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

Gallbladder cancer (GBC) is a rare but highly invasive disease compared to other gastrointestinal malignancies. First described by Maximilian Stoll in 1777, GBC is still considered a highly malignant disease with a poor survival rate (Nevin et al., 1976). The incidence of GBC varies widely among different geographic regions and ethnic groups, ranging from 1 to 23 per 100,000 individuals (Lazcano-Ponce et al., 2001), and (Randi et al., 2006). India, Pakistan, and Korea are among the countries with the highest incidence of GBC (Randi et al., 2006; Bae, 2012). Because the clinical presentation of early GBC is non-specific, a diagnosis is generally made when patients are at an advanced stage of disease (Henson et al., 1992).The overall mean survival rate associated with advanced GBC is less than 4 months, whereas the 5-year survival rate ranges from 0% to 10% (Misra et al., 2003). Recently, however, due to a higher number of


Introduction
Gallbladder cancer (GBC) is a rare but highly invasive disease compared to other gastrointestinal malignancies.First described by Maximilian Stoll in 1777, GBC is still considered a highly malignant disease with a poor survival rate (Nevin et al., 1976).
The incidence of GBC varies widely among different geographic regions and ethnic groups, ranging from 1 to 23 per 100,000 individuals (Lazcano- Ponce et al., 2001), and (Randi et al., 2006).India, Pakistan, and Korea are among the countries with the highest incidence of GBC (Randi et al., 2006;Bae, 2012).Because the clinical presentation of early GBC is non-specific, a diagnosis is generally made when patients are at an advanced stage of disease (Henson et al., 1992).The overall mean survival rate associated with advanced GBC is less than 4 months, whereas the 5-year survival rate ranges from 0% to 10%

Comparison of Clinical Outcomes of Incidental and Non-Incidental Gallbladder Cancers: A Single-Center Cross-Sectional Study
Byung Hyo Cha 1 , Jong-Myun Bae 2 * laparoscopic cholecystectomies performed, GBC is being detected at earlier stages.Incidental gallbladder cancer (IGBC), which is diagnosed during or after cholecystectomy, has better prognosis than non-incidental gallbladder cancer (NIGBC) (D'Hondt et al., 2013).We examined the clinical characteristics and outcomes of IGBC and compared them to those of NIGBC in patients of Jeju Island where the incidence of GBC is the highest among all provinces in Korea (Bae, 2012).

Materials and Methods
Consecutive patients newly diagnosed with GBC at the Digestive Disease Center and Department of Internal Medicine, Cheju Halla General Hospital, Jeju City, Jeju Special Self-Governing Province, Korea, between November 2007 and November 2011 were enrolled in this study.The diagnosis of GBC was established on the basis of radiologic findings and was further confirmed by histopathology.The radiologic evidence of GBC was based on abdominal ultrasonography, contrast-enhanced computed tomography, and magnetic resonance cholangiopancreatography or positron emission tomography-computed tomography, if clinically needed.Pathologic specimens were obtained by ultrasonographyguided needle biopsy or resection of the primary tumor.Cases in which a pathologic confirmation was not possible were diagnosed on the basis of radiologic results and associated clinical follow-up data indicative of GBC.
IGBC was defined as a carcinoma originating from the gallbladder mucosa that was detected during or after cholecystectomy on microscopic observation without suspicion of malignancy before surgery.All other GBCs were defined as NIGBC.Surgery was recommended for all patients with asymptomatic gallstones of more than 1 cm, symptomatic gallstone disease, and calculous cholecystitis.Those with a gallbladder polyp of a large size (≥1 cm), sessile shape, or changes in the number, shape, or size during follow-up imaging studies were recommended to undergo prophylactic cholecystectomy.
Demographic data (age, sex, residence, body mass index (BMI), medical history, and underlying morbidities), laboratory and imaging findings, and clinical outcomes (date of death, last follow-up, disease stage, and treatment) were collected on review of our hospital records.Continuous variables are presented as means ± standard deviation (SD) and categorical variables are presented as a frequency with percentage of RAWS.The Student's t-test was used to determine the statistical difference between groups for continuous variables, and the Pearson chisquare test was used for categorical variables.Cumulative survival was determined using the Kaplan-Meier method, and the difference between two groups was analyzed using the log-rank test.A p value of <0.05 was considered statistically significant.All statistical analyses were performed using SPSS 19.0 software (SPSS, Chicago, Illinois, USA).
This study protocol was approved by the Institutional Review Board of Cheju Halla General Hospital.

