Etiology and Pathogenesis of Gall Bladder Cancer

Abstract

Gallstones are the most important risk factor for the causation of gallbladder cancer. Long-standing gallstone disease increases the risk of gallbladder cancer. Hormonal factors play a role as gallbladder cancer is more common in females than males. Diet, lifestyle, infections (Salmonella and Helicobacter), heavy metals, and pesticides have been incriminated. Inflammation—dysplasia pathway is more commonly involved than the adenoma—carcinoma pathway in pathogenesis. Molecular changes and signaling pathways involved in gallbladder cancer are being studied.

Please also see an Invited Commentary on Etiology and Pathogenesis of Gall Bladder Cancer by Jean Michel Butte (pp **–**)

Invited Commentary on Etiology and Pathogenesis of Gallbladder Cancer

• Jean Michel Butte 

Gallbladder cancer (GBC) is an aggressive malignancy and most patients are diagnosed with advanced disease. Thus, recognizing factors associated with its origin is not only important to identify a population of patients who have a higher risk of developing this disease but also to implement national programs against these factors to decrease the progression to cancer and improve survival.

Despite the fact that GBC is a rare disease, it has a higher incidence in some areas of the world such as India, Japan, and Chile, where most of the risk factors are shared. However, local and environmental factors may produce a different disease in nonrelated areas of the world.

In this chapter, Dr. Kapoor has analyzed in detail the etiology and pathogenesis of GBC. The presence of gallstones (GS) and resultant chronic inflammation seems to be a strong risk factor for developing GBC. However, it has always been debated if there are other factors playing a major role in conjunction with GS, considering that most patients with GS do not develop this malignancy around the world. As the Author (VKK) has mentioned, GBC seems to be more commonly found in areas where GS are more frequent, when the GS have a larger size and when the symptoms are longer. This is highly associated with the socioeconomic status of the patient and there is a real option of getting an elective cholecystectomy to cut this line of cancer development. Other clinical presentations analyzed in this chapter i.e. acute cholecystitis, gallbladder empyema, Mirizzi syndrome, obstruction of the gallbladder neck, xantho-granulomatous cholecystitis (XGC), porcelain gallbladder, and cholecysto-enteric fistula confirm that chronic inflammation is a known pathway with a higher chance of developing GBC.

There are other risk factors reported in this chapter that have been associated with GBC viz. personal (age, gender, and family history), biliary (anatomical biliary anomalies and diseases and chronic infection), environmental (lifestyle, diet, heavy metals, and pesticides), and comorbid situations (obesity and diabetes). GBC may present at any age and gender, but in the majority of areas it is more frequent in females. Patients diagnosed at a younger age seems to have longer periods of symptomatic GS to explain the development of cancer, but it is not clear why in some areas there is a female preponderance but in others it is not. However, it looks like that there is a synergism among long periods of chronic inflammation secondary to GS, female gender, and hormonal status. On the other hand, family history, lifestyle, diet, obesity and diabetes are found in similar population and most of the time associated with low economic status. Thus, people with less access to fruits and vegetables (protective factors) usually have a diet based in high calorie and carbohydrate, with a higher propensity of developing GS, obesity, and diabetes, and then altering their hormonal status. This lifestyle is usually common in some communities and families, explaining a common pathway in some areas of the world, as the Author (VKK) says.

An interesting theory about developing GBC around the world has been linked to gallbladder’s chronic infection. As the Author (VKK) mentioned, after having an acute Salmonella infection, this bacteria may colonize the gallbladder and produce chronic inflammation as it has been shown in genetic models. This also has been associated with Helicobacter infection, increasing the relative risk of developing GBC. This theory also has been considered in Chile where an important epidemic of Salmonella infection occurred in the 1970s and could be related to current cases of GBC, but it is difficult to prove this with certainty. The presence of heavy metals and pesticides has been found in patients with GBC, but it seems that these factors need further investigation to prove real association with the development of GBC.

Two main pathways have been described by the Author (VKK); the first is related to chronic inflammation and the second to the development of an adenoma. The first mechanism is significantly more common and has been vastly referred and mainly associated with GS, while the second is less common and associated with the presence of polyps.

In summary, this chapter describes in detail different risk factors and pathogenesis related to GBC. Similarly, it suggests that GBC may arise from a specific pathway in different areas of the world. This is important to define clinical methods to diagnose this disease in precancerous or early stages with the aim of improving survival and having a better chance of cure.