Audit of Management of Gallbladder Cancer in a ...

Audit of Management of Gallbladder Cancer in a Nigerian Tertiary Health Facility O. I. Alatise, O. O. Lawal, A. O. Adisa, O. A. Arowolo, O. O. Ayoola, E. A. Agbakwuru, A. R. K. Adesunkanmi, G. O. OmoniyiEsan, et al. Journal of Gastrointestinal Cancer ISSN 1941-6628 Volume 43 Number 3 J Gastrointest Canc (2012) 43:472-480 DOI 10.1007/s12029-011-9335-4

1 23

Your article is protected by copyright and all rights are held exclusively by Springer Science+Business Media, LLC. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your work, please use the accepted author’s version for posting to your own website or your institution’s repository. You may further deposit the accepted author’s version on a funder’s repository at a funder’s request, provided it is not made publicly available until 12 months after publication.

1 23

Author's personal copy J Gastrointest Canc (2012) 43:472–480 DOI 10.1007/s12029-011-9335-4

ORIGINAL RESEARCH

Audit of Management of Gallbladder Cancer in a Nigerian Tertiary Health Facility O. I. Alatise & O. O. Lawal & A. O. Adisa & O. A. Arowolo & O. O. Ayoola & E. A. Agbakwuru & A. R. K. Adesunkanmi & G. O. Omoniyi-Esan & O. O. Olaofe

Published online: 26 October 2011 # Springer Science+Business Media, LLC 2011

Abstract Background Gallbladder cancer is a rare malignancy with a variable incidence worldwide. It ranks number eight among all gastrointestinal cancer seen in Nigeria. It is associated with high mortality and morbidity because it is usually diagnosed very late. Adequate surgical resection is the only modality with hope of cure. This requires advanced surgical skills which is quite rare in most developing countries like Nigeria. In this current work, we audit the management and outcome of gallbladder cancer in our hospital, highlighting peculiarity associated with our setting. Patients and Method Consecutive patients managed as cases of gallbladder cancer at Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria between January 1990 and December 2010 were studied retrospectively. Patient O. I. Alatise : O. O. Lawal : A. O. Adisa : O. A. Arowolo : E. A. Agbakwuru : A. R. K. Adesunkanmi Department of Surgery, College of Health Science, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria O. O. Ayoola Department of Radiology, College of Health Science, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria G. O. Omoniyi-Esan : O. O. Olaofe Department of Morbid Anatomy, College of Health Science, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria O. I. Alatise (*) Department of Surgery, Obafemi Awolowo University Teaching Hospitals Complex, PMB 5538, Ile-Ife, Osun State, Nigeria e-mail: [email protected] O. I. Alatise e-mail: [email protected]

demographics, disease and treatment-related variables, and outcomes were analyzed by SPSS version 16.0. Results Thirty-one cases of gallbladder cancer were diagnosed over the 21-year period, and this accounts for about 0.3% of all cancer cases seen in our hospital. The median age of this patient cohort was 58 years (range 28 to 79 years). Seventeen (54.8%) patients were age below 60 while 14 (45.2%) were age 60 and above. Twenty-seven patients (87.1%) were female and four (12.9%) were male, with a male to female ratio approximately 1:7. Over 80% of the patients presented with a triad of upper abdominal pain, weight loss, and jaundice. Majority (67.7%) of the patients were diagnosed intraoperatively. Only four patients underwent complete resection as they had radical cholecystectomy including regional lymph node dissection and wedge resection of the gallbladder fossa of the liver. The stages of the resected patients were T3 in three patients and T2 in one. Overall 1- and 5-year survival rates for our entire patient cohort were 32% and 10%, respectively. Conclusion In conclusion, this study showed that preoperative diagnosis of gallbladder cancer could be challenging in our environment. A triad of upper abdominal pain, jaundice, and weight loss with judicious use of available radiological modality will increase the chances of making the preoperative diagnosis of the cancer. It also showed that good outcome can be obtained when radical surgery is offered to these few patients within the limitation of resources in few patients with resectable tumor. Keywords Gallbladder cancer . Nigeria . Outcome

