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10.1245/s10434-006-9219-1
Annals of Surgical Oncology 14:1366-1373 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Surgical Treatment of pT2 Gallbladder Carcinoma: A Reevaluation of the Therapeutic Effect of Hepatectomy and Extrahepatic Bile Duct Resection Based on the Long-term Outcome

Hiroshi Yokomizo1, Takaaki Yamane1, Toshihiko Hirata1, Michio Hifumi2, Tetsu Kawaguchi2 and Seiji Fukuda3

1 Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine Minami, Kumamoto, 861-8520, Japan
2 Department of Gastroenterology, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine Minami, Kumamoto, 861-8520, Japan
3 Department of Pathology, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine Minami, Kumamoto, 861-8520, Japan

Correspondence: Address correspondence and reprint requests to: Hiroshi Yokomizo; E-mail: h-yokomizo{at}kumamoto-med.jrc.or.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The clinical indications for hepatectomy and extrahepatic bile duct resection (EBDR) for pT2 gallbladder carcinoma (GBC) remains controversial. The aim of this study is to elucidate the therapeutic effect of hepatectomy and extrahepatic bile duct resection on the surgical treatment of pT2 GBC.

Methods: Ninety-four patients with pT2 GBC who underwent a potentially curative resection were retrospectively analyzed regarding their pathological findings, surgical procedures, and survival.

Results: The most powerful predicting factor for the survival is the nodal status. The 5-year survival rate was 87.1% for the pN0 patients and 55.7% for the pN1 patients. With respect to surgical procedures, the 5-year survival rate was 73.3% for the 51 patients with hepatectomy, and 87.2% for the 43 patients without hepatectomy. In addition, the 5-year survival rate was 66.7% for the 11 patients with EBDR, and 81.1% for the 83 patients without EBDR. When restricting the patients to those with pN1 disease, the 5-year survival rate of the patients who received these procedures did not surpass that of the patients who did not.

Conclusion: There is no positive therapeutic effect besides providing surgical margins in hepatectomy and EBDR in the surgical treatment of pT2 GBC whereas lymph node dissection is most effective procedure for improving survival. Provided that the negative surgical margins are secured, a hepatectomy and an EBDR can therefore be withheld in the surgical treatment for the pT2 GBC.

Key Words: Gallbladder carcinoma • Hepatectomy • Extrahepatic bile duct resection • Lymph node dissection • Surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Gallbladder carcinoma diagnosed in the advanced stages has dismal prognosis. Despite an extended resection, only selected patients with pT3/pT4 GBC can receive any benefit from surgical treatment1–6 whereas for the patients with pT1 GBC, a simple cholecystectomy can be a curative surgical procedure.7,8 The pT2 GBC, also classified as advanced disease, takes middle position between pT3/pT4 and pT1 disease. The pT2 GBC has the primary lesion confined within the subserosal layer of the gallbladder wall but they are sometimes accompanied with nodal involvement.9–15 At this moment in time, appropriate surgical procedures for pT2 GBC remains controversial especially regarding the indications for a hepatectomy and an EBDR. Since pT2 GBC has no direct invasion to adjacent organs, a potentially curative resection can thus be achieved without a hepatectomy and an EBDR, provided that the involved lymph nodes can be adequately dissected. Although many authors have reported improved survival rates of GBC after radical surgery,4,11,12,14,16,17 the pT2 GBC which is the most critical stage of GBC in terms of the nature of the disease and the optimal surgical approach has not yet been analyzed in detail. It is impossible to diagnose the pT stage of GBC precisely before the histological confirmation even the forefront diagnostic modalities are employed (Fig. 1Go). However, retrospective evaluation of the therapeutic effect of each surgical procedure that composing the surgery for GBC is essential to establish the appropriate surgical procedures for pT2 GBC. These clinical informations based on surgical outcomes are useful especially for the cases diagnosed after initial simple cholecystectomy. The aim of this study is to elucidate the therapeutic impact of a hepatectomy and an EBDR on the surgical treatment of pT2 GBC based on single institutional long-term surgical outcomes.


Figure 1
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  		FIG. 1. Ultrasound imaging findings of two pT2 GBC patients. A One patient had a tumor occupying the body and fundus of the gallbladder. The hyperechoic layer bordering gallbladder and liver became thinner (arrows), suggesting the pT2 GBC with subserosal invasion. B In another patient with pT2 GBC, hyperechoic layer bordering gallbladder and liver looks like intact with endoscopic ultrasonography. However, a pathological examination revealed minute, but relatively deep cancer invasion into the subserosal layer (C, arrow heads).

