Received: 8 June 2000Accepted: 14 June 2000Published online: 1 November 2000© Springer-Verlag 2000

Abstract Background: Radicallymph node dissection in surgery for advanced gallbladder cancer iscontroversial. The purpose of thisstudy is to evaluate the role of lymph node dissection based on theclinico-pathologic results.Patients: Seventy-three patients whounderwent radical surgery includingsystematic dissection of the N1+N2region lymph node plus some of thepara-aortic nodes were reviewed.Results: pT1 patients had no lymphnode metastasis, but pT2 andpT3/pT4 patients had lymph nodemetastasis at a rate of 50.0% (13/26)and 83.3% (25/30), respectively. Asinfiltration of the hepatoduodenalligament (Binf) became severe, therate and extent of lymph node metas-tasis increased. There were four 5-year survivors with lymph node in-volvement. The 5-year survival ratesare 77.0% in pN0 cases and 27.3%in pN1 cases (P<0.01). There was nodifference in survival between pN1

and pN2 patients. However, signifi-cant differences in survival were observed between pN0/1 and pN2/3patients when these patients werelimited to Binf0/1. Examination ofthe recurrence pattern showed thatmost patients with pN0/1/2 had noregional lymph node recurrence, butthere was para-aortic lymph node recurrence in patients with pN3 out-side the dissected region. Significantprognostic factors influencing sur-vival after surgery by multivariateanalysis were pN2/3, pT, and residu-al tumor. Conclusion: Systematiclymph node dissection of N1, N2,and part of the para-aortic region im-proves survival in advanced gall-bladder cancer patients, especially inthose without either para-aorticlymph node metastases or Binf2/3.

Keywords Systematic lymph nodedissection · Radical surgery · Recurrence pattern · Clinical outcome · Indication

Langenbeck’s Arch Surg (2000) 385:509–514DOI 10.1007/s004230000163 C U R R E N T C O N C E P T S I N C L I N I C A L S U R G E RY

Hiroshi ShimadaItaru EndoYoshiro FujiiNoriyuki KamiyaHideki MasunariOsamu KunihiroKuniya TanakaKouichiro MisutaShinji Togo

Appraisal of surgical resection of gallbladder cancer with special reference to lymph node dissection

Introduction

Gallbladder cancer is a late symptomatic disease, andmost patients are treated only at an advanced stage.Prognosis is therefore poor.

The surgical management of gallbladder cancer iscontroversial, especially regarding the indications forradical resection in advanced cases. Recent Japanese re-ports suggest that extended operations combining hepaticresection with extensive lymph node dissection can im-prove long-term survival [1, 2, 3,4].

On the other hand, a French multicenter study foundthat the 5-year survival rate of patients with lymph nodemetastasis was 0%. This result led those authors to pro-pose that radical resection should only be considered inthe absence of regional lymph node metastasis [5].

The present authors [3] have already discussed the roleof extended lymph node dissection in the treatment of ad-vanced gallbladder cancer and have proposed indicationsfor patients without moderate or severe infiltration of thehepatoduodenal ligament. However, it is still unclearwhich subset of patients can benefit from radical surgery.

H. Shimada (✉ ) · I. Endo · Y. FujiiN. Kamiya · H. Masunari · O. KunihiroK. Tanaka · K. Misuta · S. TogoDepartment of Surgery II, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japane-mail: hs440312@med.yokohama-cu.ac.jpTel.: +81-45-7872650 Fax: +81-45-7829161

The purpose of the present study is to analyze the re-sults of curative resection for gallbladder cancer and todetermine the most appropriate indications for extendedlymph node dissection in advanced gallbladder cancer.

Patients and methods

During the 15 years between 1983 and 1991 at Fukui MedicalSchool, and between 1992 and 1999 at Yokohama City University,73 patients with gallbladder cancer underwent radical surgery.

There were 18 men and 55 women, with an average age of 65.7(range 33–84) years. According to the TNM classification of theUnion internationale contre le cancer (UICC) [6], patients wereclassified as follows: pT1 (n=17); pT2 (n=26); pT3/4 (n=30); pN0(n=35); pN1 (n=11); pN2 (n=13); 14 patients had positive para-aortic lymph nodes (pN3), and all patients were M0 (Table 1).

According to the Japanese Rules for Surgical and PathologicalStudies [7], infiltration of the hepatoduodenal ligament (Binf) is

categorized as negative (Binf0), mild (Binf1), moderate (Binf2),or severe (Binf3); and hepatic infiltration through the gallbladderbed (Hinf) is categorized as negative (Hinf0), suspicious (Hinf1),mild and confined to the surrounding tissues (Hinf2), or massforming (Hinf3).

The surgical procedures included extended hepatectomy andpancreatoduodenectomy (PD), and are listed in Table 2.

