The author outlines his philosophy and practice of management of gall bladder cancer based on his more than three-decade experience at a large tertiary level super-specialty referral hospital attached to a university-status teaching institution at Lucknow in northern India where GBC is very common.

Gallbladder cancer (GBC) is one of the commonest biliary malignancies seen in India, Argentina, and Japan. The disease has dismal outcome as it is detected quite late due to nonspecific symptoms and signs. Early detection is the only way to improve the outcome. There have been several advances in basic as well as clinical research in the hepatobiliary and pancreatic diseases in the West and other developed countries but not enough has been done in GBC. Therefore, it is important and the responsibility of the countries with high burden of GBC to find solutions to the many unanswered questions like etiopathogenesis, early diagnosis, treatment, and prognostication. As India being one of the largest hubs for GBC in the world, it is important to know how the country has progressed on GBC. In this review, we will discuss the outcome of the publications from India highlighting the work and the developments taken place in past several decades both in basic and clinical research.

Gallbladder cancer is a common type of biliary tract tumor. Optimal management for early stage cases typically involves radical excision as the primary treatment modality. Various surgical techniques, including laparoscopic, robotic, and navigational surgery, have demonstrated favorable clinical outcomes in radical gallbladder excision. Unfortunately, most patients are ineligible for surgical intervention because of the advanced stage of the disease upon diagnosis. Consequently, non-surgical interventions, such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy, have become the mainstay of treatment for patients in advanced stages. This review focuses on elucidating various surgical techniques as well as advancements in immunotherapy and targeted therapy in the context of recent advancements in gallbladder cancer research.

Disseminated disease (DD) is often found at (re-)exploration in gallbladder cancer (GBC) patients. We aimed to assess the yield of staging laparoscopy (SL) and identify predictors for DD.

This retrospective study included patients from all Dutch academic centres with primary GBC (pGBC) and incidentally diagnosed GBC (iGBC) planned for (re-)resection. The yield of SL was determined. In iGBC, predictive factors for DD were assessed.

In total, 290 patients were included. Of 183 included pGBC patients, 143 underwent laparotomy without SL, and 42 (29%) showed DD perioperatively. SL, conducted in 40 patients, identified DD in eight. DD was found in nine of 32 patients who underwent laparotomy after SL. Of 107 included iGBC patients, 100 underwent laparotomy without SL, and 19 showed DD perioperatively. SL, conducted in seven patients, identified DD in one. Cholecystitis (OR = 4.25; 95% CI 1.51-11.91) and primary R1/R2 resection (OR = 3.94; 95% CI 1.39-11.19) were independent predictive factors for DD.

In pGBC patients, SL may identify DD in up to 20% of patients and should be part of standard management. In iGBC patients, SL is indicated after primary resection for cholecystitis and after initial R1/R2 resection due to the association of these factors with DD.

Managing patients with incidental gallbladder cancer requires stratifying patients risk for recurrence and an appreciation for the recurrence patterns characterizing this malignancy. Although standard management includes reresection to remove sites at risk of harboring residual disease and to achieve negative resection margin status, the decision to perform surgery is tempered by an early and frequent distant recurrence, the most common cause of surgical failure. High-risk patients may benefit from neoadjuvant chemotherapy before reresection. The goal of curative-intent reresection is achieving R0 margin status and optimal staging while limiting morbidity and mortality.

Gallbladder cancer (GBC) is a rare and fatal biliary tract malignancy. Genetic derangements are one of many factors that determine the prognosis of GBC. In this study, the expression of the stratifin (SFN) gene encoding 14-3-3 sigma protein, which is reported to be associated with the metastatic property of cholangiocarcinoma cells, was investigated in GBC.

Formalin-fixed paraffin-embedded cancer (n = 37) and non-cancer control tissues (n = 14) of gallbladders from patients who underwent surgical resection from January 2006 to May 2015 were retrieved. The expression of SFN normalized with that of ACTB was determined using RT-qPCR. Multivariate analysis of factors affecting disease-free survival (DFS) and overall survival (OS) including the type of SFN expression was performed.

The average expression level of SFN in cancer was higher than that in control tissues (p = 0.002). The relative SFN expression in cancer tissue was classified as overexpression (n = 14) and control level expression (n = 23) according to the receiver operating characteristic (ROC) curves for discriminating early GBC recurrence or metastasis after surgery. The SFN overexpression group was associated with lower rates of distant metastasis and early tumor recurrence following resection. The univariate analysis demonstrated factors affecting DFS, including resection margin (p < 0.001), lymphovascular invasion (p = 0.040), perineural invasion (p = 0.046), and SFN expression (p < 0.001). The multivariate analysis revealed that the resection margin (p = 0.019) and SFN expression (P = 0.040) were independent prognostic factors of DFS.