Introduction Gallbladder cancer, first described by Stoll in 1777, is a relatively rare neoplasm and has been considered to be a

Author's personal copy J Gastrointest Canc (2012) 43:472–480

highly lethal disease [1]. It is the most common malignant neoplasm of the biliary tract and the sixth most common gastrointestinal cancer worldwide [2, 3]. The worldwide incidence of the cancer is not known; however, the incidence follows a geographic pattern with considerable variability [4, 5]. This geographic distribution correlates with the prevalence of gallstone disease [1]. The highest incidences are found in India, Asia, Eastern Europe, and South America [2, 5]. In a recent world epidemiology report on gallbladder cancer, the highest mortality rate was seen in Chile, where it accounts for the most common primary cause of cancer death in women [5, 6]. Japan is another country with a relatively high incidence, where gallbladder cancer is responsible for 3.5% of cancer deaths in women and 1.25% in men [7]. By contrast, North America is an area of low incidence, with approximately 10,000 cases diagnosed and an associated 5-year survival of only 15.3% [8]. Nigeria is believed to have similar low incidence of gallbladder cancer [9]. Unfortunately, this conclusion was made from scanty institution-based data. Akute et al. [10] and Chianakwana et al. [11] reported few cases from southwest and southeast of Nigeria, respectively, and found poor outcome of management of the disease. Obonna et al. from Benin also in southeast of Nigeria reported two cases of gallbladder cancer that were associated with gallstone and suggested high index of suspicion of gallbladder cancer in patient of cholelithiasis [12]. Abdulkareem et al. reported that gallbladder cancer rank number eight of all gastrointestinal cancer in Nigeria [13]. Despite great advancement in diagnostic techniques, majority of gallbladder malignancies are diagnosed at advanced stages [14–17]. Late presentation may be due to lack of specific symptoms associated with the early disease, aggressiveness of the tumor, or possibly due to the rich lymphatic supply of the gallbladder which can result in early spread of the disease [18]. Complete resection is the standard of care in patients with localized disease and is potentially curative [2, 4, 17, 18]. Despite this, controversy persists regarding the extent of liver resection and lymph node dissection and the benefit of empiric excision of the common bile duct and/or major hepatectomy, major vascular resection, and resection of adjacent organs [2, 4, 18]. Optimal resection extent is not well defined and tends to differ worldwide. A recent study from Asia showed that more aggressive surgical treatment is not necessarily better, with essentially the same long-term survival compared with less extensive resections [19]; a similar result had been reported by the group from Memorial Sloan Kettering Cancer Center [17]. Due to the limited healthcare resources, gallbladder cancer still poses great challenges to surgeons in subSaharan Africa especially with respect to the ability to

473

successfully diagnose and then treat these patients. In this study, we audited the cases of gallbladder cancer managed at Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria, managed from 1990 to 2010 aimed at describing the center-related uniqueness in the presentation and management outcome.

Patients and Methods This single institution, retrospective, descriptive study was conducted at Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria, which serves as a referral center for the rural and semi-urban agrarian communities in southwestern Nigeria. The medical records of all patients with gallbladder cancer managed during the period spanning from January 1990 through December 2010 were analyzed. Patients were identified using ward and operating theater records and hospital medical record database which uses the International Classification of Disease-9 code for gallbladder cancer (code 156.0). Autopsies, as well as, Ife cancer database records of the hospital were reviewed. Parameters obtained from the medical records included demographic data (patient age and sex), signs and symptoms present at the time of diagnosis, the mode of diagnosis, the operation performed, and pathologic findings. Curative surgery was performed when there was complete resection of the tumor with no gross residual cancer at the completion of the procedure. Palliative procedure was performed when there was gross residual cancer present at the completion of the operation. Preoperative investigations include blood chemistry, complete blood count, chest X-ray, abdominal ultrasound scan, and computerized tomography (CT) scan. CT scan was done in only six patients due to unavailability and cost of the procedure. Serum tumor marker was not performed in any of these patients due to unavailability. Pathologic parameters analyzed were histologic differentiation, depth of tumor invasion (T), regional lymph node status (N), and overall stage according to the American Joint Committee on Cancer staging system [5]. The socioeconomic status of the patients was calculated using the occupation of the patients and the next of kin. Patient survival data were obtained by calling or visiting the resident of the patients, as well as their next of kin when the information were lacking in patients records. Survival duration was calculated from the time of operation or time of diagnosis for patients who did not undergo any surgery, through the time of death. The survival curves for selected patient groups were determined using the method of Kaplan and Meier. Survival durations for these groups were derived from the corresponding Kaplan–Meier curves, and comparison of the groups was

