João Pedro P. O. Araújo Teixeira, Faculty of Medicine, University of Porto / CHUSJ, Department of Surgery - Porto, Portugal. Email: firstname.lastname@example.org, Mobile: 917776058.
Graduate Assistant of Surgery at CHUSJ.
Senior Graduate Assistant of Surgery at CHUSJ.
Citation: Joao Pedro P. O. Araújo Teixeira, Vítor Devesa, Carlos Ribeiro (2019) Gallbladder Cancer (analysis of 55 cases), Jou of Trans Med & Res 1:01-09
Copyrights: © 2019, João Pedro P. O. Araújo Teixeira
Gallbladder cancer (GBC) is the most frequent neoplasm of the biliary tract, appearing essentially in Latin America, unlike in western regions, including Portugal. Its prognosis is poor and the 5-year survival varies between 16% to 20%.
Contribute to the characterization of GBC in Portugal through a retrospective analysis of patients with GBC registered at the CHUSJ, in the last 10 years.
Material and Methods
Data from 55 clinical files were reviewed according to the CHUSJ Registry of Tumors from January 2007 to December 2017, regarding the following variables: age, gender, symptomatology, risk factors, stage, type of surgery, morbidity and survival.
There was a higher incidence in women (67.3%), the mean age was 67 years and in 60% of the cases were associated to lithiasis. Among the 55 neoplasms analyzed, 12 (21.8%) were considered unresectable.
On the 43 patients operated, the performed surgery corresponded to 25 laparoscopic cholecystectomies and 18 open cholecystectomies, of which 19 and 10 were associated with bisegmentectomies IV and V, respectively. The diagnosis of GBC was incidental in 29 cases (67.4%). Immediate postoperative morbidity was reported in 4 cases (9.3%) with 3 deaths (7%). The overall survival rate was 36, 43 and 6 months, in all the patients, in the operated and in the unresectable, respectively. Survival after 1, 3 and 5 years after surgery was 60.4%, 34.9% and 18.6%, respectively.
Discussion / Conclusion
Gallbladder cancer is very uncommon in western regions, including Portugal, unlike in Latin American countries such as Chile and Bolivia.
Our results confirm their poor prognosis with a non-negligible incidence of irresectability and low survival in the operated patients. Simple or radical cholecystectomy is the only recommended therapy, with an increasing use of the laparoscopic approach. Its diagnosis was incidental in an appreciable number of cases, and it is recommended to perform early surgery in the gallbladder pathology associated with risk factors.
Keywords: Gallbladder cancer; gallbladder lithiasis; polyps; cholecystectomy.
Gallbladder Cancer, first described by Stoll in 1779  occupies the sixth place among digestive tumors and is the most frequent malignant neoplasm of the biliary tract . It appears with high incidence in the populations of Chile, Bolivia, American Indians of New Mexico, Eastern Europe and Israel [3-6]. It is much less frequent in western regions, namely the USA, UK, Australia, Canada and New Zealand . In the USA, there were 11,740 gallbladder cancers with 3.830 deaths in 2017 . In Portugal, it appears in 1.5 / 100.000 inhabitants . According to the International Agency for Research on Cancer (IARC), the number of new cases in 2018 worldwide was 219.420, corresponding to an incidence of 1.2 per 100.000 population .
The vast majority of the published series only have a number below 100 patients [11-16], with only three multicenter studies with a greater number of cases [17-19]. Interest in this neoplasm led to the particular attention given to it at the 26th IASGO (International Association of Surgeons, Gastroenterologists and Oncologists) Congress in South Korea. 
Among the various risk factors are: cholelithiasis , polyps , porcelain vesicle [23,24], obesity , exposure to heavy metals , genetic factors , infections and biliopancreatic junction anomalies .
The incidence of lithiasis in gallbladder cancer varies from 0.3 to 3% , with the relative risk of its appearance in relation to the normal population of 8.3 . The diameter of the stones, in particular with more than 30 mm, in the elderly over 75 years should be valued.
Regarding polyps, their coexistence was reported in 13% of patients operated on due to gallbladder neoplasia , with special attention to those with a diameter greater than 10 mm, sessile and solitary. Chou , in 1204 polyps, registered malignancy in 13.4%.
The porcelain gallbladder was long considered a risk factor arising in 13%  of gallbladder cancer. However, more recent studies have not confirmed this incidence, occurring in only 2% of cases .
