General Information About Gallbladder Cancer

Incidence and Mortality

Estimated new cases and deaths from gallbladder (and other biliary) cancer in the United States in 2019:[1]

• New cases: 12,360.
• Deaths: 3,960.

Cancer that arises in the gallbladder is uncommon.

Clinical Features

The most common symptoms caused by gallbladder cancer are jaundice, pain, and fever.

Histopathology and Diagnostics

In patients whose superficial cancer (T1 or confined to the mucosa) is discovered on pathological examination of tissue after gallbladder removal for other reasons, the disease is often cured without further therapy. In patients who present with symptoms, the tumor is rarely diagnosed preoperatively.[2] In such cases, the tumor often cannot be removed completely by surgery and the patient cannot be cured, although palliative measures may be beneficial. For patients with T2 or greater disease, extended resection with partial hepatectomy and portal lymph node dissection may be an option.[3,4]

Other Prognostic Factors

Cholelithiasis is an associated finding in the majority of cases, but less than 1% of patients with cholelithiasis develop this cancer.

References:

1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online. Last accessed January 23, 2019.
2. Chao TC, Greager JA: Primary carcinoma of the gallbladder. J Surg Oncol 46 (4): 215-21, 1991.
3. Shoup M, Fong Y: Surgical indications and extent of resection in gallbladder cancer. Surg Oncol Clin N Am 11 (4): 985-94, 2002.
4. Sasson AR, Hoffman JP, Ross E, et al.: Trimodality therapy for advanced gallbladder cancer. Am Surg 67 (3): 277-83; discussion 284, 2001.

Cellular Classification of Gallbladder Cancer

Some histologic types of gallbladder cancer have a better prognosis than others; papillary carcinomas have the best prognosis. The histologic types of gallbladder cancer include the following:[1]

• Carcinoma in situ.
• Adenocarcinoma, not otherwise specified (NOS).
• Papillary carcinoma.
• Adenocarcinoma, intestinal type.
• Clear cell adenocarcinoma.
• Mucinous carcinoma.
• Signet-ring cell carcinoma.
• Squamous cell carcinoma.
• Adenosquamous carcinoma.
• Small cell (oat cell) carcinoma.*
• Undifferentiated carcinoma.*
  • Spindle and giant cell types.
  • Small cell types.
• Carcinoma, NOS.
• Carcinosarcoma.
• Other (specify).

*Grade 4 by definition.

References:

1. Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.

Stage Information for Gallbladder Cancer

AJCC Stage Groupings and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by the TNM classification to define gallbladder cancer.[1]

Table 1. Definitions of TNM Stage 0^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
0	Tis, N0, M0	Tis = Carcinomain situ.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 2. Definitions of TNM Stage I^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
I	T1, N0, M0	T1 = Tumor invades the lamina propria or muscular layer.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 3. Definitions of TNM Stage IIA^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
IIA	T2a, N0, M0	T2a = Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum).
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 4. Definitions of TNM Stage IIB^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
IIB	T2b, N0, M0	T2b = Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 5. Definitions of TNM Stage IIIA^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
IIIA	T3, N0, M0	T3 = Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 6. Definitions of TNM Stage IIIB^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
IIIB	T1–3, N1, M0	T1 = Tumor invades the lamina propria or muscular layer.
		–T1a = Tumor invades the lamina propria.
		–T1b = Tumor invades the muscular layer.
		T2 = Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum). Or, tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
		–T2a = Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum).
		–T2b = Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
		T3 = Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts.
		N1 = Metastases to one to three regional lymph nodes.
		M0 = No distant metastasis.

Table 7. Definitions of TNM Stage IVA^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
IVA	T4, N0–1, M0	T4 = Tumor invades the main portal vein or hepatic artery or invades two or more extrahepatic organs or structures.
		N0 = No regional lymph node metastasis.
		N1 = Metastases to one to three regional lymph nodes.
		M0 = No distant metastasis.

