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Annals of Surgical Oncology 10:447-454 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Depth of Subserosal Invasion Predicts Long-Term Survival After Resection in Patients With T2 Gallbladder Carcinoma

Toshifumi Wakai, MD, PhD, Yoshio Shirai, MD, PhD, Naoyuki Yokoyama, MD, PhD, Yoichi Ajioka, MD, PhD, Hidenobu Watanabe, MD, PhD and Katsuyoshi Hatakeyama, MD, PhD, FACS

From the Divisions of Digestive and General Surgery (TW, YS, NY, KH) and Molecular and Diagnostic Pathology (YA, HW), Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Correspondence: Address correspondence and reprint requests to: Yoshio Shirai, MD, PhD, Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata City, 951-8510 Japan; Fax: 81-25-227-0779; E-mail: shiray{at}med.niigata-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: This study aimed to identify a subgroup of patients with inapparent T2 gallbladder carcinoma who may be best suited for radical second resection.

Methods: A retrospective analysis was conducted of 126 patients with pathologic stage T2 (pT2) gallbladder carcinoma (51 with clinically evident tumor and 75 with inapparent tumor). Depth of subserosal invasion was measured histologically in each gallbladder specimen. The median follow-up period was 113 months.

Results: In all 126 patients, depth of subserosal invasion was the strongest independent prognostic factor by univariate (P < .0001) and multivariate (relative risk, 9.27; P < .0001) analyses. Among the 75 patients with inapparent tumor, the outcome after resection was significantly better in patients who had undergone radical second resection than in patients who had undergone cholecystectomy alone (P = .0006). When depth of subserosal invasion was divided into <=2 vs. >2 mm, the effectiveness of radical second resection remained only in patients with subserosal invasion >2 mm (P = .0004).

Conclusions: Depth of subserosal invasion best predicts postresectional long-term survival of pT2 gallbladder carcinoma patients. Among patients with inapparent pT2 tumors, those with subserosal invasion >2 mm are good candidates for radical second resection.

Key Words: Gallbladder neoplasms • Depth of invasion • Surgery • Lymph node dissection • Multivariate analysis • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The depth of penetration (T classification1) is a critical prognostic factor in patients with gallbladder carcinoma.2–4 Although results of surgical treatment for advanced gallbladder carcinoma remain unsatisfactory, resection is effective for tumors limited to the gallbladder wall,1,5 which include mucosal lesions, tumors invading the muscle layer, and tumors invading the subserosal (perimuscular) connective tissue without extension beyond the serosa or into the liver.1 In 1983, Morrow et al.5 proposed the significance of subserosal lesions in the treatment for gallbladder carcinoma, on the basis of the effectiveness of aggressive resection for this stage of tumor.

Cholecystectomy alone is an adequate treatment for pathologic stage T1 (pT1) gallbladder carcinoma, provided that the resection margins are uninvolved.2,4,6–10 Many authors2–5,8–25 have advocated radical resection with regional lymph node dissection for pT2 or more advanced tumors, despite the high morbidity related to the procedure.3,19,20 In 1992, we4 reported the effectiveness of radical second resection for pT2 or more advanced tumors first discovered after cholecystectomy for presumed benign disease (inapparent cancers). Fong et al.16,17 also reported similar results. However, the fact that a considerable proportion (40.5% in our previous series4) of patients with inapparent pT2 tumors survive >=5 years after cholecystectomy alone implies that radical second resection is excessive for such prognostically favorable patients.4,21 In 1997, de Aretxabala et al.21 posed the question of which patients benefit from radical second resection among patients with inapparent pT2 tumor. This question remains unresolved.