Author's personal copy 474

done using the log-rank test. Potential prognostic factors were evaluated using Cox univariate analyses. Statistical analysis was performed with SPSS 16.0 software. Significance was taken when the P value was less than 0.05.

Results Patients During the study period, 31 patients with gallbladder cancer were admitted to our hospital. This accounts for 0.3% of cancer cases seen in the hospital. The median age of this patient cohort was 58 years (range 28 to 79 years). Seventeen (54.8%) patients were age below 60 years of age while 14 (45.2%) were age 60 and above. Twentyseven (87.1%) patients were female and four (12.9%) were male, with a male to female ratio approximately 1:7. Approximately 80% of our patients had received at least basic education. Most of the patients [23 (74.2%)] were in low socioeconomic class as they were traders, while six (19.4%) and two (6.5%) patients belong to the middle and upper socioeconomic class. Presenting Symptoms and Signs The duration of symptoms ranges from 3 to 36 months (median 6 months). The frequencies with which symptoms and signs were found at the time of diagnosis in study patients are summarized in Table 1. The initial complaints in all the patients were upper abdominal pain and weight loss and jaundice; other main clinical features for all the patients include anorexia, abdominal mass, fever, hepatomegaly, and ascites. Four (14.9%) patients were hypertensive while two (6.5%) patients were diabetic at diagnosis.

J Gastrointest Canc (2012) 43:472–480 Table 1 Clinical characteristics of gallbladder cancer patients at Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria from 1990 to 2010 No. of patients Symptoms and signs Abdominal pain Weight loss Jaundice Anorexia Hepatomegaly Ascites Fever Abdominal mass Comorbidity Hypertension Diabetes Clinical diagnosis Cholecystitis Carcinoma of the head of pancreas Primary liver cell carcinoma Gall bladder cancer Cancer of the stomach How was the diagnosis suspected Surgery Imagine Clinical Autopsy

31 31 25 25 21 9 6 5

(100.0%) (100.0%) (80.6%) (80.6%) (67.7%) (29.0%) (19.4%) (25.8%)

4 (12.9%) 2 (6.5%) 12 (38.7%) 8 (25.8%) 6 (19.4%) 3 (9.7%) 2 (6.5%) 21(67.7%) 5 (16.1%) 3 (9.7%) 2 (6.5%)

patients underwent complete resection as they had radical cholecystectomy including regional lymph node dissection and wedge resection of the gallbladder fossa of the liver. The preoperative diagnosis on these patients who underwent curative surgery included cholelithiasis (two patients) and gallbladder cancer (two patients). No postoperative patho-

Diagnostic and Therapeutic Procedures In most of the patients [28 (90.3%)], the clinical diagnosis of gallbladder cancer was missed. As shown in the Table 1, the clinical diagnosis included cholecystitis, carcinoma of the head of pancreas, primary liver cell carcinoma, and gastric cancer. The suspicion of gallbladder cancer was arrived at during surgery in 21 (66.7%) patients. Only six (19.4%) patients had computerized tomography scan done. Of these, five (83.3%) were suggestive of gallbladder cancer (Figs. 1 and 2). Gallbladder was not visualized on ultrasound scan in 10 (32.3%), thickened gallbladder wall was seen in 12 (38.7%), gallstone in 15 (48.4%), ascites in 9 (29.0%), multiple liver nodules in 5 (16.1%), and liver cirrhosis in 2 (6.5%). Twenty-six (83.9%) patients underwent laparotomy. The procedures performed were shown in Table 2. Only four