Table 8. Definitions of TNM Stage IVB^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
IVB	Any T, N2, M0	TX = Primary tumor cannot be assessed.
		T0 = No evidence of primary tumor.
		Tis = Carcinomain situ.
		T1 = Tumor invades the lamina propria or muscular layer.
		–T1a = Tumor invades the lamina propria.
		–T1b = Tumor invades the muscular layer.
		T2 = Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum). Or, tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
		–T2a = Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum).
		–T2b = Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
		T3 = Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts.
		T4 = Tumor invades the main portal vein or hepatic artery or invades two or more extrahepatic organs or structures.
		N2 = Metastases to four or more regional lymph nodes.
		M0 = No distant metastasis.
	Any T, Any N, M1	TX = Primary tumor cannot be assessed.
		T0 = No evidence of primary tumor.
		Tis = Carcinomain situ.
		T1 = Tumor invades the lamina propria or muscular layer.
		–T1a = Tumor invades the lamina propria.
		–T1b = Tumor invades the muscular layer.
		T2 = Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum). Or, tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
		–T2a = Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum).
		–T2b = Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
		T3 = Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts.
		T4 = Tumor invades the main portal vein or hepatic artery or invades two or more extrahepatic organs or structures.
		NX = Regional lymph nodes cannot be assessed.
		N0 = No regional lymph node metastasis.
		N1 = Metastases to one to three regional lymph nodes.
		N2 = Metastases to four or more regional lymph nodes.
		M1 = Distant metastases.

Localized (Stage I)

Patients with localized (stage I) gallbladder cancer have cancer confined to the gallbladder wall that can be completely resected. They represent a minority of cases of gallbladder cancer. Patients with cancers confined to the mucosa have 5-year survival rates of nearly 100%.[2] Patients with muscular invasion or beyond have a survival of less than 15%. Treatment of localized disease includes removal of regional lymphatics and lymph nodes should be removed along with the gallbladder in such patients.

Unresectable (Stage II–IV)

With the exception of some patients with focal stage IIA disease, patients with stage II, III, or IV disease have cancer that cannot be completely resected. They represent the majority of cases of gallbladder cancer. Often the cancer invades directly into adjacent liver or biliary lymph nodes or has disseminated throughout the peritoneal cavity. Spread to distant parts of the body is not uncommon. At these stages, standard therapy is directed at palliation. Because of its rarity, no specific clinical trials exist; however, such patients can be included in trials aimed at improving local control by combining radiation therapy with radiosensitizer drugs.

References:

1. Gallbladder. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 303–9.
2. Shirai Y, Yoshida K, Tsukada K, et al.: Inapparent carcinoma of the gallbladder. An appraisal of a radical second operation after simple cholecystectomy. Ann Surg 215 (4): 326-31, 1992.

Localized Gallbladder Cancer Treatment

When gallbladder cancer is previously unsuspected and is discovered in the mucosa of the gallbladder at pathologic examination, it is curable in more than 80% of cases. Gallbladder cancer suspected before surgery because of symptoms, however, usually penetrates the muscularis and serosa and is curable in fewer than 5% of patients.

One study reported on patterns of lymph node spread from gallbladder cancer and outcomes of patients with metastases to lymph nodes in 111 consecutive surgical patients in a single institution from 1981 to 1995.[1][Level of evidence: 3iiiA] The standard surgical procedure was removal of the gallbladder, a wedge resection of the liver, resection of the extrahepatic bile duct, and resection of the regional (N1 and N2) lymph nodes. Kaplan-Meier estimates of the 5-year survival for node-negative tumors pathologically staged as T2 to T4 were 42.5% ± 6.5% and for similar nodepositive tumors, 31% ± 6.2%.

Standard treatment options for localized gallbladder cancer

Standard treatment options for localized gallbladder cancer include the following:

1. Surgery: In previously unsuspected gallbladder cancer, discovered in the surgical specimen following a routine gallbladder operation and confined to mucosa or muscle layer (T1), the majority of patients are cured and require no further surgical intervention.[2,3] Re-exploration to resect liver tissue near the gallbladder bed or extended or formal hepatectomy and lymphadenectomy including N1 and N2 lymph node basins may be associated with delayed recurrences or extended survival in patients with stage I or II gallbladder cancer.[4,5] Apparently localized cancers that are suspected before or during the operation can be surgically removed with a wedge of liver and lymph nodes and lymphatic tissue in the hepatoduodenal ligament. Long-term disease-free survival will occasionally be achieved. In jaundiced patients (stage III or stage IV), there should be consideration of preoperative percutaneous transhepatic biliary drainage for relief of biliary obstruction.

   Implantation of the carcinoma at all port sites (including the camera site) after laparoscopic removal of an unsuspected cancer is a problem. Even for stage I cancers, the port sites must be excised completely.[6]

2. External-beam radiation therapy (EBRT): The use of EBRT with or without chemotherapy as a primary treatment has been reported in small groups of patients to produce short-term control. Similar benefits have been reported for radiation therapy with or without chemotherapy administered following resection.[7,8]

Treatment options under clinical evaluation for localized gallbladder cancer

Treatment options under clinical evaluation for localized gallbladder cancer include the following:

