the specimens with invasive cancer, all were found to be tubular adenocarcinoma. It has been shown that mucinous carcinoma demonstrates improved survival compared with tubular,6 but this relationship cannot be studied in this series. Compared with other studies, fewer IHC markers were utilized.
Distal cholangiocarcinoma
2014, Surgical Oncology Clinics of North AmericaCitation Excerpt :IPNB can progress to either mucinous carcinoma or tubular adenocarcinoma. The biological behavior and prognosis of mucinous carcinoma are considerably more favorable than those of tubular adenocarcinoma.51,54 Tumors arising in intra-ampullary segments of the CBD are now classified as ampullary-ductal carcinomas by the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control.7
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Drs. Bickenbach and Galka share joint first authorship.