J Gastrointest Canc DOI 10.1007/s12029-015-9737-9
ORIGINAL RESEARCH
Extra-Hepatic Bile Duct Resection: an Insight in the Management of Gallbladder Cancer Durgatosh Pandey 1,3 & Pankaj Kumar Garg 1,2 & N. M. L. Manjunath 1 & Jyoti Sharma 1
# Springer Science+Business Media New York 2015
Abstract Background Involvement of extrahepatic bile duct in gallbladder cancer (GBC) is considered a sign of advanced disease; resection of extrahepatic bile duct in GBC has been a contentious issue considering the poor prognosis of the disease. Methods This retrospective study was done in two tertiary teaching hospitals of North India. The case records of all the GBC patients who underwent radical cholecystectomy with extra-hepatic bile duct resection were reviewed. Details concerning the clinical presentation, preoperative therapy, operative procedure, indication of bile duct resection, postoperative complications and outcome were retrieved from the case records. Kaplan–Meier analysis was done to estimate median disease-free survival and overall survival. Results There were 17 GBC patients who underwent radical cholecystectomy with resection of extrahepatic bile duct. Median age of the patients was 51 years (range 35–62); male to female ratio was 5:12. Six patients were diagnosed after histopathological examination of resected gallbladder specimen following cholecystectomy (incidental gallbladder cancer). All the patients had R‘0’ resection. The indication for extrahepatic bile duct resection was direct infiltration of
* Durgatosh Pandey [email protected] 1
Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India 110029
2
Department of Surgery, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India 110095
3
Department of Surgical Oncology, Dr BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, Delhi, India 201301
hepatoduodenal ligament in nine, positive cystic duct margin in two, densely adherent pericholedochal lymphnodes in one and associated ampullary growth in one patient. Kaplan– Meier analysis predicted median disease-free survival of 20 months and median overall survival of 26 months. Conclusion Extrahepatic bile duct resection to achieve R‘0’ resection in the management of advanced gallbladder cancer is safe with acceptable postoperative morbidity and has potential to improve survival. Keywords Gallbladder neoplasms . Extrahepatic bile ducts . Biliary tract surgical procedures . Obstructive jaundice . Survival analysis
Introduction Gallbladder cancer (GBC) is a common cancer in northern part of India, with the highest age adjusted incidence rates worldwide reported for women in Delhi (21.5 per 100,000) [1–3]. It is an aggressive malignancy and carries poor long term prognosis [4, 5]. The primary treatment of GBC is complete surgical resection (R‘0’resection) which has been shown to improve survival [6]; role of neoadjuvant and adjuvant therapy is still not clearly defined. Majority of the patients with GBC present at an advanced stage when cure is no longer a reasonable option. Though surgical resection is the only potentially curative modality in early GBC, aggressive surgical resection is often considered a futile exercise in advanced GBC in view of aggressive tumor biology [3]. One of the major controversies in the surgical management of gallbladder cancer is the issue of bile duct resection [7]. Involvement of extrahepatic bile duct (EHBD) has been considered as an ominous sign of the aggressive nature of GBC and an independent predictor of poor survival [8, 9]. In a
J Gastrointest Canc
recently published study, involvement of EHBD was uniformly fatal despite the addition of bile duct resection [10]. On the other hand, a few other studies have demonstrated the beneficial effect of EHBD resection in the management of gallbladder cancer [11, 12]. The present study was conducted to highlight the relevance of resection of EHBD in locally advanced gallbladder cancer.
Bilio-enteric continuity was restored using Roux-en-Y hepaticojejunostomy. Statistical analysis was done using statistical package for social sciences (SPSS, Chicago, Illinois) version 16 for windows. Kaplan–Meier analysis was done to estimate median disease-free survival and overall survival.