 

   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
In the 20 years between January 1986 and November 2005, 106 patients with pT2 GBC underwent a surgical exploration in Japanese Red Cross Kumamoto Hospital and 94 of them received a potentially curative resection. The 12 patients who received a non-curative resection were excluded from this study, in detail, three had irresectable nodal involvement around the hepatoduodenal ligament (all died of GBC within 3 years), eight did not undergo a lymphnode dissection because of an incorrect preoperative provisional diagnosis and/or poor general conditions (four died of GBC, two died of unrelated disease and two living without recurrence), and one patient had a severe dysplastic epithlium at the surgical margin of the resected bile duct (living without recurrence). The patients with a potentially curative resection were enrolled in this study. They included 39 men and 55 women, aged 48–91 at the time of operation (mean 68.6), The follow up period ranged 1–189 months (median 65 months).

Of these 94 patients, 70 were referred to our hospital due to abnormal findings of gallbladder found by the screening abdominal ultrasonography without any symptoms, 15 had abdominal pain including 4 with cholecystitis, 5 had appetite loss, and 4 were diagnosed during an examination for an unrelated disease.

The preoperative provisional diagnoses were GBC or suspected of GBC in 66, cholecystolithiasis in 13, gallbladder polyp in 7, acute cholecystitis in 4, chronic cholecystitis in 1, gallbladder debris in 2, and one patient was diagnosed by palpation during surgery for gastric cancer. Fifteen patients had initially been cholecystectomized (including six laparoscopic procedures) under an incorrect provisional diagnosis and thereafter had undergone reoperation for a potentially curative resection after histological confirmation of GBC.

The extent of the disease and curability of the surgery was described according to TNM staging system of the International Union Against Cancer (UICC).18 The location of the tumor was described according to General Rules for Surgical and Pathological Studies on Cancer of the Biliary Tract.19 Any patients whose carcinoma is confined to the Rokitansky–Aschoff sinus of the subserosal layer were classified as pT1 disease and excluded from this study. Seventy patients had stage IB disease without any nodal involvement and 24 patients had stage IIB disease with nodal involvement. Thirty-three patients had tumors affecting the Gn (neck of the gallbladder, one-third proximal portion of the gallbladder) and/or C (cystic duct), 61 patients had tumors not affecting the Gn/C. Thirty-five patients had pHinf1a tumors (subserosal invasion in the gallbladder bed) and 59 patients had pHinf0 tumors (no subserosal invasion in the gallbladder bed). Patients with pHinf1b disease (direct invasion to hepatic parenchyma of gallbladder bed within 5 mm) were excluded from this study. The diameter of the tumor including mucosal spread was less than 3 cm in 22 patients and exceeded 3 cm in 72. The histological grading of the tumors was G1 (well differentiated) in 80 patients, G2 (moderately differentiated) in 5, G3 (poorly differentiated) in 7, and G4 (undifferentiated) in 2.

Surgical Procedures
Of 94 pT2 GBC patients, a partial hepatectomy was performed in 49 patients, including a wedge resection of the gallbladder bed in 39, an S4a+S5 segmentectomy in 10. In addition, two patients received microtaze coagulation therapy of the gall-bladder bed and they are regarded to receive wedge resection of gallbladder bed in this study. Although the surgical procedures were entrusted to the operators, a hepatectomy was preferentially performed in patients with pHinf1a disease rather than those with pHinf0 disease (22 of 35, 62.8% and 29 of 59, 49.2%, respectively). Patients aged over eighty rarely tended to undergo a hepatectomy (one of ten, 10%).

An extrahepatic bile duct resection was performed in 11 patients. The reasons operator conducted EB-DRs were as follows: the presence of primary lesion in the neck of gallbladder or cystic duct in 6, the suspicion of involvement of the extrahepatic bile duct in 3, choledochopancreatomaljunction in 2.

Eight patients received a hepatectomy combined with an EBDR, three patient received a cholecystectomy combined with EBDR. Forty patients received a simple cholecystectomy. The gallbladder was dissected from gallbladder bed in all layers, in most of them.