Its diagnosis is not always easy and is often performed incidentally during the histological examination of the specimen of the cholecystectomy.
Surgery is the only possibility of a cure consisting of simple or radical cholecystectomy, enlarged to segments IV and V and lymphadenectomy according to tumor stages . It appears with poor prognosis, being only mentioned in some series 10% of the cases with indication for curative surgery . Their survival at 5 years does not exceed 16% .
The main objective of the study is to contribute towards the characterization of Gallbladder cancer concerning age, gender, symptomatology, imageology, pathology, surgery, morbidity and survival.
Retrospective analysis of 55 patients with histological confirmation of gallbladder cancer over a period of 10 years from January 2007 to December 2017, coded in the CHUSJ Tumor Registry.
Data collection took place in November 2018, after previous consent obtained from the CHUSJ Ethics Committee in October 2018.
The statistical analysis was based on processes of descriptive analysis and comparison of proportions, using the binomial test. Survival analysis was performed using the Kaplan-Meier method. Positive values were considered for p<0.05.
The results were analyzed in 58 cases, excluding 3; 2 because they had previously been operated on the gallbladder in other hospitals and another because there was insufficient information in the clinical process.
Of these 55 individuals, 12 (21.8%) were considered to be unresectable having been diagnosed by biopsy performed during laparotomy, exploratory laparoscopy or percutaneously.
There were 37 females (67.3%) and 18 males (32.7%) (p=0.076). The mean age was 67 years [47-95]. The distribution of age by the various age groups is shown in Figure. 1.
Figure 1 : Distribution of patients by age groups.
Risk factors and diseases are presented in Table 1.
Table 1: Risk factors and coexisting diseases (n=55)
There was a tumor in a patient who had undergone right hemicolectomy 8 months previous because of cancer of the colon.
The following preoperative examinations were performed: echography, in all patients, using either CT alone or with contrast in non-incidental forms; NMR in 22 individuals, associated with cholangiography in 4 of them; angiography in 2; Endoscopic Retrograde Cholangiopancreatography (ERCP) in 3; Transhepatic Percutaneous Cholangiography (PTC) in 5; aspiration biopsy under ultrasound control in 1.
There were 49 adenocarcinomas (90%), 2 neuroendocrine carcinomas (3.6%), 2 poorly differentiated carcinomas (3.6%), 1 carcinosarcoma (1.8%) and 1 carcinoma in signet cells 1.8%).The values of tumor markers were only high in cases of advanced neoplasms and diagnosed non-incidentally.
In relation to the symptomatology, there was the appearance of pain or cramps in the right hypochondrium in 69,1%, jaundice in 34,5% and vomiting in 21,8%.
Of the 55 cases, 12 (21.8%) were considered inoperable or unresectable evidenced by imaging or in the course of laparotomies or exploratory laparoscopies.
Gallbladder cancer was diagnosed incidentally, in 29 cases (67.4%) during the histological examination following cholecystectomies, performed by lithiasis, acute cholecystitis, acute pancreatitis and also by occlusion in the course of cholecysto-enteric fistula with a gallstone ileus.
In the 43 operated patients, surgical management was as follows: 25 (58.1%) initial laparoscopic cholecystectomy, 6 simple and 19 associated with bisegmentectomies IV and V; 18 (41.9%) open cholecystectomies, 8 simple and 10 associated with bisegmentectomies IV and V. (Table 2)
Bisegmentectomies IV and V were performed in a second step and always by open approach; 10 cases were associated with lymphadenectomy and excision of the main bile duct in 2. Three laparoscopic cholecystectomy required conversion.
Table 2: Surgical management and TNM staging (n=43
Tumor staging according to the TNM classification was as follows:
Immediate postoperative morbidity was reported in 7 cases (16.3%, p<0.0001), 3 deaths (7%) (Table 3).
Eight patients underwent an R1 resection (non-curative resection).
Table 3: Major morbidity
The overall survival rate was 36, 43 and 6 months, in all the patients, in the operated and in the unresectable, respectively (Figure. 2).
Survival after 1, 3 and 5 years after surgery was 60.4%, 34.9% and 18.6%, respectively. The relationship between survival and stage is shown in Fig. 3, with higher values in T1 + T2 group than in T3 + T4 group. However, the p value was = 0.432, indicating that there was no statistically significant difference in the survival curve as a function of the two groups of T (T1 + T2 and T3 + T4 ).