Fig. 1 A 62-year-old woman with CT scan showing gallbladder cancer with a thickened gallbladder wall and sludge-filled cavity


475

(15 underwent intraoperative tumor biopsy alone, 7 underwent simple cholecystectomy). One of the patients that had cholecystectomy had bile leak and subsequently died of the complication 3 weeks after surgery. Criteria for doing tumor biopsy included patients with widespread intrabdominal metastasis. Cholecystectomy was offered to patients with locally advanced gallbladder cancer in the absent of skill for hepatic resection. Stage and Pathologic Findings

Fig. 2 A 62-year-old woman with CT scan showing gallbladder cancer with a thickened gallbladder wall, sludge-filled cavity, and intrahepatic biliary dilatation

logical diagnosis was made in our cohort. The remaining 22 patients underwent nontherapeutic or palliative procedures Table 2 The surgery performed and the stage of gallbladder cancer patients at Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria from 1990 to 2010 Surgery performed Biopsy Chloecystectomy Cholecystectomy with hepatectomy Pathologic parametersa Tumor 1 2 3 4 Node 0 1 Grade (differentiation) Well Moderate Poor Positive margin Stagec 1 2 3 4

26 15 (57.7%) 7 (26.9%) 4 (15.4%) No. of patients; total n=11 0 3 4 4

(0) (27.2) (36.4) (36.4)

0 (0)b 11 (100)b

The overall tumor, nodal, and metastasis among study patients’ stage distribution and the pathologic findings for patients who underwent resection are summarized in Table 2. Seventy-seven percent of patients were found to have stage IV disease at the time of diagnosis. The pathologic findings for patients who underwent curative resection are summarized in Table 2. All tumors were adenocarcinomas (Figs. 3 and 4). Seven-three percent of patients were moderately differentiated, and 11% were poorly differentiated. In seven cases (26.9%), microscopic residual cancer at the resection margins was detected. Twenty-seven percent of the cases were T2 tumors, and 100% of specimens contained identifiable lymph nodes. Survival and Prognostic Factors Mean follow-up period was 3 months (range from 1 to 60 months). Overall 1- and 5-year survival rates for our entire patient cohort were 32% and 10%, respectively (Fig. 5). Patients who underwent complete resection had higher 1- and 5-year survival rates (100% and 75%, respectively) than patients who underwent palliative surgery or no surgery (12% and 0%, respectively; P65 years Jaundice at presentation Stage higher than 2

P value

Confidence interval

0.014 0.066 0.285 0.035

0.005–0.551 0.993–1.247 0.028–2.117 1.228–238.229

Discussion Gallbladder cancer is uncommon but not rare in Nigeria. It is the eighth most common gastrointestinal cancers and the most common biliary tract cancer [13]. Experience with managing gallbladder cancer is very scarce in most centers in low income countries like Nigeria due to relatively few cases seen in most centers. In our institution’s 21-year experience with this cancer, gallbladder cancer accounts for 0.3% of cancer cases seen. Abdulkareem et al. reported that gallbladder cancer accounts for 1.1% of the gastrointestinal cancer among their study population [13]. On the other hand, Chianakwana et al. reported that gallbladder cancer accounts for 3.04% of cancer cases seen in the general surgical unit of the hospital. The denominators in these two studies vary and very difficult to compare. Generally, Nigeria, along with Singapore and the USA, is believed to have low incidence of gallbladder cancer (2.5/100,000) [20]. The rare occurrence of gallbladder cancer in Nigeria, the most populous black country, substantiated the finding of twice more common cases of gallbladder cancer among the white compared with the black in USA [14, 20]. The wide geographical, ethnic, and cultural variations in the incidence of gallbladder carcinoma suggest that there are major genetic and environmental influences on the development of the disease, which include diet and lifestyle [20, 22, 23]. Identification and elimination of these factors can lead to the prevention and control of gallbladder carcinoma. In this current study, we found that gallbladder cancer affects women seven times more commonly than men. This finding corroborated female preponderance of gallbladder cancer in previous local and international reports [10–13, 23]. High female occurrence of the cancer has been linked to the internal and external estrogen [21]. Also, we found that over 50% of our cohort was below 60 years of age with the youngest patient being a 28-year-old woman. This finding is in consonance with the reports from Asian countries but contrary to the findings from Europe and America where the median age of occurrence of gallbladder cancer is about 70 years [4, 22–25]. The exact cause of the age disparities is not known; however, epidemiological and molecular biologic studies support the existence of different

