Next Article in Journal
Thoracic Ultrasound for Immediate Exclusion of Pneumothorax after Interventional Bronchoscopy
Next Article in Special Issue
Changed Profile of Serum Transferrin Isoforms in Primary Biliary Cholangitis
Previous Article in Journal
Temporal Trends of Emergency Department Visits of Patients with Atrial Fibrillation: A Nationwide Population-Based Study
Previous Article in Special Issue
Leakage and Stenosis of the Hepaticojejunostomy Following Surgery for Perihilar Cholangiocarcinoma
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 9
Issue 5
10.3390/jcm9051484
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Incidental Carcinoma after Cholecystectomy for Benign Disease of the Gallbladder: A Meta-Analysis

by
Jung-Soo Pyo
1,
Byoung Kwan Son
2,*,
Hyo Young Lee
2,
Il Whan Oh
2 and
Kwang Hyun Chung
2
1
Department of Pathology, Daejeon Eulji University Hospital, Eulji University School of Medicine, Daejeon 35233, Korea
2
Department of Internal Medicine, Nowon Eulji University Hospital, Eulji University School of Medicine, Seoul 01830, Korea
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(5), 1484; https://doi.org/10.3390/jcm9051484
Submission received: 23 April 2020 / Revised: 9 May 2020 / Accepted: 11 May 2020 / Published: 14 May 2020
(This article belongs to the Special Issue Gallbladder and Biliary Tract Diseases)
Browse Figures
Versions Notes

Abstract

:
This study aimed to determine the incidence and the prognosis of incidental carcinoma of the gallbladder (IGBC) after cholecystectomy through a meta-analysis. This meta-analysis included 51 studies and 436,636 patients with cholecystectomy. The incidence rate of IGBC after cholecystectomy was 0.6% (95% confidence interval (CI) 0.5–0.8%). The incidence rate of recent studies was not significantly different from those of past studies. The mean age and female ratio of the IGBC subgroup were not significantly different from those of the overall patient group. The estimated rates of IGBC were 13.0%, 34.1%, 39.7%, 22.7%, and 12.5% in the pTis, pT1, pT2, pT3, and pT4 stages, respectively. Patients with IGBC had a favorable overall survival rate compared to patients with non-IGBC (hazard ratio (HR) 0.574, 95% CI 0.445–0.739). However, there was no significant difference of disease-free survival between the IGBC and non-IGBC subgroups (HR 0.931, 95% CI 0.618–1.402). IGBC was found in 0.6% of patients with cholecystectomy. The prognosis of patients with IGBC was favorable compared to those with non-IGBC. In the pathologic examination after cholecystectomy for benign diseases, a sufficient examination for histology should be guaranteed to detect IGBC.

1. Introduction

Gallbladder cancer (GBC), which is the most common biliary tract carcinoma, has nonspecific signs and symptoms and is sometimes indistinguishable from benign disease of the gallbladder (GB) [1]. Representative radiologic findings of GBC include wall thickening or mass-forming. The most common finding of radiology is wall thickening [2]. However, because the GB wall may be thickened by coexisting benign disease, such as cholelithiasis, the masking of GBC can occur. In addition, these radiologic findings of GBC are not specific and may be overlapped with benign diseases of the GB, such as focal adenomyomatosis or GB polyps [2]. Therefore, GBCs cannot be detected in preoperative radiologic examinations. GBCs, which are identified in the pathologic examination after cholecystectomy, are defined as incidental GBC (IGBC).
The incidence rate of IGBC after cholecystectomy was found to range up to 2.9% and this varied according to reports [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. However, IGBC may be up to 50% of all GBCs [54]. GBC is the fifth most common malignant tumor of the gastrointestinal tract, with an incidence of 0.8–1.2% [55]. In healthy populations, the prevalence of cholecystectomy, which is one of the most common surgeries performed, were 1.3%, 2.9%, and 11.1% in Taiwan, Brazil, and German, respectively [10,56]. The different prevalences of cholecystectomy can affect the detection rate of IGBC. Cholelithiasis, which is an important cause for cholecystectomy, are affecting 10% to 15% of the adult population of developed countries [57]. In the diagnosis of GBC, pathologic examinations after cholecystectomy are essential for the detection of IGBC. Cholelithiasis is the most common risk factor of GBC [5]. The risk factors of IGBC include old age, female, cholelithiasis, and obesity [1]. Preoperatively, the suspicious clinical and radiologic findings of IGBC are not specific, and the risk factors of IGBC and non-IGBC are overlapped [2]. The performance rates of pathologic examinations after cholecystectomy may be varied according to the country and insurance policy [25]. If the pathologic examinations after cholecystectomy were not performed in every case, the incidence rate of IGBC might be overestimated or underestimated. When this information for IGBC is accurate, further studies for the treatment of IGBC and predictions of the prognosis will be possible. In the present study, we aimed to elucidate the incidence rate of IGBC and the prognosis of IGBC through a meta-analysis. In addition, to obtain the clinicopathologic characteristics of IGBC, the mean age and compositions of the female ratio and pT stage were analyzed and compared to those of GBC overall.

2. Materials and Methods

2.1. Published Study Search and Selection Criteria

The literature search was performed using the PubMed databases through 31 July 2019. The search was performed using the following keywords: “cholecystectomy”, “unsuspected or incidental”, and “cancer or carcinoma or malignant or malignancy.” The titles and abstracts of the searched articles were primarily screened for exclusion. Literature or systematic review articles were also screened to find additional eligible studies. The inclusion and exclusion criteria were as follows: (1) studies for the cholecystectomy by IGBCs in human samples were included and (2) non-original articles, such as case reports or review articles, were excluded.

