Predictors of incidental gallbladder cancer in elderly patients

Beijing, China

Predictors of incidental gallbladder cancer in elderly patients

Ji-Qiao Zhu, Dong-Dong Han, Xian-Liang Li, Jian-Tao Kou, Hua Fan and Qiang He

Beijing, China

BACKGROUND:At the time of diagnosis, most patients with gallbladder cancer are in advanced stage and the cancer is unresectable. Long-term survivors are usually seen in a small number of patients with incidental gallbladder cancer. This study aimed to identify preoperative predictors of incidental gallbladder cancer in elderly patients.

METHODS:A total of 4014 patients of more than 44 years old who had undergone cholecystectomy at our department from January 2000 to December 2010 were retrospectively reviewed. Univariate and multivariate modalities were used to identify the predictive factors of incidental gallbladder cancer.

RESULTS:Twenty-nine of the 4014 patients who had undergone cholecystectomy for benign gallbladder diseases were histologically diagnosed as having incidental gallbladder cancer. Multivariate analysis identifed that elevated carbohydrate antigen 19-9 combined with carcinoembryonic antigen and/ or carbohydrate antigen 125 (P=0.045), a gallbladder polyp greater than or equal to 1.2 cm (P=0.043) and focal gallbladder wall thickening of more than or equal to 5 mm (P=0.002) were predictive factors of incidental gallbladder cancer.

CONCLUSION:Cholecystectomy is suggested for patients with these predictive factors and intraoperative frozen section should be considered to rule out carcinoma. (Hepatobiliary Pancreat Dis Int 2015;14：96-100)

incidental gallbladder cancer; predictive factors; resection

Introduction

Incidental gallbladder cancer is defned as that frst diagnosed by pathological examination of the gallbladder.[1]Gallbladder cancer is the most aggressive and common tumor of the biliary duct. The only treatment of this cancer is radical resection. However, less than 10% of patients with gallbladder cancer who are considered as surgical candidates are in the early-stage of the disease.[2]The outcome of gallbladder cancer is poor with a lower survival rate.[3]Patients with gallbladder cancer are generally in the advanced stage at the time of diagnosis. Long-term survivors are those with the cancer limited to the gallbladder.[4]Thus, early diagnosis is very important to improve the patients' outcome.[5]The present study was undertaken to fnd predictive factors of gallbladder cancer via the analysis of patients with incidental gallbladder cancer.

Methods

Patients

Data of the 4014 patients of more than 44 years old who had undergone cholecystectomy for benign gallbladder diseases from January 2000 to December 2010 at the Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, were analyzed retrospectively. The preoperative diagnosis of gallbladder disease was based on imaging examinations and laboratory tests. Ultrasound imaging and tumor marker screening were performed routinely before surgery. When common bile duct stones were suspected, magnetic resonance imaging and computed tomography were selected for further examination. Laparoscopic cholecystectomy was the initial surgical procedure. This operation was converted to open cholecystectomy to safely complete the operation in case of complications such as bile duct injury or diffculty in dissecting Calot's triangle.[6,7]Incidental gallbladder cancer was diagnosed by pathological examination of the resected gallbladder. Clinical and pathological staging was based on the7th edition of theAmerican Joint Committee on Cancer Manual.[8]The patients required a second, defnitive procedure according to the histological results.

Surgical resection of gallbladder cancer

Surgical resection of gallbladder cancer was performed as follows: 1) Tis and T1a gallbladder cancers were resected by simple cholecystectomy; 2) T1b gallbladder cancer was resected by extended cholecystectomy that included cholecystectomy with a resection of a 2-cm wedge of the liver and hepatoduodenal ligament skeletonization; 3) T2 gallbladder cancer was resected by cholecystectomy and an excision of medial liver segments 4b and 5 with regional lymphadenectomy; 4) T3 gallbladder cancer was resected by cholecystectomy and regional lymphadenectomy combined with a resection of adjacent organs such as hepatopancreatoduodenectomy or a resection of the extra-hepatic bile duct; 5) T4 gallbladder cancer was not resected. Regional lymphadenectomy included a resection of lymph nodes in the portocaval areas and porta hepatis.

Clinical parameters

To identify predictive factors of incidental gallbladder cancer, we compared demographics and clinical characteristics of the patients: age, gender, history, smoking, carbohydrate antigen 19-9 (CA19-9) level higher than 108 U/mL, gallbladder stones with wall thickening, body mass index, gallbladder atrophy with porcelain gallbladder, gallbladder stones greater than or equal to 3.0 cm, elevated CA19-9 combined with carcinoembryonic antigen (CEA) and/or carbohydrate antigen 125 (CA125), a gallbladder polyp greater than or equal to 1.2 cm, and focal gallbladder wall thickening of more than or equal to 5 mm.