The extent of nodal dissection was D2 (dissection of pericholedochal, hilar, periportal, posterosuperior pancreaticoduodenal, and common hepatic nodes) in 78, D1 (dissection of pericholedochal nodes) in 13, and 3 elderly patients underwent informal sampling of pericholedochal nodes. The operation with nodal dissection and negative surgical margins around the gallbladder without any apparent unresectable metastatic lymph nodes was considered to be a potentially curative resection. The relationship between the pathological findings and surgical procedures are summarized in Table 1Go. No surgical mortality was observed in these 94 patients.


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  		TABLE 1. Pathological findings and surgical procedure for the 94 pT2 gallbladder carcinoma patients
 
Statistical Analysis
The survival was analyzed using the Kaplan–Meier method, and the log-rank test was used to evaluate any differences between the groups. Cox’s proportional hazards regression was used to analyze any factors contributing to the outcome. All tests were two sided, and p-value <0.05 was considered to be significant. All statistical evaluations were performed with the StatView 5.0J (SAS institute Inc., Cary, NC, USA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Prognostic Factors of the pT2 GBC
The cumulative overall survival rates of 94 pT2 GBC patients were 79.5 and 64.3% in 5 and 10 years, respectively. In univariate and multivariate analysis, the nodal status was the only one independent prognostic factor to predict the outcome. The 5- and 10-year survival rate was 87.1 and 75.2% for the 70 patients with pN0 disease, and 55.7 and 39.0% for the 24 patients with pN1 disease (Fig. 2Go, P = 0.0017). The fact that the tumor was located close to the liver and/or bile duct, as well as the size of the tumor and the histological grading were not related to survival (Table 2Go).


Figure 2
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  		FIG. 2. Cumulative overall survival after a potentially curative resection for pT2 GBC patients with pN0 disease (open diamonds), and with pN1 disease (solid diamonds; P = 0.0017, between pN0 and pN1).

 

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  		TABLE 2. Correlation between the pathological findings and the long time survival
 
Therapeutic Effect of Hepatectomy in pT2 GBC
The 5- and 10-year survival rates were 73.3 and 61.9%, respectively, for the 51 patients with hepatectomy, and were they 87.2 and 68.6%, respectively, for the 43 patients without hepatectomy. The survival rates of the two groups were comparable (Fig. 3AGo,P = 0.527). In patients with pN1 disease, 5- and 10-year survival rates were 46.2 and 34.6%, respectively, for the 15 patients with hepatectomy, and they were 77.8 and 51.9%, respectively, for the nine patients without hepatectomy. The survival rates of the two groups were not statistically significant (Fig. 3BGo,P = 0.473). The survival rate of the patients with hepatectomy did not surpass that of the patients without hepatectomy in this series.


Figure 3
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  		FIG. 3. The cumulative overall survival after a potentially curative resection for pT2 GBC with a hepatectomy (solid diamonds) and without a hepatectomy (open diamonds, A). Survival was also compared when restricting the patients to those with only pN1 disease (B). In both groups, no significant difference in survival was observed between the patients with a hepatectomy and those without a hepatectomy.

 
Therapeutic Effect of EBDR in pT2 GBC
The 5- and 10-year survival rates were 66.7 and 50.0%, respectively, for the 11 patients with an EBDR, and were they 81.1 and 66.2%, respectively, for the 83 patients without an EBDR. There was no statistical difference in the survival rates of the two groups (Fig. 4AGo,P = 0.134). In patients with pN1 disease, the 5- and 10-year survival rates were 64.2 and 44.9%, respectively, for the 19 without an EBDR. Three of five pN1 patients with an EBDR died of recurrence. In the pN1 patients, there was no statistical significance in the survival regarding EBDR (Fig. 4BGo,P = 0.081). The survival rate of the patients with EBDR did not surpass that of the patients without EBDR in this series.


Figure 4
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  		FIG. 4. The cumulative overall survival after a potentially curative resection for pT2 GBC with EBDR (solid diamonds) and without EBDR (open diamonds), there were no significant difference in the survival between the patients with EBDR and those without EBDR (A). Survival was also compared after limiting the patients to those with only pN1 disease (B). In both groups, no significant difference in survival was observed between the patients with EBDR and those without EBDR.

 
Mode of the Recurrence
Of the 94 patients who underwent potentially curative operations, five died of unrelated disease, three died of unknown causes, and 15 died of recurrence. The modes of recurrence were as follows: nodal recurrences in 8, liver metastasis in 6, peritoneal recurrence in 7, and distant metastasis in 5 (three lung, one skin and one bone). There was no preventable course of death by advocating an extended hepatectomy and/or an EBDR in this series (Table 3Go).


