Gallbladder cancer: Past,present and an uncertain future

Although gallbladder cancer (GBC) is the most common malignancy of the biliary tract, its relatively low incidence and confounding symptomatology result in advanced disease at the time presentation, contributing to the poor prognosis and decreased survival associated with this disease. It is therefore increasingly important to understand its pathogenesis and risk factors to allow for the earliest possible diagnosis. To date, gallbladder cancer is poorly understood compared to other malignancies, and is still most commonly discovered incidentally after cholecystectomy. Moreover, while much is known about biliary neoplasms as a whole, understanding the clinical and molecular nuances of GBC as a separate disease process will prove a cornerstone in the development of early intervention, potential screening and overall more effective treatment strategies.The present work reviews the most current understanding of the pathogenesis, diagnosis, staging and natural history of GBC, with additional focus on surgical treatment. Further, review of current adjuvant therapies for unresectable and advanced disease as well as prognostic factors provide fertile ground for the development of future studies which will hopefully improve treatment outcomes and affect overall survival for this highly morbid, poorly understood malignancy.     

Gallbladder cancer: a subtype of biliary tract cancer which is a current challenge in China

Biliary tract cancers, broadly described as malignancies that arise from the biliary tract epithelia, are usually divided into two major clinical phenotypes: cholangiocarcinoma and gallbladder cancer, differing in etiopathogenesis, risk factors, and perhaps molecular and genetic signatures. Atypical symptoms and lack of tumor biomarkers make it difficult to diagnose in early stages. At the time of presentation, few patients are candidates for potentially curative surgical resection. We here assessed and compared features of a total of 150 cases divided into extra- and intrahepatic cholangiocarcinomas and gallbladder cancers (GBC). Althought there were no significant differences in serum tumour marker levels, GBC patients had the poorest prognosis. Furthermore, gallbladder cancer respond poorly to chemotherapy or radiation therapy and approximately half of untreated patients died within 10 months. Therefore, treatment for patients with gallbladder cancer is still in challenge. Outcomes and survival of these patients had improved little over the past three decades - a period in which new successful treatments have greatly contributed to the prolonged patient survival for many other cancers.     

Gallstones and gallbladder cancer-volume and weight of gallstones are associated with gallbladder cancer: a case-control study

BACKGROUND: Gallstones are considered the most important risk factor for gallbladder cancer. AIM: To identify differences in the number, weight, volume, and density of gallstones associated with chronic cholecystitis (CC), gallbladder dysplasia (GD), and gallbladder cancer (GBC). METHODS: A total of 125 cases were selected, of which 93 had gallstones associated with GBC and 31 had gallstones associated with GD. The controls were those with CC, matched by sex and age. The number, weight, volume, and density of these gallstones were examined in order to determine differences and relative cancer risk. RESULTS: Number: Multiple gallstones were present in over 76% of cases (GBC and GD) and controls (P = ns). The average number of multiple stones was 21 in GBC versus 14 in controls (P < 0.01). Weight: The average weight of the gallstones was 9.6 g in GBC versus 6.0 g in controls (P = 0.0004). The average weight in multiple stones over 10 g had strong association with GBC (P = 0.0006). Volume: The average volume was 11.7 and 6.48 ml in GBC and controls (P = 0.0002). Average volumes of 6, 8, and 10 ml had a relative cancer risk of 5, 7, and 11 times, respectively. Size: No differences were shown between GBC, GD, and controls. CONCLUSIONS: The volume of gallstones associated with other risk factors of GBC may be helpful in prioritizing cholecystectomies in symptomatic patients.     

Comparison of Clinical Outcomes of Incidental and Non-Incidental Gallbladder Cancers: A Single-Center Cross-Sectional Study

Background: Gallbladder cancer (GBC) is a rare malignancy characterized by high invasiveness and poorsurvival. In a nation-wide cancer survey, the age-standardized incidence rate of GBC was the highest in JejuIsland compared to 15 other provinces in Korea. The purpose of this study was to compare the clinical outcomesof GBC according to the nature of diagnosis, that is, incidental versus non-incidental. Materials and Methods:Consecutive patients who were newly diagnosed with GBC at the Digestive Disease Center and Department ofInternal Medicine, Cheju Halla General Hospital, between November 2008 and November 2011, were enrolledand divided into 2 groups: incidental gallbladder cancer (IGBC) and non-incidental gallbladder cancer (NIGBC).Clinical outcomes were retrospectively compared between the two groups. Results: Seventy-nine patientswere enrolled and analyzed in our study. Thirty-three (41.8%) and 46 (58.2%) were identified as IGBC andNIGBC, respectively. The proportions of patients with gallstone disease, gallbladder polyp, and cholecystectomywere significantly different between the two groups. Additionally, the median survival rate was significantlyhigher for patients with IGBC than for those with NIGBC (11.4, 95% confidence interval, 5.6-13.7 vs 4.0, 95%confidence interval 3.03-5.96 months; p=0.01) during a median follow-up period of 5.7 months. Conclusions:Patients with IGBC showed better clinical prognosis than those with NIGBC. Therefore, patients with gallstonedisease or gallbladder polyps, major predictive risk factors for IGBC, should undergo advanced work-up forchelecystectomy.     