It should be noted that of the 8 patients with a survival of 5 years or more, two died 8 and 9 years after the surgical procedure. The occurrence of 2 relapses at the common bile duct and 2 at the gallbladder hepatic bed should be recorded.
Of the 8 R1, seven were dead at the end of one year and the other (with invasion of the cystic stump) remained alive 3 years after the surgery.
In the clinical history of a patient undergoing endocrine carcinoma, it should be noted that there was a death of the father due to gallbladder cancer and an uncle due to cholangiocarcinoma.
Adjuvant chemotherapy was used in 12 cases (28%).
Figure 2: Overall survival of all the patients (n=55), operated (n=43) and unresectable (n=12).
Figure 3: Survival and staging (T1+T2 vs. T3+T4)
The diagnosis of gallbladder cancer is not always easy, thus justifying the small number of publications, including Portugal. Thus, it was only possible to register a multicentric investigation with more than three hundred cases , included in records of ten US surgical centers.
The circumstances that the Hepato-biliary Surgery Unit of the Surgery Department of CHUSJ is a reference center in this pathology allowed a relatively significant series of 55 cases to be collected.
The analysis of the results obtained on these patients allows for several comments.
First of all, 21.8% of the patients were considered unresectable, similar to that which occurred with 33% of the tumors referred in the Clinica Alemana de Chile by Aretxabala . This confirms the high malignancy of these neoplasms and the difficulty of their early diagnosis in time to allow curative resection of the tumor, as reported by Zuh  in 10% of cases.
We verified, according to the generally mentioned predominance of gallbladder cancer in the female sex (67.2%) and over the age of 60 years.
In the analysis of this series, in addition to the presence of lithiasis in 60% of cases, there was association with gallbladder polyps (7.2%), obesity (27%), acute pancreatitis (1.8%) and mainly with acute cholecystitis (34.5%); therefore, this last situation was properly valued by Iago Justo  and Tamura .
Histological examination revealed adenocarcinomas predominantly in 95% of the cases, with two neuroendocrine carcinomas, one carcinoma of the signet cells, two small differentiated carcinomas and one carcinosarcoma.
The diagnosis of these neoplasias was incidental in 51% of the cases corresponding to surgery caused by uncomplicated lithiasis or associated with acute cholecystitis, acute pancreatitis or even the cholecysto-enteric fistula, causing ileo-biliary occlusion. In several published series, the appearance of these tumors in the operative specimens of cholecystectomy has been equally valued. Thus, this fact was reported by Charfi in 155 of 2584 cholecystectomies (0.8%) . In the CHUSJ Surgery Department, during 6035 cholecystectomies performed between 2007 and 2017, there were 29 (0.5%) incidental cancers of the gallbladder.
For the diagnosis of non-incidental cases, the data revealed by the CT scan associated with contrast and NMR, with or without cholangiography, were important. The use of aspiration biopsy, actually previously proposed by Kumar , has also been useful.
The fact that 36 cases belong to stages T2 and T3 (83.7%) justifies the association of bisegmentectomy IV and V in 29 patients (67.4%); the same happens with lymphadenectomy by 9 N1 and 1 N2; the spread of neoplasia to the cystic stump led to the excision of BPV in 2 cases.
The bisegmentectomies were performed by an open procedure and in a second surgical step, with the time elapsed between the first and second intervention as short as possible.
Laparoscopic surgery plays an important role in biliary pathology and its use has recently been advocated not only in acute cholecystitis  but more recently in gallbladder cancer by Aretxabala  and Gumbs . The initial skepticism was caused by the risk of relapses, namely at the level of the "ports" during the extraction of the gallbladder. Currently it is followed with success in several surgical centers including both simple and radical cholecystectomy . At the IASGO meeting in Seoul, there was consensus that the results are the same as those provided by open surgery . However, several contraindications to its use  are referred to as bulky tumors, invasion of the cystic, visceral invasion, previous surgery and acute cholecystitis; the fact that we recorded two relapses at the level of the hepatic vesicular bed justifies the need to involve the resected vesicle in a plastic bag.
This surgery is surrounded at times in great complexity with no negligible morbidity. Thus, there were 18.6% of complications with 7.6% mortality, results similar to the 10% reported in the literature .
