Gallbladder cancer (GBC), which is the most common type of biliary tract malignancy, has a high mortality and a poor dismal prognosis (1–4). Due to the lack of optimal treatment, GBC is considered as a highly lethal disease on the basis of depth and stage of tumor invasion with a 5-year survival of advanced tumors less than 5% (5). According to the 8th American Joint Committee on Cancer (AJCC) Staging Manual (6), simple cholecystectomy is selected for patients with Tis or T1a, while extended/radical cholecystectomy, including removal of adjacent liver parenchyma, resection of the common bile duct, and portal lymphadenectomy, is performed on patients with a histological stage greater than T1b (7).

With the development of advanced surgical devices and accumulation of clinical experience, the application of the laparoscopic approach (LA) has proved its oncologic feasibility and safety in general surgery fields, including liver cancer, gastric cancer, and colon cancer (8–10). Currently, LA has also been utilized for the treatment of GBC. Previous studies have reported favorable long-term outcomes of LA for early GBC (11, 12). For more advanced GBC such as T1b/T2, although several studies showed that the application of LA did not influence the prognosis adversely on the basis of a complete oncologic resection (13–15), there is controversy on whether to choose the primary laparoscopic approach (PLA) or open approach (OA) for T1b/T2 GBC patients. Moreover, they failed to identify risk factors in patients undergoing both two approaches.

The objective of the study was to compare the perioperative and long-term outcomes after PLA versus OA for T1b/T2 GBC patients. Furthermore, we also aimed to identify significant risk factors in patients undergoing different types of resection.

Medical databases of 181 consecutive GBC patients were obtained. After excluding patients aged >80 (n = 4), with non-T1b/T2 tumors (n = 52, [3 T1a + 49 T3]), with follow-up less than 3 months (n = 1), and with insufficient data (n = 10), a total of 114 GBC patients, consisting of 61 patients in the OA group (n =61) and 53 patients in the PLA group (n = 53), were included in the study ( Figure 1 ).

In this study, PLA was not inferior to OA regarding OS, DFS, intraoperative drainage placement, intraoperative blood loss, operation time, postoperative hospitalization, number of positive LNs, number of total harvested LNs, and recurrence rates. Moreover, subgroup analyses identified that less positive LNs and well-differentiated tumors were independent predictors for better OS after PLA, and less positive LNs were also identified for better OS after OA. Additionally, younger age, without gallbladder stone, smaller tumor size, and less positive LNs were potential risk factors for better DFS after OA.

PLA was not recommended for T1b/T2 GBC patients based on the previous Japanese Association of Biliary Surgery Guidelines (16). Notably, tumor exposure and implantation may happen during the intraoperative procedure, which was caused by the high risk of gallbladder perforation and bile spillage. Moreover, port-site recurrences after PLA were reported in GBC patients due to the technical shortcomings including nonuse of retrieval bags and poor surgeon-related operation skills (17). Meanwhile, PLA was not primarily chosen for GBC regarding the safety and feasibility of the approach. However, with the surgical techniques developed, similar oncological outcomes may be achieved in both of the PLA and OA for gastric carcinoma (18), colorectal carcinoma (19), and GBC patients (14).

Significant progress was achieved in laparoscopic resection for GBC in the year of 2011, which was approximately the turning point of the new approach (20). Laparoscopic resection for GBC is technically challenging, which requires advanced laparoscopic skills, especially when performing segment IVb/V resection or wedge resection with a complete lymphadenectomy for T2 GBC (21). There are concerns that LA may not meet the standards of OA, leading to inadequate resection, tumor cell dissemination, and poor prognosis of GBC (22). However, laparoscopic liver resection, including major and minor hepatectomy, has been confirmed feasible (8). Moreover, Agarwal et al. (13) concluded that an R0 resection with lymphadenectomy could be accomplished in T1b-T3 GBC patients without gallbladder perforation and bile spillage. Notably, developments in laparoscopic surgical instrumentation and technical innovation have contributed to the appropriate quality of extended resection for T1b/T2 GBC (23–25). Hepatectomy was performed to facilitate R0 resection by using preoperative three-dimensional reconstruction (26), intraoperative ultrasonography guidance (27), and intraoperative laparoscopic Glissonian approach (28). Although there is no consensus about lymphadenectomy extension for T1b/T2 GBC, hepatoduodenal ligament LN resection with and without extraregional LN dissection are recommended for T1b/T2 GBC patients, respectively (29, 30).

