Laparoscopic total biopsy for suspected gallbladder cancer: A case series

Abstract Background and aims Imaging diagnosis of gallbladder cancer remains difficult to achieve preoperatively. We developed a novel approach based on laparoscopic whole‐layer cholecystectomy (LWLC) and laparoscopic gallbladder bed dissection (LGBD) for total biopsy, for ultimately determining the optimal treatment strategy for suspected gallbladder cancer detected on preoperative imaging. Here, we describe a case series of patients who underwent this procedure at our institution. Methods We retrospectively examined clinicopathological data of consecutive patients with suspected gallbladder carcinoma at Yamaguchi University Graduate School of Medicine from September 2016 to July 2018 on which a laparoscopic approach was used. Preoperative imaging findings suggestive of gallbladder cancer were defined as follows: elevated lesion >10 mm in diameter, increasing tumor size over time compared with the previous imaging, sessile lesion, irregular wall thickness lesion mimicking cancer, elevated lesion with dense enhancement, or positive results on fluorodeoxyglucose positron emission tomography. LWLC was performed for early‐stage or suspected malignant lesions without liver invasion, and LGBD was performed for lesions with an unclear border between the gallbladder and the liver. When postoperative pathological examination revealed the presence of gallbladder cancer invading into the subserosal layer, additional gallbladder bed resection and regional lymphadenectomy were considered. Patient characteristics, perioperative findings, pathological findings, and postoperative outcomes of patients who underwent LWLC or LGBD were reviewed retrospectively, and the short‐term outcomes of the laparoscopic approach were analyzed. Results Fifteen consecutive patients were included in the study. The median age of the patients was 63 years (IQR 42‐76 years); 7 patients were males. We performed LWLC in 12 cases and LBGD in 3 cases. Median (IQR) operation time was 159 (140‐193) min and median blood loss was 10 (5–30) mL. No bile leakage caused by intraoperative perforation of the gallbladder was seen. Median hospital stay was 7 (5–9) days. Only one patient developed postoperative complications (abdominal abscess). Histologically, gallbladder cancer was diagnosed in five cases (pT1a, n = 2; pT2, n = 3), and two of the pT2 patients underwent additional open surgery. Conclusions Our laparoscopic‐based approach for suspected gallbladder cancer might represent a safe strategy and could play an important role in defining the optimal treatment strategy.

Conclusions: Our laparoscopic-based approach for suspected gallbladder cancer might represent a safe strategy and could play an important role in defining the optimal treatment strategy.
gallbladder bed dissection, gallbladder cancer, laparoscopic surgery, Total biopsy, whole-layer Although laparoscopic cholecystectomy is a standard approach for benign lesions such as cholecystolithiasis, laparoscopic surgery for suspected gallbladder cancer has not been widely accepted because of the potential for peritoneal dissemination and port-site recurrence (PSR) by intraoperative gallbladder perforation of the thinned gallbladder wall. 1,2 On the other hand, definitive diagnosis of gallbladder cancer and determination of the exact depth of cancer invasion remain difficult to achieve preoperatively from various imaging modalities. [3][4][5] The gold standard for definitive diagnosis of gallbladder cancer is still pathological findings, and cholecystectomy is sometimes needed to attain total biopsy. 6 In general, the diagnostic procedure should be as noninvasive as possible, and a laparoscopic approach for suspected gallbladder cancer appears reasonable in this respect. 7 However, standard laparoscopic cholecystectomy remains risky in terms of exposing and spreading cancer cells during surgery. 8 With the twin aims of both evaluating oncological safety and exploring lower invasiveness, we tested a novel approach for laparoscopic whole-layer cholecystectomy (LWLC) and laparoscopic gallbladder bed dissection (LGBD) as total biopsy methods for suspected gallbladder cancer at our institution, and here, we report on the shortterm outcomes of a series of consecutive patients who underwent these procedures.

