Carcinoma of the gallbladder is an uncommon gastrointestinal malignancy that has a very poor prognosis. Since the original description of this cancer by Maximilian de Stoll in 1777, studies have established a characteristic pattern of late diagnosis and ineffective treatment.
In this article, we review the clinical pathology of the tumor and current results of therapy.
Carcinoma of the gallbladder ranks fifth in incidence of gastrointestinal carcinomas and represents about three-fourths of extrahepatic biliary tract carcinomas . Data from the National Cancer Institute's Surveillance, Epidemiology and End-Results (SEER) Program showed that, of a total of 160,238 carcinomas diagnosed from 1973 to 1975, 750 (47%) were gallbladder carcinomas .
Piehler and Crichlow, in a 1978 review , reported 1,091 instances of gallbladder carcinoma found during 57,170 biliary tract operations during a 15-year period--a prevalence rate of 1.91%. This represented a 35% increase over the 1.41% rate reported by Strauch  in 1960. It is difficult to determine whether this increase is real or related to more accurate reporting, however. In the same review by Piehler and Crichlow,3 results of reports appearing since 1960 documented 303 patients with carcinoma of the gallbladder discovered in 55,543 autopsies--a prevalence rate of .55%.
The annual incidence of gallbladder carcinoma in the United States is 2.5 to 4.4 per 100,000 persons . The incidence of this cancer has been estimated to be six times higher in Southwest American Indians than in non-Indian populations.
Carcinoma of the gallbladder is a disease of elderly women, with a female to male ratio of about 3.2 to 1. The mean age at diagnosis, from 29 series, was 65.2 years  When stratified by age, the incidence of gallbladder carcinoma was .3% in those under 50 years of age, 3.8% in those over 50 years old, and 8.8% in those older than 65 years of age .
According to the Roswell Park experience, diabetes mellitus is present in 8.5% of patients with gallbladder carcinoma . Reports on the subsequent incidence of a second primary cancer have varied from 5% to 20% [7-9].
Although the etiology of gallbladder carcinoma is unknown, several epidemiologic risk factors have been proposed. Of these, cholelithiasis has been most frequently implicated as a possible risk factor.
Cholelithiasis is found in 68% to 98% of patients with gallbladder cancer [7,8] Interestingly, the risk of gallbladder carcinoma increases directly with gallstone size  On the other hand, numerous autopsy series have reported an incidence of gallbladder carcinoma of only 1% to 3% among all patients with cholelithiasis . Furthermore, in a series of 112 patients with asymptomatic gallstones followed for 10 to 25 years, there was not a single case of carcinoma . Finally, about 25% of gallbladder carcinomas develop without documented cholelithiasis [3,4].
Thus, controversy exists over the interpretation of the association. However, gallstones and gallbladder cancer most likely share a common risk factor rather than a causal relationship.
Gallbladder Inflammation and Calcification
A history of antecedent chronic cholecystitis was present in 40% to 50% of patients with carcinoma of the gallbladder, which led to the incrimination of cholecystitis as an etiologic factor. This association is extremely difficult to evaluate, however. Calcification of the gallbladder itself, the so-called porcelain gallbladder, is a significant risk factor for gallbladder cancer, with an incidence ranging between 12.5% and 61% [13,14]. The risk of cancer in typhoid carriers is six times higher than that in the general population .
There is a very small risk, if any, for malignant degeneration of benign tumors of the gallbladder without associated cholelithiasis. Phillips  studied 500 papilloma cases and found one case of adenocarcinoma. Christensen and Ishak  found 3 of 29 nonpapillary adenomas to contain carcinoma in situ.
Mancuso and Brennan  have reported both a higher incidence and earlier onset of gallbladder cancer in rubber industry workers than in controls. In animal models, chemical carcinogens, especially nitrosamines and methylcholanthrene, have been implicated in the etiology of gallbladder cancer .
In its early stages, carcinoma of the gallbladder is usually asymptomatic. The lack of specific signs or symptoms prevents detection of this cancer at an early and resectable stage. Moreover, when symptoms do occur, they usually resem- ble those of benign gallbladder disease.
Common symptoms include abdominal pain, nausea, vomiting, weight loss, and anorexia ( Table 1). A changing pattern of the character of the pain is usually described. The median duration of symptoms varies from 1.8 months to 3 years [4,7,8]. Physical findings may include tenderness or a mass in the right upper abdominal quadrant, jaundice, cachexia, fever, and ascites.