A Case-Control Study of Gallbladder Cancer in Hungary

Our previous study indicated an association of chili pepper consumption with gallbladder cancer (GBC) inthe presence of gallstones (GS) in Chile. We investigated whether or not a similar association was present inHungary, where mortality from GBC is high and chili peppers are frequently consumed. In a case-controlstudy, we compared 41 female GBC patients with GS and 30 gender and GS-matched hospital controls. Trainedstaff interviewed all subjects to determine socioeconomic status, family history, past history and life style habits(smoking, alcohol intake, dietary habits and elimination habits). Because mean ages differed significantly betweenthe case and control groups, age-adjusted odds ratios (ORs) were calculated. A shorter education period (< 10years / ≥16 years) was indicated to be a risk factor (age-adjusted OR (95%CI): 3.2 (1.2-8.7)). In addition, theintake of Hungarian hot pepper (yes / no) was found to be significantly higher in the GBC cases than in controls(age-adjusted OR (95%CI): 8.4 (2.3-30.4)). There were no differences between the case and control groups forother variables. Multivariate logistic regression analysis retained only Hungarian hot pepper consumption as asignificant independent risk factor for GBC. Its age-adjusted OR was 16.2 (95%CI: 2.1-126.2), while therewere no differences associated with low education, frequent consumption of fresh fruit and vegetables, lowsocioeconomic status or smoking. Hungarian hot pepper consumption was identified as a risk factor for GBCby multivariate logistic regression analysis.     

Chronic inflammation and gallbladder cancer

Gallbladder cancer (GBC) is the most common biliary tract malignancy with an extremely poor prognosis. Epidemiological data have demonstrated that chronic inflammation resulting from infection of gallbladder or gallstones predispose individuals to GBC. Recent studies have begun to elucidate molecular mechanisms underlying the development of GBC in the setting of chronic inflammation. It is possible that persistently local inflammatory reactions may contribute to the development and progression of GBC through inducing genetic alterations, and subsequent promoting survival and proliferation of mutated sells, inhibiting apoptosis, stimulating angiogenesis and metastasis. This article reviews the current understanding of the involvement of chronic inflammation in gallbladder tumorigenesis.     

饮食与胆囊癌关系的流行病学研究

目的探讨饮食因素与胆囊癌发病的关联,为采取预防措施提供科学依据.方法采用全人群病例对照研究,研究对象为1997年6月～2001年5月期间确诊的、年龄在35～74岁的上海市区368例胆囊癌新发病例以及按性别、年龄(5岁一组)频数配对的895例人群对照.采用非条件logistic回归模型分析饮食各因素与胆囊癌的关系.结果女性中,与最低四分位数组相比,葱属类蔬菜年摄入次数最高四分位组的调整OR为0.55(95%CI:0.31～0.97;Ptrend=0.06);与不吃组比较,大蒜头和洋葱最高摄入组的调整OR分别为0.59(95%CI:0.34～0.99;Ptrend=0.03)和0.52(95%CI:0.30～0.91;Ptrend=0.01).与最低四分位组比较,腌制品摄入其余各组调整OR在女性中依次为1.06、1.88、2.31,Ptrend＜0.001;与不吃乳腐组比较,余三组的调整OR依次为1.19、1.47、1.88,Ptrend＜0.01.男性结果与女性类似,腌制品和葱属类蔬菜摄入的各组OR都有不显著的升高和降低.结论新鲜蔬菜,尤其是葱属类蔬菜对胆囊癌的保护作用在女性比男性明显,而且以大蒜头、洋葱的保护作用较为显著.而腌制品摄入,尤其是乳腐,可能会增加胆囊癌的发病风险.     