| METHODS
This is a retrospective case series investigating clinicopathological data of laparoscopic total biopsy for suspected gallbladder cancer at Yamaguchi University Graduate School of Medicine. From September 2016 to July 2018, a laparoscopic approach was applied for consecutive patients with suspected gallbladder carcinoma based on preoperative ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose-positron emission tomography (FDG-PET). Preoperative imaging findings of suspected gallbladder cancer were defined as: elevated lesion >10 mm in diameter, 9,10 increasing tumor size over time compared with the previous imaging, 9 sessile lesion, 9,10 irregular wall thickness lesion mimicking cancer, 3 elevated lesion with dense enhancement, 11,12 or positive accumulation on FDG-PET 13,14 (defined as an 18 F-FDG maximum standardized uptake value >3.65). To minimize the false negative rate in imaging diagnosis, patients with gallbladders that met at least one of the preceding findings identified by experienced radiologists at Yamaguchi University Graduate School of Medicine were eligible for the current study.
Patients with gallbladder lesions located closely to the cystic duct, Glissonian sheath, and/or hepatoduodenal ligament were excluded.
The algorithm used for the laparoscopic approach to gallbladder lesions is shown in Figure 1. Intraoperative US was performed first during the operation. Contrast-enhanced ultrasound, a reliable tool in the detection of focal liver lesions, 15 was used to investigate whether the gallbladder lesion had a well-or ill-defined border with the liver parenchyma. When an early-stage or malignant lesion without liver invasion was suspected, LWLC was performed. When imaging showed an ill-defined border between the gallbladder lesion and liver, LGBD was considered, and then the resection line of the liver was determined about 1 to 2 cm away from the gallbladder bed margin.
We also intended to resect the lymph nodes around the cystic artery and cystic duct, including the sentinel lymph nodes. After laparoscopic resection, pathologic examination of the gallbladder in permanent sections was performed to achieve a definitive diagnosis.
When postoperative pathologic examination revealed the presence of gallbladder cancer invading into the subserosal layer (ie, pT2), D2 lymphadenectomy and additional gallbladder bed resection were considered as the second stage operation with curative intent. D2 lymphadenectomy is defined as removal of the lymph nodes in hepatoduodenal ligament with bile duct resection, around the common hepatic artery, and around the posterosuperior region of the pancreas head. This was performed as a routine operation in the additional surgery for pT2 cancer. After LWLC for a pT2 gallbladder cancer in contact with the liver, additional gallbladder bed dissection was performed to confirm negative margin. On the other hand, when negative margin of the gallbladder bed was proven by resected specimen during total biopsy surgery, such as a pT2 gallbladder cancer located only on the free peritoneal side and a pT2 gallbladder cancer resected with the gallbladder bed, only D2 lymphadenectomy was performed. The residual tumor status for the stump of cystic duct was also investigated carefully in permanent section, and additional bile duct resection was considered when pathologic findings of cystic duct were positive. These additional procedures were performed as open surgery.
Patient characteristics, perioperative findings, pathologic findings, and postoperative outcomes of patients who underwent LWLC or LGBD were reviewed retrospectively, and the short-term outcomes of our laparoscopic approach were analyzed. All patients were followed-up postoperatively until death or May 2019.

| Statistical analysis
Background characteristics are presented as median and interquartile range (IQR) for continuous data, and as number and percentage for categorical data. Statistical analyses were performed using JMP version 13.0 software (SAS Institute Japan, Tokyo, Japan).

| Ethical considerations
This study was approved by the institutional review board of Yamaguchi University Hospital (H2019-009). Written informed consent was obtained from all patients.

| RESULTS
Fifteen consecutive patients who underwent laparoscopic total biopsy for suspected gallbladder cancer between September 2016 and July 2018 were included in the study. The median age of the patients was 63 years (IQR 42-76 years); 7 patients were males. F I G U R E 1 Algorithm for our laparoscopic approach to suspected gallbladder cancer. After laparoscopic total biopsy for suspected gallbladder cancer, pathologic examinations of permanent sections are performed for definitive diagnosis. When postoperative pathologic examination reveals pT2 gallbladder cancer, additional open gallbladder bed resection and regional lymphadenectomy are considered Short-term outcomes for patients who underwent laparoscopic total biopsy for suspected gallbladder cancer (n = 15) Operation methods
Short-term outcomes for the 15 patients who underwent laparoscopic total biopsy for suspected gallbladder cancer are shown in Table 1. We performed LWLC in 12 cases and LGBD in 3 cases.
Median operation time was 159 minutes (IQR 140-193 min) and median blood loss was 10 mL (IQR 5-30 mL). No bile leakage caused by intraoperative perforation of the gallbladder was encountered.
Abdominal abscess without bile leakage, as a Clavien-Dindo grade 3 complication, was observed in one patient after surgery (6.7%).
Clinicopathological features of the 15 patients are shown in Thus, patients presenting with radiologically suspicious gallbladder lesions might not always receive optimal surgery when imaging diagnosis alone is used for treatment planning. According to our algorithm, pathologic findings including depth of cancer invasion in the total biopsy specimen in permanent section, which provides information for making treatment decisions, can be obtained using minimally invasive procedures. Although intraoperative frozen tissue diagnosis is fairly reliable in determining whether lesions are malignant or benign, 21,22 the accuracy of frozen-section diagnosis in terms of the depth of cancer invasion could be limited. 22 In this respect, we decide the appropriate surgical strategy depending on the final pathologic diagnosis, including depth of cancer invasion, from permanent sections made after total biopsy.
As mentioned above, pT stage is the most important prognostic factor because the depth of gallbladder cancer invasion reflects lymphatic, perineural, and vascular invasion. 23 Prognosis is good for patients diagnosed with pT1a carcinoma, and additional resection is not necessary if the surgical margins are negative. 8 Although additional resection for patients with pT1b remains controversial, the fact remains that a small number of pT1b patients show positive lymph node metastasis. 8,24 Additional radical resection including regional lymphadenectomy is recommended in patients with pT2 or more advanced gallbladder cancer because positive lymph node metastasis could be observed at high rates. 8  In the present study, our laparoscopic approach achieved good short-term outcomes, although limitations include the fact that this is a case series, with a small number of patients and a short follow-up period. We believe that this procedure may offer a feasible method for achieving total biopsy of suspected gallbladder cancer and may have an important role to play in helping determine treatment strategies depending on the stage of gallbladder cancer. Since August 2018, the Yamaguchi Pancreatic/Biliary Disease Study Group has been conducting a prospective observational study to assess the safety and feasibility of these methods in a larger sample, in the Laparoscopic Approaches for suspected GallBladder cancer in Yamaguchi study (LAGBY study: UMIN000035352).