Introduction
Background
Although uncommon, carcinoma of the gallbladder (GB) is the most common primary hepatobiliary carcinoma, is the fifth most common malignancy of the GI tract, and predominantly affects older persons with long-standing cholecystolithiasis. GB epithelial tumors tend to behave similarly to other GI adenocarcinomas. When the diagnosis is made incidentally at the time of cholecystectomy, surgical resection can be curative; however, more commonly, the tumor is unresectable and rarely diagnosed preoperatively despite patients' symptoms. Early diagnosis can improve the clinical outcome and cure rate of GB carcinoma.
Pathophysiology
The exact etiology of GB carcinoma is unknown; however, several associated factors have been identified. One hypothesis suggests that irritation of the GB mucosa by stones causes chronic inflammation and, followed by repetitive epithelial repair, may cause malignant transformation. Approximately 15 years is required for dysplasia to progress to invasive carcinoma.
Classification
- Malignant epithelial tumors include adenocarcinoma (most common), squamous cell carcinoma, adenosquamous carcinoma, and small cell carcinoma.
- Malignant mesenchymal tumors include embryonal rhabdomyosarcoma, leiomyosarcoma, and malignant fibrous histiocytoma.
- Other malignant tumors include carcinosarcoma, carcinoid tumor, lymphoma, and melanoma.
Location: In affected patients, 60% of GB tumors occur in the fundus, 30% in the GB body, and 10% in the GB neck.
Spread
- Early lymphatic spread is to the retroperitoneal, right celiac, and pancreaticoduodenal nodes.
- Direct invasion occurs in the liver, extrahepatic biliary ducts, and duodenum and colon (less common).
- Intraperitoneal seeding may occur.
Staging: Several staging systems exist. A simplified version of the American Joint Commission on Cancer (AJCC) staging (or tumor, node, metastasis [TNM] staging) is shown in Table 11 :
Table 1. AJCC Classification1Open table in new window
Table
| TNM Definition | Tumor Location |
| Tis | Carcinoma in situ |
| T1a | GB wall: mucosa |
| T1b | GB wall: muscle |
| T2 | Perimuscular connective tissue |
| T3 | Serosa or 1 organ, liver <2 cm |
| T4 | 2 or more organs, liver >2 cm |
| N1 | Hepatoduodenal ligament nodes |
| N2 | Other regional lymph nodes |
| M0 | No distant metastases |
| M1 | Distant metastases |
| TNM Definition | Tumor Location |
| Tis | Carcinoma in situ |
| T1a | GB wall: mucosa |
| T1b | GB wall: muscle |
| T2 | Perimuscular connective tissue |
| T3 | Serosa or 1 organ, liver <2 cm |
| T4 | 2 or more organs, liver >2 cm |
| N1 | Hepatoduodenal ligament nodes |
| N2 | Other regional lymph nodes |
| M0 | No distant metastases |
| M1 | Distant metastases |
Table 2. Staging of Cancer of the Gallbladder1
Open table in new window
Table
| Stage 0 | Tis | N0 | M0 |
| Stage IA | T1 | N0 | M0 |
| Stage IB | T2 | N0 | M0 |
| Stage IIA | T3 | N0 | M0 |
| Stage IIB | T1-3 | N1 | M0 |
| Stage IIIA | T4 | Nx | M0 |
| Stage IVA | Tx | Nx | M1 |
| Stage 0 | Tis | N0 | M0 |
| Stage IA | T1 | N0 | M0 |
| Stage IB | T2 | N0 | M0 |
| Stage IIA | T3 | N0 | M0 |
| Stage IIB | T1-3 | N1 | M0 |
| Stage IIIA | T4 | Nx | M0 |
| Stage IVA | Tx | Nx | M1 |
The modified Nevin-Moran staging system is more commonly used (see Table 3).
