Gallbladder: Carcinoma of the gallbladder and extrahepatic bile ducts

2007-06-01   Munechika Enjoji , Toyoma Kaku 

1.Department of Hepatology, Pancreatology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

Summary

Note

Defined as a malignant epithelial tumor arising in the gall bladder and extrahepatic bile ducts including ampulla of Vater.
Atlas Image
Extrahepatic bile duct carcinoma from the middle portion (percutaneous transhepatic cholangiography).

Classification

Note

Tumor staging is separated by TNM classification (International Classification of Diseases, ICD).

Classification

TNM classifications for carcinomas of the gallbladder, extrahepatic bile ducts and the ampulla of Vater.
The histopathological classification of biliary tract carcinoma follows WHO classification:
  • adenocarcinoma,
  • adenosquamous carcinoma,
  • squamous cell carcinoma,
  • small cell carcinoma,
  • adenoendocrine cell carcinoma,
  • undifferentiated carcinoma, and
  • carcinosarcoma.
  • Clinics and Pathology

    Etiology

    Carcinoma of the gallbladder and extrahepatic bile ducts is more common in Eastern Europe and Latin American countries, and in the yellow races. It occurs frequently in older age groups (6th to 7th decades of life). Statistical data in Japan and USA indicate that gallbladder carcinomas occur predominantly in female, whereas carcinoma of the extrahepatic bile duct occurs more frequently in males. Carcinoma of the extrahepatic bile duct is associated with primary sclerosing cholangitis, ulcerative colitis, abnormal choledochopancreatic junction, and parasitic infection (trematode). In gallbladder carcinomas, gallstones and abnormal choledochopancreatic junction are considered risk factors. Association with smoking and drinking is not established.

    Epidemiology

    One of the common carcinomas worldwide

    Clinics

    The clinical symptoms are affected by the complications such as gallstones and cholangitis. The most frequent symptom is right upper quadrant pain in gallbladder carcinomas and obstructive jaundice in extrahepatic bile duct carcinomas. Chills and fever appear when cholangitis develops. For early diagnosis, ultrasonography is useful; detection of biliary dilatation and tumor masses. For staging, computed tomography, magnetic resonance imaging, and endoscopic ultrasonography are effective. Percutaneous transhepatic cholangiography and endoscopic retrograde cholangiography are poorly available for qualitative diagnosis but performed in case of biliary drainage.
    Atlas Image
    Positive bile cytology specimen (Papanicolau stain). Isolated cells with increased nucleocytoplasmic ratio, marked anisocaryosis, loss of polarity, and prominent nucleoli.

    Cytology

    Cytology of bile duct brushings is an important diagnostic tool for tumors of biliary ductal system presenting as duct strictures from which it can be difficult to obtain a histology biopsy. Bile duct brushings have been recognized as a technique of moderate sensitivity and high specificity in identifying carcinoma. Reported diagnostic sensitivities for malignancy have ranged from 20 to 70% and specificity is almost 100%. Therefore, positive diagnoses of malignancy are of great clinical value but a negative result is relatively little clinical aid.
    Atlas Image
    Carcinoma of the gallbladder; well differentiated adenocarcinoma.

    Treatment

    Surgical resection, chemotherapy, radiotherapy, immunotherapy

    Evolution

    Recurrence should be given care to.

    Prognosis

    The prognosis of biliary carcinomas depends primarily on the extent of disease. In inoperable cases, one-year survival rates in gallbladder carcinomas and extrahepatic bile duct carcinomas are 10% or less and 20% or less, respectively.

    Cytogenetics

    Note

    Loss of heterozygosity at chromosomal loci 8p, 9p, and 18q are frequently detected.

    Genes Involved and Proteins

    Gene name

    KRAS (Kirsten rat sarcoma 2 viral oncogene homolog)

    Location

    12p12.1

    Dna rna description

    4 exons

    Protein description

    Proto-oncogene. GTP-GDP binding protein with GTPase activity. The K-ras proto-oncogene is thought to exert control over some of the mechanisms of cell growth and differentiation. This gene is converted to an active oncogene by point mutations significantly concentrated in codons 12, 13, or 61. The incidence of the mutations has variously been reported to be 17-59% of gallbladder carcinomas and 23-100% of bile duct carcinomas. K-ras mutations in biliary tract carcinomas with a background of pancreaticobiliary maljunction is significantly higher than in those without it, namely, 50-100% and 6-36%, respectively. Alteration of the K-ras oncogene may be very important in the early stages of carcinogenesis of biliary mucosa, especially in association with anomalous connections of the pancreatobiliary ducts. K-ras mutation is more frequently detected in carcinomatous and dysplastic lesions in gallbladder carcinoma cases with gall stones than in those without stones. There was a large difference in the incidence of K-ras mutations between distal (47-75%) and middle or proximal (0-8%) bile duct carcinoma. The distal portion may be to some extent influenced by pancreatic juice because of its anatomical location. K-ras mutations in biliary tract carcinomas are not statistically significantly correlated with tumor staging, histological type and age, sex, or survival of the patients.