Statistical analysis

Statistical analyses were performed by using SPSS 13.0 computer software (SPSS, Chicago, IL, USA). The Chi-square test or Fisher's exact test was used for categorical variables. Variables on univariate analysis withPvalues less than 0.05 were subjected to further analysis to identify the independent predictive factors for incidental gallbladder cancer. Relative risks were expressed as odds ratios with a 95% confdence interval.Pvalues of less than 0.05 were considered statistically signifcant.

Results

Patients diagnosed with incidental gallbladder cancerTwenty-nine patients (nine men and twenty women, aged 70.97±1.66 years) were diagnosed histologically with incidental gallbladder cancer. Among them, 16 patients were diagnosed preoperatively with cholecystolithiasis, 9 with gallbladder polyps, and 4 with both. The histological examination revealed adenocarcinoma in 27 patients, adenosquamous carcinoma in 1, and undifferentiated carcinoma in 1. The location of gallbladder cancer was identical with the site of focal wall thickening or the polyp itself in the incidental gallbladder cancer group. Eleven patients had stage I, 13 had stage II, and 5 had stage III gallbladder cancer according to AJCC staging. Surgical resections included simple cholecystectomy in 10 patients, extended cholecystectomy in 6, excision of medial liver segments 4b and 5 with regional lymphadenectomy in 10, excision of medial liver segments 4b and 5 with regional lymphadenectomy and excision of the extra-hepatic bile duct in 2, and hepatopancreatoduodenectomy in 1 patient. Four patients refused the second surgery (Table 1). The one- and three-year survival rates for stage I were 100%, 91%, for II 100%, 77%, and for III 60%, 20%, respectively. The other 3985 patients (nonincidental gallbladder cancer group) with benign gallbladder diseases were confrmed by histology.

Risk factors of incidental gallbladder cancer

The clinical factors of incidental gallbladder cancer are summarized in Table 2. Elevated CA19-9 combined with CEA and/or CA125, gallbladder atrophy with porcelain gallbladder, gallbladder stones greater than or equal to 3.0 cm, focal wall thickening of more than or equal to 5 mm, and a polyp larger than or equal to 1.2 cm were signifcantly more frequent in the group with incidental gallbladder cancer than those in the group with non-incidental gallbladder cancer (P<0.05). Age, gender, history, smoking, body mass index, CA19-9 level higher than108 U/mL or gallbladder stones with wall thickening were similar between the incidental gallbladder cancer group and the non-incidental gallbladder cancer group (P>0.05).

Table 1.AJCC staging of incidental gallbladder cancer and extent of surgical treatment (n=29)

Table 2.Clinical factors of incidental gallbladder cancer

Table 3.Multivariate analysis of independent risk factors of incidental gallbladder cancer

Logistic regression analysis

Using multiple logistic regression analysis, we found that elevated CA19-9 combined with CEA and/or CA125 [odds ratio (OR): 0.096; 95% confdence interval (CI): 0.010-0.953;P=0.045], a polyp greater than or equal to 1.2 cm (OR: 9.833; 95% CI: 1.071-90.254;P=0.043) and focal gallbladder wall thickness of more than or equal to 5 mm (OR: 40.076; 95% CI: 4.073-394.381;P=0.002) were signifcant independent risk factors (Table 3). Gallbladder atrophy with porcelain gallbladder or gallbladder stones greater than or equal to 3.0 cm were not considered as signifcant independent risk factors (P>0.05).

Discussion

Patients with gallbladder cancer have a high mortality, but the 5-year survival rates are as low as 5% to 10%.[9]The early stage of gallbladder cancer, especially incidental gallbladder cancer, is the only realistic hope for long-term survival because the tumor is limited to the gallbladder with 5-year survival rates of 57%-72% after resection.[10]Surgery for patients with incidental gallbladder cancer is likely to achieve a good outcome. In this series, most patients found in early-stage had a cumulative 3-year survival rate of 91% for stage I and 77% for stage II, respectively, in contrast to 20% for stage III. The patients could beneft from early diagnosis. Therefore, identifying predictive factors for incidental gallbladder cancer is very important for early diagnosis.