Laboratory findings in patients with gallbladder carcinoma are nonspecific. Liver function abnormality is the most common lab finding in these patients. Serum alkaline phosphatase, direct bilirubin, and serum aspartate aminotransferase levels are elevated in 50% or more of cases. The typical patient is mildly hypoalbuminemic. Only 10% of patients have a hemoglobin level lower than 11 g/dL .
Ultrasonography is abnormal in 98% of patients (with findings including cholelithiasis, a thickened gallbladder, a mass in the gallbladder, or some combination) and is diagnostic for cancer in 22% of cases.20 In other review articles [7,8] none of 146 patients with gallbladder cancer was diagnosed prior to surgical exploration.
Impact of Advances in Imaging
To study the effect of recent advances in diagnosis and their impact on survival of patients with gallbladder cancer, Ouchi and colleagues  compared two groups of patients: Group I, who underwent resection between 1960 and 1978, and group II, who had surgery between 1979 and 1991. Preoperative diagnosis, including suspected carcinoma, was made in 42% of group I patients and 60% of group II. A definitive preoperative diagnosis of gallbladder carcinoma was made in 8% of group I and 36% of group II. The diagnostic accuracy of ultrasonography and CT scanning in the two groups was 36% and 70%, respectively.
In another study, CT was diagnostic in 6 of 12 patients (50%) . Of 157 histologically proven positive nodes in 51 patients with gallbladder carcinoma, 60 (38%) were visualized at CT scanning .
In summary, preoperative diagnosis of gallbladder carcinoma is uncommon. Nevertheless, recent advances in biliary tract imaging have increased the diagnostic yield.
The first staging system for gallbladder carcinoma was developed by Nevin and coworkers in 1976 (Table 2) . It is based on the level of tumor invasion. Recently, a TNM system was adopted (Table 3) . Both systems correlate very well with prognosis [20,23,25].
1. Vaittinen E: Carcinoma of gallbladder: A study of 390 cases diagnosed in Finland, 1953-1967. Ann Chir Gynaecol 168(suppl):7-81, 1970.
2. Myers MH, Ries LA: Cancer patient survival rates: SEER program results for 10 years of follow-up. CA Cancer J Clin 39:21-32, 1989.
3. Piehler JM, Crichlow RW: Primary carcinoma of the gallbladder. Surg Gynecol Obstet 147:929-942, 1978.
4. Strauch GO: Primary carcinoma of the gallbladder. Surgery 47:368-383, 1960.
5. Nagorney DM, McPherson GAD: Carcinoma of the gallbladder and extrahepatic bile ducts. Semin Oncol 15:106-115, 1988.
6. Thorbjarnarson B, Glenn F: Carcinoma of the gallbladder. Cancer 12:1009-1015, 1959.
7. Silk YN, Douglass HO, Nava HR, et al: Carcinoma of the gallbladder: The Roswell Park experience. Ann Surg 210:751-757, 1989.
8. Perpetuo MO, Valdivieso M, Heilburn LK, et al: Natural history study of gallbladder cancer. Cancer 42:330-335, 1978.
9. Richard PF, Cantin J: Primary carcinoma of the gallbladder: Study of 108 cases. Can J Surg 19:27-31, 1976.
10. Diehl AK: Gallstone size and the risk of gallbladder cancer. JAMA 250:2323-2326, 1983.
11. Burdette WJ: Carcinoma of the gallbladder. Ann Surg 145:832-840, 1957.
12. Comfort MW, Gray HK, Wilson JM: The silent gallstone: A ten to twenty year follow-up study of 112 cases. Ann Surg 128:931-937, 1948.
13. Polk HC: Carcinoma of the calcified gallbladder. Gastroenterology 50:582-585, 1966.
14. Berk RN, Armbuster TG, Saltzstein SL: Carcinoma in porcelain gallbladder. Radiology 106:29-31, 1973.
15. Welton JC, Marr JS, Friedman SM: Association between hepatobiliary cancer and typhoid carrier state. Lancet 1:791-794, 1979.
16. Phillips JR: Papilloma of the gallbladder. Am J Surg 21:38-42, 1933.
17. Christensen AH, Ishak KG: Benign tumors and pseudotumors of the gallbladder; report of 180 cases. Arch Pathol 90:423-432, 1970.
