Abstract
Background/Aim: The aim of the present study was to clarify if the degree of hepatic infiltration and lymph node swelling of gallbladder carcinoma (GBC) should be held as deciding factors for T2-4 GBC patients to undergo surgery. Patients and Methods: Fifty consecutive patients with T2-4 GBC who underwent surgery were reviewed retrospectively. We investigated the preoperative information and imaging factors as predictors of survival. Results: The estimated overall survival in all patients was lower in patients with hepatic infiltration ≥5 mm (n=12) than in those with <5 mm (n=38) (p=0.003). Multivariate analyses demonstrated that liver infiltration ≥5 mm (OR=2.251; 95%CI=0.906-5.596, p=0.081) and lymph node swelling (OR=2.462; 95%CI=1.034-5.859, p=0.042) were risk factors of poor survival. Conclusion: Our results suggested that ≥5 mm liver infiltration and lymph node swelling may serve as deciding factors for surgery consideration in GBC patients.
Gallbladder carcinoma (GBC) rapidly invades the serosa and adjacent organs as the gallbladder wall lacks a muscularis mucosae layer (1). A national study of 4,770 GBC patients in Japan revealed high morbidity and mortality rates in these patients despite aggressive surgical resection and adjuvant chemotherapy (2, 3). Although half the patients with T2-4 GBC experienced recurrence within one year even after complete resection through extended surgery such as hepatopancreatoduodenectomy (3-6), the characteristics of GBC patients who are at increased risk of early recurrence have not been discussed. Therefore, an investigation whether radical resection is the only curative option for GBC is necessary (7). With the advancement of chemotherapy (8-12) or radiation therapy (13), one should reconsider the therapeutic balance between tumor biology and extended surgery (7, 14, 15). Recent studies revealed that patients with inoperable/metastatic GBC who underwent chemotherapy have better prognosis with 9.5 to 20.3 months median overall survival (8-12).
The National comprehensive cancer network (NCCN) clinical practice guidelines are based on two almost identical popular staging systems from the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM), respectively (16, 17). However, the current TNM classification of T2-4 GBC describes only the liver infiltration itself and not the degree of liver infiltration as a factor for surgical indication. Extensive surgery is still considered a curative therapy even when the advanced GBC massively infiltrates the liver. A further study of operative procedures is required to determine the survival advantages of radical surgery in patients with advanced GBC (2). While precise preoperative TNM staging for GBC is difficult (18), recent studies reported that advancement in imaging study has allowed evaluation of adjacent organs (19, 20) and lymph node metastasis more precisely. Therefore, the degree of hepatic infiltration and lymph node swelling of GBC, measured by multidetector computerized tomography (MD-CT) should be re-evaluated to avoid unnecessary surgery. The aim of the present study was to clarify if the degree of hepatic infiltration and lymph node swelling of GBC should be held as deciding factors for T2-4 GBC patients to undergo surgery.
Patients and Methods
Patients' characteristics. Between September 2000 and January 2015, 50 consecutive patients who underwent surgery with/without node dissection (D0: n=1; D1: n=3; D2: n=43; D3: n=3), including four (8%) extended right hepatectomy, one (2%) extended left hepatectomy, 10 (20%) hepatectomy of segment 4a and 5 (S4a+5), 18 (36%) gallbladder bed resection, 6 (12%) cholecystectomy, 3 (6%) pancreaticoduodenectomy, and 8 (16%) hepatopancreatoduodenectomy for T2-4 GBC at the Wakayama Medical University Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
All patients underwent peritoneal lavage for cytological analysis right after laparotomy. One patient with distant metastasis including a tiny peritoneal dissemination or liver metastasis was excluded from this study. All tumor specimens contained the adenocarcinoma component. Gallbladder bed resection was defined as wedge resection of the liver surrounding the gallbladder bed (21). Regional lymph nodes were classified according to a previous study (18). A D2 lymph node dissection was performed along the hepatic artery and peripancreatic region around the pancreatic head (18). Routine resection of the bile duct during the lymph node was not performed. The para-aortic nodes were not dissected except to retrieve the swelling para-aortic nodes. The stages of GBC were based on the TNM classification. All patients with GBC had postoperative adjuvant chemotherapy with one who also received neoadjuvant therapy.
The outcomes of the operation in patients with T2-4 GBC are discussed in terms of the preoperative available information, complications and survival. Every patient was followed-up every one to three months in the outpatient clinic. The clinical data and follow-up information for each patient were obtained from the medical records.
Preoperatively available information in patients with gallbladder carcinoma. We defined preoperatively available information as follows; clinical factors including sex (2), age, the presence of bile duct invasion (3), and the presence of pancreaticobiliary maljunction identified radiological examination; imaging factors which included significant lymph node swelling defined as a minimum of >10 mm in diameter regardless of the shape (round/flat), the depth of the direct liver invasion of >5 mm, portal vein invasion, and hepatic artery invasion. The 5 mm depth of direct invasion was selected as a criterion of the histopathological border between pathological T3 (Stage III) and pathological T4 (Stage IVA) in terms of direct liver invasion based on the previous Japanese General Rules for Surgical and Pathological Studies on Cancer of the Biliary Tract, 5th edition (22).