2.2. Data Extraction

For the meta-analysis, data were extracted from the eligible studies [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53] as follows: the first author’s name, study location, study year, type of study and initial surgery, number of patients analyzed, patients’ age and sex, tumor stage of IGBC, and survival rate. For the quantitative aggregation of the survival results, the correlation between IGBC and survival rate was analyzed according to the hazard ratio (HR), using one of three methods. In studies not reporting the HR or its confidence interval (CI), these variables were calculated from the presented data using the HR point estimate, log-rank statistic or its p-value, and the O-E statistic (the difference between the number of observed and expected events) or its variance.
If those data were unavailable, the HR was estimated using the total number of events, the number of patients at risk in each group, and the log-rank statistic or its p-value. Finally, if the only useful data were in the form of graphical representations of survival distributions, the survival rates were extracted at specified times to reconstruct the HR estimate and its variance under the assumption that the patients were censored at a constant rate during the time intervals. The published survival curves were evaluated independently by two authors to reduce variability. The HRs were then combined into an overall HR using Peto’s method [58].

2.3. Statistical Analyses

In the present meta-analysis, all data were analyzed and obtained through the Comprehensive Meta-Analysis software package (Biostat, Englewood, NJ, USA). The incidence rates of IGBC after cholecystectomy were investigated from individual studies and analyzed through a meta-analysis. We performed the subgroup analysis based on the type of initial surgery and study, and the study year. The patient’s age and sex were compared between IGBC and overall GBC patients. In this meta-analysis, among fixed and random effect models, for interpretation we used the values of a random-effects model. The heterogeneity between eligible studies was assessed using Q and I2 statistics and presented using p-values. In addition, the sensitivity analysis was conducted to assess the heterogeneity of eligible studies and the impact of each study on the combined effect. Subgroup analyses were performed based on the type of initial surgery and study, the patients’ age and sex, and the pT stage. The statistical significances between subgroups were evaluated through a meta-regression test. To consider the publication bias, Egger’s test was used. If a significant publication bias was found, the fail-safe N and trim-fill tests were performed to confirm the degree of publication bias. A p-value <0.05 was considered significant.

3. Results

3.1. Selection and Characteristics of Studies

A total of 478 studies were identified in the database searching for the meta-analysis. Finally, 51 studies were selected according to the inclusion and exclusion criteria. Among the searched studies, 184 studies were excluded due to a lack of sufficient information. In addition, 160 reports were excluded due to being non-original articles. Other remaining reports were excluded for the following reasons: focusing on other diseases (n = 52), articles in a language other than English (n = 29), and duplicate articles (n = 2) (Figure 1). The characteristics of the eligible studies are shown in Table 1.

3.2. The Incidence Rate of IGBC after Cholecystectomy

The incidence rate of IGBC after cholecystectomy was 0.6% (95% confidence interval (CI) 0.5–0.8%) in overall patients (Table 2). The incidence rate of IGBC after laparoscopic cholecystectomy was 0.7% (95% CI 0.5–0.9%). The incidence rate of the subgroup using the patients’ registry was significantly lower than that of subgroup using individual hospital data (0.2% vs. 0.7%; p = 0.002 in the meta-regression test). However, there were no significant differences of incidence rates between study years.
Next, the patients’ age and sex of IGBC were investigated and compared with overall GBC. Patients with IGBC had a significantly older age than the overall patients (p < 0.001 in meta-regression test). The patients’ age of IGBC and overall GBC were 65.291 (95% CI 63.867–66.715) and 52.023 (95% CI 49.208–54.839), respectively (Table 3). The female ratio of IGBC was 69.4% (95% CI 66.0–72.7%). There was no significant difference of female ratio between IBC and overall GBC (p = 0.817 in the meta-regression test). The age and female ratio was higher in the subgroup using the registry than in the subgroup using the individual hospital data. The IGBC showed the highest rate in the pT2 stage than in other pT stages (Table 4). The estimated rates of IGBC were 13.0% (95% CI 7.9–20.6%), 34.1% (95% CI 28.3–40.3%), 39.7% (95% CI 34.8–44.8%), 22.7% (95% CI 19.5–26.4%), and 12.5% (95% CI 7.3–20.6%) in the pTis, pT1, pT2, pT3, and pT4 stages, respectively.

3.3. Comparison of Prognosis between IGBC and Non-IGBC

The prognosis of IGBC was evaluated by comparing it to non-IGBC. Patients with IGBC had a better overall survival rate than patients with non-IGBC (HR 0.574, 95% CI 0.445–0.739; Figure 2). However, there was no significant difference of the disease-free survival rate between patients with IGBC and non-IGBC (HR 0.931, 95% CI 0.618–1.402).