One of the strongest predictors among GBC patients is the regional LN status (31), and patients have worse prognosis with an increasing number of positive LNs. The study identified that the potential risk factor for OS in T1b/T2 GBC patients undergoing PLA was the number of positive resected LNs. The 8th AJCC staging recommended that at least six LNs should be harvested and evaluated (32, 33), and PLA is similar to OA with respect to the resection of total LNs in the present study. After achieving a systematic and complete resection, the accurate prediction of the prognosis of T1b/T2 GBC patients is associated with the LN staging, which is based on the number of positive ones (34, 35). Tumor immune responses would be the mechanism for the number of positive LNs affecting prognosis of GBC after surgery. Similar to colorectal cancer (36), the benefits associated with less positive LNs may reflect weaker effects of LN micrometastasis and higher host lymphocytic response to the GBC, which meant that more infiltrating dendritic cells correlated with fewer further metastasis to LNs. Moreover, dendritic cells were found to significantly correlate with OS (37). Besides the assessment of LN status after dissection, further improvement in identifying positive LNs from preoperative imaging and increasing the number of positive/total resected LNs is required for better OS for T1b/T2 GBC patients.

Tumor differentiation is another potential risk factor for long-term outcomes in T1b/T2 GBC patients undergoing PLA. Histological tumor differentiation represents the biological characteristics of GBC which tend to positively correlate with tumor aggressiveness. Compared with poorly and moderately differentiated GBC, well-differentiated GBC usually have a glandular structure with less cellular density (38), in which patient pericholecystic infiltration and regional LN enlargement are infrequently observed, leading to poor prognosis. Several studies used tumor differentiation to predict long-term outcomes in GBC patients (39, 40). For example, a nomogram was developed and validated based on clinicopathological factors, such as tumor differentiation, to predict 1-, 3-, and 5-year OS in resected GBC patients (39). Notably, Min et al. (41) have found that the apparent diffusion coefficient value on diffusion-weighted magnetic resonance imaging was significantly associated with tumor differentiation and long-term outcomes after surgery. Despite that tumor differentiation is based on the histopathological results currently, diffusion-weighted magnetic resonance imaging may be utilized for preoperative prediction for tumor differentiation.

There are an increasing number of studies comparing the outcomes of laparoscopic and open radical surgery for GBC patients. Although a latest Chinese single-center study concluded that LA had comparable intraoperative, perioperative, and survival outcomes with OA for incidental GBC patients of T1b/T2, it merely included 50 patients, which meant the sample size was too small to convince surgeons to decide the optimal approach preoperatively (42). Another retrospective study (43) conducted by Hamad et al. demonstrated that GBC patients undergoing radical resection had similar rates of harvested LNs regardless of the operation approach, but the study also included patients before 2011 and no definite surgical strategy was provided. What is more, a meta-analysis, which included seven comparative studies and eight non-comparative studies, confirmed that LA was safe and feasible with comparable operation-related and survival outcomes for T1b/T2 GBC (44). However, different from previous studies, the current study focused on comparing PLA with OA for GBC patients after the year 2011, which is the year of technological innovation, and identifying which patients may benefit most from operation approaches.

The study has several limitations that need to be considered. First, this is a single and retrospective study, whose sample size is too small to provide a high-level evidence. As the baseline characteristics of included patients are balanced between PLA and OA groups, the drawbacks may be partly avoided. Additionally, the specific hepatectomy strategy for T2 GBC patients was not distinguished for further analysis in the study. Whether to choose wedge resection or the more radical segment IVb/V resection for T2 GBC patients remains controversial, and surgeons should rely on surgical skills and patients’ medical records to choose the optimal approach (21). Besides, the study did not concern intraoperative complications (bile duct injury, air embolus, electrolyte/glucose abnormalities, hemodynamic instability, respiratory compromise, and renal dysfunction) and postoperative complications (infection, bile leakage, bleeding, and liver dysfunction), owing that it was focused on exploring and comparing the prognosis of the primary surgical approach for T1b/T2 GBC patients. Therefore, multicenter retrospective or even prospective studies of large sample size should be performed to compare the outcomes of LA and OA for T1b/T2 GBC patients; meanwhile, subgroup analysis of PLA and pure LA would be considered.

In conclusion, PLA was not inferior to OA regarding perioperative outcomes, OS, and DFS for T1b/T2 GBC patients. Less positive LNs and well-differentiated tumors were two independent predictors for better OS after PLA, and less positive LNs were also identified for better OS after OA. Additionally, younger age, without gallbladder stone, smaller tumor size, and less positive LNs were potential risk factors for better DFS after OA.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the institutional ethics review board of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China (20210625-30). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

JC, YW, BZ, XC, and MC designed the study and collected the data. JH, WT, SL, and SJ analyzed and interpreted the data. JC, YW, BZ, ZL, and MC wrote the manuscript. MC revised the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the Zhejiang Medical and Health Science and Technology Project (grant number 2019321842), National Natural Science Foundation of China (grant number 81827804), Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases (grant number 2018E50003), and Key Research and Development Project of Zhejiang Province (grant number 2018C03083).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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