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  		TABLE 3. Histological findings, surgical procedures and the mode of recurrence of the 15 patients who died of recurrent disease after a potentially curative operation for pT2 gallbladder carcinoma
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Gallbladder carcinoma is the most common disease in the malignancy of the biliary tract. Owing to its anatomical features, GBC exhibits no clinical symptoms in its early stages and once affecting the adjacent organs, it normally results in a dismal prognosis. Recently some authors have reported long time survivors after radical surgery for the advanced GBC.4,11,12,14,16,17 These authors established a surgical strategy for the disease and provided a chance to survive for the selected patients with advanced GBC. The surgical procedures described in these reports include an extended resection accompanied with a major hepatectomy, an EBDR, and in some cases, pancreatoduodenectomy. Since pT3 and pT4 disease have serosal exposure and/or direct invasion to the adjacent organs, such extended challenging surgery is needed to achieve a curative resection. On the other hand, the recent spread of screening abdominal ultrasonography has resulted in the detection of many patients with GBC at a relatively early stage without any symptoms.20,21 The one most sensitive prognostic factor of GBC is the depth of invasion, which correlates closely with the incidence of nodal involvement.9–15 There is currently a consensus that a simple cholecystectomy is a curative procedure for the pT1 GBC.7,8 pT2 GBC, which distinct from pT1, sometimes has nodal metastasis,11–14 and in contrast to pT3 and pT4, the primary lesion is confined to within the subserosal layer of gallbladder wall.18,19 Thus, appropriate curative procedures for pT2 GBC should be discussed separately from either pT1 or pT3/pT4 disease. Although many authors have reported the use of aggressive surgery accompanied with hepatectomy and EBDR,4,11,12,14,17 the efficacy of these procedures on pT2 GBC is not assessed yet because these studies enrolled modest numbers of pT2 patients. Hence, adequate surgical procedure for the pT2 GBC, especially regarding the need to perform a hepatectomy and EBDR, thus remained to be elucidated. Since most of the patients with GBC tend to be elderly, the establishment of less invasive surgical procedures without these extended resection will beneficial for such patients.

There are three reasons to perform a hepatectomy for the surgical treatment of GBC. First, to avoid a violation of the tumor, the gallbladder bed of the liver was resected since the earliest surgical treatments for GBC.22 Second, if tumor involves the hepatic hilar, then an extended right hepatic lobectomy and EBDR should be performed to obtain a cancer free hepatojejunostomy. Third, to resect the occult hepatic metastasis and prevent recurrence by liver metastasis, some authors stress the performance of a hepatectomy encompassing the draining area of the gall-bladder vein.23–25 The former two procedures are intuitively adopted if necessary to ensure the surgical margins. The third reasons to perform a hepatectomy, to prevent recurrence by liver metastasis, should be examined prudently in terms of the clinical outcome. In our experience of treating 94 pT2 GBC, there was no significant difference in the survival rates between the 51 with a hepatectomy and the 43 without a hepatectomy. Even in the pT2 patients with nodal involvement, the survival rate of the patients with a hepatectomy did not surpass that of the patients without a hepatectomy. Although liver metastasis was observed in 6 patients among the 15 patients who died of recurrence, an extension of a hepatic resection could not have prevented the recurrence because three of six were inoperative multiple metastases and while the other three were miscellaneous recurrence. Moreover, none of eight pHinf1a patients without a hepatectomy suffered from liver metastasis notwithstanding the close surgical margins. These outcomes collectively demonstrates that a hepatectomy has no meaning more than providing surgical margins in the surgical treatment of pT2 GBC. In comparison, there are no clinical conditions that require a prophylactic hepatectomy to resect occult liver metastasis in any other gastrointestinal malignancies. It would be impossible to prevent hematogenous liver metastasis by a partial hepatectomy or an extension of resected hepatic segments.26 If recurrent disease is confined in the liver and resectable, then a secondary surgical exploration should be conducted.