Result Materials and Methods This retrospective study included GBC patients who underwent radical cholecystectomy with EHBD resection performed by a single surgeon (DP) between January 2009 and December 2014 in two tertiary teaching hospitals in North India: Institute of Medical Sciences, Banaras Hindu University, Varanasi (January 2009 to April 2012) and All India Institute of Medical Sciences, New Delhi (May 2012 to December 2014). The case records of all these patients were reviewed; details concerning the clinical presentation, preoperative therapy, operative procedure, indication of bile duct resection, postoperative complications and outcome were retrieved. Preoperative Workup Preoperative workup of the patients included abdominal ultrasonography and contrast enhanced computed tomography (CECT). Magnetic resonance imagining (MRI) with magnetic resonance cholangio-pancreaticography (MRCP) was done in jaundiced patients to assess the biliary tree. For patients of GBC who have obstructive jaundice at presentation, neoadjuvant chemotherapy (NACT) was advised. These patients underwent image-guided fine-needle aspiration biopsy (FNAB) for confirmation of diagnosis; biliary drainage was undertaken to optimize them for chemotherapy. However, surgery has been considered upfront in a few jaundiced patients without NACT in whom two attempts at FNAB did not confirm malignancy. Operative Procedure All the patients underwent radical cholecystectomy which entails cholecystectomy with a partial hepatectomy and regional lymphadenectomy to encompass the tumor with negative margins—R‘0’ resection, as per the technique described by first author in a previously published article [13]. Extent of liver resection is guided by the invasion of liver so as to achieve a negative surgical margin while preserving the maximal amount of liver parenchyma. All the patients underwent systematic regional lymphadenectomy which included clearance of pericaval, retropancreatic, superior pancreatico-duodenal, common hepatic, celiac, pericholedochal, retroportal and hilar group of lymphnodes. Aortocaval nodes were sampled.
There were 17 GBC patients who underwent radical cholecystectomy with resection of extrahepatic bile duct. Median age of the patients was 51 years (range 35–62); male to female ratio was 5:12. Six patients were diagnosed after histopathological examination of resected gallbladder specimen following cholecystectomy (incidental gallbladder cancer). Nine patients had jaundice at presentation- three of them underwent percutaneous Trans-hepatic Biliary Drainage (PTBD), two patients had T-tube drainage during previous laparoscopic converted open cholecystectomy, one patient underwent endoscopic biliary drainage, and three patients were operated upfront. Five patients underwent NACT following histologic or cytologic confirmation of diagnosis—four were prescribed gemcitabine and oxaliplatin, while one was advised cisplatin and 5-fluorouracil. Twelve patients were operated upfront. All the patients had R‘0’ resection—11 patient had 2–3-cm nonanatomical wedge resection of gallbladder bed, four had segment 4B+5 resection while two underwent extended right hepatectomy. The indication for extra-hepatic bile duct resection was direct infiltration of hepatoduodenal ligament in thirteen, positive cystic duct margin in two, densely adherent pericholedochal lymphnodes in one, and associated ampullary growth in one patient (he underwent a combined radical cholecystectomy with pancreaticoduodenectomy). Postoperative complications were seen in three patients—one developed viral hepatitis A-related jaundice a month after surgery [14], and two patients had transient bile leak that was successfully managed conservatively. Table 1 displays the perioperative characteristics of the patients. There was no perioperative mortality. The median number of lymph nodes harvested was 12 (IQR range 10–13, minimum 4, maximum 15), out of which the median number of metastatic nodes was 0 (IQR 0–2, minimum 0, maximum 15). Microscopic tumor infiltration of liver was present in 8 (47.0 %) while bile duct invasion was seen in 13 (76.47 %). Eight patients developed recurrence—five patients had multiple liver metastases, two patients had abdominal wall surgical site recurrence, two had malignant ascites and two had nodal recurrence. Seven of these patients succumbed to progressive disease; one patient is on best supportive care. Nine patients are alive and free of disease. Table 2 displays the outcome of patients. Kaplan–Meier analysis predicted
35 51 62 58 55 41
12 13 14 15 16 17
Yes No Yes No Yes No
No Yes
None Lap Cholecystectomy with CBD exploration and T-tube PTBD Lap Cholecystectomy PTBD Lap Cholecystectomy PTBD Open cholecystectomy and T tube Yes No No No Yes No
Segment 4b+5 resection Segment 4b+5 resection Wedge resection Wedge resection Wedge resection Wedge resection
Segment 4b+5 resection Wedge resection
Abbreviations: PTBD percutaneous transhepatic biliary drainage, CBD common bile duct, PD pancreaticoduodenectomy
M F M F F F
F F
No No
50 39
Wedge resection Wedge resection Segment 4b+5 resection Extended right hepatectomy Wedge resection Wedge resection Wedge resection Extended right hepatectomy Wedge resection+PD
10 11
Lap Chole None Open partial cholecystectomy None None ERCP stenting none none None
No No Yes No No yes no yes No
No Yes No No Yes Yes No Yes Yes
60 55 56 48 52 35 46 56 42
1 2 3 4 5 6 7 8 9
F M F F F M F F M
Neoadjuvant Liver chemotherapy resection
Perioperative characteristics of the patients
Sl. Age (years) Gender Jaundice at Prior no. presentation intervention
Table 1
Direct infiltration of bile duct Lymph nodes densely adherent to CBD Direct infiltration of bile duct Cystic duct margin positive Direct infiltration of bile duct Direct infiltration of bile duct
Direct infiltration of bile duct Direct infiltration of bile duct
Cystic duct margin positive Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Associated Ampullary growth
Reason for CBD resection
None None None None None None
None Bile leak
Jaundice due to viral hepatitis None None None None None None None Bile leak
Postoperative complications
J Gastrointest Canc
J Gastrointest Canc Table 2
Postoperative outcome of the patients
Sl. no.
