The standardized surgical approach improves outcome of gallbladder cancer
© Scheingraber et al; licensee BioMed Central Ltd. 2007
Received: 04 January 2007
Accepted: 21 May 2007
Published: 21 May 2007
The objective of this study was to examine the extent of surgical procedures, pathological findings, complications and outcome of patients treated in the last 12 years for gallbladder cancer.
The impact of a standardized more aggressive approach compared with historical controls of our center with an individual approach was examined. Of 53 patients, 21 underwent resection for cure and 32 for palliation.
Overall hospital mortality was 9% and procedure related mortality was 4%. The standardized approach in UICC stage IIa, IIb and III led to a significantly improved outcome compared to patients with an individual approach (Median survival: 14 vs. 7 months, mean+/-SEM: 26+/-7 vs. 17+/-5 months, p = 0.014). The main differences between the standardized and the individual approach were anatomical vs. atypical liver resection, performance of systematic lymph dissection of the hepaticoduodenal ligament and the resection of the common bile duct.
Anatomical liver resection, proof for bile duct infiltration and, in case of tumor invasion, radical resection and lymph dissection of the hepaticoduodenal ligament are essential to improve outcome of locally advanced gallbladder cancer.
In the recent surgical literature therapy of gallbladder cancer (GC), which has traditionally been viewed with therapeutic nihilism, has documented an increase of 5 year survival rates from 5–12% up to 38% . Because the survival of patients treated by palliative chemotherapy or radiation is poor, limited to months, an aggressive approach to locally confined disease is justified. However, there is considerable controversy what exactly constitutes that "aggressive surgical approach" . The armamentarium of surgical procedures mainly comprised liver resection, common bile duct resection, lymph node dissection in the hepaticoduodenal ligament and -especially practiced in Japan- concomitant pancreatoduodenectomy or lymph dissection of the interaortocaval compartment. With respect to the liver resection, the variety of procedures ranged from non-anatomical wedge resections, to anatomical parenchyma sparing segment IVb/V resections up to extended right or left hemi-hepatectomies. The indications for several procedures depend more on center specific algorithms than on randomized trials. In our department there was a switch in March 2001 to a more aggressive surgical approach in the treatment of gallbladder cancer with a standardized approach comprising anatomical segment IV (round ligament approach resection)/segment V resection, systematic lymph dissection of the hepaticoduodenal ligament (HL) and resection of the common bile duct (CBD) to reach tumor free margins. Before March 2001, the surgical approach to gallbladder cancer was largely dependent on the individual surgeon's decision. The aim of this study was to examine the extent of resection, the complication rate, the intraoperative and microscopic findings and at least survival rates of patients treated in the time period of the last 12 years with special respect to the impact of the standardized approach on outcome.
Patients and methods
Patients seen at the Department of General Surgery of the University Hospital of the Saarland from November 1994 to January 2006 with the histologically proven diagnosis of GC were identified from the national tumor registry, the admission diagnosis and surgical procedures data bank. Data were collected retrospectively from chart review including operation reports and histological examination and survival time was calculated after telephone interviews with patients or practitioners of the patients. All patients with a curative or a palliative surgical intention were included, as well as patients reoperated for recurrent GC.
As no lymph node metastases and a good survival were reported in T1a tumors  simple CHE was considered as adequate radical for this group. In contrast, in patients with T1b tumors, we perform extended resections according to the findings of the French Surgical Association Survey .
The survival rates were estimated and plots constructed by the Kaplan-Meier method with the aid of a statistic software (SigmaStat 3.0®, SPSS). Tumors were staged according the TNM-classification and the actual classification of the International Union Against Cancer (UICC) . Differences among the survival rates were compared with the log-rank test. A p-value of less than 0.05 was considered significant. Numerical data were expressed as mean ± standard deviation for normal distributed and as median with range for non-normal distributed values. Differences of mean values were compared with the student t-test and for median values with the Mann-Whitney-U-test.
Fifty three patients with GC were identified. Thirty nine were female and fifteen male, with an average age at first presentation of 67 (39–88) years. Median hospital stay was 15 (3–77) days. Twenty one patients were operated with a curative intention. Of these seventeen patients had undergone previous CHE and were reoperated. In the remaining patients there was only a palliative procedure possible due to advanced tumor stages with distant metastases, recurrent disease or because of significant medical co morbidity. About half of the patients in palliative therapy group underwent staging laparotomy (n = 14) or laparoscopy (n = 1). In eight patients reoperation due to recurrent disease was performed. Even when tumor resection was performed in this group, the operation was considered as palliative. In the remaining patients varying palliative procedures were performed ranging from cyrotherapy of liver metastases to implantation of a venous port system for palliative chemotherapy. In three patients bypass surgery was done, two patients with gastroduodenal stenosis received gastroenterostomy and in one patient with colonic infiltration of the right flexure received ileotransversostomy.