pathways of carcinogenesis, as well as the potential for regional pathogenetic differences [4, 26–29]. We found that majority of the patients in this current study are in the low socioeconomic group. While excess intake of fatty diet and obesity may be responsible for the cause of gallbladder cancer in people of high socioeconomic status [21–23], low intake of antioxidant and frequent occurrence of Salmonella Typhi carrier state due to poor hygiene may be responsible for the occurrence of gallbladder cancer in people of low socioeconomic status [21, 30, 31]. The most compelling evidence supporting the role of Salmonella infection in gallbladder cancer comes from a cohort study by Caygill et al. based on a typhoid outbreak in Scotland in 1964 where 507 cases of typhoid or paratyphoid were reported [30]. Patients who became chronic carriers developed a greater than 150-fold increased risk of developing gallbladder cancer. A more recent case– control study in India found that there is greater than an eightfold increased risk of developing gallbladder cancer in culture-positive typhoid carriers when compared with noncarriers [32]. The vague symptoms associated with primary cancer of the gallbladder make the early diagnosis of the disease difficult. Early diagnosis of gallbladder cancer is usually made incidentally following the procedure for acute cholecystitis [33]. In Nigeria, the incidences of gallstone diseases are very few and the few occurrences of these are usually under diagnosed. In our series, we found no incidence of incidental gallbladder cancer. Essentially, our patients present with a triad of upper hypochondriac pain, jaundice, and weight loss. Though this trial may not be specific for gallbladder cancer, a high index of suspicion of gallbladder cancer should be borne in mind when reviewing patients with this trial in a low resource center. Such a high index of suspicion will help make more preoperative diagnosis of gallbladder cancer than what we found in this study where most diagnosis was made intraoperatively. Jaundice was found in over 80% of our patients. Jaundice is a common sign in patients with advanced gallbladder cancer and implies tumor involvement of the porta hepatis. The presence of jaundice was an independent predictor of survival, highly correlated with advanced stage disease [34]. It is believed that tumors that invade the biliary tree suggest tumor with aggressive biology with microscopic and macroscopic spread of the tumor [34]. Recently, however, Agarwal et al. reported that extended surgery involving major resection of the liver in patients with biliary obstruction from gallbladder cancer had favorable 5-year survival rate [35]. Increase preoperative diagnosis of gallbladder cancer can be achieved by judicious and careful use of imaging techniques such as ultrasound scan and computerized tomographic scan. The ultrasound and CT scan finding in