We hypothesized that the depth of subserosal invasion predicts well the postresectional long-term survival of patients with pT2 gallbladder carcinoma. The aims of this study were to test this hypothesis and to identify, on the basis of the depth of subserosal invasion, a subgroup of patients who may be suitable for radical second resection among patients with inapparent pT2 tumor.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
A total of 622 patients with gallbladder carcinoma underwent surgical resection in Niigata University Medical Hospital and its affiliated institutions in the 17 years between October 1981 and July 1999. Patients with carcinoma arising in the cystic duct were excluded according to the tumor-node-metastasis staging system.1 Among these patients, 180 underwent either a cholecystectomy alone or a radical resection for pT2 gallbladder carcinoma. Seventeen patients who also had a primary malignant tumor in other organs and 37 patients who underwent a palliative resection with gross residual tumor (R2)1 were excluded from this study. The remaining 126 patients with pT2 tumor who underwent either a cholecystectomy alone or a radical resection without gross residual tumor (R0 or R1) formed the basis of this retrospective study, which included 87 women and 39 men with ages ranging from 38 to 94 years (median, 69 years).

Clinically evident carcinoma of the gallbladder was defined as a tumor diagnosed or suspected before or at the time of operation. Inapparent carcinoma of the gallbladder was defined as a tumor first discovered histologically after cholecystectomy alone for presumed benign gallbladder disease.4 In this series, 51 patients (40%) had a clinically evident tumor, which was suspected or diagnosed before surgery (by ultrasonography) in 35 patients and during surgery (by operative findings, operative ultrasonography, or both) in 16 patients. Of the 75 patients (60%) who had an inapparent tumor, 72 had a preoperative diagnosis of gallstone disease, and the remaining 3 were diagnosed with benign polypoid lesions.

Patients with a clinically evident tumor underwent either a cholecystectomy alone (n = 22 patients) or a radical resection (n = 29 patients) as the initial treatment (Table 1); the selection of cholecystectomy alone or initial radical resection depended on the surgeon’s preference. In contrast, cholecystectomy alone was performed as the initial procedure in all 75 patients with inapparent tumor (62 open; 13 laparoscopic), of whom 20 subsequently had a radical second resection after the initial cholecystectomy (13 open; 7 laparoscopic). In 7 of the 20 patients undergoing a radical second resection, cancer tissue missed during the initial cholecystectomy was detected by routine histological examination in the radically resected specimens. The interval between the initial cholecystectomy and the radical second resection was 9 to 140 days (median, 44 days).


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  		TABLE 1. Type of resection for pT2 gallbladder carcinoma according to the timing of diagnosis
 
In this study, radical resection was defined as an en-bloc resection of both the primary tumor and the regional lymph nodes of the gallbladder (Table 2). Regional lymph nodes of the gallbladder include the cystic duct, pericholedochal, posterosuperior pancreaticoduodenal, retroportal, right celiac, and hepatic artery node groups.1,4,26 In 5 patients undergoing Whipple pancreaticoduodenectomy, the right portion of the superior mesenteric node group was also dissected. Twenty-four patients also underwent dissection of the interaortocaval node group26 in addition to the regional lymph node dissection. Involvement of the aortocaval lymph nodes was classified as distant metastasis (M1).1


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  		TABLE 2. Radical resections for pT2 gallbladder carcinoma
 
Although 12 complications occurred in 10 of the 49 patients undergoing radical resection, there were no in-hospital deaths in this series. Adjuvant chemotherapy after resection depended on the surgeon’s preference; 92 patients received oral administration of 5-fluorouracil or its derivatives within approximately 1 year. No patients received adjuvant radiotherapy. Thereafter, all patients were regularly followed up in outpatient clinics every 1 to 6 months. The follow-up periods ranged from 6 to 249 months (median, 113 months) after resection.

At the time of writing, 45 patients have died of tumor relapse and 24 patients have died of other causes (with no evidence of disease), including cerebral infarction/hemorrhage (n = 8), other malignant diseases (n = 4), sudden death of unknown etiology (n = 4), pneumonia (n = 4), acute myocardial infarction (n = 2), gastrointestinal bleeding (n = 1), and severe hepatic steatonecrosis after a Whipple pancreaticoduodenectomy (n = 1). The remaining 57 patients are alive without disease.

Histological Examination
Resected specimens were submitted to the Division of Molecular and Diagnostic Pathology in our institution for histological examination. Two of the authors (H.W. and Y.A.), experienced pathologists, examined all of the specimens without knowledge of the clinical details.

The depth of subserosal invasion, defined as the distance between the lower border of the muscularis propria of the gallbladder and the deepest advancing margin of tumor invasion (Fig. 1), was measured histologically by examination of multiple sections (median, 12 sections; range, 2–70) of the whole lesion in each gallbladder specimen. Discrimination between mucosal lesions spreading deeply along Rokitansky-Aschoff sinuses (pseudoinvasion) and invasive subserosal lesions (true invasion) was made on the basis of the authors’ histological criteria, proposed previously27,28; only the depth of "true invasion" was measured. In patients with multiple lesions, the depth of subserosal invasion was represented by that of the deepest lesion. Histological findings were described according to the tumor-node-metastasis staging system.1



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  		FIG. 1. Measurement of depth of subserosal invasion in the gallbladder specimen. Depth of subserosal invasion was defined as the distance (D; two-headed arrow) between the lower border of the muscularis propria of the gallbladder (broken line) and the deepest advancing margin of tumor (stain, hematoxylin and eosin; original magnification x40).

 
With gallbladder specimens removed for presumed benign disease, initial histological examination was made by using one or two representative sections of each specimen. Once an inapparent carcinoma was found in the specimen, the depth of penetration (T classification) was determined on multiple sections of the whole tumor. If the tumor was classified as pT2, the depth of subserosal invasion was measured on multiple sections as described previously.

Adenocarcinoma was identified as the primary tumor in 123 patients, and adenosquamous carcinoma was identified as such in 3 patients. A total of 950 lymph nodes taken from 49 patients undergoing either initial radical resection or radical second resection (median, 17 per patient) were examined histologically for metastasis; a representative section 3 µm thick was cut from each lymph node and stained with hematoxylin and eosin. Although none of our patients had any gross residual tumor, microscopic residual tumor (R1) was found on resection margins in nine patients.

Prognostic Factors
To determine factors that may influence postresectional survival, 12 variableswere entered into univariate and multivariate analyses (Tables 3 and 4). Nodalstatus was not entered into the analyses because of the uncertainty of nodal status in patients undergoing cholecystectomy alone.


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  		TABLE 3. Univariate analysis of prognostic factors in 126 patients with pT2 gallbladder carcinoma
 

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  		TABLE 4. Independent prognostic factors in 126 patients with pT2 gallbladder carcinoma
 
Statistical Analysis
Medical records and survival data were obtained for all 126 patients. The causes of death were determined from medical records. Deaths from other causes were treated as censored cases. Survival time in each patient was defined as the interval between the date of the resection and that of the last follow-up; in patients with inapparent tumor, it was defined as the interval from the date of radical second resection. Survival curves were constructed by using the Kaplan-Meier method, and differences in survival were evaluated with the log-rank test. Cox’s proportional hazards model, in which a stepwise selection is used for variable selection with entry and removal limits ofP < .1 andP > .15, respectively, was performed to identify factors that were independently associated with postresectional survival. The stability of this model was confirmed by using a step-backward and step-forward fitting procedure; the variables identified as having an independent influence on survival were identical with both procedures. Fisher’s exact test was used to evaluate the correlation between depth of subserosal invasion and nodal status in 49 patients undergoing radical resection. All statistical evaluations were performed with theSPSS 9.0J software package (SPSS Japan Inc., Tokyo, Japan). All tests were two sided, andP < .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Survival rates after resection in all 126 patients were 75% at 3 years and 66% at 5 years. The depth of subserosal invasion ranged from .2 to 17.0 mm (median, 2.5 mm), with 60 patients having a depth of subserosal invasion of <=2 mm and 66 patients having a depth of >2 mm.

Effectiveness of Initial Radical Resection for Clinically Evident pT2 Tumors
Among the 51 patients with clinically evident pT2 tumor, the outcome after resection was significantly better in patients who underwent initial radical resection than in patients who underwent cholecystectomy alone (P = .0027;Fig. 2). When these 51 patients were divided into two groups according to the depth of subserosal invasion (<=2 vs. >2 mm), the effectiveness of initial radical resection remained only in the group of patients with subserosal invasion >2 mm (P = .0149;Fig. 3).



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  		FIG. 2. Kaplan-Meier survival estimates according to type of resection in 51 patients with clinically evident pT2 tumor. Postresectional survival was significantly better in patients undergoing initial radical resection (cumulative 5-year survival rate of 82%) than in patients undergoing cholecystectomy alone (47%;P = .0027).

 


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  		FIG. 3. Kaplan-Meier survival estimates according to type of resection in patients with clinically evident tumor. (A) In 24 patients with depth of subserosal invasion <=2 mm, the outcome after initial radical resection (cumulative 5-year survival rate of 100%) was comparable to that after cholecystectomy alone (88%;P = .1722). (B) In 27 patients with depth of subserosal invasion >2 mm, postresectional survival was significantly better in patients undergoing initial radical resection (59%) than in patients undergoing cholecystectomy alone (17%;P = .0149).

 
Effectiveness of Radical Second Resection for Inapparent pT2 Tumors
Among the 75 patients with inapparent pT2 tumor, the outcome after resection was significantly better in patients who underwent radical second resection than in patients who underwent cholecystectomy alone (P = .0006;Fig. 4). When these 75 patients were divided into two groups according to the depth of subserosal invasion (<=2 vs. >2 mm), the effectiveness of radical second resection remained only in the group of patients with subserosal invasion >2 mm (P = .0004;Fig. 5).



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  		FIG. 4. Kaplan-Meier survival estimates according to type of resection in 75 patients with inapparent pT2 tumor. Postresectional survival was significantly better in patients undergoing radical second resection (cumulative 5-year survival rate of 95%) than in patients undergoing cholecystectomy alone (52%;P = .0006).

 


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  		FIG. 5. Kaplan-Meier survival estimates according to type of resection in patients with inapparent tumor. (A) In 36 patients with depth of subserosal invasion <=2 mm, the outcome after radical second resection (cumulative 5-year survival rate of 100%) was comparable to that after cholecystectomy alone (85%;P = .2229). (B) In 39 patients with depth of subserosal invasion >2 mm, postresectional survival was significantly better in patients undergoing radical second resection (90%) than in patients undergoing cholecystectomy alone (22%;P = .0004).

 
Factors Influencing Long-Term Survival After Resection
Univariate analysis revealed that depth of subserosal invasion (P < .0001), type of resection (P < .0001), residual tumor status (P < .0001), and blood vessel invasion (P = .0041) were significant prognostic factors (Table 3). All 12 variables were entered into multivariate analysis. Five variables—depth of subserosal invasion (P < .0001), type of resection (P = .0001), residual tumor status (P = .0133), gallstone status (P = .0723), and age (P = .0807)—were independent prognostic factors (Table 4). Thus, depth of subserosal invasion was the strongest independent prognostic factor in patients with resectable pT2 tumor.

Correlation Between Depth of Subserosal Invasion and Nodal Status
Of 49 radically resected patients, 21 (43%) had 54 positive lymph nodes (median, 2 per patient). They included 18 patients with pN1 disease and 3 with aortocaval lymph node metastasis (M1). To date, there have been fourteen 5-year survivors with positive lymph nodes; this includes 13 patients with pN1 disease and 1 with M1 nodal disease (Fig. 6). The incidence of nodal disease was significantly higher in patients with subserosal invasion >2 mm (14 of 23; 61%) than in patients with subserosal invasion <=2 mm (7 of 26; 27%;P = .022).



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  		FIG. 6. Kaplan-Meier survival estimates according to nodal status in 49 patients who underwent either initial radical resection (n = 29) or radical second resection (n = 20). The median length of survival was 76 months, with a cumulative 5-year survival rate of 96% in patients without nodal metastasis. The median length of survival was 118 months, with a cumulative 5-year survival rate of 75% in patients with nodal metastasis. Postresectional survival was significantly worse in patients with nodal metastasis than in patients without nodal metastasis (P = .0104).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study is the first to demonstrate that the depth of subserosal invasion is the strongest independent prognostic factor in patients with resectable pT2 gallbladder carcinoma. The depth of subserosal invasion may predict long-term survival in patients because it reflects the bulk of the invasive tumor. When the depth of subserosal invasion was >2 mm, radical resection provided significant survival benefits for both patients with clinically evident pT2 gallbladder carcinoma and patients with inapparent pT2 tumor.

The depth of subserosal invasion is particularly important when managing patients with inapparent pT2 gallbladder carcinoma, because it can be determined histologically in the cholecystectomized specimen before a radical second resection is considered for the patient. In this study, radical second resection provided a significant survival benefit only for patients with deep subserosal invasion (>2 mm), and therefore these patients seem to be good candidates for radical second resection. However, considering that patients with shallow subserosal invasion (<=2 mm) showed a 27% incidence of nodal disease in this series, these patients should not be disregarded for radical second resection, provided that they are robust.

Nodal status is another important prognostic factor in gallbladder carcinoma.9,10,16,29 Fahim et al.30 reported that lymph node metastasis may occur before involvement develops of the liver and/or other adjacent organs in gallbladder carcinoma. This is consistent with the fact that half of our patients had nodal disease despite no other organ involvement. Thus, metastasis to the regional lymph nodes seems a relatively early event in the development of metastatic involvement from gallbladder carcinoma.

In 1954, Glenn and Hays12 first proposed the significance of lymph node dissection in surgical treatment for gallbladder carcinoma. In 1963, Fahim et al.14 also advocated regional lymphadenectomy for this disease. Accordingly, we have used systematic regional lymph node dissection for pT2 or more advanced tumors since the early 1980s.4,31–33 The fact that two thirds of our patients with positive nodes have survived >=5 years after radical resection suggests that regional lymph node dissection is effective for pT2 gallbladder carcinoma.

Residual tumor status was also identified as an independent prognostic factor in this study; positive resection margins provided an unfavorable prognosis after resection. Earlier studies have shown similar results.4,6,9,29 Therefore, surgeons should pursue negative resection margins whenever they perform a resection for gallbladder carcinoma. In this context, it may be appropriate to perform a second resection to achieve a negative margin when residual tumor is found in the cholecystectomized specimen.

Multiple sections of the whole tumor were examined histologically to determine the depth of subserosal invasion in this series. The results of this study, thus, may be applicable only to patients in whom the depth of subserosal invasion was determined on multiple sections. Because the depth of subserosal invasion affects the surgical strategy for inapparent pT2 gallbladder carcinoma, determination of depth of subserosal invasion by using multiple sections is recommended when managing patients with inapparent pT2 tumor.

This is the largest study dealing with pT2 gallbladder carcinoma, but it has limitations. First, it was a retrospective analysis of a small number of patients, and second, the follow-up period in 19 patients was <60 months. However, we believe that these limitations do not significantly influence the outcome of the study, because the differences between groups were too marked to have resulted from these biases.

In conclusion, depth of subserosal invasion best predicts long-term survival after resection in patients with pT2 gallbladder carcinoma. Among patients with inapparent pT2 tumors, those with subserosal invasion >2 mm are good candidates for radical second resection. Because one in four of these patients with subserosal invasion <=2 mm will have nodal disease, radical second resection should not be ruled out, provided the patient is robust.


   Footnotes
 
Depth of subserosal invasion best predicts postresectional long-term survival in patients with T2 gallbladder carcinoma. Among patients with inapparent T2 tumor, those with subserosal invasion >2 mm are strong candidates for radical second resection.

Received for publication June 20, 2002. Accepted for publication November 14, 2002.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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