18. Mancuso TF, Brennan MJ: Epidemiological considerations of cancer of the gallbladder, bile ducts, and salivary glands in the rubber industry. J Occup Med 12:333-341, 1970.
19. Fortner JG: The experimental induction of primary carcinoma of the gallbladder. Cancer 8:689-700, 1955.
20. Donohue JH, Nagorney DM, Grant CS, et al: Carcinoma of the gallbladder. Arch Surg 125:237-241, 1990.
21. Ouchi K, Suzuki M, Saijo S, et al: Do recent advances in diagnosis and operative management improve the outcome of gallbladder carcinoma? Surgery 113:324-329,1993.
22. Ohtani T, Shirai Y, Tsukada K, et al: Carcinoma of the gallbladder: CT evaluation of lymphatic spread. Radiology 189:875-880, 1993.
23. Nevin JE, Moran TH, Kay S, et al: Carcinoma of gallbladder. Cancer 37:141-148, 1976.
24. Beahrs OH, Henson DE, et al: Handbook for Staging of Cancer, p 111. Philadelphia, JB Lippincott, 1993.
25. Gagner M, Rossi RL: Radical operations for carcinoma of the gallbladder: Present status in North America. World J Surg 15:344-347, 1991.
26. Johnstone AK, Zuch RH, Anders KH: Oat cell carcinoma of the gallbladder. Arch Pathol Lab Med 117:1009-1012, 1993.
27. Fahim RB, McDonald JR, Richards JC, et al: Carcinoma of gallbladder; a study of its modes of spread. Ann Surg 156:114 124, 1962.
28. Hart J, Modan B: Factors affecting survival of patients with gallbladder neoplasms. Arch Intern Med 129:931-934, 1972.
29. Morrow CH, Sutherland DE, Florack G, et al: Primary gallbladder carcinoma: Significance of subserosal lesions and results of aggressive surgical treatment and adjuvant chemotherapy. Surgery 94:709-714, 1983.
30. Wanebo HJ, Vezeridis MP: Carcinoma of gallbladder. J Surg Oncol 3(suppl):134-139, 1993.
31. Kopelson G, Harisiadis L, Tretter P, et al: The role of radiation therapy in cancer of extra-hepatic biliary system: An analysis of 13 patients and a review of the literature of the effectiveness of surgery, chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 2:883-894, 1977.
32. Hanna SS, Rider WD: Carcinoma of the gallbladder or extrahepatic bile ducts: The role of radiotherapy. Can Med Assoc J 118:59-61, 1978.
33. Houry S, Schlienger M, Huguier M, et al: Gallbladder carcinoma, role of radiation therapy. Br J Surg 76:448-450, 1989.
34. Bosset JF, Mantion G, Gillet M, et al: Primary carcinoma of the gallbladder. Cancer 64:1843-1847, 1989.
35. Busse PM, Cady B, Bothe A, et al: Intraoperative radiation therapy for carcinoma of the gallbladder. World J Surg 15:352-356, 1991.
36. Todoroki T, Iwasaki Y, Okamura T, et al: Intraoperative radiotherapy for advanced carcinoma of the biliary system. Cancer 46:2179-2184, 1980.
37. Todoroki T, Iwasaki Y, Orii K, et al: Resection combined with intraoperative radiation therapy (IORT) for stage IV (TNM) gallbladder carcinoma. World J Surg 15:357-366, 1991.
38. Falkson G, MacIntyre JM, Moertel CG: Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 54:965-969, 1984.
39. Taal BG, Audisio RA, Bleiberg H, et al: Phase II trial of mitomycin (MMC) in advanced gallbladder and biliary tree carcinoma: An EORTC Gastrointestinal Tract Cancer Cooperative Group Study. Ann Oncol 4:607-609, 1993.
40. Smith GW, Bukowski RM, Hewlett JS, et al: Hepatic artery infusion of 5-fluorouracil and mitomycin C in cholangiocarcinoma and gallbladder carcinoma. Cancer 54:1513-1516, 1984.
41. Makela JT, Kairaluoma MI: Superselective intra-arterial chemotherapy with mitomycin for gallbladder cancer. Br J Surg 80:912-915, 1993.