4. Discussion

To the best of our knowledge, the present study is the first meta-analysis to investigate the incidence rate of IGBC and to compare the prognosis of IGBC and non-IGBC patients. Previous studies, including systematic reviews and meta-analyses, have reported IGBC after cholecystectomy. The previous meta-analysis showed the incidence rate and the prevalence of pT stage of IGBC using 26 eligible studies [59]. However, the information for the prognosis of IGBC cannot be obtained in the previous meta-analysis. We also analyzed the incidence rates according to the type of surgery and study and the patients’ age and sex.
Eligible studies of the current meta-analysis showed the information for the combined group with laparoscopic and open cholecystectomy or laparoscopic cholecystectomy alone. Among the eligible studies, data for the incidence of IGBC after open cholecystectomy could not be obtained. In daily practice, laparoscopic cholecystectomy is a gold standard for benign diseases of GB rather than open cholecystectomy. However, the comparison of the incidence rate of IGBC between laparoscopic and open cholecystectomies could not be performed due to no information for open cholecystectomy.
We indirectly compared the incidence rates between patients with laparoscopic cholecystectomy and overall patients. The estimated incidence rates of IGBC were 0.7% and 0.6% in patients with laparoscopic cholecystectomy and overall patients, respectively. The incidence rates ranged from 0.1% to 2.9% in the eligible studies. Eligible studies obtained the information from a single individual hospital or public registry. The estimated incidence rate of the single individual hospital was significantly higher than that of the public registry (0.7% vs. 0.2%). This discrepancy may be caused by the size of the population and different hospitals. In addition, because single individual hospital data may be obtained from tertiary hospitals or training hospital, the ratio of elective cholecystectomy with benign diseases can be lowered.
Unlike the previous meta-analysis, we performed the meta-analysis for the overall and disease-free survival rates of IGBC compared to non-IGBC. However, the information for the disease-free survival rate was only shown in one study [48]. As this study showed the disease-free survival rates divided into pT2 and pT3 stages, the meta-analysis could be performed. However, there was no significant difference of the disease-free survival between patients with IGBC and non-IGBC. In the comparison of overall survival rates, patients with IGBC had a favorable prognosis compared to patients with non-IGBC. However, among eligible studies, some studies demonstrated no significant difference of overall survival rates [12,51].
This difference of prognosis between IGBC and non-IGBC may be caused by the difference of the tumor stage at the initial diagnosis (pT stage) in IGBC than in non-IGBC. In the current meta-analysis, IGBCs were detected from pTis to pT4. The highest rate of pT stage was the pT2 stage in IGBC (39.7%, 95% CI 34.8–44.8%). In the current study, patients with IGBC were frequently confirmed to pTis to pT2 stages. The pT3 and pT4 stages were 22.7% and 12.5%, respectively. However, the previous meta-analysis reported that the pT4 stage rate of IGBC was 4.2% (Choi KS 2015). In addition, patients with a lower pT stage had better survival rates than those with a higher pT stage, regardless of preoperative suspicion [12,33]. Thus, the lower pT stage of IGBC may impact the better prognosis of IGBC compared to non-IGBC. Further evaluation for the prognosis of IGBC and non-IGBC will be needed based on the stratification of pT stage. As the extent of pathologic examination can impact the pT stage, further evaluations are needed.
A previous study reported that the preoperative nonsuspicious cases were 50–70% of the overall GBCs [54,60]. For the detection of GBC in the postoperative pathologic examination, the appropriate sections are needed for the suspicious lesion. However, in daily practice, because all portions of GB cannot be evaluated in the microscopic examination, the careful macroscopic examination from expert pathologists may be important. Previous studies suggested the effect of frozen sections on the detection of IGBC [4,36].
The intraoperative detection of IGBC with pT2 or higher stages via frozen sections can be useful for the prompt conversion of radical surgery [47]. The rates of pTis and pT1 stages were 13.0% and 34.1%, and the frozen section was not useful for non-mass-forming GBC. Therefore, in pT2 and higher stages, the intraoperative frozen may be useful for infiltrative lesions into the adjacent tissue. Nitta et al. [36] suggested that the examination for the full thickness of the gallbladder through the frozen section could be useful for the detection of IGBC and differentiation between pTis/T1a and others. The most common macroscopic feature is the wall thickening of GBC. As there are limitations on the extent and time of examination of frozen sections, the impact on the detection of IGBC is limited. Frozen sections can be useful for suspicious lesions detected by surgeons [4].
Some limitations in the current meta-analysis exist. First, in this meta-analysis, the pN stage and nodal disease were not analyzed. Laparoscopic cholecystectomy is enough for treatment for IGBC with the pTis to pT1 stage. Therefore, lymph node dissection could not be performed in many cases with IGBC. Second, by definition, missing cases in the preoperative radiologic examination should be considered for non-IGBC. However, the detailed information for preoperative radiologic findings could not be found in the eligible studies. Based on this limitation, the incidence rate of IGBC may be lower. Third, the present study was not performed for the subgroup analysis for tumor types, such as lymphoma and squamous cell carcinoma, due to the very low incidence of other tumor types. Fourth, the detailed comparisons between IGBC and benign diseases could not be performed due to insufficient information on eligible studies. However, IGBC frequently occurred with older age and male subjects, compared to benign diseases. Fifth, the impact of histologic examination on the detection rate of IGBC could not be investigated due to insufficient information of the examined section or extent. Sixth, the impact of pT stages of IGBC on survival rates could not be obtained due to insufficient information. Seventh, subgroup analysis based on the types of benign diseases, such as acute/chronic cholecystitis, could not be obtained due to insufficient information.

5. Conclusions

In conclusion, IGBC was found in 0.6% of cholecystectomy with benign diseases. IGBCs had higher rates in the pT1 and pT2 stages and frequently occurred in older patients. In addition, patients with IGBCs had a better prognosis than those with non-IGBCs. To detect IGBC after cholecystectomy, a sufficient examination for histology is needed in the pathologic examination.

Author Contributions

Conceptualization, J.-S.P. and B.K.S.; supervision, B.K.S.; methodology, J.-S.P.; software, J.-S.P. and B.K.S.; writing—original draft preparation, J.-S.P.; writing—review and editing, H.Y.L., I.W.O., K.H.C., and B.K.S. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare that they have no conflict of interest.

