Gallbladder cancer

Introduction

Biliary tract cancers are invasive adenocarcinomas that arise from the epithelial lining of the gallbladder and intrahepatic and extra hepatic bile ducts. Although anatomically these malignancies are related and have similar metastatic patterns, each has a distinct clinical presentation, molecular pathology, and prognosis (1).

Gallbladder cancer is the most common malignancy of the biliary tract, representing 80-95% of biliary tract cancers worldwide (2,3). It ranks fifth among gastrointestinal cancers.

The global rates for gallbladder cancer shows differences, reaching epidemic levels for some regions and ethnicities. Gallbladder cancer has a particularly high incidence in Chile, Japan, and northern India (2).

The basis for this variance likely resides in differences in environmental exposure and intrinsic genetic predisposition to carcinogenesis. For gallbladder cancer, several conditions associated with chronic inflammation are considered risk factors, which include gallstone disease, porcelain gallbladder, gallbladder polyps, chronic Salmonella infection, congenital biliary cysts, and abnormal pancreaticobiliary duct junction (1,2).

The percentage of patients diagnosed to have gallbladder cancer after simple cholecystectomy for presumed gallbladder stone disease is 0.5-1.5% (4-6).

In most instances, gallbladder cancer develops over 5 to 15 years, when metaplasia progresses to dysplasia, carcinoma in situ, and then, invasive cancer (1).

A satisfactory outcome depends on an early diagnosis and surgical resection. Despite this potential for cure, less than 10% of patients have tumors that are resectable at the time of surgery, while nearly 50% have lymph node metastasis (4). Even with surgery, most progress to metastatic disease, highlighting the importance of improving adjuvant therapies (5).

This tumour is traditionally regarded as a highly lethal disease with an overall 5-year survival of less than 5% (5). The overall mean survival rate for patients with gallbladder cancer is 6 months (6).

Risk factors

The identification of risk factors is critical, providing insight into the pathogenetic mechanism that drives geographic and ethnic variance, and yielding strategies for prevention and treatment.

Gallbladder cancer rates tend to increase with advancing age. The median age was 67 years in a Memorial Sloan-Kettering report of 435 gallbladder cancer patients (5).

Gender differences demonstrate a marked predominance of women over men worldwide (7). Women are affected 2-6 times more often than men (8).

There is a widely variable geographic pattern for gallbladder cancer, Asia is a high risk continent, while the United States and most western and Mediterranean European countries (e.g., UK, France, and Norway) represent low risk areas (5,6,9,10).

Ethnicity plays a role even in different geographic locations. The Korean people have the highest incidence rate (per 100,000) of gallbladder cancer in Asia. Korean males living in Los Angeles County, California also carry the highest US ethnic incidence rate (10).

Gallstones represent a most important association for this malignancy, being present in most (~85%) patients with gallbladder cancer. The incidence of gallbladder cancer in a population with gallstones varies from 0.3% to 3% (11).The higher risk of gallbladder cancer development in larger stones possibly reflects the greater duration and intensity of mucosal irritation causing chronic inflamation (12,13). Prophylactic cholecystectomy would appear reasonable in these individuals (14).

Chronic inflammation causing deoxyribonucleic acid (DNA) damage, provoking repeated tissue proliferative attempts at restoration, releasing cytokines and growth factors, and thus, predisposing cells to oncogenic transformation (15). Chronic inflammation can also result in calcium being deposited in the gallbladder wall. When calcium deposits become extensive, the gallbladder acquires a bluish hue and becomes fragile, even brittle—hence the term “porcelain gallbladder” (16). The porcelain gallbladder is frequently (average 25%, range, 12-61%) associated with gallbladder cancer (17,18).

Chronic bacterial cholangitis poses a clear risk for biliary tract malignancy. The organisms that have been most implicated are Salmonella (e.g., S. typhi and S. paratyphi) and Helicobacter (e.g., H. bilis) spp (19,20). Bacterial colonization may induce hydrolysis of primary bile acids forming. Malignant transformation is further implicated via chronic inflammation itself and alterations of tumor suppressor genes [such as tumor protein 53 (p53)] or proto-oncogenes [such as mutations of Kirsten ras oncogene homolog (K-ras)] (15,21).

Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory syndrome linking chronic inflammation to carcinogenesis (22). Facilitating a metaplasia-dysplasia-carcinoma sequence (23,24).

Various environmental exposures have been hypothesized to contribute to gallbladder cancer, such as: heavy metals, tobacco, radon (25-28).

Obese people have an increased risk of developing gallbladder cancer (29-31). The risk of developing gallbladder cancer in those with diabetes mellitus is increased (32).