Depth of direct liver infiltration. Plain/dynamic multidetector computerized tomography (MD-CT) was used to determine the depth of direct liver infiltration. We previously described the conditions for dynamic MD-CT imaging (23). The depth of liver infiltration was determined blindly and independently by attending radiologists measuring the invasion distance in the direction of perpendicular to gallblader wall on axial/coronal/sagittal images by the computed tomography (CT) (Figure 1). The distance was measured in the portal venous and equilibrium phase. The maximum value was defined as the depth of the direct liver infiltration.
Definition of postoperative complications. Biliary fistula, surgical site infections and intra-abdominal abscess were defined as previously reported (23). The global morbidity rate and the type of complications were evaluated by Dindo's classification (24). Mortality was defined as all deaths related to surgery.
Baseline and operative characteristics of T2-4 gallbladder patients.
Statistical analysis. The statistical analysis methods used in the study were described previously (25). A value of p<0.05 was considered significantly different. All of the analyses were performed using the statistical software package SPSS II (version 20.0; SPSS, Inc., Chicago, IL, USA).
Results
Patients' characteristics and postoperative complications. Table I shows patients' characteristics and operative outcomes. There were 16 patients with T2, 31 with T3, and three with T4. Cytological analysis via peritoneal lavage revealed positive for cancer cells in one patient (2%) who underwent gallbladder bed resection without node dissection. R0 resection was performed in 47 (94%) patients in this series. Para-aortic node was positive for metastasis in three patients. Histopathological examination revealed vascular invasion in portal vein in four patients and the artery in two patients. However, these patients underwent pathologically radical surgery at the dissection margins. Table I also shows the postoperative complications evaluated by Dindo's classification in patients who underwent surgery in the present study. Two patients expired; one had aspiration pneumonia while the other had liver failure.
Depth of the liver infiltration was measured using the method for measuring shortest distance on axial/coronal/sagittal images, where appropriate, in the deepest part by the computed tomography. The maximum value was defined as the depth of the direct liver infiltration.
Survival. The median follow-up for all patients was 16 months. The estimated one-year and two-year survival rates after surgery were 74% and 55% respectively. The estimated median survival time was 26 months. Estimated recurrence-free survival of all cases was 87 months; nine patients survived without recurrence beyond five years after surgery. The first recurrence site was diagnosed by CT at 30 sites in 22 patients as a solitary or a multiple simultaneous lesion; liver (n=13), lymph node (n=9), peritoneum (n=5), lung (n=1), spleen (n=1), and bone (n=1). The estimated overall survival in all patients was lower in patients with hepatic infiltration of ≥5 mm (n=12) than in those with <5 mm (n=38) (p=0.003, log-rank test) (Figure 2A). The estimated recurrence-free survival in all patients was lower in patients with hepatic infiltration of ≥5 mm (n=12) than in those with <5 mm (n=38) (p=0.083, log-rank test) (Figure 2b). Six of seven (86%) patients with hepatic infiltration of ≥5 mm experienced recurrence within a year. Comparison of survival curves according to positive/negative invasion of portal vein (p=0.262) or artery (p=0.811) revealed no differences between groups. The correlation between imaging diagnosis and pathological result of liver infiltration and lymph node metastasis.
Correlation between image-hepatic infiltration and pathological result.
Correlation between image-N and pN.
Tables II and III show the correlation between liver infiltration of ≥5 mm and pathological liver infiltration depth of ≥5 mm, and that of the lymph node swelling and pathological lymph node metastasis, respectively. The sensitivity, specificity and accuracy were 92%, 100% and 98%, respectively, in liver infiltration; 54%, 86% and 68%, respectively, in lymph node swelling. MD-CT provided excellent accuracy in the diagnosis of the liver infiltration of ≥5 mm.
Preoperative predictors of survival in GBC. Univariate analysis identified three factors that were associated with decreased survival time (Table IV): liver infiltration of ≥5 mm (OR=2.903; 95%CI=0.921-9.148, p=0.069), the presence of bile duct invasion (OR=3.879; 95%CI=0.840-17.918, p=0.083), and lymph node swelling (OR=2.653; 95%CI=1.053-6.679, p=0.038). Table 4 illustrates the two factors retained in multivariate logistic regression analysis. Liver infiltration of ≥5 mm (OR=2.251; 95%CI=0.906–5.596, p=0.081) and lymph node swelling (OR=2.462; 95%CI=1.034-5.859, p=0.042) remained risk factors for poor survival. The estimated overall survival rate in patients with liver infiltration of ≥5 mm and lymph node swelling (n=13) was lower than that of the other patients (n=37) (p=0.001, log-rank test) (Figure 3). In the former group, seven out of 13 (54%) patients died from early GBC recurrence within a year.