References

  1. WHO Classification of Tumors Editorial Board. WHO Classification of Tumours of the Digestive System, 5th ed.; International Agency for Research on Cancer: Lyon, France, 2019. [Google Scholar]
  2. Levy, A.D.; Murakata, L.A.; Abbott, R.M.; Rohrmann, C.A., Jr. From the archives of the AFIP. Benign tumors and tumorlike lesions of the gallbladder and extrahepatic bile ducts: Radiologic-pathologic correlation. Armed Forces Institute of Pathology. Radiographics 2002, 22, 387–413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Ahn, Y.; Park, C.-S.; Hwang, S.; Jang, H.-J.; Choi, K.-M.; Lee, S.-G. Incidental gallbladder cancer after routine cholecystectomy: When should we suspect it preoperatively and what are predictors of patient survival? Ann. Surg. Treat. Res. 2016, 90, 131–138. [Google Scholar] [CrossRef] [PubMed]
  4. Aoki, T.; Tsuchida, A.; Kasuya, K.; Inoue, K.; Saito, H.; Koyanagi, Y. Is frozen section effective for diagnosis of unsuspected gallbladder cancer during laparoscopic cholecystectomy? Surg. Endosc. 2001, 16, 197–200. [Google Scholar] [CrossRef] [PubMed]
  5. Apodaca-Rueda, M.; Cazzo, E.; De-Carvalho, R.B.; Chaim, E.A. Prevalência do câncer de vesícula biliar em pacientes submetidos à colecistectomia: Experiência do Hospital de Clínicas da Faculdade de Ciências Médicas da Universidade Estadual de Campinas–UNICAMP. Revista Colégio Bras. Cir. 2017, 44, 252–256. [Google Scholar] [CrossRef] [Green Version]
  6. Basak, F.; Hasbahceci, M.; Canbak, T.; Sisik, A.; Acar, A.; Yucel, M.; Bas, G.; Alimoĝlu, O. Incidental findings during routine pathological evaluation of gallbladder specimens: Review of 1747 elective laparoscopic cholecystectomy cases. Ann. R. Coll. Surg. Engl. 2016, 98, 280–283. [Google Scholar] [CrossRef] [Green Version]
  7. Braghetto, I.; Bastias, J.; Csendes, A.; Chiong, H.; Compan, A.; Valladares, H.; Rojas, J. Gallbladder carcinoma during laparoscopic cholecystectomy: Is it associated with bad prognosis? Int. Surg. 1999, 84, 344–349. [Google Scholar]
  8. Cavallaro, A.S.; Piccolo, G.; Panebianco, V.; Menzo, E.L.; Berretta, M.; Zanghì, A.; Di Vita, M.; Cappellani, A. Incidental gallbladder cancer during laparoscopic cholecystectomy: Managing an unexpected finding. World J. Gastroenterol. 2012, 18, 4019–4027. [Google Scholar] [CrossRef]
  9. Chan, C.-P.; Chang, H.-C.; Chen, Y.-L.; Yang, L.; Chen, S.-T.; Kuo, S.-J.; Tsai, P.-C. A 10-year experience of unsuspected gallbladder cancer after laparoscopic cholecystectomy. Int. Surg. 2003, 88, 175–179. [Google Scholar]
  10. Charfi, S.; Gouiaa, N.; Mnif, H.; Chtourou, L.; Tahri, N.; Abid, B.; Mzali, R.; Boudawara, T.S. Histopathological findings in cholecystectomies specimens: A single institution study of 20 584 cases. Hepatobiliary Pancreat. Dis. Int. 2018, 17, 345–348. [Google Scholar] [CrossRef]
  11. Choi, S.B.; Han, H.J.; Kim, C.Y.; Kim, W.B.; Song, T.-J.; Suh, S.O.; Kim, Y.C.; Choi, S.Y. Incidental Gallbladder Cancer Diagnosed Following Laparoscopic Cholecystectomy. World J. Surg. 2009, 33, 2657–2663. [Google Scholar] [CrossRef]
  12. Cziupka, K.; Partecke, L.I.; Mirow, L.; Heidecke, C.-D.; Emde, C.; Hoffmann, W.; Siewert, U.; Berg, N.V.D.; Von Bernstorff, W.; Stier, A. Outcomes and prognostic factors in gallbladder cancer: A single-centre experience. Langenbeck’s Arch. Surg. 2012, 397, 899–907. [Google Scholar] [CrossRef] [PubMed]
  13. D’Hondt, M.; Lapointe, R.; Benamira, Z.; Pottel, H.; Plasse, M.; Letourneau, R.; Roy, A.; Dagenais, M.; Vandenbroucke-Menu, F. Carcinoma of the gallbladder: Patterns of presentation, prognostic factors and survival rate. An 11-year single centre experience. Eur. J. Surg. Oncol. (EJSO) 2013, 39, 548–553. [Google Scholar] [CrossRef] [PubMed]
  14. Chabowski, M.; Dorobisz, T.; Dorobisz, K.; Pawlowski, W.; Janczak, D.; Patrzalek, D.; Janczak, D. Incidental gallbladder cancer after cholecystectomy: 1990 to 2014. OncoTargets Ther. 2016, 9, 4913–4916. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Duzkoylu, Y.; Bektas, H.; Kozluklu, Z.D. Incidental gallbladder cancers: Our clinical experience and review of the literature. Turk. J. Surg. 2015, 32, 107–110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Ferrarese, A.; Solej, M.; Enrico, S.; Falcone, A.; Catalano, S.; Pozzi, G.; Marola, S.; Martino, V. Diagnosis of incidental gallbladder cancer after laparoscopic cholecystectomy: Our experience. BMC Surg. 2013, 13, S20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Firat, Y.D.; Idiz, U.O.; Cakir, C.; Yardimci, E.; Yazici, P.; Bektasoglu, H.; Bozkurt, E.; Ucak, R.; Gucin, Z.; Uresin, T.; et al. Prospective multi-center study of surgeon’s assessment of the gallbladder compared to histopathological examination to detect incidental malignancy. Langenbeck’s Arch. Surg. 2019, 404, 573–579. [Google Scholar] [CrossRef]
