Indications for extrahepatic bile duct resection due to perineural invasion in patients with gallbladder cancer

Between 2001 and 2017, 68 patients with gallbladder cancer underwent surgical resection at the University of Yamanashi Hospital. Patients who underwent non-curative resection were excluded from the study. Thus, 50 patients who underwent surgery were included in this retrospective study. We diagnosed all cases as gallbladder cancer using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS) before surgery; therefore, there was no incidental cancer. None of the patients received preoperative chemotherapy or chemoradiotherapy. In principle, cholecystectomy with EHBD resection was performed in patients with gallbladder cancer except for those patients with mucosal cancer. The clinicopathological features of the cases were reviewed based on data recorded in the hospital database. Tumor specimens and resected lymph nodes were obtained at the time of surgery, fixed immediately in 10% neutral-buffered formalin, and embedded in paraffin. Macroscopic and microscopic classification of gallbladder cancer was based on the Union for International Cancer Control classification, 7th edition. Complications were defined using the Clavien classification, and grade ≥ 2 complications were recorded [10]. Tumors invading the neck or the cystic duct of the gallbladder were defined as proximal-type, and those localized in the body or the fundus were defined as distal-type. Circumferential tumor locations were categorized as hepatic and non-hepatic, and circumferential involvement was recorded as hepatic.

Postoperative follow-up comprised evaluation of hematological parameters, computed tomography, and ultrasonography. Follow-up procedures were performed every 3 months for at least 2 years and subsequently continued periodically for at least 5 years. The study was approved by the Ethics Committee of the Yamanashi University and performed in accordance with the ethical standards of the Declaration of Helsinki and its later amendments.

Comparisons between two groups were made using the Student’s t test. Associations between PNI and categorical variables were evaluated using the χ² test. Survival curves were constructed using the Kaplan–Meier method and compared using the log-rank test. Multivariate analyses of prognostic factors related to survival were performed using the Cox proportional hazards test. Statistical significance was set at a p < 0.05. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [11].

The clinicopathological characteristics of the patients included in the present study are summarized in Table 1. PNI adjacent to the tumor lesion was detected in 13 of the 50 cases (26.0%). Representative photomicrographic images of PNI are shown in Fig. 1. PNI was correlated significantly with male sex (p = 0.021), presence of postoperative chemotherapy (p < 0.001), presence of postoperative complications (p = 0.049), proximal-type tumor (p = 0.003), lymphatic invasion (p = 0.003), vascular invasion (p < 0.001), and advanced T stage (p = 0.010). PNI was not detected in patients with stage T1 cancer. PNI did not correlate with other clinicopathological factors such as N stage, numbers of resected lymph nodes, and lymph node ratio (Table 2).

The median follow-up period of the study cohort was 63 months. Figure 2 shows the survival curves stratified according to the PNI status. Briefly, the overall and disease-free survival rates were significantly lower in the PNI-positive patients compared with the PNI-negative patients (p < 0.005 and p < 0.001, respectively).

Univariate analysis identified lymphatic and vascular invasion as well as the N stage as significant prognostic factors, whereas age, sex, tumor size, tumor location, EHBD resection, and the T stage were not found to be significantly associated with prognosis (Table 3). Subsequent multivariate analysis demonstrated that the presence of PNI was an independent prognostic factor (p < 0.001), as were lymphatic invasion (p = 0.007) and N stage (p < 0.001) (Table 3).

In this series, PNI was found in only three of the 30 cases with distal-type gallbladder cancer; all three patients were treated by cholecystectomy with EHBD resection. However, all patients developed various types of recurrences even after R0 resection; therefore, the extended procedures were found not to have clinical therapeutic efficacy in these patients.