A: Estimated overall survival in all patients was lower in those with image-hepatic infiltration of ≥5 mm (dotted line, n=12) than in those with <5 mm (solid line, n=38) (p=0.003, log-rank test). B: The estimated recurrence-free survival in all patients was lower in patients with hepatic infiltration of ≥5 mm (dotted line, n=12) than in those with <5 mm (solid line, n=38) (p=0.083, log-rank test).
Discussion
In the present study, we identified two factors that may be considered when deciding surgery for T2-4 GBC patients based on preoperative information. The two factors are liver infiltration of ≥5 mm and lymph node swelling as their presence showed a poorer prognosis after surgery. Half of these patients died from early GBC recurrence within a year even after the curative surgery. Although these results of this study are not surprising findings, the current TNM classification of GBC describes only the liver infiltration itself and not the degree of liver infiltration as a factor for surgical indication.
T2 GBC is infiltrating the perimuscular connective tissue or subserosal layer without macroscopic liver invasion, however, we included T2 GBC in the present study since there are significant differences of prognosis between stage II and III GBC patients and the preoperative diagnosis regarding presence or absence of liver invasion is critical.
For GBC surgery, vascular invasion itself is rarely treated as a contraindication for surgery except for patients with severe encasement of the portal vein or the proper hepatic artery. Recent literature reported that portal invasion, lymph node metastasis, surgical margin, and the final curability were independent prognostic factors (5, 6, 26). The incidence of portal invasion is low and hence would fail to exclude patients with high risk of early recurrence. Kokudo et al. proposed that algorithms for the surgical treatment of GBC by integrating image-T classification and data from the intraoperative histopathological examination of key lymph nodes (18). However, the feasibility of the examination depends on the presence of pathologist and the accuracy of frozen section depends on the institution-to-institution variations which is usually lower compared with permanent specimens. In addition, the resolution of MD-CT is still advancing through technology innovation. Therefore, we repeated the investigation on the preoperatively available prognostic factors to categorize GBC patients at increased risk of early recurrence.
Estimated overall survival rate in patients with image-liver infiltration ≥5 mm and significant lymph node swelling (dotted line, n=13) was lower than that of other patients (solid line, n=37) (p=0.001, log-rank test).
Kokudo et al. reported the overall diagnostic accuracy for image-T was lower especially in patients with pT1 and pT2 GBC (18). Here, we showed overall diagnostic accuracy for liver infiltration of ≥5 mm (98%), and this factor was easy to be detected and measurable using the latest MD-CT. This result reflects that the detection of liver infiltration is more difficult than that of the depth of liver infiltration. A recent study also demonstrated that the addition of multiplanar reconstruction images to the axial CT data increased the accuracy in T-staging of GBC. In regard to lymph node swelling, the overall diagnostic accuracy of lymph node swelling was not decisive and sensitivity is low, possibly due to the influence of obstructive jaundice, cholangitis and micrometastasis (27). Therefore, the lymph node swelling might be useless by itself in considering surgery. However, the lymph node swelling is still a relatively strong consideration factor for surgery among the preoperatively available information. In fact, combination screening of the two factors identified patients with significantly poorer prognosis.
Univariate and multivariate analyses: preoperative risk factors of overall survival.
Specific chemotherapy or radiation therapy for GBC has yet to be established. Recent studies reported several regimens merit further investigation in the neoadjuvant setting in GBC surgical strategy (9, 12). In the present study, we investigated GBC characteristics with a high risk of recurrence. These patients might gain survival benefit if they received more intensive preoperative and postoperative chemotherapy, and subsequent optimal surgery (28-31).
The major limitations of this study were the small number of patients and the relatively short follow-up period. They might have affected the data of survival curves between the groups and those of prognostic factors. Recurrence-free survivals between GBC patients with hepatic infiltration of ≥5 mm, and those with <5 mm were not significantly different. In addition, these series contain various kinds of operation. We could not lead the suitable procedures for GBC with hepatic infiltration of ≥5 mm. Furthermore, the depth of hepatic infiltration detected by preoperative imaging study was not an independent prognostic factor by multivatiate analysis. Additional studies with a larger number for limited patients with hepatic side T2-4 GBC who undergo same procedure and with a longer follow-up period are warranted to confirm our present findings (32).
In conclusion, our results suggested that liver infiltration of ≥5 mm together with lymph node swelling may be reliable factors when considering surgery for T2-4 GBC patients.
Acknowledgements
The Authors would like to thank Shenli Hew from the Department of Clinical Research Center, Wakayama Medical University, for proofreading and editing the manuscript.
Footnotes
Funding
There is no funding or material support on this study.
Conflicts of Interests
All Authors declare that they have no conflict of interest.
- Received April 3, 2016.
- Revision received May 11, 2016.
- Accepted May 17, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.