Open table in new window
Table
| Stage | Tumor Location |
| I | In situ carcinoma |
| II | Mucosa or muscularis involvement |
| III | Transmural direct liver invasion involved |
| IVA | Lymph node metastasis |
| IVB | Lymph node metastasis and/or distant metastases involved |
| Stage | Tumor Location |
| I | In situ carcinoma |
| II | Mucosa or muscularis involvement |
| III | Transmural direct liver invasion involved |
| IVA | Lymph node metastasis |
| IVB | Lymph node metastasis and/or distant metastases involved |
Frequency
United States
In the general population, the reported incidence of GB carcinoma is 3 cases per 100,000 persons, with more than 6500 new patients diagnosed annually. This condition is found incidentally in 1-3% of cholecystectomy specimens and in 0.5-2.4% of postmortem examinations.
International
Worldwide, Chile and Bolivia have the highest prevalence of GB carcinoma. In Japan, there are 4.8 cases per 100,000 males and 5 cases per 100,000 females. In Israel, there are 7.5 cases per 100,000 males and 13.8 cases per 100,000 females. In Poland, the incidence rate is 4.8 cases per 100,000 males and 23.1 cases per 100,000 females. The disease is also seen in Northern Europe and South Africa.
Mortality/Morbidity
Patients with GB carcinoma have an overall mean survival rate of 6 months, and the 5-year survival rate is 5%.3
Race
In Native Americans, GB carcinoma is the most commonly seen gastrointestinal malignancy, with a reported incidence rate of 5.1 cases per 100,000 males and 8.7 cases per 100,000 females. This condition is also seen in Hispanic Americans and Latin Americans. In addition, GB carcinoma is twice as common in whites as in blacks.
Sex
GB carcinoma has a female preponderance. The female-to-male ratio is 3:1.
Age
The greatest incidence of GB carcinoma is in persons older than 65 years.
Presentation
Associated findings and risk factors for GB carcinoma are as follows:
- Cholecystolithiasis, which is present in 70-90% of patients (duration may be a key factor in development of cancer)
- Composition of the bile with cholesterol stones (most commonly implicated)
- Genetic factors
- Calcification of the GB wall (carcinoma in 25% of patients with "porcelain" GB)
- Anomalous pancreatic-biliary duct junction
- Congenital biliary cysts
- Infections by Salmonella typhi
- Environmental carcinogens
Presentation
The signs and symptoms of GB carcinoma are nonspecific.
- Patients in Nevin-Moran stages I-III show signs and symptoms that mimic cholelithiasis and/or cholecystitis (see Pathophysiology, Table 3).
- Patients in Nevin-Moran stage IV present with weight loss, hepatomegaly, and jaundice, which are considered poor prognostic signs (see Pathophysiology, Table 3).
- Duodenal or colonic obstruction or cholecystoenteric fistula may signal GB carcinoma.
Treatment and prognosis
No established treatment protocol exists. Radical surgery with negative tumor margins is an accepted treatment for advanced disease. If there are negative tumor margins, 5-year survival rates are as follows, according to the AJCC2 :
- Stage I: 29-50%
- Stage II: 7-9%
- Stage III: 3%
- Stage IV: 2%
Clinical problems
In most patients, the diagnosis of GB carcinoma is made postoperatively and at an advanced stage of the disease because of the poorly defined GB muscularis that allows early spread into the perimuscular tissue and, frequently, beyond the GB to involve the liver and extrahepatic biliary ducts.
Preferred Examination
Ultrasound (US), which is readily available, noninvasive, and cost-effective, is the imaging modality of choice.
Limitations of Techniques
US cannot stage the tumor. The visualization of lymph nodes, intraperitoneal disease, and distant metastases is difficult.
Differential Diagnoses
Cholecystitis, Acute
Hepatocellular Carcinoma
Liver, Metastases
Porcelain Gallbladder
Other Problems to Be Considered
Chronic cholecystitis
Carcinoma of the pancreatic head
More on Gallbladder, Carcinoma |
 Overview: Gallbladder, Carcinoma |
| Imaging: Gallbladder, Carcinoma |
| Multimedia: Gallbladder, Carcinoma |
| References |
| Next Page » |
References
National Cancer Institute. Treatment statement for health professionals: gallbladder cancer. Updated 2/15/07. Med News. Available at http://www.meb.uni-bonn.de/cancer.gov/CDR0000062904.html. Accessed August 23, 2007.
