Is laparoscopic radical cholecystectomy an effective and safe approach for advanced gallbladder cancer?

Li-Ming Jin Yu-Hu Zhng Cheng-Wu Zhng Wei-Ding Wu Ji Wu Chng-Wei Dou Fng-Qing Wei Zhi-Fei Wng Zhi-Ming Hu Shu-Sen Zheng c ∗

a Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310 0 03, China

b Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China

c Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China

Although laparoscopy has been widely used in the surgical field and is even considered the first-line to diagnose various diseases,laparoscopic radical cholecystectomy (LRC) for gallbladder cancer(GBC) has always been relatively contraindicated. Inadequate lymphadenectomy, complicated liver resection, specific biological behavior of GBC cells, and chimney and aerosol effects from the pneumoperitoneum are the previously misunderstood areas in laparoscopic surgery [1] . Initially, laparoscopic approach was used for intra-abdominal GBC exploration to determine the presence of peritoneal metastasis, intraoperative staging, and palliative treatment. With the advancement of laparoscopic surgery, laparoscopic liver resection, laparoscopic pancreaticoduodenectomy, and laparoscopic radical gastrectomy have been routinely performed in several medical centers. Kim et al. [2] recently demonstrated that laparoscopic technique is feasible for GBC. However, the feasibility of LRC depends on the following factors.

Laparoscopic cholecystectomy alone has been a widely accepted approach for the early diagnosis of GBC. However, a high rate of residual lesions occurs in the gallbladder bed (up to 13%) in T1b GBC [3] ; thus, a revised cholecystectomy including gallbladder bed wedge resection would be required at T1b stage and above [4 , 5] . Although whether GBC surgery requires additional anatomical segment IVb/V resection remains controversial, the non-anatomic liver resection (2-4 cm liver tissue from the gallbladder bed) can be performed to achieve similar survival compared to anatomic segment IVb/V resection; however, the anatomic segment IVb/V resection decreases morbidity [6] .

The rate of lymph nodal metastasis in T2b disease is 46%,and once the disease progresses to T3, its incidence reaches up to 76% [7] . Therefore, regional lymphadenectomy for GBC is an essential part of LRC. Although regional lymph nodal metastases in GBC were distributed along the common bile duct, hepatic artery,portal vein, and gallbladder duct [8] , posterosuperior pancreatic head lymph nodes must be dissected in the radical gallbladder surgery [9] .

Moreover, in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, the N-stage of GBC was divided by the number of positive lymph nodal metastases, and a minimum of 6 nodes was recommended. As the lymph nodes were used to determine the prognosis of patients undergoing GBC surgery [10] , several clinical studies demonstrated that dissected lymph nodes in LRC for GBC was not lower than those of open radical cholecystectomy (ORC) for GBC [1 , 5 , 11] . In terms of lymph node dissection, the advantages of LRC over traditional open surgery include wider surgical view and multi-angle transformation. The average number of dissected lymph nodes in LRC,which can reach up to 9 to 10, is even higher than that of ORC. To achieve a homogeneous result of lymphadenectomy in GBC as LRC or ORC evolves, enforcing consensus guidelines will optimize the outcomes.

Recently, an expert consensus statement recommended that radical GBC resection for early T-stage (T1b-T3) should include en bloc resection of the adjacent liver parenchyma [12] . Naturally, for patients with GBC, en bloc resection is a general principle that should be followed by all surgeons. Consequently, surgeons should try their best to combine the medical history and enhanced computed tomography or magnetic resonance imaging to achieve a definitive diagnosis preoperatively. However, this is very difficult to diagnose preoperatively because some GBCs are incidentally diagnosed through intraoperative freezing pathology. The incidence of incidental GBC after laparoscopic cholecystectomy is up to 2.1%,and approximately 50%-70% of all GBCs is incidentally diagnosed following cholecystectomy [13] . For the gallbladder highly suspected with cancer, en bloc anatomic liver resection combined with the gallbladder decreases the risk. We encountered several cases of highly suspected GBC who were confirmed to be yellow granulomas postoperatively. Based on a multivariable logistic regression analysis, Goussous et al. [13] found that gallbladder wall thickening without pericholecystic fluid based on ultrasound imaging and age were the strongest predictors of incidental GBC. Therefore, we recommend that the en bloc technique is performed for the accurate preoperative diagnosis of GBC. For intraoperative incidental GBC,complete resection of the gallbladder bed with liver tissues cannot be performed. Although the liver tissue (gallbladder bed) and gallbladder may be separated specimens, lymph tissue clearance should be prioritized following theenblocresection principle.