Almost 5% of adults harbor gallbladder polyps (33,34). Most of them are pseudopolyps, without neoplastic potential (35). Features that predict malignancy are: large polyps (>10 mm), a solitary or sessile mass, associated gallstones, the patient’s age over 50 years old, and most importantly, rapid polyp growth (7,29).

Anomalous junction of the pancreaticobiliary duct is a congenital malformation in which the pancreatic duct drains into the biliary tract outside the papilae Vateri. Such a long common channel defeats the gatekeeper function of the sphincter of Oddi, potentially allowing pancreatic secretions to regurgitate into the bile ducts and gallbladder, thus leading to malignant changes in the mucosa (36).

Gallbladder cancer seems to result from a combination of genetic predisposition and exposure to environmental risk factors (37). One proposed carcinogenic pathways suggest that: gallstone mediated inflammation → p53 mutation (↓) → K-ras mutation (↑) (21).

Diagnosis

Clinical presentation is similar to biliary colic or chronic cholecystitis. The most common symptoms are: persistent right upper quadrant pain, jaundice, nausea and weight loss. In some patients palpable mass is present (38,39).

Imaging can detect malignancy. Transabdominal ultrasound is a useful initial modality for investigating patients with upper abdominal pain and jaundice (40).

Endoscopic ultrasound (EUS) is currently the definitive modality for staging gallbladder cancer. EUS also offers sampling via fine needle aspiration (41).

Computerized tomography (CT) helps identify any extension to lymph nodes, liver involvement, or distant metastases, performed preoperatively, determines gallbladder resectability with a high accuracy (up to 93%) (42).

Standard magnetic resonance imaging (MRI) is generally less valuable. Magnetic resonance (MR) cholangiography and MR angiography quite accurately detects bile duct or vascular invasion, with sensitivity and specificity approaching 100%.

Positron emission computed tomography (PET) scans are useful in differentiating malignant from benign disease, in preoperative staging, and in detecting postoperative residual disease (43).

Staging system

Gallbladder cancer staging, based on the American Joint Committee on Cancer (AJCC) guidelines, focuses on tumor invasion and the extent of spread (44).

Adenocarcinoma is the most frequent histologic type, accounting for 98% of all gallbladder tumors (45). The other histopathologic variants include the papillary, mucinous, squamous, and adenosquamous subtypes. The disease stage determines the treatment options. The best outcomes are reserved for patients who qualify for cholecystectomy. In stage I disease, according to AJCC criteria, tumor invades the lamina propria or the muscle layer. Stage II is designated by the perforation of the serosa and/or involvement of adjacent organs or structures. T1 to T3 tumor invasion with any nodal involvement is automatically classified as stage II. Both stage I and II are potentially resectable with curative intent. Stage III generally indicates locally unresectable disease, as a consequence of vascular invasion or the involvement of multiple adjacent organs. Stage IV represents nonresectability because of distant metastases (46).

Surgical management

Primary tumor invasion (T) is the most important factor in the AJCC staging criteria; it determines the surgical approach (44). The overall 5-year survival for patients with gallbladder cancer who underwent R0 curative resection was reported to range from 21% to 69%, and 0% for patients who did not get R0 resection. So the R0 curative resection is objective of surgical management for gallbader cancer (40).

Type of liver resection for carcinoma of the gallbladder varies from atipical resection of segments IVb at V to right hepatectomy.

By the Union for internatonal Cancer Control (UICC)/AJCC are two types of regional lymphadenectomy for gallbladder cancer:

N1—lymphnodes of hepatoduodenal ligament (cystic duct, pericholedochal and hilar lymph nodes);

N2—peripancreatic, periductal, periportal, common hepatic artery, coeliac and superior mesenteric artery lymph nodes.

Laparoscopic cholecystectomy is absolutely contraindicated when gallbladder cancer is known or suspected pre-operatively. Patients with a pre-operative suspicion of gallbladder cancer should undergo open exploration and cholecystectomy after proper pre-operative assessment, or immediately with suspicion made during laparoscopy. If the diagnosis is confirmed on frozen section radical surgical resection should be performed in the same session (5).

Incidental gallbladder cancers are detected histologically after the fact in 0.3-3% of laparoscopic cholecystectomies performed for cholelithiasis. For these patients a second radical resection is indicated after adequate diagnostic and treatment preparation, except for Tis and T1a disease.

Port-site recurrences can follow laparoscopic cholecystectomies in up to 17% of cases where unsuspected gallbladder cancer is discovered (47). Here, accidental bile spillage implants tumor cells at the trocar or incision site, leading to recurrence so the excision of the port sites are indicated during the radical reoperation.

