Gallbladder - Gallbladder carcinoma

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Gallbladder

Malignant gallbladder tumors

Gallbladder carcinoma

Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
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● Relatively uncommon
● Age 60+ years (mean 72 years), 75% women, usually not resectable
● Metastases to peritoneum and liver, pericholedochal lymph nodes of lesser omentum, occasionally to lungs and pleura
● 90% are adenocarcinoma, 5% squamous cell or adenosquamous, 5% undifferentiated

Epidemiology
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● 2.5 per 100,000 population
● Lower incidence in Asia, where pyogenic and parasitic disease of biliary tree are more common
● More common in American Indians and Hispanics; very rare in blacks
● 6,500 annual deaths in US, but largest cause of cancer death for women in Chile

Clinical features
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● Associated with gallstones (2/3); also adenomyomatosis, anomalous connection between common bile duct and pancreatic duct, cholecystoenteric fistula, Peutz-Jeghers syndrome, polyposis coli / Gardner’s syndrome, porcelain gallbladder, ulcerative colitis
● Often invades liver, common bile duct, stomach, duodenum and transverse colon
● 70% involve liver at diagnosis, 50% involve regional lymph nodes

5 year survival:
● Overall 1% (J Surg Oncol 2008;98:485)
● 85-100% for T1, 30-40% for T2
● Median survival 6 months

Diagnosis
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● Adenomyomatosis-positive gallbladder cancer is more often diagnosed clinically in the advanced stages; therefore, preventive cholecystectomy in cases of asymptomatic adenomyomatosis should be considered (Virchows Arch 2011;459:573)
● Intraoperative bile cytology useful to detect in situ and early invasive carcinoma (Cancer 2005;105:277)

Prognostic factors
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● Favorable: papillary histology, low stage
● Unfavorable: small cell or undifferentiated types, angiolymphatic invasion, poorly differentiated, high stage, tumor budding and dedifferentiation (Virchows Arch 2011;459:449, Asian Pac J Cancer Prev 2012;13:2511)

Molecular markers, poor prognosis:
● Overexpression of MCM2 or loss of expression of Tat-interacting protein 30 (Hum Pathol 2011;42:1676), overexpression of PEG10 and TSG101 (Pathol Oncol Res 2011;17:859), reduced expression of Raf-1 kinase inhibitory protein (Hum Pathol 2010;41:1609)
● L1 adhesion molecule (Hum Pathol 2011;42:1476)
● Strong cytoplasmic expression of COX2 at invasive fronts (J Clin Pathol 2010;63:1048)

Case reports
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● 22 year old African American man with lack of choleliths (Int J Surg Pathol 2010;18:358)
● 77 year old woman presenting as meningeal carcinomatosis (Arch Pathol Lab Med 2001;125:1120)

Treatment
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● Cholecystectomy (T1 tumors), uncertain for more advanced tumors
● Tumor may recur at trochar site after laparoscopic cholecystectomy

Gross description
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● Fibrosis and thickening of wall, may be papillary and diffuse
● Often associated with gallstones > 3 cm
● Tumor may not be obvious, although liver spread is usually evident at time of diagnosis

Gross images
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Various images

Micro description
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● Infiltrative (diffuse thickening and induration of wall with possible fistula formation due to deep ulceration) or exophytic (irregular, cauliflower mass that grows into lumen and invades wall)
● Well formed glands in papillary architecture with wide lumina, atypical cuboidal cells, high grade
● May extend to Rokitansky-Aschoff sinuses (but this does not signify deep invasion)
● Superficial portion is often better differentiated than deeper portion
● May have foci of intestinal differentiation

Micro images
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Various images

Positive stains
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● Keratin, CEA, P504S
● New Biomarker: S100A8 (Dig Dis Sci 2012 Jul 18 [Epub ahead of print])

Molecular / cytogenetics description
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● Methylation in the promotor gene is a crucial early event in gall bladder carcinogenesis
● K-ras mutations (Mod Pathol 2003;16:299, Histopathology 2009;55:218), microsatellite instability (small subset) are noted in dysplastic lesions and gall bladder carcinomas (Rev Med Chil 2010;138:595)
● p16 protein overexpression is an early and relatively common event in carcinogenesis of gallbladder (Hepatogastroenterology 2010;57:18, Ann Diagn Pathol 2008;12:161)
● Loss of heterozygosity has been in several chromosomes in dysplasia and carcinomas (Mod Pathol 1999;12:763)
● Significantly higher hTERT indices are seen in low and high grade dysplastic epithelia and in gallbladder adenocarcinomas (J Clin Pathol 2005;58:820)

Differential diagnosis
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● Reactive atypia (see table below)

Table

Additional references
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● Am J Surg Pathol 2002;26:758, Radiographics 2001;21:295, Arch Pathol Lab Med 2010;134:1621

End of Gallbladder > Malignant gallbladder tumors > Gallbladder carcinoma

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