Author's personal copy 478

gallbladder cancer had been previously reviewed in literature [36–38]. Abdominal ultrasound scan is the first procedure of choice for gallbladder cancer and may be the only procedure available in less developed countries due to the cost of the CT scan. In an experienced hand, the sensitivity could be as high as 85% [36, 37]. In the current report, gallbladder was not visualized in 30% of cases. This may be due to the advanced nature of the disease which causes the obliteration of the interface between the gallbladder and the liver. In about 40% of our patients, there were features of gallstones on ultrasound scan. Though the accurate etiology of gallbladder cancer is not known, the most important risk factor for the development of gallbladder cancer is cholelithiasis [20, 23]. Up to 95% of gallbladder cancers are associated with gallstones [38]. In a cohort and case– control study, the relative risk of developing gallbladder cancer in patients with gallstone disease was 8.3 compared to the general population [23, 39]. There also appears to be an association between gallstone size and the risk of developing gallbladder cancer. Patients with gallstones larger than 3 cm have an approximately tenfold higher risk of developing gallbladder cancer [40]. However, gallbladder carcinoma is not thought to be associated with a specific type of gallstones [20]. Surgery is the only potentially curative therapy for gallbladder carcinoma until now. Unfortunately, most patients with this cancer have unresectable disease—only 10–30% of patients can be considered for surgery on presentation in literatures [20]. Our finding corroborated this in the sense that only about 13% of patients underwent curative surgery. The 5-year survival rate for patients who had complete resection with negative margin was 75%. This outstanding finding underscores the fact that every effort must be made to diagnose the disease early and treat it. Surgical procedures offered depend on the stage of the disease. Options include simple cholecystectomy; radical or extended cholecystectomy—involving removal of gallbladder plus at least 2 cm of the gallbladder bed and dissection of lymph nodes from the hepatoduodenal ligament behind the second part of duodenum, head of pancreas, and the coeliac axis; radical cholecystectomy with liver (segmental or lobar) resection; radical cholecystectomy with extensive lymph node (para-aortic) dissection; radical cholecystectomy with resection of bile duct or pancreaticoduodenectomy; and any of the above surgical options in addition to resection of port sites in patients who were initially treated by laparoscopic cholecystectomy [41, 42]. The use of palliative simple cholecystectomy for patients with advanced unresectable disease has been the object of controversy in literature [43, 44]. Some authors believe that it improves survival in such patients [43]. Our finding confirmed this finding as the median survival in patients

J Gastrointest Canc (2012) 43:472–480

who had simple cholecystectomy was 8 months as compared with 4 and 3 months for those who were not operated and those who had explorative laparotomy and biopsy. In fact, it appears that open biopsy reduces the median survival of patients as previously stated by Alfred Blalock in 1924 in which he states, “in malignancy of the gallbladder, when a diagnosis can be made without exploration, no operation should be performed, inasmuch as it only shortens the patient’s life” [45]. We suggest endoscopic, laparoscopic, or percutaneous biopsy in patients with advanced disease. One of the patients who had cholecystectomy had bile leak. Bile leak in such patient is due to involvement of the cystic duct in the tumor. This made it difficult for the suture to hold in such a situation. We suggest that cholecystectomy should be avoided as much as possible in patients with spread of the tumor to the cystic duct. It should be mentioned that involvement of cystic duct in the tumor has been shown to be an independent prognostic factor in gallbladder cancer. This may be due to the high incidence of concomitant perineural invasion and lymph node metastasis associated with cancer spread to the cystic duct [46, 47]. Recent evidence had shown encouraging results with the use of chemotherapy in locally advanced gallbladder cancer. The combination therapy of gemcitabine and ciplastin or gemcitabine and capecitabine had been used to downstage the advanced tumor which can later be resected [48, 49]. Until recently, most of these agents are not available in Nigeria. Though the agents are now available, the cost and lack of supportive therapy will limit the use of the agent for the privileged few. Due to the relatively few number of cases on chemotherapy in the current report, it was difficult to make a reasonable deduction from the use in our cohort. The high incidence of locoregional spread and recurrence in patients with gallbladder cancer makes primary or adjuvant chemotherapy an attractive therapeutic option. Despite the limitation of the study due to its retrospective nature and sample size, this index study confirms that the higher the stage of the disease, the worse the outcome of treatment. All over the world, gallbladder cancer is diagnosed late due to lack of screening modalities to detect the disease early. We suggest that all efforts should be made to identify the high risk group and also to identify the screening modality for the disease. In conclusion, this study showed that preoperative diagnosis of gallbladder cancer could be challenging in our environment. A triad of upper abdominal pain, jaundice, and weight loss with judicious use of available radiological modality will increase the chances of making the preoperative diagnosis of the disease. It also showed that good outcome can be obtained when radical surgery is offered to the patients within the limitation of resources in few patients with resectable tumor.