Tis and T1a gallblader cancer (tumor is limited to mucosa) are usually diagnosed after cholecystectomy. There is consensus that simple cholecystectomy is an adequate treatment which offers a surgical cure with 100% 5-year survival (47).

In T1b gallbladder cancer (tumor invades the muscular layer) there is still controversy for the optimal management. Reported incidence of occult lymphatic metastasis is 15-25% in this stage with 10% incidence of residual disease in liver bed (47,48). Given the frequency of positive lymph nodes and residual disease in this stage, recommended procedure is cholecystectomy with radical resection which encompasses 3 cm of liver parenchyma segment IVb and V, plus adequate lymphadenectomy (48,49). The outcome after simple cholecystectomy in this stage is 75% 10-year survival vs. 100% for radical operation.

T2 lesions of gallbladder cancer invade perimuscular connective tissue with no extension beyond the serosa or into the liver. The reported 5-year survival for patients with this stage of disease treated with simple cholecystectomy where 10-61% and 54-100% after radical resection. Yamaguchi reported that over 40% of these patients had positive margins after simple cholecystectomy with rate of positive lymph nodes of 19-62%. So radical resection is the method of choice for these patients. This often requires a more formal resection of segments IVb and V (48-50).

In T3 disease, the tumor may extend to the serosa, liver, and/or adjacent organs/structures. Under these circumstances, resection becomes more radical, including an extended right hepatectomy with possible caudate lobectomy (47), regional lymphadenectomy, and extirpation of other affected structures (46). Some centers further advocate pancreaticoduodenectomy to improve outcomes (47). There is 45-70% incidence of lymph node dissemination with 36% of residual disease (51).

T4 disease is widely disseminated through vascular invasion and/or metastasis. Lesions here are commonly unresectable and it is impossible to achieve R0 resection in this stage. Consequently palliative therapy which includes adequate pain control, surgical or non-surgical biliary drainage is more appropriate in this stage.

The goal of surgical intervention is to obtain R0 resection. Surgical resection for advanced gallbaldder cancer is recommended only if a potentially curative R0 resection is technically possible (46,47,52).

Adjuvant therapy

Patients with gallbladder cancer often present in advanced stage of disease. In these patients adjuvant therapy with palliative therapy is the only way to treat though there is still no effective adjuvant therapy for gallbladder cancer.

Three classes of chemotherapeutics may be used: gemcitabine, fluoropyrimidine, and platinum compounds. Monotherapy has limited effect (43). Combination chemotherapy using gemcitabine and cisplatin offers a significant survival advantage for patients with advanced disease (51).

Radiotherapy has proven to be marginally useful in the setting of advanced disease.

Therapeutic agents, targeting cellular and molecular pathways, can impede tumor growth. Targeted therapy against epidermal growth factor receptor (EGFR) has demonstrated an antiproliferative effect in vitro and provides some optimism for a changing treatment paradigm in the future (53).

Unfortunately, the data supporting the use of adjuvant or neoadjuvant chemoradiotherapy is largely based on Phase II trials, with no conclusive evidence favoring benefit (46).

Prognosis

The most important prognostic factors that can predict survival after resection are: T staging of the original lesion; extent of nodal involvement; metastasis; and jaundice (which can signify biliary invasion and possible obstruction) (46).

The advent of gallbladder cancer staging has witnessed an improvement in overall 5-year survival rates, what is the merit of radical and successful surgical curing and advances in diagnosis (2). Further improvement in the treatment of this disease is expected from the progress of chemotherapy (53).

The AJCC “Cancer Staging Manual” assessed 10,000 patients diagnosed with gallbladder cancer from 1989 to 1996. The 5-year survival rates start at 80% for stage 0, then progressively fall to 50% for stage I, 28% for stage II, 8% for stage IIIa, 7% for stage IIIb, 4% for stage IVa, and finally, 2% for stage IVb (44).

Conclusions

Gallbladder cancer is the fifth most common cancer involving gastrointestinal tract, but it is the most common malignancy of the biliary tract with a highly variable prevalence in different parts of the world. Histopathological type is almost always adenocarcinoma.

This distinctive malignancy has disastrous outcomes with an overall 5-year survival of less than 5% and mean survival mere than 6 months.

Chronic inflammation caused with cholelithiasis is the most important risk factor.

Diagnosis may come at the time of cholecystectomy for gallstones, although preoperative imaging with transabdominal and EUS, multisliced computed tomography (MSCT) and MR is providing an important advance.