It is sometimes difficult to compare the results of survival in the various investigations, since they are not always sufficiently enlightening, including in some series operated and unresectable patients and even curative and residual surgery.
The analysis of the survival of these patients demonstrated quite clearly the poor prognosis of this neoplasia. Thus, an overall average survival of 36 months was recorded, higher in the operated patients (44 months) than in the irresectable ones (6 months). Five or more years after the surgery there were only 8 patients (18.6%) alive, with 4 incidental carcinomas; this incidence is similar to that reported in the literature: 16% , 20%  and 31.6% .
The Chemotherapy, used in 12 cases, was not able to produce significant results according to what is referred in literature .
In conclusion, the high malignancy of these neoplasms and the small percentage of patients alive 5 years after surgery was confirmed. Simple cholecystectomy or associated with IV and V segmentectomies is the only recommended therapy. It is important to mention the need to increase surgery in lithiasis patients with predisposing risk factors for these tumors.
We thank Professor Luís Moreira for the statistical calculations.
Nevin JE, Moran TJ, Kay S, King R (1976) Carcinoma of the gallbladder: staging, treatment, and prognosis. Cancer 37:141-148.
Hundal R, Shaffer EA (2014) Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 6:99-109.
Villanueva L (2016) Cancer of the gallbladder-Chilean statistics. Ecancermedicalscience. 10: 704.
Kanthan R, Senger JL, Ahmed S, Kanthan SC (2015) Gallbladder cancer in the 21st century. J Oncol 15:967-972.
Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A (2017) Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol. 23:3978-3998.
Al Manasra AR, Bani Hani M, Qandeel H, Al Asmar S, Alqudah M et al. (2018) Trends of Gallbladder Cancer in Jordan Over 2 Decades: Where Are We? Clin Med Insights Case Rep 11: 1-5.
Vijayakumar A, Vijayakumar A, Patil V, Mallikarjuna MN, Shivaswamy BS et al. (2012). Early diagnosis of gallbladder carcinoma: an algorithm approach. ISRN Radiol. 18:239-424.
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 67:7-30.
Globocan 2018 (IARC). Estimated age-standardized incidence rates (World).
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA et al. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394-424.
Tatli F, Ozgönül A, Yucel Y, Yalcin HC, Ciftci R, Gümer M et al. (2017) Incidental gallbladder cancer at cholecystectomy. Ann Ital Chir 6:399-402.
Tomimaru Y, Noguchi K, Nagase H, Hamabe A, Hirota M et al.(2016) Clinicopathological Study of Incidental Gallbladder Cancer Diagnosed after Laparoscopic Cholecystectomy. Gan To Kagaku Ryoho. 43:1605-1607.
Castro CM, Santibañez SP, Rivas TC, Cassis NJ (2018) Totally Laparoscopic Radical Resection of Gallbladder Cancer: Technical Aspects and Long-Term Results. World J Surg 42:92-98.
Palanisamy S, Patel N, Sabnis S et al (2016). Laparoscopic radical cholecystectomy for suspected early gall bladder carcinoma: thinking beyond convention. Surg Endosc. 30:42-48.
Justo I, Marcacuzco A, Nutu OA, Manrique A, Calvo J et al (2018). A retrospective analysis of patients with gallbladder cancer, surgical treatment and survival according to tumor stage. Rev Esp Enferm Dig 110:485-492.
Pandey M, Pathak AK, Gautam A, Aryya NC, Shukla VK (2001). Carcinoma of the gallbladder: a retrospective review of 99 cases. Dig Dis Sci 46:1145-1151.
Buettner S, Margonis GA, Kim Y, Gani F, Ethun CG et al (2016). Changing Odds of Survival Over Time among Patients Undergoing Surgical Resection of Gallbladder Carcinoma. Ann Surg Oncol 23:4401-4409.
Charfi S, Gouiaa N, Mnif H, Chtourou L, Tahri N et al (2018). Histopathological findings in cholecystectomies specimens: A single institution study of 20 584 cases. Hepatobiliary Pancreat Dis Int 17:345-348.
Chen C, Geng Z, Shen H, Song H, Zhao Y et al (2016). Long-Term Outcomes and Prognostic Factors in Advanced Gallbladder Cancer: Focus on the Advanced T Stage 15:11.
IASGO (2016) 26th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists (IASGO) Seoul, Korea 16: 8-10.