References 1. Reid KM, Medina AR, Donohue JH. Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg. 2007;11:671–81. 2. Hueman M, Vollmer C, Pawlik T. Evolving treatment strategies for gallbladder cancer. Ann Surg Oncol. 2009;16:2101–15. 3. Cobourn N, Cleary S, Tan J, et al. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg. 2008;207:371–82. 4. Butte JM, Matsuo K, Gönen M, D’Angelica MI, et al. Gallbladder cancer: differences in presentation, surgical treatment, and survival in patients treated at centers in three countries. J Am Coll Surg. 2011;212:50–61. 5. Randi G, Malvezzi M, Levi F, et al. Epidemiology of biliary tract cancers: An update. Ann Oncol. 2009;20:146–59. 6. Andia M, Gederlini A, Ferreccio C. Gallbladder cancer: trend and risk distribution in Chile. Rev Med Chile. 2006;134:565–74. 7. Kayahara M, Nagajawa T. Recent trends of gallbladder cancer in Japan. Cancer. 2007;100:572–80. 8. Mayo CS, Shore AD, Nathan H, Edil B, et al. National trends in the management and survival of surgically managed gallbladder adenocarcinoma over 15 years: a population-based analysis. J Gastrointest Surg. 2010;14:1578–91. 9. Gourgiotis S, Kocher HM, Solaini L, Yarollahi A. Gallbladder cancer. Am J Surg. 2008;196:252–64. 10. Akute OO, Ayantunde AA, Obajimi MO. A review of gall bladder carcinoma in Ibadan. Niger Postgrad Med J. 2003;10(4):228–30. 11. Chianakwana GU, Okafor PI, Anyanwu SN. Carcinoma of the gallbladder at the Nnamdi Azikiwe University Teaching Hospital —a 5-year retrospective study. Niger J Clin Pract. 2005;8(1):10–3. 12. Obonna GC, Njoku T, Okoro E, Osime U. Gallbladder carcinoma not associated with cholelithiasis: report of 2 cases. Niger J Surg Sci. 2007;17:113–5. 13. Abdulkareem FB, Faduyile FA, Daramola AO, Rotimi OA, et al. Malignant gastrointestinal tumours in south western Nigeria: a histopathologic analysis of 713 cases. WAJM. 2009;28(3):173–6. 14. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;118:1591–602. 15. Wistuba I, Gazdar A. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4:695–706. 16. Hsing AW, Bai Y, Andreotti G, et al. Family history of gallstones and the risk of biliary tract cancer and gallstones: a populationbased study in Shanghai, China. Int J Cancer. 2007;121:832–8. 17. D’Angelica M, Moore Dalal K, DeMatteo R, et al. Analysis of the extent of resection for adenocarcinoma of the gallbladder. Ann Surg Oncol. 2009;16:806–16. 18. Reddy S, Marroquin C, Kuo P, et al. Extended hepatic resection for gallbladder cancer. Am J Surg. 2007;194:355–61. 19. Araida T, Higuchi R, Hamano M, et al. Hepatic resection in 485R0 pT2 and pT3 cases of advanced carcinoma of the gallbladder: results of a Japanese Society of Biliary Surgery survey. A multicenter study. J Hepatobiliary Pancreat Surg. 2009;16:204–15. 20. Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol. 2003;4:167–76. 21. Strom BL, Soloway RD, Rios-Dalenz JL, et al. Risk factors for gallbladder cancer: an international collaborative case–control study. Cancer. 1995;76:1747–56. 22. Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba II, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin. 2001;51:349–64. 23. Randi G, Franceschi S, Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;118:1591–602.