  18. Volkan, G.; Kirimker, E.O.; Akyol, C.; Kocaay, A.F.; Karabörk, A.; Tüzüner, A.; Erden, E.; Karayalçin, K. Incidental gallbladder cancer diagnosed during or after laparoscopic cholecystectomy in members of the Turkish population with gallstone disease. Turk J. Gastroenterol. 2011, 22, 513–516. [Google Scholar]
  19. Geramizadeh, B.; Kashkooe, A. Incidental Gall Bladder Adenocarcinoma in Cholecystectomy Specimens; A Single Center Experience and Review of the Literature. Middle East J. Dig. Dis. 2018, 10, 249–253. [Google Scholar] [CrossRef] [Green Version]
  20. Glauser, P.M.; Strub, D.; Käser, S.A.; Mattiello, D.; Rieben, F.; Maurer, C.A. Incidence, management, and outcome of incidental gallbladder carcinoma: Analysis of the database of the Swiss association of laparoscopic and thoracoscopic surgery. Surg. Endosc. 2010, 24, 2281–2286. [Google Scholar] [CrossRef]
  21. Goussous, N.; Maqsood, H.; Patel, K.; Ferdosi, H.; Muhammad, N.; Sill, A.M.; Kowdley, G.C.; Cunningham, S.C. Clues to predict incidental gallbladder cancer. Hepatobiliary Pancreat. Dis. Int. 2018, 17, 149–154. [Google Scholar] [CrossRef]
  22. Gulwani, H.V.; Gupta, S.; Kaur, S. Incidental Detection of Carcinoma Gall Bladder in Laparoscopic Cholecystectomy Specimens: A Thirteen Year Study of 23 Cases and Literature Review. Indian J. Surg. Oncol. 2015, 6, 30–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Horkoff, M.J.; Ahmed, Z.; Xu, Y.; Sutherland, F.R.; Dixon, E.; Ball, C.G.; Bathe, O.F. Adverse Outcomes After Bile Spillage in Incidental Gallbladder Cancers. Ann. Surg. 2019. [Google Scholar] [CrossRef] [PubMed]
  24. Ioannidis, O.; Paraskevas, G.; Varnalidis, I.; Ntoumpara, M.; Tsigkriki, L.; Gatzos, S.; Malakozis, S.G.; Papapostolou, D.; Papadopoulou, A.; Makrantonakis, A.; et al. Primary gallbladder cancer discovered postoperatively after elective and emergency cholecystectomy. Klin. Onkol. 2013, 26, 31–34. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Jha, V.; Sharma, P.; Mandal, K.A. Incidental gallbladder carcinoma: Utility of histopathological evaluation of routine cholecystectomy specimens. South Asian J. Cancer 2018, 7, 21–23. [Google Scholar] [CrossRef]
  26. Kalita, D.; Pant, L.; Singh, S.; Jain, G.; Kudesia, M.; Gupta, K.; Kaur, C. Impact of routine histopathological examination of gall bladder specimens on early detection of malignancy-a study of 4115 cholecystectomy specimens. Asian Pac. J. Cancer Prev. 2013, 14, 3315–3318. [Google Scholar] [CrossRef] [Green Version]
  27. Kim, J.H.; Kim, W.H.; Kim, J.H.; Yoo, B.M.; Kim, M.W. Unsuspected gallbladder cancer diagnosed after laparoscopic cholecystectomy: Focus on acute cholecystitis. World J. Surg. 2010, 34, 114–120. [Google Scholar] [CrossRef]
  28. Koppatz, H.; Nordin, A.; Scheinin, T.; Sallinen, V. The risk of incidental gallbladder cancer is negligible in macroscopically normal cholecystectomy specimens. HPB 2018, 20, 456–461. [Google Scholar] [CrossRef]
  29. Kwon, S.Y.; Chang, H.J. A clinicopathological study of unsuspected carcinoma of the gallbladder. J. Korean Med. Sci. 1997, 12, 519–522. [Google Scholar] [CrossRef] [Green Version]
  30. Kwon, A.H.; Imamura, A.; Kitade, H.; Kamiyama, Y. Unsuspected gallbladder cancer diagnosed during or after laparoscopic cholecystectomy. J. Surg. Oncol. 2008, 97, 241–245. [Google Scholar] [CrossRef]
  31. Lundgren, L.; Muszynska, C.; Ros, A.; Persson, G.; Gimm, O.; Valter, L.; Andersson, B.; Sandström, P. Are Incidental Gallbladder Cancers Missed with a Selective Approach of Gallbladder Histology at Cholecystectomy? World J. Surg. 2018, 42, 1092–1099. [Google Scholar] [CrossRef]
  32. Martins-Filho, E.D.; Batista, T.; Kreimer, F.; Iwanaga, T.C.; Leão, C.D.S.; Martins, A.C.D.A. Prevalence of incidental gallbladder cancer in a tertiary-care hospital from Pernambuco, Brazil. Arq. Gastroenterol. 2015, 52, 247–249. [Google Scholar] [CrossRef] [PubMed]
  33. Mazer, L.M.; Losada, H.F.; Chaudhry, R.M.; Velazquez-Ramirez, G.A.; Donohue, J.H.; Kooby, D.A.; Nagorney, D.M.; Adsay, N.V.; Sarmiento, J.M. Tumor characteristics and survival analysis of incidental versus suspected gallbladder carcinoma. J. Gastrointest. Surg. 2012, 16, 1311–1317. [Google Scholar] [CrossRef] [PubMed]