Surgery represents the only potential cure. Unfortunately, the usual late presentation means an advanced stage with potential nodal involvement and leads to recurrences despite attempted resection.

Laparoscopic cholecystectomy is contraindicated when gallbladder cancer is suspected preoperatively. After incidental finding of gallbladder cancer on pathohistological review following cholecystectomy for cholelithiasis, a second radical resection is indicated except for T1a stage.

There is still no effective adjuvant therapy for gallbladder cancer so R0 surgical resection is the only treatment with potential cure. Aggressive surgical approach should be based on a balance between the risk of surgery (morbidity, mortality) and the outcome.

Acknowledgements

Disclosure: The authors declare no conflict of interest.

References

1. Zhu AX, Hong TS, Hezel AF, et al. Current management of gallbladder carcinoma. Oncologist 2010;15:168-81. [PubMed]
2. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol 2014;6:99-109. [PubMed]
3. Lazcano-Ponce EC, Miquel JF, Muñoz N, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 2001;51:349-64. [PubMed]
4. Sheth S, Bedford A, Chopra S. Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol 2000;95:1402-10. [PubMed]
5. Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol 2008;98:485-9. [PubMed]
6. Lai CH, Lau WY. Gallbladder cancer--a comprehensive review. Surgeon 2008;6:101-10. [PubMed]
7. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006;118:1591-602. [PubMed]
8. Konstantinidis IT, Deshpande V, Genevay M, et al. Trends in presentation and survival for gallbladder cancer during a period of more than 4 decades: a single-institution experience. Arch Surg 2009;144:441-7; discussion 447. [PubMed]
9. Curado MP, Edwards B, Shin HR, et al. eds. Cancer incidence in five continents. IX. Lyon: International Agency for Research on Cancer Scientific Publications, 2007.
10. Surveillance, Epidemiology and End-Results Program (SEER). The Four Most Common Cancers for Different Ethnic Populations 2013. Bethesda, MD: National Cancer Institute; 2013.
11. Singh V, Trikha B, Nain C, et al. Epidemiology of gallstone disease in Chandigarh: a community-based study. J Gastroenterol Hepatol 2001;16:560-3. [PubMed]
12. Csendes A, Becerra M, Rojas J, et al. Number and size of stones in patients with asymptomatic and symptomatic gallstones and gallbladder carcinoma: a prospective study of 592 cases. J Gastrointest Surg 2000;4:481-5. [PubMed]
13. Mlinarić-Vrbica S, Vrbica Z. Correlation between cholelithiasis and gallbladder carcinoma in surgical and autopsy specimens. Coll Antropol 2009;33:533-7. [PubMed]
14. Le MD, Henson D, Young H, et al. Is gallbladder cancer decreasing in view of increasing laparoscopic cholecystectomy? Ann Hepatol 2011;10:306-14. [PubMed]
15. Rashid A, Ueki T, Gao YT, et al. K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China. Clin Cancer Res 2002;8:3156-63. [PubMed]
16. Berk RN, Armbuster TG, Saltzstein SL. Carcinoma in the porcelain gallbladder. Radiology 1973;106:29-31. [PubMed]
17. Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery 2001;129:699-703. [PubMed]
18. Cunningham SC, Alexander HR. Porcelain gallbladder and cancer: ethnicity explains a discrepant literature? Am J Med 2007;120:e17-8. [PubMed]
19. Kumar S. Infection as a risk factor for gallbladder cancer. J Surg Oncol 2006;93:633-9. [PubMed]
20. Gonzalez-Escobedo G, Marshall JM, Gunn JS. Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state. Nat Rev Microbiol 2011;9:9-14. [PubMed]
21. Saetta AA. K-ras, p53 mutations, and microsatellite instability (MSI) in gallbladder cancer. J Surg Oncol 2006;93:644-9. [PubMed]
22. Razumilava N, Gores GJ, Lindor KD. Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 2011;54:1842-52. [PubMed]
23. Lewis JT, Talwalkar JA, Rosen CB, et al. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a Metaplasia-Dysplasia-Carcinoma Sequence. Am J Surg Pathol. 2007;31:907-13. [PubMed]
24. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660-78. [PubMed]
25. Pandey M. Environmental pollutants in gallbladder carcinogenesis. J Surg Oncol 2006;93:640-3. [PubMed]