Many authors already have reported that lymph node dissection is the most essential surgical procedure to improve survival of GBC patient unless paraaotic nodes are involved.11,12,27,28 Controversy remains regarding whether the extrahepatic bile duct should be resected12,29 or preserved30 to eradicate any cancer cells in the hepatoduodenal ligament. Shimizu et al.29 found cancer cells in the hepatoduodenal ligament in 30 of 50 GBC patients, including 21 without macroscopic extrahepatic bile duct involvement and recommend EBDR for gallbldder carcinoma extending into subserosa or beyond. However, despite EBDR, the 3-year survival of the patients with invasion to the hepatoduodenal ligament was 6% in their series. Similarly, in our series, three of five patients with nodal involvement who underwent EBDR died within 3 years. These three patients had bulky lymph node metastasis around the extrahepatic bile duct so that the surgeons employed EBDR. However this did not prevent cancer recurrence of the patients. In contrast, the 5-year survival rates of the patients with a preserved extrahepatic bile duct in our series was 81.1 and 64.2%, for the 83 pT2 patients and 19 pT2 patients with nodal involvement, respectively. Thus, even in the patients with nodal involvement, the positive effect of an EBDR besides providing a surgical margin was not proven, whereas these outcomes demonstrate the positive contribution of a lymph node dissection on survival of pT2 GBC patients to be undeniable. Tsukada et al.12 described that the posterosuperior pancreaticoduodenal nodes at the head of the pancreas could be dissected without a pancreatoduodenectomy unless the metastatic nodes involve the pancreatic parenchyma. This rationale was applicable not only for the pancreas head but also for the extrahepatic bile duct. Kosuge et al.30 reported a similar survival rate regardless of the resection or preservation of extrahepatic bile duct in 55 GBC patients, and thus recommended preservation of the extrahepatic bile duct when the tumor was less advanced than stage IV and it does not extend to the hepatoduodenal ligament. We agree with them and appreciate the effect of a lymph node dissection without EBDR. However, the surgical stump of the cystic duct should be examined by intraoperative frozen section to confirm a negative surgical margin, because GBC is sometimes accompanied with superficial mucosal cancer spread out of main gross tumor,31 and if the surgical stump of cystic duct is involved, EBDR should thus be carried out.

Although our surgical outcomes of 94 pT2 GBC with a 5-year survival of 79.5% may seem to be far better than those previously reported, this is not a surprising result. In fact, de Aretxabala et al.4 and Wakai et al.15 reported comparable 5-year survival rates in 20 of pT2 GBC patients, respectively, who received secondary curative resections after initial cholecystectomies. The paucity of pT2 GBC cases treated at a single institution has been an obstacle to elucidate the nature of GBC at this critical stage. We enrolled the largest number of patients with pT2 GBC in comparison to a previously reported single institution study. Although the number of the patients may not be sufficient to conclude the need of hepatectomy and EBDR in the surgical treatment of pT2 GBC, it is important to note that comparable survival rates were achieved without these procedures.

Another factor influencing our result is the large distribution of pT2 GBC patients who were discovered by screening ultrasonography without any symptoms. They were mainly diagnosed in Japanese Red Cross Kumamoto Health Care Center attached to our hosipital.21 Most GBC patients exhibiting symptoms such as jaundice, abdominal pain, have inoperative lesions. The early detection of GBC by screening ultrasonography and adequate surgical treatment has thus shown that pT2 GBC to be a ‘curable lesion’.

Based on above mentioned findings, it is suggested that neither a hepatectomy nor an EBDR showed any positive therapeutic effect as a surgical treatment for pT2 GBC except for securing the surgical margins, and that a lymph node dissection is therefore considered to be an essential procedure for improving survival and it can be an effective treatment even without performing an EBDR. Of course, pT2 GBC occupying the gallbladder bed or suspected the involvement of the bile duct should be removed using these procedures because a violation of the tumor can result in cancer dissemination and recurrence at the surgical margins. However, provided that the surgical margins are ensured, it is not beneficial for all pT2 GBC patients to undergo these procedures, especially in poor risk or aged patients. Hence, the optimal surgical procedures for pT2 GBC cannot be uniformly standardized. Considering the location of tumor and the general conditions of patient, the most suitable surgical procedures for each patient should be constructed in a tailor-made manner.


   ACKNOWLEDGMENTS
 
We thank to Dr. Hidenobu Matsukane, Dr. Takayuki Matsuoka, Dr. Masato Shimamoto (Surgeons) and Dr. Nobumasa Ninomura (Pathologist), who have already retired from the Japanese Red Cross Kumamoto Hospital for their valuable contributions to this study.

Received for publication June 24, 2006. Accepted for publication August 8, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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