  34. Mitrovic, F.; Krdzalic, G.; Musanovic, N.; Osmic, H. Incidental gallbladder carcinoma in regional clinical centre. Acta Chir. Iugosl. 2010, 57, 95–97. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Mori, T.; Souda, S.; Hashimoto, J.; Yoshikawa, Y.; Ohshima, M. Unsuspected gallbladder cancer diagnosed by laparoscopic cholecystectomy: A clinicopathological study. Surg. Today 1997, 27, 710–713. [Google Scholar] [CrossRef]
  36. Nitta, T.; Kataoka, J.; Ohta, M.; Fujii, K.; Takashima, Y.; Inoue, Y.; Ishibashi, T. Surgical strategy for suspected early gallbladder carcinoma including incidental gallbladder carcinoma diagnosed during or after cholecystectomy. Ann. Med. Surg. 2018, 33, 56–59. [Google Scholar] [CrossRef]
  37. Panebianco, A.; Volpi, A.; Lozito, C.; Prestera, A.; Ialongo, P.; Palasciano, N.A.M. Incidental gallbladder carcinoma: Our experience. G. Chir. J. Surg. 2013, 34, 167–169. [Google Scholar] [CrossRef] [Green Version]
  38. Patel, K.; Dajani, K.; Iype, S.; Chatzizacharias, N.A.; Vickramarajah, S.; Singh, P.; Davies, S.; Brais, R.; Liau, S.S.; Harper, S.; et al. Incidental non-benign gallbladder histopathology after cholecystectomy in an United Kingdom population: Need for routine histological analysis? World J. Gastrointest. Surg. 2016, 8, 685–692. [Google Scholar] [CrossRef]
  39. Pitt, S.C.; Jin, L.X.; Hall, B.L.; Strasberg, S.M.; Pitt, H.A. Incidental Gallbladder Cancer at Cholecystectomy. Ann. Surg. 2014, 260, 128–133. [Google Scholar] [CrossRef]
  40. Sarli, L.; Contini, S.; Sansebastiano, G.; Gobbi, S.; Costi, R.; Roncoroni, L. Does laparoscopic cholecystectomy worsen the prognosis of unsuspected gallbladder cancer? Arch. Surg. 2000, 135, 1340–1344. [Google Scholar] [CrossRef] [Green Version]
  41. Shimizu, T.; Arima, Y.; Yokomuro, S.; Yoshida, H.; Mamada, Y.; Nomura, T.; Taniai, N.; Aimoto, T.; Nakamura, Y.; Mizuguchi, Y.; et al. Incidental gallbladder cancer diagnosed during and after laparoscopic cholecystectomy. J. Nippon. Med. Sch. 2006, 73, 136–140. [Google Scholar] [CrossRef]
  42. Solaini, L.; Sharma, A.; Watt, J.; Iosifidou, S.; Aleong, J.-A.C.; Kocher, H. Predictive factors for incidental gallbladder dysplasia and carcinoma. J. Surg. Res. 2014, 189, 17–21. [Google Scholar] [CrossRef]
  43. Talreja, V.; Ali, A.; Khawaja, R.; Rani, K.; Samnani, S.S.; Farid, F.N. Surgically Resected Gall Bladder: Is Histopathology Needed for All? Surg. Res. Pract. 2016, 2016, 9319147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Tantia, O.; Jain, M.; Khanna, S.; Sen, B. Incidental carcinoma gall bladder during laparoscopic cholecystectomy for symptomatic gall stone disease. Surg. Endosc. 2008, 23, 2041–2046. [Google Scholar] [CrossRef] [PubMed]
  45. Tatli, F.; Ozgönül, O.; Yucel, Y.; Yalcin, H.C.; Ciftci, R.; Gümer, M.; Erkmen, F.; Altuntas, R.; Uzunkoy, C. Incidental gallbladder cancer at cholecystectomy. Ann. Ital. Chir. 2017, 6, 399–402. [Google Scholar]
  46. Tian, Y.-H.; Ji, X.; Liu, B.; Yang, G.-Y.; Meng, X.-F.; Xia, H.-T.; Wang, J.; Huang, Z.; Dong, J.-H. Surgical Treatment of Incidental Gallbladder Cancer Discovered During or Following Laparoscopic Cholecystectomy. World J. Surg. 2014, 39, 746–752. [Google Scholar] [CrossRef] [PubMed]
  47. Utsumi, M.; Aoki, H.; Kunitomo, T.; Mushiake, Y.; Yasuhara, I.; Arata, T.; Katsuda, K.; Tanakaya, K.; Takeuchi, H. Evaluation of surgical treatment for incidental gallbladder carcinoma diagnosed during or after laparoscopic cholecystectomy: Single center results. BMC Res. Notes 2017, 10, 56. [Google Scholar] [CrossRef] [Green Version]
  48. Vega, E.A.; Vinuela, E.; Sanhueza, M.; Mege, R.; Caracci, M.; Diaz, C.; Diaz, A.; Okuno, M.; Joechle, K.; Goumard, C.; et al. Positive cystic duct margin at index cholecystectomy in incidental gallbladder cancer is an important negative prognosticator. Eur. J. Surg. Oncol. (EJSO) 2019, 45, 1061–1068. [Google Scholar] [CrossRef]
  49. Xu, X.; Liu, W.; Li, B.; Hong, T.; Zheng, C.-J.; Wang, C.; Zhao, Y. Unsuspected Gallbladder Cancer During or After Laparoscopic Cholecystectomy. Chin. Med. Sci. J. 2013, 28, 102–106. [Google Scholar] [CrossRef]
  50. Yamamoto, H.; Hayakawa, N.; Kitagawa, Y.; Katohno, Y.; Sasaya, T.; Takara, D.; Nagino, M.; Nimura, Y. Unsuspected gallbladder carcinoma after laparoscopic cholecystectomy. J. Hepato Biliary Pancreat. Surg. 2005, 12, 391–398. [Google Scholar] [CrossRef]