26. Lubin JH, Boice JD Jr, Edling C, et al. Lung cancer in radon-exposed miners and estimation of risk from indoor exposure. J Natl Cancer Inst 1995;87:817-27. [PubMed]
27. Darby SC, Whitley E, Howe GR, et al. Radon and cancers other than lung cancer in underground miners: a collaborative analysis of 11 studies. J Natl Cancer Inst 1995;87:378-84. [PubMed]
28. Jain K, Sreenivas V, Velpandian T, et al. Risk factors for gallbladder cancer: a case-control study. Int J Cancer 2013;132:1660-6. [PubMed]
29. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver 2012;6:172-87. [PubMed]
30. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625-38. [PubMed]
31. Wolin KY, Carson K, Colditz GA. Obesity and cancer. Oncologist 2010;15:556-65. [PubMed]
32. Lai HC, Chang SN, Lin CC, et al. Does diabetes mellitus with or without gallstones increase the risk of gallbladder cancer? Results from a population-based cohort study. J Gastroenterol 2013;48:856-65. [PubMed]
33. Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for gallbladder cancer across the world. HPB (Oxford) 2008;10:327-31. [PubMed]
34. Myers RP, Shaffer EA, Beck PL. Gallbladder polyps: epidemiology, natural history and management. Can J Gastroenterol 2002;16:187-94. [PubMed]
35. Gallahan WC, Conway JD. Diagnosis and management of gallbladder polyps. Gastroenterol Clin North Am 2010;39:359-67. [PubMed]
36. Nomura T, Shirai Y, Sandoh N, et al. Cholangiographic criteria for anomalous union of the pancreatic and biliary ducts. Gastrointest Endosc 2002;55:204-8. [PubMed]
37. Dutta U, Nagi B, Garg PK, et al. Patients with gallstones develop gallbladder cancer at an earlier age. Eur J Cancer Prev 2005;14:381-5. [PubMed]
38. Roa I, de Aretxabala X, Morgan R, et al. Clinicopathological features of gallbladder polyps and adenomas. Rev Med Chil 2004;132:673-9. [PubMed]
39. Terzi C, Sökmen S, Seçkin S, et al. Polypoid lesions of the gallbladder: report of 100 cases with special reference to operative indications. Surgery 2000;127:622-7. [PubMed]
40. Joo I, Lee JY, Kim JH, et al. Differentiation of adenomyomatosis of the gallbladder from early-stage, wall-thickening-type gallbladder cancer using high-resolution ultrasound. Eur Radiol 2013;23:730-8. [PubMed]
41. Kim HJ, Lee SK, Jang JW, et al. Diagnostic role of endoscopic ultrasonography-guided fine needle aspiration of gallbladder lesions. Hepatogastroenterology 2012;59:1691-5. [PubMed]
42. Kumaran V, Gulati S, Paul B, et al. The role of dual-phase helical CT in assessing resectability of carcinoma of the gallbladder. Eur Radiol 2002;12:1993-9. [PubMed]
43. Dutta U. Gallbladder cancer: can newer insights improve the outcome? J Gastroenterol Hepatol 2012;27:642-53. [PubMed]
44. Edge SB, Byrd DR, Compton CC, et al. eds. AJCC Cancer Staging Manual. New York: Springer, 2010.
45. Goldin RD, Roa JC. Gallbladder cancer: a morphological and molecular update. Histopathology 2009;55:218-29. [PubMed]
46. Jayaraman S, Jarnagin WR. Management of gallbladder cancer. Gastroenterol Clin North Am 2010;39:331-42. [PubMed]
47. Reid KM, Ramos-De la Medina A, Donohue JH. Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg 2007;11:671-81. [PubMed]
48. Cavallaro A, Piccolo G, Panebianco V, et al. Incidental gallbladder cancer during laparoscopic cholecystectomy: managing an unexpected finding. World J Gastroenterol 2012;18:4019-27. [PubMed]
49. Fong Y, Brennan MF, Turnbull A, et al. Gallbladder cancer discovered during laparoscopic surgery. Potential for iatrogenic tumor dissemination. Arch Surg 1993;128:1054-6. [PubMed]
50. Ouchi K, Mikuni J, Kakugawa Y, et al. Laparoscopic cholecystectomy for gallbladder carcinoma: results of a Japanese survey of 498 patients. J Hepatobiliary Pancreat Surg 2002;9:256-60. [PubMed]
51. Pawlik TM, Gleisner AL, Vigano L, et al. Incidence of finding residual disease for incidental gallbladder carcinoma: implications for re-resection. J Gastrointest Surg 2007;11:1478-86; discussion 1486-7. [PubMed]
52. Ogura Y, Mizumoto R, Isaji S, et al. Radical operations for carcinoma of the gallbladder: present status in Japan. World J Surg 1991;15:337-43. [PubMed]
53. Benson AB 3rd, Abrams TA, Ben-Josef E, et al. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Canc Netw 2009;7:350-91. [PubMed]