Chronic heavy metal exposure and gallbladder cancer risk in India, a comparative study with Japan

Background: High incidence of gallbladder cancer (GBC) is reported from North India, with elevatedconcentrations of heavy metals in water and soil. This Indo-Japan collaborative study compared presence ofheavy metals in gallbladder tissues. Methods: Heavy metal concentrations were estimated in Indian GBC andcholecystitis tissues and compared with Japanese GBC and cholecystitis tissues. Spectrophotometry was donefor 13 Indian gallbladder tissues (8 GBC, 5 cholecystitis) and 9 Japanese (5 GBC, 4 cholecystitis). Transmissionelectron microscopy (TEM) thin foil element analysis was done in 10 Indian samples (6 GBC, 4 cholecystitis).Results: Chromium, lead, arsenic and zinc were significantly high in Indian GBC compared with Japanese GBC.Chromium, lead and arsenic were significantly high in the Indian cholecystitis tissues compared to the Japanese.TEM of Indian tissues demonstrated electron dense deposits in GBC. Conclusion: Heavy metals- chromium,lead, arsenic and zinc are potential carcinogens in Indian GBC from endemic areas. This preliminary studylinks presence of heavy metals in gallbladder cancer tissues in endemic areas.     

Mustard oil consumption,cooking method,diet and gallbladder cancer risk in high- and low-risk regions of India

The current study aimed to investigate the role of cooking with mustard oil and other dietary factors in relation to gallbladder cancer (GBC) in high- and low-incidence regions of India. A case–control study was conducted including 1,170 histologically confirmed cases and 2,525 group-matched visitor controls from the largest cancer hospital in India. Dietary data were collected through a food frequency questionnaire. For oil consumption, we enquired about monthly consumption of 11 different types of cooking oil per family and the number of individuals usually sharing the meal to estimate per-individual consumption of oil. Information about method of cooking was also requested. Odds ratios (ORs) and 95% confidence intervals (CIs) quantifying the association of GBC risk consumption of different types of oil, method of cooking, and dietary food items, were estimated using logistic regression models, after adjusting for potential confounders. High consumption of mustard oil was associated with GBC risk in both high- and low-risk regions (OR = 1.33, 95% CI = 0.99–1.78; OR = 3.01, 95% CI = 1.66–5.45), respectively. An increased risk of GBC was observed with deep frying of fresh fish in mustard oil (OR = 1.57, 95% CI = 0.99–2.47, p-value = 0.052). A protective association was observed with consumption of leafy vegetables, fruits, onion and garlic. No association was observed between consumption of meat, spicy food, turmeric, pulses or with any other oil as a cooking medium. The effect of high consumption of mustard oil on GBC risk, if confirmed, has implications for the primary prevention of GBC, via a reduced consumption.     

Diet, alcohol, tobacco and risk of cancer of the pancreas: a case-control study

In view of the increased incidence of pancreatic cancer and the possible aetiological role of certain dietary factors, a retrospective epidemiological study was undertaken to investigate the roles of tobacco, alcohol, fat, protein and carbohydrate intakes. Sixty-nine patients with pancreatic adenocarcinoma, and 199 normal subjects were interviewed. Data were obtained on life time drinking, smoking and dietary habits. Conditional logistic regression models were used to analyse the relative risk variations. It was shown that the relative risk of cancer of the pancreas increases with fat and alcohol intakes, does not vary with protein intake, and decreases with carbohydrate intake and duration of alcohol consumption. Alcohol may be not directly involved in the aetiology of cancer of the pancreas: its effect could be due to the contents of some alcoholic beverages.     

Association of chili pepper consumption,low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population

We explored the risk factors for gallbladder cancer and explanations for its sharp and constant incidence increase in Chile since the 1970s. We compared 114 consecutive patients with verified gallbladder cancer, diagnosed 1992-1995, to 114 matched hospital patients with gallstones, using conditional logistic regression analysis. Low education showed a nonsignificant positive relationship with gallbladder cancer [odds ratio (OR) = 2.3, 95% confidence interval (CI) 0.8-6.2], and low socioeconomic level showed a significant relationship (OR = 5.0, 95% CI 1.5-17.3). A very long history of gallstone disease was significantly more prevalent among cases (OR = 11.0, 95% CI 1.4-85.2). Significant red chili pepper consumption was observed in gallbladder cancer patients (OR = 2.9, 95% CI 1.6-5.2). Low intake of both fresh fruit and sugar as soft drinks was associated with gallbladder cancer, with ORs of 6.4 (95% CI 1.4-30.3) and 3.6 (95% CI 1.3-10.1), respectively. Multivariate analysis kept only a very low socioeconomic status and red chili pepper consumption as significant independent risk factors for gallbladder cancer, ORs of 6.3 (95% CI 1.7-23.0) and 3.2 (95% CI 1.7-5.9). Longstanding gallstone cases were removed from the multivariate model because all were in the low and very low socioeconomic groups, reinforcing the association. Patients with gallbladder cancer differed from matched controls by exhibiting lower socioeconomic levels, having a much longer history of gallstone disease and presenting a dietary pattern characterized by high red chili pepper consumption and low fresh fruit intake.     