In the authors’ department, the standard radical surgical proce-dure for gallbladder cancer patients with pT2 and some with pT3and pT4 ranges from cholecystectomy with hepatic wedge resec-tion of the gallbladder bed to extended right hepatectomy, accord-ing to the extent of hepatic invasion, but includes resection of thesuprapancreatic extrahepatic bile duct, sometimes with PD, and enbloc dissection of the regional lymph nodes with the para-aorticlymph nodes, as previously reported [3].

PD was indicated for patients with marked lymph node metas-tasis around the head of the pancreas or direct invasion of the duo-denum.

The names of the regional lymph nodes of the gallbladder havenot been standardized internationally. Therefore, the authors [3]have used names and stages such as N1, N2, and para-aortic, asproposed by Shirai et al. [8], as a modification of the nomencla-ture of Fahin et al. [9].

The specimens were cut into 5-mm-thick tissue sections afterfixation in formaldehyde for 7–10 days. The fixed lymph nodeswere sectioned in the region of their maximum diameters.

Histologic findings were also evaluated according to the Japa-nese Rules for Surgical and Pathological Study [7].

The postoperative survival of patients was calculated by theproduct-limit mode of the Kaplan-Meier method, and differencesbetween the curves were measured using the generalized Wilcoxontest. Statistical comparisons were made by chi-squared analysis.Univariate and multivariate analyses were carried out using theCox proportional hazards model for significant prognostic factorsinfluencing survival.

Results

Lymph node involvement relative to depth of cancer invasion

Patients with pT1 disease had no lymph node metastasis.However, 50% (13/26) and 83.3% (25/30) of patientswith pT2 and pT3/pT4 disease, respectively, had lym-phatic metastasis (Table 3).

As the depth of cancer invasion became greater, thefrequency and extent of lymph node metastasis also in-creased.

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Table 1 Profile of patientswith resected gallbladder carci-noma

Age (years) 65.7 (33–84)

GenderMale 18Female 55

Histologyb

pap 24tub1 21tub2 12por 11ad-sq 2muc 2undiff 1

pTa

1a 101b 72 263 114 19

pNa

0 351 112 133 (para-aortic) 14

Stagea

1 172 133 104A 64B 27

Binfb

0–1 532–3 20

Hinfb

0–1 562–3 17

Residual tumora

R0 31R1 28R2 14

a According to the JapaneseRules for Surgical and Pathological Studies [7]b According to the Union inter-nationale contre le cancer(UICC) [6]

Table 2 Surgical procedures

Procedure Number of cases

Cholecystectomy with or without bile duct resection 19Liver bed resection with or without bile duct resection 23S4a + S5 hepatectomy 19Anterior segmentectomy 2Posterior segmentectomy + S5 + S4a 1Right trisegmentectomy with caudate lobectomy 2Extended right hepatectomy with caudate lobectomy 6Central bisegmentectomy 1

Lymph node involvement relative to invasion of the hepatoduodenal ligament

The proportion of lymph node involvement in patients withBinf0/1 was 35.8%. However, 95.0% of patients withBinf2/3 had lymph node metastasis, metastasis to the para-aortic lymph nodes being especially frequent (Table 4).

Survival rate

There were four 5-year survivors with lymph node me-tastasis (one pN1, two pN2, and one pN3 patients). The

overall 3- and 5-year survival rates were 49.3% and44.0%, respectively, based on the depth of cancer inva-sion; the 5-year survival rate was 85.7% in pT1 patients,48.5% in pT2 patients (P<0.05), and 18.4% in pT3/pT4patients (pT2 vs pT3/4: P<0.01). The 5-year survivalrates were 77.0% in pN0 patients, 27.3% in pN1(P<0.01), 10.0% in pN2, and 8.3% in pN3 patients andwere 58.3% in Binf0/1, 0% in Binf2/3 patients (P<0.01),and 50.7% in Hinf0/1, and 0% in Hinf2/3 patients(P<0.01; Table 5).

The survival curve of pN0/1 in the patients withBinf0/1 was significantly higher than that of pN2/3 re-gardless of the extent of Hinf, but this was not the casein the patients with Binf2 or 3 (Fig. 1).

Pattern of recurrence after radical operation

Of 15 patients without lymph node involvement, 3 diedas a result of recurrence. One of these three cases (pT4and Hinf3) showed para-aortic lymph node recurrence,while the other two patients (both pT2 and Hinf0) diedof carcinomatous peritonitis and liver metastasis, respec-tively. Of the ten pN1 cases, seven patients died becauseof recurrence. Two of the seven had hepatic metastasis,one had liver and lung metastasis, two had carcinoma-tous peritonitis, while one had pT4, Hinf2, and Binf3;and the last one, with pT2, fell victim to para-aorticlymph node recurrence. Out of nine pN2 cases, recur-rence in the para-aortic lymph nodes was seen in three.In four of the six cases of para-aortic lymph node metas-tasis, para-aortic lymph node metastasis was found out-side the dissected region, but control of the other twocases was achieved by extensive lymph node dissection(Table 6).

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Table 3 Lymph node metastasis in relation to depth of invasion.Definitions according to the Union Internationale Contre le Can-cer (UICC) [6]

pN0 pN1 pN2 pN3 (para-aortic)

pT1a 10 0 0 0pT1b 7 0 0 0 * ***pT2 13 5 4 4 **pT3/pT4 5 6 9 10

pN0 vs pN1+2+3: *P<0.01; **P<0.05; ***P<0.01

Table 4 Lymph node metastasis in relation to infiltration of thehepatoduodenal ligament

pN0a pN1 pN2 pN3 (para-aortic)

Binf0–1b 34 9 6 4 *Binf 2–3 1 2 7 10

pN0 vs pN1+2+3: *P<0.01a According to the Union internationale contre le cancer (UICC)[6]b According to the Japanese Rules for Surgical and PathologicalStudies [7]

Table 5 Cumulative survivalrates (excluding hospital deathsand death unrelated to gallblad-der cancer)

n One Three Five year years years

pTa1 15 100 86.7 86.7P<0.05pT2 26 88.0 52.9 48.5

P<0.01pT3/4 28 48.9 27.6 18.4Binf0+1b 51 88.2 65.4 58.3Binf2+3 18 32.7 0 0Hinf0+1b 54 81.1 57.4 50.7Hinf2+3 15 50.9 21.8 0pN0a 33 100 77.0 77.0

P<0.01pN1 11 54.5 27.3 27.3 ns pN0+1 vs pN2+3: P<0.01pN2 13 59.8 39.9 10.0 nspN3 13 33.3 8.3 8.3Stagea 1 15 100 86.7 86.7Stage 2 13 100 73.3 73.3Stage 3 10 70.0 40.0 40.0Stage 4A 6 66.7 22.2 0Stage 4B 25 48.5 24.8 9.9

a Subject to the Union interna-tionale contre le cancer (UICC)[6]b Subject to Japanese Rules forSurgical and Pathological Stud-ies [7]

Prognostic factors influencing survival

Univariate analysis revealed that survival was signifi-cantly related to seven factors: pT, pN (pN0/1 vs pN2/3),TNM stage, residual tumor, Binf (Binf0/1 vs Binf2/3),Hinf (Hinf0/1 vs Hinf2/3), and hepatectomy with vascu-lar resection.

Multivariate analysis revealed that of these seven fac-tors, pN (pN0/1 vs pN2/3), residual tumors and pT resid-ual tumor and pT were independent prognostic factorsinfluencing survival (Table 7).

Discussion

In the past, most surgeons had a pessimistic view of sur-gical treatment for patients with advanced gallbladdercancer, believing that surgery contributes to cure only inthe early stages of the disease [10,11].

However, most Japanese surgeons have become awareof the various spread patterns of advanced gallbladdercancer, which include lymphatic invasion, hepatic inva-sion via the gallbladder bed, bile duct invasion, and inva-sion to adjacent organs. Of these, lymphatic invasion andhepatic invasion via the gallbladder bed are classified asspread patterns curable by radical surgery [12, 13, 14,15].

Lymph node involvement is an important prognosticfactor in gallbladder cancer. In 1962, Fahin et al. [9] ad-vocated lymph node dissection for gallbladder cancer.Shirai et al. [16] and the present authors [3] reported sev-eral cases of long-term survival of patients with ad-vanced gallbladder cancer and lymph node involvementof N1 and part of the N2 region in which treatment bysystematic lymph node dissection of N1+N2+part of thepara-aortic region was performed.

By contrast, a recent French multicenter study [5]found that the 5-year survival rate for patients withlymph node metastasis was 0%. No information was pro-vided regarding the rigorousness of the approach to theindications, the surgical procedures employed for lymph

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Fig. 1 Cumulative survival ofpatients with pT*2/3/4 accord-ing to lymph node metastasis(excluding hospital deaths andR*0+1 patients). *According tothe Union internationale contrele cancer (UICC) [6]; †Accord-ing to the Japanese Rules forSurgical and Pathological Stud-ies [7]

Table 6 Recurrence patterns in patients with pT2/3/4 (excludingR*0+1)

Local Liver Lymph Peritoneum Distant node organ

Hinf0–1a

pN0b (2/12) 1 1pN1 (4/7) 2 1 2pN2+3 (7/10) 1 2 5 2 1

Hinf2/3pN0 (1/3) 1pN1 (3/3) 2 1 1 1pN2+3 (5/6) 2 4 2 1

a According to the Union internationale contre le cancer (UICC)[6]b According to the Japanese Rules for Surgical and PathologicalStudies [7]

Table 7 Multivariate analysis of prognostic factors using Cox’sproportional hazard regression model (Bm bile duct margins, Emexcisional margins)

Variables Grading Regression Standard Chi- P valuecoefficient error square

pNa 1: pN0+1 0.7535 0.3814 3.9037 0.04822: pN2+3

Bmb 1: Bm0 0.7592 0.3086 6.0520 0.01392: Bm13: Bm2

Emb 1: Em0 0.7846 0.2409 10.6131 0.00112: Em13: Em2

pTa 1: pT2 0.5232 0.22346 5.4761 0.01932: pT33: pT4

a According to the Union Internationale Contre le Cancer (UICC)[6]b SAccording to the Japanese Rules for Surgical and PathologicalStudies [7]

node dissection, or the histologic examination of the re-sected lymph node specimens. However, it is well withinthe bounds of possibility that strictly adhering to the pro-tocol in a multicenter study presented many difficulties,and the reason for the absence of any long-term survivorwith lymph node metastasis may have been that most pa-tients with lymph node metastasis also had Binf2/3.

It is necessary to clarify whether lymph node dissec-tion improves the survival of patients with advancedgallbladder cancer and at what stage systematic lymphnode dissection is advisable or valuable.

The authors [3] have already reported on the use ofsystematic lymph node dissection with or without PD foradvanced gallbladder cancer and on the correlation of thefrequency and extent of lymph node involvement with thedepth of cancer invasion and with the extent of hepatodu-odenal ligament invasion. This result was almost thesame as that stated in the Japanese literature [13,15].

In the current series, the patient with pT1 disease hadno lymph node involvement, and those with pT2 diseasewith invasion of the subserosal layer had a high frequen-cy of lymph node involvement, as was the case in the se-ries reported by Yoshikawa et al. [17]. This result is alsosupported by the fact that in the subserosal layer of thegallbladder wall, there are rich networks of blood andlymph vessels through which invading cancer cells canspread, but it is controversial as to whether or not gall-bladder cancer that has invaded as deep as the muscularlayer is actually accompanied by lymph node metastasis.

Regarding infiltration of the hepatoduodenal liga-ment, half of the patients with moderate-to-severe infil-tration of the hepatoduodenal ligament had undergonepara-aortic lymph node metastasis.

This result is also supported by the fact there is a richabundance of lymph and blood vessels and of autonomicnerve fibers in the hepatoduodenal ligament.

In the present study, four patients with positive lymphnodes, comprising one pN1, two pN2, and one pN3 pa-tients, survived for more than 5 years. The 5-year surviv-al were 77.0% for pN0 patients, 27.3% for pN1, and

10% for pN2/3 patients. These results, which were al-most the same as those of the other Japanese reports,were superior to those reported in the French survey [5].

Systematic lymph node dissection is performed in theN1+N2 regions and in part of the para-aortic region, anda significant difference in survival between pN1 and pN2patients or between pN1/2 and pN3 patients might be ex-pected. However, there was no such significant differ-ence in this study. When the patients were limited tothose with Binf0/1, there was a significant difference insurvival between pN0/1 and pN2/3 patients.

The present authors [3] also proposed that lymph nodedissection of N1 and the posterior pancreaticoduodenal(N2) lymph nodes and partial para-aortic lymph node isimportant to improve the prognosis of pT2 disease.

Noie et al. [18] reported that based on the relationshipbetween recurrence patterns and the extent of lymphnode dissection in the patients undergoing radical sur-gery, two out of eight patients with recurrence mighthave been cured by extensive regional lymph node dis-section, including dissection of the para-aortic lymphnodes and the nodes around the head of the pancreas. Incomparison with Noie et al.’s report [18], our seriesshowed less recurrence, involving fewer lymph nodesites, with no regional bias because of the wider scope ofthe lymph node dissection. Shirai et al. [19] has also re-ported that the 5-year survival of stages II–IV was 29%and that N2 tumors should be considered for curative re-section because prolonged survival is possible.

To determine the usefulness and limitations of our ex-tended lymph node dissection, we analyzed the mostlikely predictive factors for survival by univariate andmultivariate analysis. N2 (not N1), para-aortic node me-tastasis, pT, and residual tumors influenced 5-year sur-vival. These results led the authors to conclude that pa-tients with regional lymph node involvement must beconsidered for curative resection, because long-term sur-vival is indeed possible. However, for the pN2, pN3 pa-tient with Binf2,3, adjuvant chemotherapy to prevent re-currence is necessary to achieve long-term survival.

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