    Gene name

    TP53 (Tumour protein p53 (Li-Fraumeni syndrome))

    Location

    17p13.1

    Dna rna description

    11 exons

    Protein description

    Tumor suppressor. Wild-type p53 plays an important role in the regulation of the cell cycle process, cell growth, and apoptosis in the event of DNA damage. The mutant proteins from the mutated genes disrupt critical growth-regulating mechanisms and may play a crucial role in the carcinogenesis. The reported incidence of p53 mutation is 31-92% in gallbladder carcinoma and 33-73% in bile duct carcinoma. In general, there is a tendency for higher grade carcinomas to express more p53 protein. p53 abnormalities may appear early during the transition from low-grade to higher-grade tumors and may play a role in the development of more malignant tumor phenotypes. A statistically significant difference is found for the incidence of p53 protein expression between extrahepatic bile duct carcinomas from the distal portion and those from the lower mid-region. This tendency is the same as that for K-ras mutations and the pancreaticobiliary maljunction may override the effect of p53 gene mutations.

    Gene name

    CDKN2A (cyclin dependent kinase 2a / p16)

    Location

    9p21.3

    Dna rna description

    3 exons

    Protein description

    Regulatory protein in the cell cycle and cyclin-dependent kinase (cdk4/cdk6) inhibitor. The tumor suppressor gene p16 is commonly inactivated in many neoplasms. Three distinct mechanisms of p16 inactivation have been reported in biliary neoplasms: deletion and point mutations of the p16 gene, and hypermethylation of 5¹ regulatory regions of p16. It has been reported that 60-80% of primary biliary tract carcinomas had point mutations in the p16 gene. Allelic loss at the p16 locus on chromosome 9p21 or p16 promoter hypermethylation occurred with sufficient frequency in extrahepatic bile duct carcinomas and in gallbladder carcinomas. Therefore, the p16 gene may possibly be crucial for biliary tract carcinogenesis and progression.

    Gene name

    ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))

    Location

    17q12

    Dna rna description

    7 exons

    Protein description

    Proto-oncogene. Amplification and overexpression of c-erbB-2 are frequently shown in biliary tract carcinomas. It is suggested that c-erbB-2 expression may be associated with neoplastic progression in biliary tracts.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    86750981996K-ras gene mutation in gall bladder carcinomas and dysplasia.Ajiki T et al
    118022102002Inactivation of the INK4a/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines.Caca K et al
    166869422006Preliminary study of p53 and c-erbB-2 expression in gallbladder cancer in Indian patients manuscript id: 8962091628764582.Chaube A et al
    76572821995p53 protein immunoreactivity in extrahepatic bile duct and gallbladder cancer: correlation with tumor grade and survival.Diamantis I et al
    86309511996K-ras and p53 mutations in stage I gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct.Hanada K et al
    103640371999Gene mutations of K-ras in gallbladder mucosae and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct.Hanada K et al
    81940131994K-ras codon 12 mutations in biliary tract tumors detected by polymerase chain reaction denaturing gradient gel electrophoresis.Imai M et al
    94146541997p16INK4 gene mutations are relatively frequent in ampullary carcinomas.Imai Y et al
    92935321997Correlation of p53 protein expression with gene mutation in gall-bladder carcinomas.Itoi T et al
    81008541993p53 and c-erbB-2 protein expression in adenocarcinomas and epithelial dysplasias of the gall bladder.Kamel D et al
    16759331991Multiple K-ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique.Levi S et al
    109826142000Relation between K-ras codon 12 mutation and p53 protein overexpression in gallbladder cancer and biliary ductal epithelia in patients with pancreaticobiliary maljunction.Masuhara S et al
    86085741996K-ras point mutations in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction.Matsubara T et al
    103368111999p53 expression as a prognostic determinant in resected distal bile duct carcinoma.Rijken AM et al
    97012131998Diagnostic and prognostic value of incidence of K-ras codon 12 mutations in resected distal bile duct carcinoma.Rijken AM et al
    98649691998Prognostic significance of Ki-67 and p53 antigen expression in carcinomas of bile duct and gallbladder.Shrestha ML et al
    94284831998Assessment of the expression of p53, MIB-1 (Ki-67 antigen), and argyrophilic nucleolar organizer regions in carcinoma of the extrahepatic bile duct.Suto T et al
    85368611996Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease.Tada M et al
    80734401994Mutation of the p53 gene in gallbladder cancer.Takagi S et al
    75203481994An immunohistochemical study of p53 protein in gallbladder and extrahepatic bile duct/ampullary carcinomas.Teh M et al
    87408421996Expression of p53 in adenocarcinoma of the gallbladder and bile ducts.Washington K et al
    79264621994Point mutation of K-ras gene codon 12 in biliary tract tumors.Watanabe M et al
    80273991994Clinical importance of p53 protein in gall bladder carcinoma and its precursor lesions.Wee A et al
    77809591995Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile.Wistuba II et al
    77964001995Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers.Yoshida S et al

    External Links

    Citation

    Munechika Enjoji ; Toyoma Kaku

    Gallbladder: Carcinoma of the gallbladder and extrahepatic bile ducts

    Atlas Genet Cytogenet Oncol Haematol. 2007-06-01

    Online version: http://atlasgeneticsoncology.org/solid-tumor/5275/gallbladder-carcinoma-of-the-gallbladder-and-extrahepatic-bile-ducts