Results
Of the 79 patients with GBC, 33 (41.8 %) and 46 (58.2 %) were diagnosed as having IGBC and NIGBC, respectively.The preoperative diagnosis for each case of IGBC is listed in Table 1.The two main reasons for gallbladder resection were gallbladder polyps and gallstones with or without symptoms.
The two groups did not differ significantly in age, sex, medical history, and personal history (Table 2).The number of patients diagnosed at an early stage was higher in the IGBC group than in the NIGBC group.Using the   Kaplan-Meier method, we found a significant difference in the survival rate between the two groups (Figure 1).Multivariate analysis using the Cox regression model showed that an incidental versus non-incidental diagnosis of GBC and disease stage were significant factors affecting the survival rates of patients with GBC (Table 3).

Discussion
GBC is a malignant disease, which is prevalent in certain geographic areas.Early diagnosis with curative surgical resection is the only management strategy that ensures good prognosis.However, most patients with GBC are diagnosed at advanced stages (Henson et al., 1992).
In our study, we compared the clinical outcomes of IGBC and NIGBC and found significant differences in disease stage and overall survival between these groups.We also found that the two main reasons for cholecystectomy in the IGBC group were gallbladder polyps and gallstones, with or without cholecystitis.
Previous epidemiological studies have suggested that a history of gallstones is a potential risk factor for GBC (Maringhini et al., 1987;Chow et al., 1999).Recent studies have shown that gallstone disease is the main reason for cholecystectomy in patients with IGBC Koshenkov et al.. 2013).However, the incidence of IGBC among patients undergoing cholecystectomy was very low (0.25%, 67 of 26,572 patients) in these studies.Further, there is no evidence to support the performance of prophylactic cholecystectomy for asymptomatic gallstone disease to prevent GBC.Thus, the clinical conditions or radiologic clues that could predict early GBC or benign premalignant lesions in patients with gallstones are still unknown.In contrast, gallbladder polyps, especially adenomatous polyps, are well known as potential pre-cancerous lesions.Many researchers have attempted to determine the demographic and radiologic factors that differentiate the malignant potential from the benign nature of a polyp.Typically, prophylactic cholecystectomy is recommended for high-risk groups, which include patients with diabetes, polyps larger than 1 cm, and certain sonographic findings (Kwon et al., 2009;Cha et al., 2011).
There are important implications to our finding that IGBC has better clinical outcomes than NIGBC.Higher proportion of earlier stages included in IGBC group might be considered to contribute the better prognosis, but we cannot exactly assess the patients with GB stone and GB polyp at the time of cholecystectomy because they were not suspicioused as cancer.Even if the physicians did not recommended the patients to undergo cholecystectomy, they would have been discovered as advanced GBC later.Therfore we need to make efforts to differentiate the patients with high risks for IGBC from benign diseases before the decision of operation regardless of symptoms.Determination of valid predisposing risk factors for early GBC among patients with gallbladder polyps and gallstone disease can help improve the clinical outcomes of GBC by establishing more strict or advanced guidelines for cholecystectomy.Despite the limitations of our study, including the retrospective observational study design and small sample size, due to the relative rarity of GBC, we compared two different GBC patient populations and found significantly better clinical outcomes in patients with IGBC than in those with NIGBC.