Fong Y, Wagman L, Gonen M, et al. Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database. Ann Surg. Jun 2006;243(6):767-71; discussion 771-4. [Medline]. [Full Text].
Levy AD, Murakata LA, Rohrmann CA Jr. Gallbladder carcinoma: radiologic-pathologic correlation. Radiographics. Mar-Apr 2001;21(2):295-314; questionnaire, 549-55. [Medline]. [Full Text].
Douglass HO Jr, Kim SY, Merpol NJ. Neoplasms of the gallbladder. In: Holland JF, Frei E III, Best RC Jr, eds. Cancer Medicine. Vol 2. 4th ed. Baltimore, Md: Williams & Wilkins; 1997:1955-63.
Dudiak CM, Lawson TL. Carcinoma of the gallbladder. Diagnostic Ultrasound (Second Series) Test and Syllabus. St Louis, Mo: Mosby-Year Book; 1994:324-62.
Elsayes KM, Oliveira EP, Narra VR, El-Merhi FM, Brown JJ. Magnetic resonance imaging of the gallbladder: spectrum of abnormalities. Acta Radiol. Jun 2007;48(5):476-82. [Medline].
Grainger RG, Allison E. Grainger and Allison's Diagnostic Radiology: a Textbook of Medical Imaging. Vol 2. 3rd ed. New York, NY: Churchill Livingstone; 1996:1224.
Greene FL, Page DL, Fleming ID, eds. Gallbladder. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2002:139-44.
Haubrich WS, Schaffner F, Berk JE, eds. Bockus Gastroenterology. Vol 3. 5th ed. Philadelphia, Pa: WB Saunders; 1995:2739-44.
Kai M, Chijiiwa K, Ohuchida J, et al. A curative resection improves the postoperative survival rate even in patients with advanced gallbladder carcinoma. J Gastrointest Surg. Aug 2007;11(8):1025-32. [Medline].
Kim MJ, Kim KW, Kim HC, et al. Unusual malignant tumors of the gallbladder. AJR Am J Roentgenol. Aug 2006;187(2):473-80. [Medline]. [Full Text].
Mekeel KL, Hemming AW. Surgical management of gallbladder carcinoma: a review. J Gastrointest Surg. Sep 2007;11(9):1188-93. [Medline].
Memel DS, Balfe DM, Semelka RC. The biliary tract. In: Lee JKT, Sagel SS, Stanley RJ, eds. Computed Body Tomography With MRI Correlation. Vol 2. 3rd ed. Philadelphia, Pa: Lippincott-Raven; 1997:810-3.
Miller G, Schwartz LH, D'Angelica M. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am. Apr 2007;16(2):343-68. [Medline].
Numata K, Oka H, Morimoto M, et al. Differential diagnosis of gallbladder diseases with contrast-enhanced harmonic gray scale ultrasonography. J Ultrasound Med. Jun 2007;26(6):763-74. [Medline].
Oe A, Kawabe J, Torii K, et al. Distinguishing benign from malignant gallbladder wall thickening using FDG-PET. Ann Nucl Med. Dec 2006;20(10):699-703. [Medline].
Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg. Jun 2007;245(6):893-901. [Medline].
Srivastava AK, Singh B, Gupta SL. Prevalence of Toxoplasma antibodies in sheep and goats in India. Trop Anim Health Prod. Nov 1983;15(4):207-8. [Medline].
Vitetta L, Sali A, Little P, Mrazek L. Gallstones and gall bladder carcinoma. Aust N Z J Surg. Sep 2000;70(9):667-73. [Medline].
Yamada T, Alpers DH, Owyang C, Powell DW, Silverstein FE, eds. Textbook of Gastroenterology. Vol 2. 2nd ed. Baltimore, Md: Lippincott Williams & Wilkins; 1999:2335-40.
Further Reading
Keywords
GB carcinoma, gallbladder cancer, hepatobiliary carcinoma