479 24. Kiran RP, Pokala N, Dudrick SJ. Incidence pattern and survival for gallbladder cancer over three decades—an analysis of 10301 patients. Ann Surg Oncol. 2006;14(2):827–32. 25. Dutta U, Nagi B, Garg PK, et al. Patients with gallstones develop gallbladder cancer at an earlier age. Eur J Cancer Prev. 2005;14:381–5. 26. Kayahara M, Nagakawa T, Nakagawara H, et al. Prognostic factors for gallbladder cancer in Japan. Ann Surg. 2008;248:807– 14. 27. Goldin RD, Roa JC. Gallbladder cancer: a morphological and molecular update. Histopathology. 2009;55:218–29. 28. Nakayama K, Konno M, Kanzaki A, et al. Allelotype analysis of gallbladder carcinoma associated with anomalous junction of pancreaticobiliary duct. Cancer Lett. 2001;166:135–41. 29. Yokoyama N, Hitomi J, Watanabe H, et al. Mutations of p53 in gallbladder carcinomas in high-incidence areas of Japan and Chile. Cancer Epidemiol Biomarkers Prev. 1998;7:297–301. 30. Caygill CP, Hill MJ, Braddick M, Sharp JC. Cancer mortality in chronic typhoid and paratyphoid carriers. Lancet. 1994;343:83–4. 31. Dutta U, Garg PK, Kumar R, Tandon RK. Typhoid carriers among patients with gallstones are at increased risk for carcinoma of the gallbladder. Am J Gastroenterol. 2000;95:784–7. 32. Shukla VK, Singh H, Pandey M, Upadhyay SK, Nath G. Carcinoma of the gallbladder—is it a sequel of typhoid? Dig Dis Sci. 2000;45:900–3. 33. Lam CM, Yuen AW, Wai AC, et al. Gallbladder cancer presenting with acute cholecystitis: a population-based study. Surg Endosc. 2005;19:697–701. 34. Hawkins WG, DeMatteo RP, MD, Jarnagin WR, Ben-Porat L, MS, Blumgart LH, Fong Y. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol. 11(3):310–5. 35. Agarwal AK, Mandal S, Singh S, Bhojwani R, Sakhuja P, Uppal R. Biliary obstruction in gall bladder cancer is not sine qua non of inoperability. Ann Surg Oncol. 2006;14(10):2831–7. 36. Chijiiwa K, Sumiyoshi K, Nakayama F. Impact of recent advances in hepatobiliary imaging techniques on the preoperative diagnosis of carcinoma of the gallbladder. World J Surg. 1991;15:332–7. 37. Hederstrom E, Forsberg L. Ultrasonography in carcinoma of the gallbladder: diagnostic difficulties and pitfalls. Acta Radiol. 1987;28:715–21. 38. Kumar A, Aggarwal S. Carcinoma of the gallbladder: CT finding in 50 cases. Abdom Imaging. 1994;19:304–8. 39. Serra I, Calvo A, Baez S, Yamamoto M, Endoh K, Aranda W. Risk factors for gallbladder cancer. An international collaborative case control study. Cancer. 1996;78:1515–7. 40. Miller G, Jarnagin WR. Gallbladder carcinoma. EJSO. 2008;34:306e312. 41. Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA. 1983;250:2323–6. 42. Puhalla H, Laengle F. Gallbladder cancer—only surgery is curative. Eur Surg. 2006;38:100–6. 43. Tewari M, Kumar V, Mishra RR, Kumar M, Shukla HS. Is there a role for cholecystectomy in gallbladder carcinoma discovered to be unresectable for cure at laparotomy? World J Surg. 2008;32:2683–7. 44. Xiao WD, Peng CH, Zhou GW, Zhou GW, Wu WD, et al. Surgical treatment for Nevin stage IV and V gallbladder carcinoma: report of 70 cases. Hepatobiliary Pancreat Dis Int. 2005;4:589–92. 45. Blalock A. A statistical study of 888 cases of biliary tract disease. Johns Hopkins Hosp Bull. 1924;35:391–409. 46. Kondo S, Nimura Y, Kamiya J, et al. Mode of tumor spread and surgical strategy in gallbladder carcinoma. Langenbecks Arch Surg. 2002;387:222.

Author's personal copy 480 47. Kaneoka Y, Yamaguchi A, Isogai M, et al. Hepatoduodenal ligament invasion by gallbladder carcinoma: histologic patterns and surgical recommendation. World J Surg. 2003;27:260–5. 48. Iyer RV, Gibbs J, Kuvshinoff B, Fakih M, Kepner J, Soehnlein N, et al. A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: a

J Gastrointest Canc (2012) 43:472–480 single-institution prospective study. Ann Surg Oncol. 2007;14 (11):3202–9. 49. Malik IA, Aziz Z, Zaidi SH, Sethuraman G. Gemcitabine and cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. Am J Clin Oncol. 2003;26(2):174–7.