Lai CH, Lau WY (2008) Gallbladder cancer, a comprehensive review. Surgeon 6:101-110.
Chou SC, Chen SC, Shyr YM, Wang SE (2017) Polypoid lesions of the gallbladder: analysis of 1204 patients with long-term follow-up. Surg Endosc 31:2776-2782.
Stephen AE, Berger DL (2001) Carcinoma in the porcelain gallbladder, A relationship revisited. Surgery 129:699–703.
DesJardins H, Duy L, Scheirey C, Schnelldorfer T (2018) Porcelain Gallbladder Is Observation a Safe Option in Select Populations? J Am Coll Surg 226:1064-1069.
Wolin KY, Carson K, Colditz GA (2010) Obesity and cancer. Oncologist 15:556-565.
Basu S, Singh MK, Singh TB, Bhartiya SK, Singh SP et al. (2013) Heavy and trace metals in carcinoma of the gallbladder. World J Surg 37:2641-2646.
Maurya SK, Tewari M, Mishra RR, Shukla HS (2012) Genetic aberrations in gallbladder cancer. Surg Oncol 21:37-43.
Maringhini A, Moreau JA, Melton LJ (1987) Gallstones, gallbladder cancer, and other gastrointestinal malignancies. An epidemiologic study in Rochester, Minnesota. Ann Intern Med 107:30-35.
Sternby Eilard M, Lundgren L, Cahlin C, Strandell A, Svanberg T et.al (2017) Surgical treatment for gallbladder cancer - a systematic literature review. Scand J Gastroenterol. 52:505-514.
Zhu AX, Hong TS, Hezel AF, Kooby DA (2010) Current management of gallbladder carcinoma. Oncologist 15:168-181.
Löhe F, Meimarakis G, Schauer C, Angele M, Jauch KW et al. (2009) The time of diagnosis impacts surgical management but not the outcome of patients with gallbladder carcinoma. Eur J Med Res 14:345-351.
De Aretxabala X, Oppliger F, Solano N, Rencoret G, Vivanco M et al. (2018) Laparoscopic management of incidental gallbladder cancer. Surg Endosc 32:10.
Tamura T, Yoshikawa T, So S, Maeda T, Wakahara T et al. (2018). Early Surgery for Acute Cholecystitis Complicated with Gallbladder Cancer. Gan To Kagaku Ryoho. 45:112-114.
Kumar R, Srinivasan R, Gupta N, Dey P (2017) Spectrum of gallbladder malignancies on fine-needle aspiration cytology: 5 years retrospective single institutional study with emphasis on uncommon variants. Diagn Cytopathol 45:36-42.
Teixeira JP, Ribeiro C, Pinto A, Goulart A, Maia JC et al. (2011) Surgical management of acute cholecystitis (experience of 249 cases). Hepatogastroenterology 58:281-284.
De Aretxabala X, Leon J, Hepp J, Maluenda F, Roa I (2010) Gallbladder cancer: role of laparoscopy in the management of potentially resectable tumors. Surg Endosc. 24:2192-2196.
Gumbs AA, Hoffman JP (2010) Laparoscopic completion radical cholecystectomy for T2 gallbladder cancer. Surg Endosc 24:3221-3223.
Agarwal AK, Javed A, Kalayarasan R, Sakhuja P (2015) Minimally invasive versus the conventional open surgical approach of a radical cholecystectomy for gallbladder cancer: a retrospective comparative study. HPB (Oxford) 17:536-541.
Di Carlo I, Toro A (2017) Gallbladder cancer: results achieved and future challenges. Future Oncol 13:209-211.
Yoon YS, Han HS, Agarwal A, Belli G, Itano O et al. (2019) Survey Results of the Expert Meeting on Laparoscopic Surgery for Gallbladder Cancer and a Review of Relevant Literature. Dig Surg 36:7-12.
Ueda N, Fujii Y, Miura S, Fujita J, Kaida D, Tomita Y et al (2016) Radical Resection of cT3a Gallbladder Cancer after Neoadjuvant Chemotherapy - A Case Report. Gan To Kagaku Ryoho 43:1597-1599.
(GBC) Gallbladder Cancer
(LC) Laparoscopic Cholecystectomy
(OC) Open Cholecystectomy
(CHUSJ) Centro Hospitalar e Universitária de São João