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Gallbladder & extrahepatic bile ducts

Gallbladder dysplasia and malignancy

Gallbladder carcinoma

Author: Ashwin S. Akki, M.D, Ph.D.

Deputy Editor-in-Chief: Raul S. Gonzalez, M.D.

Last author update: 21 April 2020

Last staff update: 1 June 2021

Copyright: 2003-2024, PathologyOutlines.com, Inc.

PubMed Search: Gallbladder carcinoma[TI] bile ducts

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Table of Contents

Cite this page: Akki A. Gallbladder carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/gallbladdercarcinoma.html. Accessed April 19th, 2024.

Definition / general

Carcinoma arising from the gallbladder epithelium (WHO Classification of Tumours Editorial Board: Digestive System Tumours (Medicine), 5th Edition, 2019)

Essential features

Aggressive cancer, with an overall 5 year survival rate of < 10%
Cholelithiasis is a major risk factor
Up to 50% are detected incidentally in routine cholecystectomy specimens due to absence of gross abnormalities; systematic sampling of these specimens is therefore crucial to detect incidental gallbladder adenocarcinomas (Am J Surg Pathol 2019;43:1668)

Terminology

Carcinoma of gallbladder; adenocarcinoma of gallbladder; malignant epithelial neoplasm of gallbladder

ICD coding

C23 - malignant neoplasm of gallbladder

8140/3 - adenocarcinoma NOS
8070/3 - squamous cell carcinoma NOS
8020/3 - carcinoma, undifferentiated, NOS

2C13.z - malignant neoplasms of gallbladder, unspecified

Epidemiology

Commonly occurs in the sixth and seventh decades
F:M = 3:1
Highest incidence in women from Chile (27.3/100 000), India (21.5/100 000), Pakistan (13.8/100 000) and Ecuador (12.9/100 000) (Int J Cancer 2010;127:2446, Histopathology 2009;55:218)
Incidence 1.1 per 100,000 in the United States (Cancer Epidemiol Biomarkers Prev 2015;24:1319)
Overall 5 year survival rate of < 10%

Sites

Primarily affects the fundus (60%), body (30%) or neck (10%) of gallbladder
Advanced tumors involve the liver and extrahepatic biliary tree

Pathophysiology

Longstanding cholelithiasis and cholecystitis give rise to metaplastic changes (intestinal or pseudopyloric types) in the gallbladder mucosa (Cancer 1993;72:1878)
Metaplasia (especially intestinal type) gives rise to epithelial dysplasia and carcinoma in situ (J Hepatobiliary Pancreat Surg 2000;7:556)
Progression from dysplasia to advanced gallbladder carcinoma takes around 15 years (Gastroenterology 1996;111:232)

Etiology

Risk factors include:
- Cholelithiasis (major risk factor)
- Chronic cholecystitis, especially hyalinizing cholecystitis
- Obesity
- Infections (esp. Salmonella and Opisthorchis viverrini)
- Porcelain gallbladder
- Primary sclerosing cholangitis
- Pancreaticobiliary maljunction (supra-Oddi union of common bile duct with the main pancreatic duct)
- Occasionally occurs in patients with Lynch syndrome or familial adenomatous polyposis (FAP)

Clinical features

Asymptomatic in a large majority of patients
Symptoms when present are vague
- Right upper quadrant pain (most common)
- Weight loss
- Fever
Disease is usually advanced by the time patient develops symptoms

Diagnosis

50% are diagnosed incidentally on routine cholecystectomy specimens
Finding a thickened gallbladder wall or polypoid lesions in the gallbladder on imaging done for other reasons should prompt surgical resection

Laboratory

Elevated alkaline phosphatase in advanced cancers (HPB (Oxford) 2008;10:446)
CEA only has 50% sensitivity (Int J Cancer 1990;45:821)

Radiology description

Imaging findings are variable from subtle (in early disease) to obvious (in late disease)
- Thickening of the gallbladder wall
- Raised / polypoid lesion in the gallbladder wall / lumen
- Mass occupying or replacing the gallbladder lumen
- Gallbladder mass invading the liver (in advanced disease)
Ultrasound is the primary imaging modality for screening purposes in suspected cases
Abnormal findings on ultrasound are further investigated by CT and MRI that provide detailed information, including staging parameters