To achieve the longest survival, margin-free resection is recommended. The overexpression of SFN in GBC is associated with better prognosis, lower rates of early cancer recurrence, and distant metastasis following resection. SFN expression might be a novel prognostic biomarker in GBC treatment. Further studies to elucidate the role of SFN might unveil its clinical benefit in cancer treatment regimens.

Accurate preoperative radiological staging of biliary cancers remains difficult. Despite the improvement in imaging techniques, a number of patients with biliary cancers who undergo laparotomy are ultimately found to have unresectable diseases. The goals of staging laparoscopy (SL) are to rule out metastatic and locally advanced unresectable diseases and better define locally advanced unresectable diseases. This study evaluates the efficiency of SL in ruling out unresectable disease in a subset of biliary cancers.

Literature published between January 2000 and December 2015 on the use of SL for patients with biliary cancers was retrieved from five electronic databases. Summary estimates of sensitivity, specificity and diagnostic odds ratio were calculated.

Eight studies were included in the meta-analysis. During the laparoscopy, unresectable disease was found in 316 of 1062 patients (29.8%), of whom 32.4% were patients with suspected hilar cholangiocarcinoma (HC) and 27.6% were patients with suspected gallbladder cancer (GBC). The sensitivities were 0.556 (95% confidence interval (CI): 0.495-0.616) for patients with HC and 0.642 (95% CI: 0.579-0.701) for patients with GBC. The pooled specificity for the SL was 100% (95% CI: 0.993-1.000) for all studies.

This meta-analysis revealed that 32.4% of patients with HC and 27.6% of patients with GBC may avoid unnecessary laparotomy with the use of SL. It is worthwhile to perform SL combined with an intraoperative ultrasound in patients with suspected GBC or HC.

Laparoscopic treatment for gallbladder cancer (GBC) has long been contraindicated, but few studies have demonstrated the oncologic outcomes of this treatment. The purpose of this study was to evaluate long-term survival after intended laparoscopic surgery for early-stage GBC based on our 10 years of experience.

Between May 2004 and April 2014, eighty-three patients suspected of having early-stage GBC with no evidence of liver invasion were enrolled in the prospective protocol for laparoscopic surgery. Data for 45 of these patients with pathologically proven GBC were analyzed to determine the safety and oncologic outcomes of a laparoscopic approach to GBC. Twenty-six patients whose postoperative follow-up exceeded 5 years were investigated to determine the 5-year actual survival outcomes.

Extended cholecystectomy, including laparoscopic lymphadenectomy, was performed in 32 patients and simple cholecystectomy in 13 patients. The T stages based on final pathologic results were Tis (n = 2), T1a (n = 10), T1b (n = 8), and T2 (n = 25). After a median follow-up of 60 months after surgery, recurrence was detected in 4 patients as distant metastases. There was no local recurrence around the gallbladder bed or lymphadenectomy. Disease-specific 5-year survival rate of the 45 patients was 94.2%. Disease-specific actual survival rate of 26 patients whose postoperative follow-up period exceeded 5 years was 92.3% at 5 years.

The favorable long-term oncologic results shown in this study confirm the oncologic safety of laparoscopic cholecystectomy, including laparoscopic lymphadenectomy in selected patients with GBC.

Among biliary tract cancers, gallbladder cancer (GBC) is a potentially lethal malignancy with abysmal long-term survival. Surgery is central to the management of GBC, and presently, provides the only ray of hope for long-term survival. Radical cholecystectomy, which includes cholecystectomy with a limited hepatic resection, regional lymphadenectomy and adjacent organ resection if required is used to encompass the tumor with negative margins - R'0' resection is the standard surgical treatment for the management of GBC. Absence of randomized controlled trials to address various surgical controversies due to rarity of disease in western world, advanced disease at presentation, high frequency of unresectability/inoperability at surgery, deficient neoadjuvant/adjuvant strategies and nihilistic views of oncologists due to aggressive disease biology has resulted in marked heterogeneity in surgical strategies employed to manage GBC across the surgical centers globally.

Radical resection to achieve R0 status remains the only potential curative option in patients with gall bladder cancer (GBC). This study was aimed to evaluate the efficacy of an extended criterion of radical resection to achieve R0 status in GBC.

A triple-phase CT with 3D reconstruction was done in all patients. A standard resectability criterion was followed in all patients. A minimum of liver segment 4B + 5 resection and radical lymphadenectomy including the para-aortic areas were undertaken in all patients. Adjacent organectomy was added as required.

Between November 2008 and April 2011, 59 patients with GBC underwent operation and 40 (resectability, 68 %) underwent resection. The resectional procedures performed were segmentectomy 4B + 5 in 31 (78 %), median sectorectomy in 2 (5 %), extended right hepatectomy in 3 (8 %), and hepatopancreaticoduodenectomy in 4 (10 %) patients. Postoperative complications occurred in 24 (60 %) patients. Two patients died postoperatively. A total of 829 lymph nodes were harvested and the median lymph node count was 18 (4-77). Twenty-three (58 %) patients had lymph node metastases. Twenty-eight of 40 (70 %) had disease limited till N1 nodes. Metastases up to N2 lymph nodes were seen in 12 (30 %). American Joint Committee on Cancer seventh edition stages were I-2 (5 %) patients, II-5 (13 %), III-19 (48 %), and IV-14 (35 %). R0 resection was achieved in 33 (83 %) patients. Four patients had recurrence and one died of recurrence. All other patients are alive till the last follow-up.

Assessment with triple-phase CT with 3D reconstruction can produce high resectability rate in GBC. Extended criterion of radical resection results in R0 status in more than 80 % of patients with GBC.

To evaluate the role of staging laparoscopy (SL) in the management of gallbladder cancer (GBC).

A prospective study of primary GBC patients between May 2006 and December 2011. The SL was performed using an umbilical port with a 30-degree telescope. Early GBC included clinical stage T1/T2. A detectable lesion (DL) was defined as one that could be detected on SL alone, without doing any dissection or using laparoscopic ultrasound (surface liver metastasis and peritoneal deposits). Other metastatic and locally advanced unresectable disease qualified as undetectable lesions (UDL).

Of the 409 primary GBC patients who underwent SL, 95 had disseminated disease [(surface liver metastasis (n = 29) and peritoneal deposits (n = 66)]. The overall yield of SL was 23.2% (95/409). Of the 314 patients who underwent laparotomy, an additional 75 had unresectable disease due to surface liver metastasis (n = 5), deep parenchymal liver metastasis (n = 4), peritoneal deposits (n = 1), nonlocoregional lymph nodes (n = 47), and locally advanced unresectable disease (n = 18), that is, 6-DL and 69-UDL. The accuracy of SL for detecting unresectable disease and DL was 55.9% (95/170) and 94.1% (95/101), respectively. Compared with early GBC, the yield was significantly higher in locally advanced tumors (n = 353) [25.2% (89/353) vs 10.7% (6/56), P = 0.02]. However, the accuracy in detecting unresectable disease and a DL in locally advanced tumors was similar to early GBC [56.0%, (89/159) and 94.1%, (89/95) vs 54.6% (6/11) and 100% (6/6), P = 1.00].

In the present series with an overall resectability rate of 58.4%, SL identified 94.1% of the DLs and thereby obviated a nontherapeutic laparotomy in 55.9% of patients with unresectable disease and 23.2% of overall GBC patients. It had a higher yield in locally advanced tumors than in early-stage tumors; however, the accuracy in detecting unresectable disease and a DL were similar.

Duodenal involvement occurs frequently in gallbladder cancer (GBC) as a result of the proximity of the duodenum to the gallbladder.

The study group included 74 GBC patients assessed between August 2009 and March 2011 in whom computed tomography (CT) of the abdomen indicated suspicion for duodenal involvement.

Of 172 patients with resectable GBC, 74 (43.0%) had suspected duodenal involvement on imaging. Of these, 51 (68.9%) had suspected duodenal involvement on upper gastrointestinal endoscopy (UGIE). Symptoms of gastric outlet obstruction (GOO) were present in only 14 (18.9%) patients. Thirteen (17.6%) patients underwent staging laparoscopy alone. Of the 61 patients who underwent laparotomy, 31 (50.8%) were found to have actual duodenal involvement. The positive predictive value (PPV) of CT of the abdomen for duodenal involvement was 50.8% (31 of 61 patients). The addition of UGIE increased the PPV to 65.9% (27 of 41 patients). In the subgroup with evidence of duodenal mural thickening or mucosal irregularity on CT of the abdomen (n= 9) or duodenal mucosal infiltration on UGIE (n= 14), the PPV increased to 100%. A total of 33 (44.6%) patients underwent curative resection. The resectability rate was significantly lower in patients with symptoms of GOO [two of 14 (14.3%) vs. 31 of 60 (51.7%); P= 0.010], CT findings of duodenal mural thickening or mucosal irregularity compared with only loss of the fat plane [two of 12 (16.7%) vs. 31 of 62 (50.0%); P= 0.032], and UGIE evidence of duodenal infiltration compared with extrinsic compression or normal endoscopic findings [three of 16 (18.8%) vs. 18 of 35 (51.4%) and 12 of 23 (52.2%), respectively; P= 0.027 and P= 0.036, respectively].

Overall, CT of the abdomen demonstrated a PPV of 50.8% in detecting duodenal involvement, which increased to 65.9% with the addition of UGIE. The combined presence of GOO symptoms, CT findings of duodenal mural thickening and mucosal irregularity, and UGIE findings of infiltration of the duodenal mucosa significantly decreases resectability but does not preclude resection.

The role of staging laparoscopy (SL) in patients with incidental gallbladder cancer (IGBC) is ill defined. This study evaluates the utility of SL with the aim of identifying variables associated with disseminated disease (DD).

Consecutive patients with IGBC who underwent re-exploration between 1998 and 2009 were identified from a prospective database. The yield and accuracy of SL were calculated. Demographics, tumour- and treatment-related variables were correlated with findings of DD.

Of the 136 patients submitted to re-exploration for possible definitive resection, 19 (14.0%) had DD. Staging laparoscopy was carried out in 46 (33.8%) patients, of whom 10 (21.8%) had DD (peritoneal disease [n = 6], liver metastases [n = 3], retroperitoneal disease [n = 1]). Disseminated disease was identified by SL in two patients (yield = 4.3%), whereas eight were diagnosed after conversion to laparotomy (accuracy = 20.0%). The likelihood of DD correlated closely with T-stage (T1b, n = 0; T2, n = 5 [7.0%], T3, n = 14 [26.0%]; P = 0.004). A positive margin at initial cholecystectomy (odds ratio [OR] 5.44, 95% confidence interval [CI] 1.51-24.37; P = 0.004) and tumour differentiation (OR 7.64, 95% CI 1.1-NA; P= 0.006) were independent predictors of DD on multivariate analysis.

Disseminated disease is relatively uncommon in patients with IGBC and SL provides a very low yield. However, patients with poorly differentiated, T3 or positive-margin gallbladder tumours are at high risk for DD and targeting these patients may increase the yield of SL.

Gallbladder cancer is the fifth most common cancer involving the gastrointestinal tract, but it is the most common malignant tumour of the biliary tract worldwide. The percentage of patients diagnosed to have gallbladder cancer after simple cholecystectomy for presumed gallbladder stone disease is 0.5-1.5%. This tumour is traditionally regarded as a highly lethal disease with an overall 5-year survival of less than 5%. The marked improvement in the outcome of patients with gallbladder cancer in the last decade is because of the aggressive radical surgical approach that has been adopted, and improvements in surgical techniques and peri-operative care. This article aims to review the current approach to the management of gallbladder cancer.

A Medline, PubMed database search was performed to identify articles published from 1990 to 2007 using the keywords 'carcinoma of gallbladder', 'gallbladder cancer', 'gallbladder neoplasm' and 'cholecystectomy'.

The overall 5-year survival for patients with gallbladder cancer who underwent Ro curative resection was reported to range from 21% to 69%. Laparoscopic cholecystectomy is absolutely contraindicated when gallbladder cancer is known or suspected pre-operatively. Patients with a pre-operative suspicion of gallbladder cancer should undergo open exploration and cholecystectomy after proper pre-operative assessment. For patients whose cancer is an incidental finding on pathological review, a second radical resection is indicated except for Tis and T1a disease. There is still controversy for the optimal management of T1b disease. Although the role of surgery for advanced disease remains controversial, patients with advanced gallbladder cancer can benefit from radical resection, provided a potentially curative Ro resection is possible. There is still no effective adjuvant therapy for gallbladder cancer.

Gallbladder cancer (GBC) is common in northern India. The western world has a pessimistic attitude towards GBC resulting in inadequate management of even early GBC. At the other extreme is the Japanese aggressivism with high mortality but very few actual long-term survivors. The Indian surgeons have adopted a Buddhist "middle path"--aggressive surgical approach for "less advanced" GBC and non-surgical palliative approach for "more advanced" GBC. We rely heavily on staging laparoscopy to detect metastatic deposits on liver, peritoneum and omentum, and upper gastrointestinal endoscopy (UGIE) to detect duodenal infiltration which indicates unresectability as we do not perform pancreatico-duodenectomy for GBC. Our favoured procedure is extended cholecystectomy (EC) which includes a 2 cm nonanatomical wedge of liver in the GB bed and the lymph nodes in hepatoduodenal ligament, behind the duodenum and head of pancreas and along the hepatic artery to the right of celiac axis. EC can achieve R0 resection in patients with T1-T2 and T3 (fundus/body--hepatic bed type) disease. For T3 (neck--hepatic hilum type) and T4 disease major hepatic resection is required. In selected patients with nodally advanced GBC, a non-curative simple cholecystectomy with post-operative chemoradiotherapy may improve survival. GBC is an "Indian disease" and Indian surgeons have to be prepared to accept the "challenge" of GBC.