Environmental pollutants in gallbladder carcinogenesis

Gallbladder cancer is a common malignancy of the gastrointestinal tract that shows wide geographical variation in its distribution. Cause of gallbladder cancer is still obscure; however, various etiological factors have been proposed. Of these gallstones and inflammation of the gallbladder is commonest. Despite three decades of active research no conclusive evidence is available as to what causes gallbladder cancer? In this article we reviewed the evidence on the role of environmental pollutants on gallbladder carcinogenesis. A detailed search of Medline was carried out which revealed only 12 articles. A number of heavy metals like nickel, cadmium, etc. have been implicated; however, the evidence is not robust enough to conclude its association. Role of radiation and pesticides in river water have also been evaluated without any conclusive evidence of its association with gallbladder cancer. Better designed case-control studies or cohort studies looking at exposure are required before it could be accepted as one of the causes of GBC.     

Aspects of the rationale for the Women's Health Trial

A 5.5-fold range in breast cancer incidence rates in 21 countries shows strong correlation with national estimates of per capita intake of dietary fat, but not with other caloric sources (proteins and carbohydrates). It is argued that certain breast cancer and hormone factors may contribute little to the explanation of such international variations in incidence of this neoplasm. It is further argued that experimental studies in animals support a specific role for dietary fat in the promotion of mammary tumors, but the effects of calories alone seem to be largely restricted to tumor initiation. Finally, data from international, migrant-population, and analytic epidemiologic investigations are used to motivate the basic relative risk assumption of study designs thus far proposed for the Women's Health Trial, and some continuing motivations for a dietary intervention (low-fat diet) trial are discussed.     

Risk Factors for Gallbladder Cancer and Cholangiocarcinoma: Similarities,Differences and Updates

Introduction  

Far-ranging variation in the incidence of gallbladder cancer (GBC) and cholangiocarcinoma (CCA) in different geographic regions on the globe may reflect the risk factor distribution for these tumors     

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16–1.70 for 17 years and older vs. 13–14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50–4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08–2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.     

Incidental gallbladder cancer: what management?

Gallbladder cancer (GBC) represents 3.8% of all gastrointestinal cancers and usually known to be of a poor prognosis. In 0.2–2.9% of cases, this cancer is found in cholecystectomy specimens. A better understanding of spread mode of this tumor helps a better surgical management. The aim of the present review is to underline the management of GBC based on the comprehension of risk factors and anatomic features. A Medline, PubMed database search was performed to identify articles published from 2000 to 2011 using the keywords ‘carcinoma of gallbladder’, ‘incidental gallbladder cancer’, ‘gallbladder neoplasm’ and ‘cholecystectomy’. Some pathological situations such as chronic lithiasis and biliopancreatic junction abnormalities have been clearly identified as predisposing to GBC. Laparoscopy increases peritoneal and parietal tumor dissemination, thus, it should not be performed when GBC is suspected. Most determinant prognostic factors are nodal, perineural and venous involvement, invasion of the cystic duct and the tumor differentiation. The simple cholecystectomy is sufficient for tumors classified as T1a; for other cancers exceeding the muscularis, radical re-resection is required due to the high risk of recurrence. This aggressive surgery improved the overall survival of patients. There is still no standard adjuvant treatment; patients should be included in prospective trials.     

Clinicopathological Study of Gall Bladder Carcinoma with Special Reference to Gallstones: Our 8-year Experience from Eastern India

Gallbladder carcinoma (GBC) is the commonest cancer of the biliary tree and the most frequent cause of deathfrom biliary malignancies. The incidence of GBC shows prominent geographic, age, race, and gender-relateddifferences and is 4-7 times higher in patients with gallstones. This prompted us to study the clinicopathologicalaspects of the disease and the incidence of gallstones in gallbladder carcinoma patients, in this part of India. Inthis, combined retrospective (Jan 2004-March 2010) and prospective study (April 2010-Dec 2011) of eight years,198 patients of gallbladder carcinoma (50 males and 148 females), (range 28-82 years; mean 55 years) were studied.Most of the patients were poor and presented with abdominal pain and mass, with abnormal lab parameters.Gallstones were present in 86% of patients. Surgical exploration was performed in 130, with gallbladder resectionin 60 (including 7 incidental GBC). Adenocarcinoma (87.7%) was the commonest histological type. The studyindicates that GBC is common in our scenario. It is a disease of elderly females, has a strong association withgallstones and every cholecystectomy specimen should be examined histopathologically.