  51. Yi, X.; Long, X.; Zai, H.; Xiao, D.; Li, W.; Li, Y. Unsuspected gallbladder carcinoma discovered during or after cholecystectomy: Focus on appropriate radical re-resection according to the T-stage. Clin. Transl. Oncol. 2013, 15, 652–658. [Google Scholar] [CrossRef]
  52. Zhang, W.; Xu, G.-F.; Tian, Z.-Q.; Wu, G.-Z.; Wang, H.; Guan, W.-X. Surgical approach does not influence the outcome of incidental gallbladder carcinoma. Int. J. Clin. Exp. Med. 2015, 8, 869–875. [Google Scholar] [PubMed]
  53. Zhu, J.-Q.; Han, D.-D.; Li, X.-L.; Kou, J.-T.; Fan, H.; He, Q. Predictors of incidental gallbladder cancer in elderly patients. Hepatobiliary Pancreat. Dis. Int. 2015, 14, 96–100. [Google Scholar] [CrossRef]
  54. Shih, S.P.; Schulick, R.D.; Cameron, J.L.; Lillemoe, K.D.; Pitt, H.A.; Choti, M.A.; Campbell, K.A.; Yeo, C.J.; Talamini, M.A. Gallbladder Cancer: The Role of Laparoscopy and Radical Resection. Ann. Surg. 2007, 245, 893–901. [Google Scholar] [CrossRef] [PubMed]
  55. Jemal, A.; Siegel, R.; Ward, E.; Murray, T.; Xu, J.; Smigal, C.; Thun, M.J. Cancer statistics, 2006. CA. Cancer J. Clin. 2006, 56, 106–130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Alves, K.R.; Goulart, A.C.; Ladeira, R.M.; de Oliveira, I.R.S.; Benseñor, I.M. Frequency of Cholecystectomy and Associated Sociodemographic and Clinical Risk Factors in the ELSA-Brasil Study. Sao Paulo Med. J. 2016, 134, 240–250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Stinton, L.M.; Shaffer, E.A. Epidemiology of Gallbladder Disease: Cholelithiasis and Cancer. Gut Liver. 2012, 6, 172–187. [Google Scholar] [CrossRef] [Green Version]
  58. Yusuf, S.; Peto, R.; Lewis, J.; Collins, R.; Sleight, P. Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog. Cardiovasc. Dis. 1985, 27, 335–371. [Google Scholar] [CrossRef]
  59. Choi, K.S.; Choi, S.B.; Park, P.; Kim, W.B.; Choi, S.Y. Clinical characteristics of incidental or unsuspected gallbladder cancers diagnosed during or after cholecystectomy: A systematic review and meta-analysis. World J. Gastroenterol. 2015, 21, 1315–1323. [Google Scholar] [CrossRef] [Green Version]
  60. Goetze, T.; Paolucci, V. Does laparoscopy worsen the prognosis for incidental gallbladder cancer? Surg. Endosc. 2005, 20, 286–293. [Google Scholar] [CrossRef]
Jcm 09 01484 g001 550
Figure 1. Flow chart of the study search and selection methods.
Figure 1. Flow chart of the study search and selection methods.
Jcm 09 01484 g001
Jcm 09 01484 g002 550
Figure 2. Forest plots for the differences of the survival rates between incidental gallbladder cancer (IGBC) and non-IGBC. (A) Overall survival and (B) disease-free survival.
Figure 2. Forest plots for the differences of the survival rates between incidental gallbladder cancer (IGBC) and non-IGBC. (A) Overall survival and (B) disease-free survival.
Jcm 09 01484 g002
Table
Table 1. Main characteristics of the eligible studies.
Table 1. Main characteristics of the eligible studies.
First Author, YearLocationStudy YearUsing
Registry		Initial
Surgery		No of PatientsTumor Stage
TotalIGBCTxTisT1T2T3T4
Ahn 2016Korea1998−2014 ND462973
Aoki 2002Japan1990−1999 LC99011 5 6
Apodaca-Rueda 2017Brazil2010−2015 ND89313
Basak 2016Turkey2009−2013 LC/Open17474 31
Braghetto 1999Chile1992−1998 LC650015 456
Cavallaro 2012Italy1998−2008 LC14809 144
Chan 2003Taiwan1992−2000 LC182511 3431
Charfi 2018Tunisia2003−2016 LC/Open20,584155 18683633
Choi 2009Korea2002−2007 LC314533 12174
Cziupka 2012Germany2001−2009 NDND12 3531
D’Hondt 2013Belgium1998−2008 LC/OpenND45
Dorobisz 2016Poland1990−2014 LC/Open731464
Duzkoylu 2015Turkey2005−2013 LC869815 3253
Ferrarese 2013Italy2008−2012 LC5087 52
Firat 2019Turkey2015−2017 LC/Open11127 133
Genc 2011Turkey1999−2010 LC51645 1112
Geramizadeh 2018Iran2010−2016 LC/Open487218 108
Glauser 2011SwitzerlandNDYesLC/Open30,96069 21434145
Goussous 2018USA2000−2013 LC/Open579626
Gulwani 2015India2001−2013 LC292623 5144
Horkoff 2019Canada2001−2015YesLC/Open11,4951129
Ioannidis 2013Greece1992−2001 LC/Open153614 563
Jha2018India2014−2016 LC/Open480020 182
Kalita 2013India2009−2012 LC/Open410718 1710
Kim 2010 Korea1997−2008 LC/Open260726 16172
Koppatz 2018Finland2010−2012 LC/Open203410
Kwon 1997Korea1990−1996 ND52710 532
Kwon 2008Japan1992−2004 LC179338 20171
Lundgren 2018Sweden2007−2014YesLC/Open36,010213231441725112
Martins-Filho 2015Brazil2007−2010 LC/Open201810
Mazer 2012USA1984−2008 NDND443
Mitrovic 2010Bosnia et al.ND LC/Open300721