Staging (UICC 2002 classification) and percentage of R0 resection of the gallbladder cancers
Percentage of R0 resections
Patients treated with recurrent disease after previous curative surgery for gallbladder cancer (n = 8).
Time until reintervention [months]
non anatomical liver resection after previous open CHE, no lymph dissection, no exploration of CBD
40 months later alive
non anatomical liver resection after previous open CHE, no lymph dissection, no exploration of CBD
liver metastases seg. VII, tumour recurrence seg. IV/V
bisegmentectomy seg. IVb/V, cryotherapy seg. VII
died 4 months later
non anatomical liver resection Seg. IVb after previous laparoscopic CHE, radical lymph dissection, excision of port sites and tumour free resection margins CBD
seg. III-bypass, gastroenterostomy
died 3 months later
T2 GBC after open CHE, no completion operation
tumour between hepaticoduodenal lig. and pancreas
died 6 months later
anatomical liver resection Seg. IVb/V after open CHE, lymph dissection, no tumour free resection margin CBD
gastric stenosis, liver abscess
interventional abscess drainage, implantation venous port system
died 1 month later
anatomical liver resection Seg. IVb/V after open CHE, no lymph dissection, tumour free resection margin CBD
died 1 month later
bisegmentectomy seg. IVb/V en bloc with CHE, no lymph dissection tumour free resection margin of CBD,
died 13 months later
non-anatomical wedge resection of seg. IVb during CHE, no lymph dissection, no tumour free resection margin of CBD
tumour progress with liver infiltration
lost for follow up
Operative procedures and histological findings
Operative procedures according to tumor staging (UICC 2002 classification).
Liver Resection (liver infiltration)
Dissection of Hepatico-Duodenal Ligament (lymph node infiltration)
Biopsy coeliac trunc nodes (lymph node infiltration)
CBD resection/R0 cysticus (CHDB infiltration)
T1b n = 1
T2 n = 17
T3 n = 14
liver n = 1 peritoneal carcinosis n = 3
T4 n = 17
liver n = 5, pancreas n = 1, lung n = 1, peritoneal carcinosis n = 6
Tx n = 4
liver n = 1, peritoneal carcinosis n = 2
Demographic data for the Standardized and Individual approach in 21 patients treated with curative intention (R0 resections).
Individual Approach n = 9
Standardized Approach n = 12
[Mean ± SE (Range)]
65 ± 12 (60–80)
71 ± 6 (40–78)
Postoperative complications and mortality
A total of 30 of 53 patients had an uneventful postoperative course during their hospital stay. There were some minor complications like postoperative urinary tract infection in one patient, delayed wound healing in one patient, pleural effusion in 4 patients, pneumonia in 2 patients and prolonged intestinal atonia in 3 patients. In three cases there was an anastomotic leakage of the hepaticojejunostomy which made reoperation necessary. Two of these patients developed liver abscess. Five patients died during the hospital stay. Two deaths could be directly related to the surgical procedure in one patient with postoperative bleeding due to erosion of the hepatic artery after radical lymph dissection and in another patient who developed postoperative liver failure. Two other patients died due to medical reasons (cardiac failure and pulmonary embolism). Finally one patient died due to tumor progress already during her hospital stay after staging laparoscopy.
Until the last 10 years GC has always been associated with dismal prognosis, due to the asymptomatic growth of the tumor and finally the infiltration of the surrounding structures as the hepatic artery, the portal vein or the wide spread lymph infiltration making a curative resection impossible. In the retrospective analysis of the surgical treatment of 724 patients with GC treated primarily in Europe between 1980 and 1989 no progress has been observed with respect to survival . However, since the last years there are increasing number of studies giving hope for improvement of survival after an aggressive surgical approach in resectable lesions [6–8]. This was especially relevant for tumors infiltrating the liver, the bile duct or the lymphatic nodes. Whereas survival in T1a tumors without infiltration of the muscle layer is generally good and extended CHE (e.g. with wedge resection of the gallbladder bed) is unlikely to improve the outcome in this group, there is still a debate whether T1b tumors (tumor invading through the mucosa into the muscle layer) should be treated like T2 tumors and liver resection combined with lymph dissection of the HL should be performed . In this study there was only one patient with a T1b tumor, but we think that treatment in T1b tumors should not differ from T2 tumors. Thereby we focus mainly on the lymphatic spread of the tumor. It has been shown that lymphatic spread occurs early, before liver involvement and that nodal involvement is a poor prognostic factor [10–14]. However, there were many patients reported in the literature, in whom lymph node metastases had been excised and who survived more than 5 years. Our finding of early involvement of the HL in GC and an incidence of 25% in T2 tumors confirms these reports. Lessons we learned from the course of our patients presenting with recurrent tumors after intended curative resections (see table 2) revealed that treatment strategies in the past focused too much on liver infiltration thereby forgetting the lymphatic spread. In the past, in our department infiltration of the HL has not usually been an indication for lymph dissection or was used as an argument against the feasibility of curative resection. The preliminary report of the German CAE-S/CAMIC registry of CHEs with a postoperative incidental finding of cancer comprises about 245 patients with GC . In the registry there were 118 patients with T2 tumors, 44 patients with T3 tumors and 20 patients with T4 tumors. Altogether, there were only 70 reoperations performed. This demonstrates that an aggressive surgical approach is still not performed everywhere. One major problem in simple CHE is that no definite statement about lymph node infiltration can be done macroscopically and the tumor stage might be underestimated. The missing of lymph node infiltration might result in progressive lymphatic tumor spread especially into coeliacal, peripancreatic and interaortocaval lymphatic nodes leading to rapid and disseminated tumor growth and dismal prognosis. Of importance, there were therefore 70 patients in the CAE-S/CAMIC registry with recurrent disease after a median follow-up of 27 months.
In this study we could demonstrate a better survival of R0-resections in patients after the implementation of a standardized surgical approach for GC ranging from UICC stage Ia (T1b tumors) to stage III (T4 tumors with and without regional lymphatic node metastases). To our opinion the marked difference of the standardized approach in comparison to the individual resections, was the radial dissection of the HL and the resection of the CBD.
Before the implementation of the standard operation, liver resection was usually performed as non-anatomical wedge resection of the gallbladder bed to reach tumor free resection margins. Although this study could not clarify whether anatomic segmentectomy is superior to a non-anatomic wedge resection, we nowadays advocate the anatomical segment IVb/V liver resection with the selective extrahepatic vascular approach. By some authors right sided hemihepatectomy is recommended to respect a security distance of the tumor of about 3 cm. Ogura et al. measured the distance between the front of the carcinoma invasion and the resection plane in the hepatic parenchyma . The distance ranged between 12–20 mm after wedge resection, 16–35 mm after resections of segments IV+V and 28–58 mm after extended hepatic resections. By the analysis of the pathological reports of our liver resection specimen we found that a 3 cm distance can also be achieved by 77% of segment IVb/V resections. Moreover we demonstrate in this study that this procedure can usually be done without requiring blood transfusions. Therefore segment IVb/V liver resection is a better alternative than hemihepatectomy as it is sufficient in most cases to achieve a R0 resection and is much less invasive. Only in some cases of T4 tumors hemihepatectomy might be still necessary to completely remove the tumor. Nevertheless, radicality of resection is usually more dependent on lymph dissection than resection of the infiltrated liver tissue or surrounding organs like the small intestine and colon.
Metastatic disease is usually no indication for surgery. In this study we could not demonstrate any difference of solid organ metastases compared to peritoneal tumor seeding in terms of remaining survival time. There is also no benefit of palliative CHE.
Whereas we are convinced of the benefit of the standardized approach, some – primarily Japanese authors – advocate the need of the resection of a "fourths or fifths component", that is the necessity of the routine paraaortal lymph node dissection or even the hepatopancreatoduodenectomy (HPD). Since the pioneer report of HPD by Hanyu et al.,  a large number of patients with UICC stage III GCs was undergoing HPD and five year survival rates from 29% – 87% were reported [17, 18]. Despite the evident pathoanatomical rational of this approach, as there is a high incidence of peripancreatic infiltrated lymph nodes, nearly all Western surgeons are hesitant to pursue such an aggressive approach due to its high mortality and morbidity.
Tsukada et al. found lymph node metastases in 12% of patients who underwent paraaortic node dissection . However, paraaortic lymphadenectomy provided no survival benefit and led to the same prognosis to that of distant metastases . We did not routinely perform lymph dissection in the interaortocaval compartment. In our series we found every second lymph node biopsy at the celiac trunk positive in T3 tumors and even every biopsy positive in T4 tumors. But in the case of tumor infiltration at the celiac trunk there were usually already metastases detected, thus lymph dissection of the interaortocaval compartment would have rarely been a real curative option.
The standardized approach is an efficacious treatment for locally advanced gallbladder carcinoma and did improve survival compared to less aggressive surgical resections even in our small cohort. In advanced tumor stages with presence of peripancreatic lymph node disease a more aggressive approach with HPD is limited by its high morbidity. In metastatic disease, palliative surgical procedures should be restricted to bypass measures like the segment III bypass, gastroenterostomy or palliative intestinal resection to ensure quality of life. Our study should encourage other centers to incorporate more aggressive standardized procedures in the treatment of GC. Hopefully, this will enable us to compare multicenter treatment results in the future to better estimate the improvement in the surgical therapy of the usually rare and prognostically serious GC.
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