Final diagnosis
Adjuvant therapy
Recurrence
DFS (months)
OS (months)
Status
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
T3N1M0 T2N2M0 T4N0M0 T4N2M0 T2N0M0 T3N0M0 T3N0M0 T3N1M0 T4N0M0 T2N0M0 T3N0M0 T3N2M0 T3N2M0 T3N1M0 T2N0M0 T3N1M0 T2N0M0
None CT CT CT None CT CT CT CT+RT CT+RT None CT+RT CT+RT CT+RT CT CT+RT CT
No Multiple liver mets No Multiple liver, ascites No Multiple liver mets No Scar site recurrence, nodal recurrence, ascites No Liver mets Liver mets Liver mets No No No No No
48 20 28 14 60 2 10 6 24 8 18 8 6 12 18 23 5
50 26 35 18 62 10 12 12 25 13 19 14 8 13 19 28 9
NED Dead NED Dead NED dead NED dead NED dead dead dead disease NED NED NED NED
Abbreviations: DFS disease-free survival, OS overall survival, NED no evidence of disease, CT chemotherapy, RT Radiotherapy
median disease-free survival of 20 months (95 % CI 10.3– 29.6) and median overall survival of 26 months (95 % CI 7.7–44.2) (Fig. 1).
Discussion Resection of EHBD has been a matter of debate in the surgical management of GBC. EHBD resection can be undertaken routinely (in absence of involvement of bile duct) as a part of radical cholecystectomy, or selectively as and when
Fig. 1 Survival curves show a disease-free survival b overall survival
required. A number of reasons have been put forward for routine resection of EHBD in the absence of its direct invasion—it facilitates lymphadenectomy, takes care of perineural invasion, clears occult disease in connective tissue around the bile duct, and precludes the possibility of bile duct stricture which can result in view of jeopardized vascularity following skeletonization of bile duct with radical lymphadenectomy [3, 15, 16]. While some surgeons have recommended routine resection of EHBD in surgery for gallbladder cancer [17–19], this view has not found support in most centers across the world [20–23]. With a standardized surgical
J Gastrointest Canc
technique, we have shown that optimal regional lymphadenectomy can be successfully accomplished without routine resection of the EHBD [13]. Perhaps the most compelling evidence against routine resection of uninvolved EHBD came from a survey conducted by Japanese Society of Biliary Surgery. In this questionnaire based retrospective study of 114 member institutions, Araida et al. [21] reported that there is no preventive value of extrahepatic bile duct resection in advanced gallbladder carcinoma without a direct infiltration of the hepatoduodenal ligament and the cystic duct. They identified 838 patients of GBC (pT2-T4) who had extra hepatic bile duct resection without pancreaticoduodenectomy and there was no hepatoduodenal ligament invasion and no cystic duct involvement. They did not find any difference in the 5-year cumulative survival between the preserved bile duct and the resected bile cut groups (75 vs. 66 %, p value 0.09); moreover, the overall recurrence rate and the local recurrence rate along the hepatoduodenal ligament were also not different in two groups, 21.8 vs. 27.4 % in node negative and 45.1 vs. 53.8 % in node positive group. On the other side, direct involvement of bile duct or presence of jaundice in advanced GBC indicates aggressive nature of tumor where radical resection involving resection of EHBD is often perceived to be futile and of little benefit to the patient. Invasion of bile duct or hepatoduodenal ligament and presence of jaundice have been considered as a poor prognostic feature in gallbladder cancer [24–30]. A few recent publications, however, have challenged this nihilistic view and supported aggressive resection of GBC to achieve R‘0’ resection provided it as achievable and there are no distant metastases. Agrawal et al. [12] published their experience of 14 patients of advanced GBC with biliary obstruction who underwent curative resection and reported an overall median disease-free survival of 26 months; seven patients were alive for more than 2 years. They concluded that presence of jaundice in GBC does not preclude the possibility of curative resection which does result in significant improvement in survival. Nishio et al. [11], in their study of 100 pT3-4 pN0-1 GBC patients who had radical resection with combined extrahepatic bile duct resection, concluded that GBC with EHBD involvement is worthy of resection. The 5-year survival was 54 % and median survival was 15.4 years when pathological invasion of bile duct was absent; more importantly, the 5-year survival was 23 % and median survival was 1.5 years when pathological invasion was present; there were twelve patients who survived for more than 5-years. These two studies of Agrawal et al. and Nishio et al. provided a much needed optimism in the surgical management of advanced GBC. Our current practice of EHBD resection in advanced GBC is confined to: direct invasion of hepatoduodenal ligament/ bile duct, cystic duct margin being positive, densely adherent nodal disease to bile duct, and in a jaundiced patient. The basic premise is the ability to achieve R‘0’ resection and absence of distant
metastasis. Though the role of NACT in GBC patients with jaundice is not well proven, we follow a policy of NACT in these patients to increase the possibility of complete resection; we also believe that NACT allows us to test the biology of the tumor. It cannot be overstressed that there is an urgent need to perform randomized controlled trial to address the issue of NACT in GBC patients. In our study of 17 patients of advanced GBC who had resection of EHBD as a part of radical resection, median disease-free survival of 20 months and median overall survival of 26 months further corroborates to the oncological soundness of the philosophy of EHBD resection in selected patients. Moreover, the associated postoperative morbidity was low in our patients—only two patients developed transient bile leak which could be successfully managed conservatively. There was no postoperative mortality. Though this study is limited by its small sample size, we believe that it bestows an insight in an important surgical issue of EHBD resection in locally advanced GBC. Although there are encouraging reports of hepatopancreaticoduodenectomy for biliary tract cancers from Japan [31–33], the outcome of this procedure in gallbladder cancer has been dismal [34–36]. We routinely do not offer hepato-pancreatoduodenectomy for advanced GBC. One patient in our series underwent EHBD resection as a part of combined radical cholecystectomy and pancreaticoduodenectomy, and is doing well a year after surgery. He had an ampullary cancer synchronous with GBC and this combined resection was performed to address both primary tumors. We believe that the debate between surgical conservatism and heroism should be abandoned in favor of a middle path of surgical pragmatism. While resection of bile duct and adjacent organs in gallbladder cancer may be unnecessary when they are not involved, and often futile when their involvement is associated with other features of advanced disease; there are situations when the only limiting factor to curative resection is the involvement of bile duct. Reluctance of the surgeon to resect the bile duct in such situations may deny the patient of a potential chance of cure. In conclusion, resection of EHBD to achieve R‘0’ resection in the management of advanced GBC can be safely performed with acceptable postoperative morbidity and has potential to improve survival.
Conflict of Interest None to declare.
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Bartlett DL, Fong Y, Fortner JG, et al. Long-term results after resection for gallbladder cancer. Implications for staging and management. Ann Surg. 1996;224:639–46. 21. Araida T, Higuchi R, Hamano M, et al. Should the extrahepatic bile duct be resected or preserved in R0 radical surgery for advanced gallbladder carcinoma? Results of a Japanese Society of Biliary Surgery Survey: a multicenter study. Surg Today. 2009;39:770–9. 22. Wiggers JK, Groot Koerkamp B, Ovadia Z, et al. Patterns of recurrence after resection of gallbladder cancer without routine extrahepatic bile duct resection. HPB (Oxford). 2013. doi:10.1111/hpb. 12188. 23. Choi SB, Han HJ, Kim WB, et al. Surgical strategy for T2 and T3 gallbladder cancer: is extrahepatic bile duct resection always necessary? Langenbecks Arch Surg. 2013;398:1137–44. 24. Yagi H, Shimazu M, Kawachi S, et al. Retrospective analysis of outcome in 63 gallbladder carcinoma patients after radical resection. J Hepatobiliary Pancreat Surg. 2006;13:530–6. 25. Endo I, Shimada H, Fujii Y, et al. Indications for curative resection of advanced gallbladder cancer with hepatoduodenal ligament invasion. J Hepatobiliary Pancreat Surg. 2001;8:505–10. 26. 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. 27. Chan KM, Yeh TS, Yu MC, et al. Gallbladder carcinoma with biliary invasion: clinical analysis of the differences from nonbiliary invasion. World J Surg. 2005;29:72–5. 28. Shukla PJ, Neve R, Barreto SG, et al. A new scoring system for gallbladder cancer (aiding treatment algorithm): an analysis of 335 patients. Ann Surg Oncol. 2008;15:3132–7. 29. Kokudo N, Makuuchi M, Natori T, et al. Strategies for surgical treatment of gallbladder carcinoma based on information available before resection. Arch Surg. 2003;138:741–50. 30. Hawkins WG, DeMatteo RP, Jarnagin WR, et al. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol. 2004;11:310–5. 31. Nimura Y. Radical surgery: vascular and pancreatic resection for cholangiocarcinoma. HPB (Oxford). 2008;10:183–5. 32. Ebata T, Yokoyama Y, Igami T, et al. Hepatopancreatoduodenectomy for cholangiocarcinoma: a single center review of 85 consecutive patients. Ann Surg. 2012;256:297–305. 33. Sasaki R, Takahashi M, Funato O, et al. Hepatopancreatoduodenectomy with wide lymph node dissection for locally advanced carcinoma of the gallbladder: long term results. Hepatogastroenterology. 2002;49:912–5. 34. Sakamoto Y, Nara S, Kishi Y, et al. Is extended hemihepatectomy plus pancreaticoduodenectomy justified for advanced bile duct cancer and gallbladder cancer? Surgery. 2013;153:794–800. 3 5 . L i m C S , J a n g J Y, L e e S E , e t a l . R e a p p r a i s a l o f hepatopancreatoduodenectomy as a treatment modality for bile duct and gallbladder cancer. J Gastrointest Surg. 2012;16:1012–8. 3 6 . K a n e o k a Y, Ya m a g u c h i A , I s o g a i M , e t a l . Hepatopancreatoduodenectomy: its suitability for bile duct cancer versus gallbladder cancer. J Hepatobiliary Pancreat Surg. 2007;14:142–8.
ORIGINAL RESEARCH
Extra-Hepatic Bile Duct Resection: an Insight in the Management of Gallbladder Cancer Durgatosh Pandey 1,3 & Pankaj Kumar Garg 1,2 & N. M. L. Manjunath 1 & Jyoti Sharma 1
# Springer Science+Business Media New York 2015
Abstract Background Involvement of extrahepatic bile duct in gallbladder cancer (GBC) is considered a sign of advanced disease; resection of extrahepatic bile duct in GBC has been a contentious issue considering the poor prognosis of the disease. Methods This retrospective study was done in two tertiary teaching hospitals of North India. The case records of all the GBC patients who underwent radical cholecystectomy with extra-hepatic bile duct resection were reviewed. Details concerning the clinical presentation, preoperative therapy, operative procedure, indication of bile duct resection, postoperative complications and outcome were retrieved from the case records. Kaplan–Meier analysis was done to estimate median disease-free survival and overall survival. Results There were 17 GBC patients who underwent radical cholecystectomy with resection of extrahepatic bile duct. Median age of the patients was 51 years (range 35–62); male to female ratio was 5:12. Six patients were diagnosed after histopathological examination of resected gallbladder specimen following cholecystectomy (incidental gallbladder cancer). All the patients had R‘0’ resection. The indication for extrahepatic bile duct resection was direct infiltration of
* Durgatosh Pandey [email protected] 1
Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India 110029
2
Department of Surgery, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India 110095
3
Department of Surgical Oncology, Dr BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, Delhi, India 201301
hepatoduodenal ligament in nine, positive cystic duct margin in two, densely adherent pericholedochal lymphnodes in one and associated ampullary growth in one patient. Kaplan– Meier analysis predicted median disease-free survival of 20 months and median overall survival of 26 months. Conclusion Extrahepatic bile duct resection to achieve R‘0’ resection in the management of advanced gallbladder cancer is safe with acceptable postoperative morbidity and has potential to improve survival. Keywords Gallbladder neoplasms . Extrahepatic bile ducts . Biliary tract surgical procedures . Obstructive jaundice . Survival analysis
Introduction Gallbladder cancer (GBC) is a common cancer in northern part of India, with the highest age adjusted incidence rates worldwide reported for women in Delhi (21.5 per 100,000) [1–3]. It is an aggressive malignancy and carries poor long term prognosis [4, 5]. The primary treatment of GBC is complete surgical resection (R‘0’resection) which has been shown to improve survival [6]; role of neoadjuvant and adjuvant therapy is still not clearly defined. Majority of the patients with GBC present at an advanced stage when cure is no longer a reasonable option. Though surgical resection is the only potentially curative modality in early GBC, aggressive surgical resection is often considered a futile exercise in advanced GBC in view of aggressive tumor biology [3]. One of the major controversies in the surgical management of gallbladder cancer is the issue of bile duct resection [7]. Involvement of extrahepatic bile duct (EHBD) has been considered as an ominous sign of the aggressive nature of GBC and an independent predictor of poor survival [8, 9]. In a
J Gastrointest Canc
recently published study, involvement of EHBD was uniformly fatal despite the addition of bile duct resection [10]. On the other hand, a few other studies have demonstrated the beneficial effect of EHBD resection in the management of gallbladder cancer [11, 12]. The present study was conducted to highlight the relevance of resection of EHBD in locally advanced gallbladder cancer.
Bilio-enteric continuity was restored using Roux-en-Y hepaticojejunostomy. Statistical analysis was done using statistical package for social sciences (SPSS, Chicago, Illinois) version 16 for windows. Kaplan–Meier analysis was done to estimate median disease-free survival and overall survival.
Result Materials and Methods This retrospective study included GBC patients who underwent radical cholecystectomy with EHBD resection performed by a single surgeon (DP) between January 2009 and December 2014 in two tertiary teaching hospitals in North India: Institute of Medical Sciences, Banaras Hindu University, Varanasi (January 2009 to April 2012) and All India Institute of Medical Sciences, New Delhi (May 2012 to December 2014). The case records of all these patients were reviewed; details concerning the clinical presentation, preoperative therapy, operative procedure, indication of bile duct resection, postoperative complications and outcome were retrieved. Preoperative Workup Preoperative workup of the patients included abdominal ultrasonography and contrast enhanced computed tomography (CECT). Magnetic resonance imagining (MRI) with magnetic resonance cholangio-pancreaticography (MRCP) was done in jaundiced patients to assess the biliary tree. For patients of GBC who have obstructive jaundice at presentation, neoadjuvant chemotherapy (NACT) was advised. These patients underwent image-guided fine-needle aspiration biopsy (FNAB) for confirmation of diagnosis; biliary drainage was undertaken to optimize them for chemotherapy. However, surgery has been considered upfront in a few jaundiced patients without NACT in whom two attempts at FNAB did not confirm malignancy. Operative Procedure All the patients underwent radical cholecystectomy which entails cholecystectomy with a partial hepatectomy and regional lymphadenectomy to encompass the tumor with negative margins—R‘0’ resection, as per the technique described by first author in a previously published article [13]. Extent of liver resection is guided by the invasion of liver so as to achieve a negative surgical margin while preserving the maximal amount of liver parenchyma. All the patients underwent systematic regional lymphadenectomy which included clearance of pericaval, retropancreatic, superior pancreatico-duodenal, common hepatic, celiac, pericholedochal, retroportal and hilar group of lymphnodes. Aortocaval nodes were sampled.
There were 17 GBC patients who underwent radical cholecystectomy with resection of extrahepatic bile duct. Median age of the patients was 51 years (range 35–62); male to female ratio was 5:12. Six patients were diagnosed after histopathological examination of resected gallbladder specimen following cholecystectomy (incidental gallbladder cancer). Nine patients had jaundice at presentation- three of them underwent percutaneous Trans-hepatic Biliary Drainage (PTBD), two patients had T-tube drainage during previous laparoscopic converted open cholecystectomy, one patient underwent endoscopic biliary drainage, and three patients were operated upfront. Five patients underwent NACT following histologic or cytologic confirmation of diagnosis—four were prescribed gemcitabine and oxaliplatin, while one was advised cisplatin and 5-fluorouracil. Twelve patients were operated upfront. All the patients had R‘0’ resection—11 patient had 2–3-cm nonanatomical wedge resection of gallbladder bed, four had segment 4B+5 resection while two underwent extended right hepatectomy. The indication for extra-hepatic bile duct resection was direct infiltration of hepatoduodenal ligament in thirteen, positive cystic duct margin in two, densely adherent pericholedochal lymphnodes in one, and associated ampullary growth in one patient (he underwent a combined radical cholecystectomy with pancreaticoduodenectomy). Postoperative complications were seen in three patients—one developed viral hepatitis A-related jaundice a month after surgery [14], and two patients had transient bile leak that was successfully managed conservatively. Table 1 displays the perioperative characteristics of the patients. There was no perioperative mortality. The median number of lymph nodes harvested was 12 (IQR range 10–13, minimum 4, maximum 15), out of which the median number of metastatic nodes was 0 (IQR 0–2, minimum 0, maximum 15). Microscopic tumor infiltration of liver was present in 8 (47.0 %) while bile duct invasion was seen in 13 (76.47 %). Eight patients developed recurrence—five patients had multiple liver metastases, two patients had abdominal wall surgical site recurrence, two had malignant ascites and two had nodal recurrence. Seven of these patients succumbed to progressive disease; one patient is on best supportive care. Nine patients are alive and free of disease. Table 2 displays the outcome of patients. Kaplan–Meier analysis predicted
35 51 62 58 55 41
12 13 14 15 16 17
Yes No Yes No Yes No
No Yes
None Lap Cholecystectomy with CBD exploration and T-tube PTBD Lap Cholecystectomy PTBD Lap Cholecystectomy PTBD Open cholecystectomy and T tube Yes No No No Yes No
Segment 4b+5 resection Segment 4b+5 resection Wedge resection Wedge resection Wedge resection Wedge resection
Segment 4b+5 resection Wedge resection
Abbreviations: PTBD percutaneous transhepatic biliary drainage, CBD common bile duct, PD pancreaticoduodenectomy
M F M F F F
F F
No No
50 39
Wedge resection Wedge resection Segment 4b+5 resection Extended right hepatectomy Wedge resection Wedge resection Wedge resection Extended right hepatectomy Wedge resection+PD
10 11
Lap Chole None Open partial cholecystectomy None None ERCP stenting none none None
No No Yes No No yes no yes No
No Yes No No Yes Yes No Yes Yes
60 55 56 48 52 35 46 56 42
1 2 3 4 5 6 7 8 9
F M F F F M F F M
Neoadjuvant Liver chemotherapy resection
Perioperative characteristics of the patients
Sl. Age (years) Gender Jaundice at Prior no. presentation intervention
Table 1
Direct infiltration of bile duct Lymph nodes densely adherent to CBD Direct infiltration of bile duct Cystic duct margin positive Direct infiltration of bile duct Direct infiltration of bile duct
Direct infiltration of bile duct Direct infiltration of bile duct
Cystic duct margin positive Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Direct infiltration of bile duct Associated Ampullary growth
Reason for CBD resection
None None None None None None
None Bile leak
Jaundice due to viral hepatitis None None None None None None None Bile leak
Postoperative complications
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J Gastrointest Canc Table 2
Postoperative outcome of the patients
Sl. no.
Final diagnosis
Adjuvant therapy
Recurrence
DFS (months)
OS (months)
Status
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
T3N1M0 T2N2M0 T4N0M0 T4N2M0 T2N0M0 T3N0M0 T3N0M0 T3N1M0 T4N0M0 T2N0M0 T3N0M0 T3N2M0 T3N2M0 T3N1M0 T2N0M0 T3N1M0 T2N0M0
None CT CT CT None CT CT CT CT+RT CT+RT None CT+RT CT+RT CT+RT CT CT+RT CT
No Multiple liver mets No Multiple liver, ascites No Multiple liver mets No Scar site recurrence, nodal recurrence, ascites No Liver mets Liver mets Liver mets No No No No No
48 20 28 14 60 2 10 6 24 8 18 8 6 12 18 23 5
50 26 35 18 62 10 12 12 25 13 19 14 8 13 19 28 9
NED Dead NED Dead NED dead NED dead NED dead dead dead disease NED NED NED NED
Abbreviations: DFS disease-free survival, OS overall survival, NED no evidence of disease, CT chemotherapy, RT Radiotherapy
median disease-free survival of 20 months (95 % CI 10.3– 29.6) and median overall survival of 26 months (95 % CI 7.7–44.2) (Fig. 1).
Discussion Resection of EHBD has been a matter of debate in the surgical management of GBC. EHBD resection can be undertaken routinely (in absence of involvement of bile duct) as a part of radical cholecystectomy, or selectively as and when
Fig. 1 Survival curves show a disease-free survival b overall survival
required. A number of reasons have been put forward for routine resection of EHBD in the absence of its direct invasion—it facilitates lymphadenectomy, takes care of perineural invasion, clears occult disease in connective tissue around the bile duct, and precludes the possibility of bile duct stricture which can result in view of jeopardized vascularity following skeletonization of bile duct with radical lymphadenectomy [3, 15, 16]. While some surgeons have recommended routine resection of EHBD in surgery for gallbladder cancer [17–19], this view has not found support in most centers across the world [20–23]. With a standardized surgical
J Gastrointest Canc
technique, we have shown that optimal regional lymphadenectomy can be successfully accomplished without routine resection of the EHBD [13]. Perhaps the most compelling evidence against routine resection of uninvolved EHBD came from a survey conducted by Japanese Society of Biliary Surgery. In this questionnaire based retrospective study of 114 member institutions, Araida et al. [21] reported that there is no preventive value of extrahepatic bile duct resection in advanced gallbladder carcinoma without a direct infiltration of the hepatoduodenal ligament and the cystic duct. They identified 838 patients of GBC (pT2-T4) who had extra hepatic bile duct resection without pancreaticoduodenectomy and there was no hepatoduodenal ligament invasion and no cystic duct involvement. They did not find any difference in the 5-year cumulative survival between the preserved bile duct and the resected bile cut groups (75 vs. 66 %, p value 0.09); moreover, the overall recurrence rate and the local recurrence rate along the hepatoduodenal ligament were also not different in two groups, 21.8 vs. 27.4 % in node negative and 45.1 vs. 53.8 % in node positive group. On the other side, direct involvement of bile duct or presence of jaundice in advanced GBC indicates aggressive nature of tumor where radical resection involving resection of EHBD is often perceived to be futile and of little benefit to the patient. Invasion of bile duct or hepatoduodenal ligament and presence of jaundice have been considered as a poor prognostic feature in gallbladder cancer [24–30]. A few recent publications, however, have challenged this nihilistic view and supported aggressive resection of GBC to achieve R‘0’ resection provided it as achievable and there are no distant metastases. Agrawal et al. [12] published their experience of 14 patients of advanced GBC with biliary obstruction who underwent curative resection and reported an overall median disease-free survival of 26 months; seven patients were alive for more than 2 years. They concluded that presence of jaundice in GBC does not preclude the possibility of curative resection which does result in significant improvement in survival. Nishio et al. [11], in their study of 100 pT3-4 pN0-1 GBC patients who had radical resection with combined extrahepatic bile duct resection, concluded that GBC with EHBD involvement is worthy of resection. The 5-year survival was 54 % and median survival was 15.4 years when pathological invasion of bile duct was absent; more importantly, the 5-year survival was 23 % and median survival was 1.5 years when pathological invasion was present; there were twelve patients who survived for more than 5-years. These two studies of Agrawal et al. and Nishio et al. provided a much needed optimism in the surgical management of advanced GBC. Our current practice of EHBD resection in advanced GBC is confined to: direct invasion of hepatoduodenal ligament/ bile duct, cystic duct margin being positive, densely adherent nodal disease to bile duct, and in a jaundiced patient. The basic premise is the ability to achieve R‘0’ resection and absence of distant
metastasis. Though the role of NACT in GBC patients with jaundice is not well proven, we follow a policy of NACT in these patients to increase the possibility of complete resection; we also believe that NACT allows us to test the biology of the tumor. It cannot be overstressed that there is an urgent need to perform randomized controlled trial to address the issue of NACT in GBC patients. In our study of 17 patients of advanced GBC who had resection of EHBD as a part of radical resection, median disease-free survival of 20 months and median overall survival of 26 months further corroborates to the oncological soundness of the philosophy of EHBD resection in selected patients. Moreover, the associated postoperative morbidity was low in our patients—only two patients developed transient bile leak which could be successfully managed conservatively. There was no postoperative mortality. Though this study is limited by its small sample size, we believe that it bestows an insight in an important surgical issue of EHBD resection in locally advanced GBC. Although there are encouraging reports of hepatopancreaticoduodenectomy for biliary tract cancers from Japan [31–33], the outcome of this procedure in gallbladder cancer has been dismal [34–36]. We routinely do not offer hepato-pancreatoduodenectomy for advanced GBC. One patient in our series underwent EHBD resection as a part of combined radical cholecystectomy and pancreaticoduodenectomy, and is doing well a year after surgery. He had an ampullary cancer synchronous with GBC and this combined resection was performed to address both primary tumors. We believe that the debate between surgical conservatism and heroism should be abandoned in favor of a middle path of surgical pragmatism. While resection of bile duct and adjacent organs in gallbladder cancer may be unnecessary when they are not involved, and often futile when their involvement is associated with other features of advanced disease; there are situations when the only limiting factor to curative resection is the involvement of bile duct. Reluctance of the surgeon to resect the bile duct in such situations may deny the patient of a potential chance of cure. In conclusion, resection of EHBD to achieve R‘0’ resection in the management of advanced GBC can be safely performed with acceptable postoperative morbidity and has potential to improve survival.
Conflict of Interest None to declare.
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