Mori 1997Japan1991−1995 LC45613 931
Nitta 2018Japan2009−2017 LC/Open5298 2132
Panebianco 2013Italy2003−2011 LC11886 123
Patel 2016UK2008−2013 LC/Open40277 1222
Pitt 2014USA2005−2009YesLC/Open91,260170
Sarli 2000Italy1992−1999 LC/Open230020 1649
Shimizu 2006Japan1991−2004 LC119510 451
Solaini 2014UK2005−2012 LC/Open8647
Talreja 2016Pakistan2005−2015 LC96411 146
Tantia 2009India2004−2007 LC320519 883
Tatli 2017Italy2013−2016 LC/Open3417 34
Tian 2015China2002−2012 LC758269 22161318
Utsumi 2017Japan2008−2015 LC3528 341
Vega 2019USA1999−2016 NDND11
Xu 2013China1993−2011 LC800536 16119
Yamamoto 2005Japan1991−2003 LC16639 135
Yi 2013China1992−2009 LC/Open1407338 144137
Zhang 2015China1999−2007 LC1157428 49852
Zhu 2015China2000−2010 LC401429 11144
No, number; IGBC, incidental gallbladder cancer; Tis, in situ; ND, no description; LC, laparoscopic cholecystectomy.
Table
Table 2. The estimated rates of incidental gallbladder cancer after cholecystectomy.
Table 2. The estimated rates of incidental gallbladder cancer after cholecystectomy.
SubgroupNumber of SubsetsFixed Effect
[95% CI]		Heterogeneity Test (p-Value)Random Effect [95% CI]Egger’s Test
(p-Value)
Overall470.005 [0.005, 0.005]<0.0010.006 [0.005, 0.008]0.070
Laparoscopic210.007 [0.007, 0.008]<0.0010.007 [0.005, 0.009]0.517
Using registry40.003 [0.002, 0.003]<0.0010.002 [0.001, 0.005]0.499
Individual430.007 [0.007, 0.008]<0.0010.007 [0.006, 0.008]0.294
Included 1990’s190.007 [0.006, 0.007]<0.0010.007 [0.004, 0.010]0.972
Included 2000’s210.004 [0.004, 0.004]<0.0010.006 [0.004, 0.008]0.253
after 2010 year60.006 [0.005, 0.008]<0.0010.007 [0.004, 0.012]0.198
CI, Confidence interval.
Table
Table 3. Comparisons of age and female ratio between incidental and non-incidental gallbladder cancers.
Table 3. Comparisons of age and female ratio between incidental and non-incidental gallbladder cancers.
SubgroupNumber of SubsetsFixed Effect [95% CI]Heterogeneity Test (p-Value)Random Effect [95% CI]Egger’s Test (p-Value)
Age
IGBC4170.239 [69.945, 70.534]<0.00165.291 [63.867, 66.715]<0.001
Laparoscopic1969.234 [68.703, 69.765]<0.00164.179 [61.280, 67.077]<0.001
Using registry371.613 [71.208, 72.017]0.08371.149 [69.890, 72.408]0.524
Individual3868.695 [68.265, 69.124]<0.00164.629 [62.801, 66.458]<0.001
Overall1749.797 [49.770, 49.824]<0.00152.023 [49.208, 54.839]0.199
Laparoscopic448.289 [48.048, 48.529]<0.00149.014 [43.925, 54.103]0.938
Individual1749.797 [49.770, 49.824]<0.00152.023 [49.208, 54.839]0.199
Female ratio
IGBC410.695 [0.668, 0.721]0.1130.694 [0.660, 0.727]0.980
Laparoscopic190.658 [0.607, 0.705]0.6710.658 [0.607, 0.705]0.333
Using registry30.735 [0.691, 0.775]0.0010.761 [0.628, 0.857]0.588
Individual380.673 [0.638, 0.706]0.7440.673 [0.638, 0.706]0.147
Overall230.683 [0.681, 0.685]<0.0010.689 [0.659, 0.717]0.891
Laparoscopic60.661 [0.652, 0.669]<0.0010.635 [0.584, 0.683]0.187
Individual230.683 [0.681, 0.685]<0.0010.689 [0.659, 0.717]0.891
CI, Confidence interval; IGBC, incidental gallbladder cancer.
Table
Table 4. The estimated rates of tumor stages of incidental gallbladder cancer after cholecystectomy.
Table 4. The estimated rates of tumor stages of incidental gallbladder cancer after cholecystectomy.
SubgroupNumber of SubsetsFixed Effect [95% CI]Heterogeneity Test (p-Value)Random Effect [95% CI]Egger’s Test (p-Value)
Tumor stage
pTis170.125 [0.094, 0.163]0.0020.130 [0.079, 0.206]0.853
pT1340.300 [0.270, 0.331]<0.0010.341 [0.283, 0.403]0.022
pT2370.395 [0.364, 0.426]0.0010.397 [0.348, 0.448]0.957
pT3270.230 [0.203, 0.260]0.2530.227 [0.195, 0.264]0.311
pT480.156 [0.126, 0.191]<0.0010.125 [0.073, 0.206]0.255
CI, Confidence interval.

Share and Cite

MDPI and ACS Style

Pyo, J.-S.; Son, B.K.; Lee, H.Y.; Oh, I.W.; Chung, K.H. Incidental Carcinoma after Cholecystectomy for Benign Disease of the Gallbladder: A Meta-Analysis. J. Clin. Med. 2020, 9, 1484. https://doi.org/10.3390/jcm9051484

AMA Style

Pyo J-S, Son BK, Lee HY, Oh IW, Chung KH. Incidental Carcinoma after Cholecystectomy for Benign Disease of the Gallbladder: A Meta-Analysis. Journal of Clinical Medicine. 2020; 9(5):1484. https://doi.org/10.3390/jcm9051484

Chicago/Turabian Style

Pyo, Jung-Soo, Byoung Kwan Son, Hyo Young Lee, Il Whan Oh, and Kwang Hyun Chung. 2020. "Incidental Carcinoma after Cholecystectomy for Benign Disease of the Gallbladder: A Meta-Analysis" Journal of Clinical Medicine 9, no. 5: 1484. https://doi.org/10.3390/jcm9051484

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop