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Prognostic factors for gallbladder cancer in the laparoscopy era

Purpose Hepatobiliary surgery has changed dramatically in recent decades with the advent of laparoscopic techniques. The aim of this retrospective study was to compare survival rates according to stages, adjusting for important prognostic factors. Methods A retrospective study of a 17-year period from January 1994 to April 2011 was carried out. The cases studied were divided into two time period cohorts, those treated in the first 9-years (n = 109) and those treated in the last 7-years (n = 109). Results An operation with curative intent was performed on 218 patients. The 5-year survival rates according to the depth of invasion were 86% (T1), 56% (T2), 45% (T3), and 5% (T4). The number of cases of incidental gallbladder cancer found during 3,919 laparoscopic cholecystectomies was 96 (2.4%). Incidental gallbladder cancer revealed a better survival rate (P = 0.003). Iatrogenic bile spillage was found in 20 perforations of the gallbladder during laparoscopic cholecystectomies, 16 preoperative percutaneous transhepatic gallbladder drainages and 16 percutaneous transhepatic biliary drainages; only percutaneous transhepatic biliary drainage patients showed a significantly lower survival rate than patients without iatrogenic bile spillage (P < 0.034). Chemoradiation appeared to improve overall survival (P < 0.001). Multivariate analysis also revealed that time period, type of surgery, surgical margin, lymphovascular invasion, lymph node involvement, and chemoradiation therapy had significant effects. Conclusion This study found that the prognosis of gallbladder cancer is still determined by the stage at presentation due to the aggressive biology of this tumor. Early diagnosis, radical resection and appropriate adjuvant therapy can increase overall survival.


INTRODUCTION
The incidence of gallbladder cancer (GBC) shows wide racial and geographical variation, and some genetic and environmental factors have been suggested with regards to etiologic association in the development of GBC. These factors include gallstones, presence of chronic inflammation, adenoma, anomalous pancreatobiliary duct union, sex, age, obesity, and parity. The incidence of GBC is high in Korea, Japan, and Central and Eastern European thesurgery.or.kr countries [1]. GBC is an uncommon cancer that has traditionally been associated with a poor prognosis. This poor prognosis is considered to be related to advanced stage at diagnosis, which is due to both the anatomic position of the gallbladder, and the vagueness and non-specificity of symptoms. In the era of laparoscopic cholecystectomy (LC), incidental GBC has dramatically increased and is now the major way patients present with GBC [2,3]. In many cases, the diagnosis is made after a cholecystectomy has been performed and an incidental tumor is identified in the specimen. Frozen section diagnosis is often challenging and has its own limitations because of sampling problems and freezing artifacts [4]. The risk of peritoneal seeding caused by inadvertent spillage of cancer contaminated bile during percutaneous transhepatic gallbladder drainage (PTGBD) and percutaneous transhepatic biliary drainage (PTBD) may be high, but has rarely been reported [5]. GBC is a fatal disease that can only be cured by radical surgical resection. The goal of radical resection should be cholecystectomy with en bloc resection of the invaded organs (most commonly the liver) around the tumor to provide reasonable margins and to resect regional lymph nodes. However, there is still a debate about the extent of hepatic resection and the extent of regional lymphadenectomy [6,7].
The aim of this retrospective study was to compare survival rates according to tumor stages, using Cox regression comparison of survival by stage adjusting for important prognostic factors.

METHODS
A retrospective study spanning a 17-year period from January 1994 to April 2011 was performed, and 218 consecutive inpatients were identified. Cases were divided into two time-period cohorts: those treated in the first 9 years (n = 109) and those treated in the last 7 years (n = 109). Median survival was not estimate since Kaplan-Meier curve did not reach 50% of the survival probability. b) Five-year OS estimate.

Disease stage
Between January 1994 and April 2011, 218 patients underwent evaluation and surgical treatment for adenocarcinoma of gallbladder. There was no postoperative death.   (Fig. 1). Overall median survival improved comparing early and late periods (Fig. 2). LC operations were more frequently performed in the late period and appeared to result in the earlier discovery of GBC, resulting in increased probability of survival.

Incidentality
During the 17-year period evaluated in this study, 3,919   LCs were performed, of which 96 (2.4%) cases of GBC were incidentally discovered, and GBC was found incidentally in 112 of the 218 patients (50%) by permanent histological examination. Eighty nine (89%) of those patients whose GBC was found incidentally were stage T1 or T2. Patients who were found to have GBC incidentally at LC had a significant increase in survival when compared with those who were admitted electively with a known diagnosis (P = 0.014) (Fig. 3).  (Fig. 4).

Surgical treatment (type of surgery)
The procedures performed as resection with curative intent included 11 (5%) major liver resection (≥hemi-

Pathology
The distribution of histologic subtypes in the current re-

Survival
We examined the prognostic significance of the follow-

DISCUSSION
The advent of LC has lowered the threshold for symptomatic patients with gallbladder disease. It appears possible that if gallbladder disease in general is operated on earlier, incidental GBCs may also be detected at an earlier stage, increasing the chance for survival.
As increasing numbers of LCs are being performed, their role in the management of potentially malignant disease must be carefully examined. LC should not be performed when GBC has been diagnosed or is suspected preoperatively [8,9]. On the other hand, LC is now performed by surgeons with a reasonable degree of confidence, even in cases of possible malignant lesions [2,10].
GBC has one of the poorest OS rates of all the gastrointestinal malignancies. The dismal results are due to the aggressive biology of this tumor [11].
In a review of the literature, GBC was suspected pre-operatively in only 30% of patients and, in the remaining 70% of cases, GBC was incidentally discovered by the attending pathologist [3]. In our series, 80% of the patients that were found incidentally were stage I or II, and OS im- can convert potentially curable GBC to an incurable disease [12]. Thus, patients with preoperative findings suspicious for GBC should undergo open exploration with an intent to perform a radical cancer operation as a primary procedure if the diagnosis is confirmed intraoperatively [8,12].
Increasing numbers of reports have documented that mean survival is statistically shorter when complications (gallbladder perforation, injury to common bile duct, or tumor violation) occur during LC for GBC. It is thought that in addition to perioperative bile leak, factors such as the biological properties of the tumor, tumor stage, operative maneuvers and impact of pneumoperitoneum pressure may be involved in the onset of peritoneal and port site recurrence [9].
Recently, the single port LC technique was reported to also increase the risk of bile leakage into the abdomen because of "critical view of safety" [13]. It is undoubtedly a consequence of cancer-contaminated bile spillage through the liver pores created by PTGBD or PTBD, and subsequent cancer growth on the peritoneum [5].  [4,14].
Patients found to have GBC incidentally during LC appear to have a survival advantage if resected with curative intent. There have been suggestions that prognosis after two operations is less favorable than for patients treated with a single procedure [19]. Also, if GBC is diagnosed postoperatively after LC, only about one-third of patients eventually undergo a second procedure after LC for GBC [7,20].
Recently, some reports showed the feasibility and safety of total laparoscopic completion radical cholecystectomy for incidentally detected early GBC [21,22]. The magnitude of partial hepatectomy in terms of number of excised nodes and integrity of the specimen did not differ between the open and laparoscopic approach [23]. Larger and prospective studies are needed to support the oncologic safety and efficacy of laparoscopic completion radical surgery in early GBC.
Features of GBC are characterized by a wide range of tumor extent, cancer stage-dependent survival and extent of standard resection are not yet established. Tumor-nodemetastasis stage was found to be a significant prognostic factor. The prognosis worsened with increasing disease stage and the survival rate decreased with increasing age, especially after the age of 75 [24]. Our study demonstrated a similar result, but the age factor did not influence survival rate.
No consensus regarding the optimal extent of liver resection has been established. In our series, we obtained 2 to 3 cm of negative margin for the standard resection.
Perineural invasion also has been reported as a factor responsible for poor prognosis [9,25]. Also, lymph node micrometastasis has a significant survival impact in patients with GBC [26]. The results of the current study are similar to previous publication from other centers [27,28].
The effectiveness of a radical surgical approach for GBC has been the subject of a number of reports. When considering the optimal operation for GBC, there are two major issues: the extent of hepatic resection and the extent of regional lymphadenectomy. Extended lymphadenectomy may prolong survival in selected patients with GBC, but the extent of lymph node resection for the optimal treatment of GBC has not been clearly established [15,27] to Western studies [26,28]. Lymph node dissection at our institution involves complete portal dissection, skeletonization of the biliary tree, hepatic artery and portal vein, and the pericholedochal and retropancreatic lymph nodes those are the most frequently involved nodal basins.
Optimal extent of lymph node dissection for the GBC should be decided keeping in mind various factors including the patients' general condition and tumor stage.
Complete surgical resection is the only potential curative treatment. The role of chemotherapy and radiation therapy in the management of GBC remains undefined. A better understanding of the pathogenesis of the disease is needed to develop a more effective targeted adjuvant therapy [29,30]. The heterogenecity of the patient and the regimen used makes it difficult to extrapolate any conclusion.
In our series, after adjusting for the stage parameters, the data supported the view that adjuvant chemoradiotherpy might improve OS for patients with GBC. The main limitation of this study was its retrospective, nonrandomized, short follow-up period, which prevented survival curve analysis. On the other hand, by comparing outcomes in the later 7 years to those in the first 9 years, we used historical controls as a reference point for the new surgical approach. The main drawback to this type of comparison is that it is possible that the overall management of these patients has changed over time and is variable among surgeons, irrespective of surgical factors.
In conclusion, the stage of disease at presentation af-

CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.