• Clinical trials are exploring ways of improving local control with radiation therapy combined with radiosensitizer drugs. When possible, such patients are appropriately considered candidates for these studies.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Tsukada K, Kurosaki I, Uchida K, et al.: Lymph node spread from carcinoma of the gallbladder. Cancer 80 (4): 661-7, 1997.
2. Fong Y, Brennan MF, Turnbull A, et al.: Gallbladder cancer discovered during laparoscopic surgery. Potential for iatrogenic tumor dissemination. Arch Surg 128 (9): 1054-6, 1993.
3. Chijiiwa K, Tanaka M: Carcinoma of the gallbladder: an appraisal of surgical resection. Surgery 115 (6): 751-6, 1994.
4. Shirai Y, Yoshida K, Tsukada K, et al.: Inapparent carcinoma of the gallbladder. An appraisal of a radical second operation after simple cholecystectomy. Ann Surg 215 (4): 326-31, 1992.
5. Yamaguchi K, Chijiiwa K, Saiki S, et al.: Retrospective analysis of 70 operations for gallbladder carcinoma. Br J Surg 84 (2): 200-4, 1997.
6. Wibbenmeyer LA, Wade TP, Chen RC, et al.: Laparoscopic cholecystectomy can disseminate in situ carcinoma of the gallbladder. J Am Coll Surg 181 (6): 504-10, 1995.
7. Smoron GL: Radiation therapy of carcinoma of gallbladder and biliary tract. Cancer 40 (4): 1422-4, 1977.
8. Hejna M, Pruckmayer M, Raderer M: The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer 34 (7): 977-86, 1998.

Unresectable, Recurrent, or Metastatic Gallbladder Cancer Treatment

Patients with unresectable, recurrent, or metastatic gallbladder cancer are not curable. Significant symptomatic benefit can often be achieved with relief of biliary obstruction. A few patients have very slow-growing tumors and may live several years. Patients with unresectable, recurrent, or metastatic gallbladder cancer should be considered for inclusion in clinical trials whenever possible. Information about ongoing clinical trials is available from the NCI website.

Treatment options for unresectable, recurrent, or metastatic gallbladder cancer

Treatment options for unresectable, recurrent, or metastatic gallbladder cancer include the following:

1. Relief of biliary obstruction is warranted when symptoms such as pruritus and hepatic dysfunction outweigh other symptoms of the cancer. The preferred approach is percutaneous transhepatic drainage or endoscopically placed stents;[1] surgical bypass may be appropriate when these approaches are infeasible.

   Palliative radiation therapy after biliary drainage may be beneficial, and patients may be candidates for inclusion in clinical trials that explore ways to improve the effects of radiation therapy with various radiation sensitizers such as hyperthermia, radiosensitizer drugs, or cytotoxic chemotherapeutic agents.

2. Systemic chemotherapy is appropriate for selected patients with adequate performance status and intact organ function. Fluoropyrimidines, gemcitabine, platinum agents, and docetaxel have been reported to produce transient partial remissions in a minority of patients.

   A randomized, phase III study of up to 6 months of gemcitabine versus gemcitabine and cisplatin in 410 patients with unresectable, recurrent, or metastatic gallbladder cancer demonstrated an improvement in median overall survival (OS) among patients treated with combination therapy (11.7 months vs. 8.1 months; hazard ratio, 0.64; [95% confidence interval, 0.52–0.80], P < .001).[2][Level of evidence: 1iiA] A similar median OS benefit was demonstrated in all subgroups, including 149 patients with gallbladder cancer. Grade 3 and 4 toxicities occurred with similar frequency in both study arms, with the exception of increased hematologic toxic effects in patients randomly assigned to gemcitabine-cisplatin and increased hepatotoxicity in patients randomly assigned to single-agent gemcitabine.

   A multi-institutional, randomized, phase III study (NCT01149122) of advanced biliary cancers that evaluated the benefit of chemotherapy (gemcitabine and oxaliplatin) with or without erlotinib failed to meet its endpoint of improvement in OS and progression-free survival.[3][Level of evidence: 1iiD]

Other drugs and drug combinations await evaluation in randomized trials.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
2. Valle J, Wasan H, Palmer DH, et al.: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362 (14): 1273-81, 2010.
3. Lee J, Park SH, Chang HM, et al.: Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 13 (2): 181-8, 2012.

Changes to This Summary (03 / 23 / 2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stage Information for Gallbladder Cancer

Editorial changes were made to this section.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® – NCI’s Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of gallbladder cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Gallbladder Cancer Treatment is:

• Valerie Lee, MD (Johns Hopkins University)

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PDQ® Adult Treatment Editorial Board. PDQ Gallbladder Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/gallbladder/hp/gallbladder-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389371]

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Last Revised: 2019-03-23