Identifcation and diagnosis of incidental gallbladder cancer presents a challenge. The etiology of the disease remains unknown while some risk factors for gallbladder cancer have been reported in the literature. Gallstones which are present in most patients with gallbladder cancer have long been considered as a risk factor for gallbladder cancer.[9,11]The incidence of gallbladder cancer usually parallels with the prevalence of gallstones, but this seems not the case in south India.[12]The lack of cofactors might explain the situation.[13]In our cohort, 13 patients (44.8%) had larger gallstones (≥3.0 cm) in the incidental gallbladder cancer group, which was higher than those found in the control group (20.3%). Multivariate analysis did not show the signifcant difference. Koshenkov et al[14]reported a similar result. The presence of anomalous pancreaticobiliary ductal junction is thought to be associated with incidental gallbladder cancer. Kang et al[15]found that 10 of the 218 patients (4.6%) with gallbladder carcinoma were associated with anomalous pancreaticobiliary ductal junction. Chao et al[16]reported that four of 25 patients (16.0%) with gallbladder cancer exhibited anomalous pancreaticobiliary ductal junction. Hu et al[17]also identifed that the frequency of anomalous pancreaticobiliary ductal junction was signifcantly higher in patients with gallbladder carcinoma. However, anomalous pancreaticobiliary ductal junction did not affect the survival of patients with gallbladder cancer.[11,15]Porcelain gallbladder was another risk factor for incidental gallbladder cancer but recent results are inconsistent. Khan et al[18]demonstrated that porcelain gallbladder was only weakly associated with gallbladder cancer. Focal calcifcation was a risk factor of gallbladder cancer whereas diffuse calcifcation was not.[19]Gallstones were probably associated with calcium deposits which contributes to chronic infammation.[20]Patient age is also an important factor for gallbladder cancer.[11,14]Hence the present study focused on elderlypatients (>44 years old). Twelve patients (41.4%) in the incidental gallbladder cancer group and 1104 (27.7%) in the non-incidental gallbladder cancer group were older than 60 years, respectively. However, multivariate analysis did not show any statistical signifcance.

Our cohort showed that elevated CA19-9 combined with CEA and/or CA125, a polyp greater than or equal to 1.2 cm, and focal gallbladder wall thickening of more than or equal to 5 mm indicated a higher risk of developing incidental gallbladder cancer.

CA19-9, CEA and CA125 are traditionally used as tumor markers for gallbladder cancer.[21]Generally, the blood level of CA19-9 is very low in patients with benign gallbladder disorders.[22]CEA is widely used in monitoring patients with colorectal cancer. Higher levels of CEA and CA19-9 were signifcantly associated with a malignant tumor.[23]CA125 levels higher than 11 U/mL had a sensitivity of 64% and a specifcity of 90% in differentiating benign from malignant gallbladder disease.[24]Our study indicated that elevated CA19-9 combined with CEA and/or CA125 raised the suspicion of gallbladder cancer (P=0.045). Wang et al[25]also found that diagnostic accuracy was highest with a combination of tumor markers.

Gallbladder cancer may present as polypoidal lesion.[26]Our fndings showed that a polyp larger than or equal to 1.2 cm was more likely to be malignant (P=0.043). The size of a polyp is the most important factor for predicting whether it is malignant, but it is diffcult to differentiate preoperatively. It is recommended that patients with gallbladder polyps greater than or equal to 10 mm should be subjected to cholecystectomy whatever they had symptoms or not;[27,28]but a study from Korea did not agree to this recommendation.[29]

Gallbladder cancer often has an irregular internal surface with a thickened wall. The presence of thickened gallbladder wall layers, especially mucosa layers, is more likely to be associated with cancer while thin gallbladder wall layers is indicative of chronic cholecystitis.[21,30]In this series, we found that patients with a thickened focal wall of more than or equal to 5 mm were more likely to develop incidental gallbladder cancer (41.4%,P=0.002) as gallbladder cancer is often manifested as a focal soft-tissue mass invading or thickening the gallbladder wall.[31,32]

Obviously, the small number of patients in the incidental gallbladder cancer group limited the accuracy of this study. The low incidence of gallbladder cancer makes it diffcult to acquire larger cohorts. The results in the present study need to be confrmed by multicenter studies in future.

In conclusion, our fndings suggest that elevated CA19-9 combined with CEA and/or CA125, a gallbladder polyp greater than or equal to 1.2 cm, and focal gallbladder wall thickening of more than or equal to 5 mm are signifcant predictive factors of incidental gallbladder cancer. Cholecystectomy is suggested for patients with these predictive factors, and intraoperative frozen sections should be considered to rule out this cancer.

Contributors:ZJQ, HDD and HQ proposed the study. ZJQ and LXL wrote the frst draft, collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. HQ is the guarantor.

Funding:None.

Ethical approval:The study protocol was reviewed and approved by the Institutional Review Board of the hospital.

Competing interest:No benefts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received August 9, 2013

Accepted after revision April 19, 2014

AuthorAffliations:Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing 100020, China (Zhu JQ, Han DD, Li XL, Kou JT, Fan H and He Q)

Qiang He, MD, Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing 100020, China (Tel: +86-10-85231504; Email: heqiang349@sina.com)

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(14)60292-7

Published online August 21, 2014.