Radiology images

Images hosted on other servers:

Heterogeneous mass

Prognostic factors

Noninvasive papillary carcinomas, regardless of size and differentiation, do not metastasize
Invasive papillary carcinomas have the most favorable prognosis (Arch Pathol Lab Med 2005;129:905)
Prognosis of adenocarcinoma, NOS depends on tumor stage:
- Superficially invasive cancers limited to the lamina propria (pT1a) have excellent prognosis as they are completely cured by cholecystectomy (Ann Surg 2017;266:625)
- Advanced cancers (i.e. muscle invasive and beyond; pT1b - pT4) have a higher chance of recurrence and have poorer outcomes (J Gastrointest Surg 2007;11:631, Ann Surg 2011;254:320)
- High histologic grade (poor differentiation) and vascular invasion have adverse outcomes (Cancer 1992;70:1493)
- Rokitansky-Aschoff sinus involvement by carcinoma and cystic duct margin status are suspected predictors of progression (Am J Clin Pathol 2014;141:675)

Case reports

22 year old man with primary signet ring cell carcinoma of gallbladder in the absence of choleliths (Int J Surg Pathol 2010;18:358)
56 year old woman with clear cell carcinoma of the gallbladder (Int J Surg Case Rep 2017;32:36)
59 year old woman with hepatoid carcinoma of the gallbladder (World J Surg Oncol 2011;9:103)
62 year old man with carcinosarcoma of the gallbladder with chondroid differentiation (Int J Clin Exp Pathol 2015;8:7464)

Treatment

Cholecystectomy with a negative cystic duct margin is curative in pT1a tumors (Ann Surg 2017;266:625)
Hilar / portal lymphadenectomy, plus resection of hepatic bed and the common bile duct to achieve negative margins, is necessary for tumors that extend into a muscle or beyond (pT1b - pT3) (HPB (Oxford) 2015;17:681)
Chemotherapy or radiation for metastatic tumors

Gross description

Incidental gallbladder cancer in routine cholecystectomy specimens can be grossly subtle, with areas of mucosal granularity / irregularity, minimally raised / polypoid mucosal lesions or focally thickened fundus / body (Am J Surg Pathol 2019;43:1668)
Frank tumors may have one or more of the following features:
- Thickened and indurated gallbladder wall
- Exophytic or polypoid friable mucosal lesions (especially those arising from intracholecystic papillary neoplasm)
- Firm, gritty, tan-white to yellow-gray cut surface

Gross images

Contributed by Ashwin S. Akki, M.D., Ph.D.

Papillary proliferation

Carcinoma in a polyp

Gallbladder cancer invading liver

Diffusely thickened gallbladder wall

Microscopic (histologic) description

Histologic variants recognized by WHO include:
- Biliary type adenocarcinoma (~75%):
  - Similar to pancreatic ductal adenocarcinoma
  - Includes adenocarcinoma, NOS (most common), papillary, micropapillary
  - Composed of tubules (lined by cuboidal to columnar cells) embedded in a desmoplastic stroma
  - Moderately differentiated is more common but has a wide histologic spectrum, from deceptively bland to poorly differentiated
- Intestinal type adenocarcinoma:
  - Tubules lined by columnar cells with elongated hyperchromatic nuclei, very similar to colonic adenocarcinomas
- Mucinous carcinoma:
  - Comprised of > 50% extracellular mucin
- Clear cell carcinoma:
  - Sheets of clear cells in an alveolar arrangement separated by blood vessels, similar in appearance to metastatic clear cell renal carcinoma
- Signet ring cell carcinoma:
  - Signet ring cells are the predominant or exclusive component
- Hepatoid carcinoma:
  - > 50% with abundant eosinophilic cytoplasm, enlarged nuclei and prominent nucleoli arranged in a trabecular pattern
- Sarcomatoid carcinoma (carcinosarcoma):
  - Predominant spindle cell morphology with or without heterologous differentiation (e.g. skeletal muscle, bone and cartilage)
Differentiation
- Well differentiated:
  - Well formed glands lined by columnar cells with minimal cytologic abnormality
  - Glands in perimuscular connective tissue, nuclear irregularities and mitoses may be the only clues
  - Desmoplasia may be subtle
- Moderately differentiated:
  - Irregular / angulated glands lined by polygonal tumor cells with enlarged nuclei showing vesicular chromatin, prominent nucleoli and increased mitoses
  - Desmoplasia is usually prominent
- Poorly differentiated:
  - Incomplete or poorly formed tubules / glands, single cells or sheets of pleomorphic tumor cells with bizarre nuclei

Microscopic (histologic) images

Contributed by Ashwin S. Akki, M.D., Ph.D.