For patients with GBC, the 5-year survival was＜5%. Improving the postoperative long-term survival is the fundamental goal of the radical resection of GBC. Moreover, the short-term efficacy of LRC for GBC should be evaluated rationally. A growing number of studies confirmed that LRC is more advantageous over the conventional ORC for GBC, such as shorter operative time, lesser intraoperative blood loss, and shorter postoperative hospital stay [6 , 11 , 12 , 14] .Recently, intraoperative harmonic scalpel combined with Cavitron Ultrasonic Surgical Aspirator (CUSA) was used to dissect the liver parenchyma in over 30 cases of LRC, which could potentially reduce the intraoperative blood loss and perioperative morbidity [11] .

Postoperative mortality was associated with tumor grade,lymphovascular invasion, tumor stage, and pathological type. Yoon et al. [15] reported that the 5-year survival for patients with GBC stage T1a or T1b who underwent LRC is up to 100%; for GBC of stage T2, the 5-year survival is＞90%, which is similar with or better than previous reports on ORC. A systematic review showed that the 5-year survival is significantly higher in the LRC than that in the ORC group [16] . A stratified research [11] was performed on GBC patients with T3, TNM III/IV stages following LRC or ORC.The results showed that the 1-year overall survival of TNM III/IV is comparable and GBC patients with T3 stage following LRC achieved a better 1-year overall survival. However, whether LRC should be performed for patients with GBC of T3 or more advanced stages remains controversial. Additionally, no randomized prospective studies that compared LRC and ORC were carried out. A study [1] has shown that laparoscopic surgery does not increase the rate of incision metastasis, and the recurrence at the port site can be minimized in LRC. In our study, intra-abdominal and port site metastases were not observed in LRC cases [11] . Therefore, careful manipulation to avoid gallbladder perforation and employment of plastic specimen bags to prevent tumor contamination may be effective measures to reduce recurrence in the abdominal cavity and incision metastasis. Moreover, performing trocar tunnel resection is unnecessary.

In summary, LRC is a safe and effective approach to treat GBC with TNM I/II stage; however, it should be performed cautiously at experienced surgical centers for GBC with TNM III stage. In order to achieve better outcomes, GBC patients indicated for LRC should be screened rigorously. More randomized controlled trials and realworld studies should be conducted to assess the safety and feasibility of LRC in advanced GBC stages.

Acknowledgments

None.

CRediT authorship contribution statement

Li-MingJin:Conceptualization, Data curation, Funding acquisition, Writing - original draft.Yu-HuaZhang:Writing - review &editing.Cheng-WuZhang:Supervision.Wei-DingWu:Writing -review & editing.JiaWu:Writing - review & editing.Chang-Wei Dou:Data curation.Fang-QiangWei:Data curation.Zhi-FeiWang:Funding acquisition, Writing - review & editing.Zhi-MingHu:Supervision.Shu-SenZheng:Conceptualization, Supervision, Writing- review & editing.

Funding

This study was supported by grants from the Scientific Research Foundation of Traditional Chinese Medicine of Zhejiang Province(2015ZA085), National Key Research and Development Program of China (2018YFB1107104) and the Key Project of the Science and Technology Department of Zhejiang Province ( 2017C01020 ).

Ethicalapproval

Not needed.

Competinginterest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.