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
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References
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Further Reading
Keywords
GB carcinoma, gallbladder cancer, hepatobiliary carcinoma
Overview: Gallbladder, Carcinoma