Desmoplasia

Well formed glands

Intermediate gland formation

Poor gland formation

Sarcomatoid differentiation

Papillary proliferation with invasion

Virtual slides

Images hosted on other servers:

Invasive adenocarcinoma

Positive stains

CK7 (strong and diffuse) (Arch Pathol Lab Med 2000;124:1196), p53 (majority), CEA and CA19-9 (70 - 90%), IMP3 (80%) (Arch Pathol Lab Med 2017;141:1155), Maspin (60 - 100%), S100P and MUC1 (75%), HER2 (> 60%), CK20 and CDX2 (focal)
Hep par1 and alpha-fetoprotein (AFP) (Positive in hepatoid variant)

Negative stains

p16 (not expressed in a majority of cases akin to normal gallbladder) (Hepatogastroenterology 2010;57:18)
PAX8, CD10 and CAIX

Molecular / cytogenetics description

Common genetic alterations include TP53 (seen in > 50% of cases), CDKN2A (20%), ARID1A (13%), PIK3CA (10%) and CTNNB1 (10%) (WHO Classification of Tumours Editorial Board: Digestive System Tumours (Medicine), 5th Edition, 2019)
Amplifications of ERBB2 (HER2) have been reported in 16% of cases and microsatellite instability (MSI) in 10% of cancers, both of which have therapeutic implications (Cancer 2016;122:3838, Histopathology 2009;55:218)
A higher KRAS mutation rate is noted in lesions related to pancreatobiliary maljunction (Hum Pathol 1999;30:21)

Videos

Extended cholecystectomy

Sample pathology report

Gallbladder; cholecystectomy:
- Invasive adenocarcinoma, moderately differentiated, biliary type (2.7 cm in largest dimension), arising in a background of extensive high grade biliary intraepithelial neoplasia (BilIN).
- Adenocarcinoma invades perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum).
- Cystic duct margin is free from biliary intraepithelial neoplasia (BilIN) or carcinoma.
- One lymph node, negative for carcinoma (0/1).
- Lymphovascular invasion is not identified.
- pT2a, N0, M-not applicable (AJCC 8th edition). Please see synoptic report
- Background gallbladder with chronic cholecystitis.
- Cholelithiasis.

Differential diagnosis

Pancreatic ductal adenocarcinoma:
- Epicenter in pancreas; presence of IPMN, MCN or PanIN
Cholangiocarcinoma (both intrahepatic and extrahepatic):
- Epicenter in the bile ducts; CK19+
Colonic adenocarcinoma:
- Epicenter in the colon, intestinal phenotype, CK20 strong and diffuse

Board review style question #1

Has aggressive dissemination potential
Has a more favorable prognosis than conventional nonpapillary gallbladder adenocarcinomas
Immunoreactive to hepatocellular markers
Is not detected early on imaging

Board review style answer #1

B. Invasive papillary carcinomas have the most favorable prognosis than conventional nonpapillary gallbladder adenocarcinomas because they have an exophytic growth pattern, exhibit delayed invasion into the gallbladder wall, and are detected early due to obstructive symptoms (Arch Pathol Lab Med 2005;129:905).

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Reference: Gallbladder carcinoma

Board review style question #2

> 25%
> 30%
> 50%
> 90%

Board review style answer #2

C. > 50% extracellular mucin

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Reference: Gallbladder carcinoma

Board review style question #3

HER2 and MSI
KRAS and ARID1A
TP53 and CDKN2A
PIK3CA and CTNNB1 (beta-catenin)
p16

Board review style answer #3

A. HER2 and MSI

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Reference: Gallbladder carcinoma

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