Totally Laparoscopic Radical Resection of Gallbladder Cancer: Technical Aspects and Long-Term Results

World Journal of Surgery, Mar 2018

César Muñoz Castro, Sergio Pacheco Santibañez, Tomás Contreras Rivas, Nicolás Jarufe Cassis

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Totally Laparoscopic Radical Resection of Gallbladder Cancer: Technical Aspects and Long-Term Results

Totally Laparoscopic Radical Resection of Gallbladder Cancer: Technical Aspects and Long-Term Results Ce´sar Mun˜ oz Castro 0 2 3 4 Sergio Pacheco Santiban˜ ez 0 2 3 4 Toma´s Contreras Rivas 0 2 3 4 Nicola´ s Jarufe Cassis 0 2 3 4 0 Medicine School, Universidad Cato ́lica del Maule , Talca , Chile 1 1951 , Talca , Chile 2 Digestive Surgery, Hospital Regional de Talca , 1 North 3 & Ce ́sar Mun ̃oz Castro 4 Digestive Surgery, Hospital Clinico, Pontificia Universidad Cato ́lica de Chile , Santiago , Chile Introduction Gallbladder cancer (GBC) is a rare tumor in developed countries. Chile has one of the highest incidences worldwide. For patients affected by resectable T1b or more advanced GBC, radical cholecystectomy (RC) is considered the standard therapy. Our aim is to describe the surgical technique and clinical-pathological results of patients undergoing totally laparoscopic radical resection of GBC. Methods Patients undergo laparoscopic radical resection for primary and incidental GBC, between the years 2009 and 2016 in two centers from Chile. Patients in whom suspected bile duct invasion, frozen biopsy did not confirm cancer and para-aortic lymph node sampling was positive were excluded. Results Eighteen patients were operated, 77.8% were female with median age of 60.5 year, and 16 patients had previous cholecystectomy with incidental cancer finding. The median operative time was 490 min (400-550). No conversion to open surgery occurred. All patients achieved a R0 resection. Postoperative complications occurred in 2 patients (11.1%), and there was not mortality. After a median follow-up of 59 months, the 5-year survival was 80.7%. Conclusion This study shows the technical feasibility of the totally laparoscopic approach for radical resection of GBC with the same principles of classical open surgery. It appears that long-term oncological findings would also be similar at least in less advanced lesions. Introduction Gallbladder cancer (GBC) is a rare tumor in developed countries [1]. Chile has one of the highest incidences and mortality from GBC in both sexes [2]. Surgery is the only potentially curative treatment in early stages of this disease [3–5]. For patients affected by resectable T1b or more advanced GBC, radical cholecystectomy (RC), consisting in wedge liver resection [6] or 4b-5 bi-segmentectomy [7] with locoregional lymphadenectomy, is considered the standard therapy [8–10]. The evidence is limited to define if a 4b-5 bi-segmentectomy is better than a wedge bed resection for early tumors [11]. The lymph node involvement is directly related to the degree of tumoral infiltration in the gallbladder wall [7, 12]. In the last years, laparoscopic liver surgery has been greatly improved since the first international consensus conference [3, 4]. In experienced hands, laparoscopic liver resections are safe with acceptable morbidity and mortality. Oncologically, the survival rates reported are comparable to open resection [5]. Traditionally, curative laparoscopic surgery has been contraindicated in patients with suspected GBC [13]. However, a few studies have advocated the use of minimally invasive laparoscopic approach [13–17]. The aim of this study is to describe the surgical technique, clinical–pathological characteristics and results of patients undergoing totally laparoscopic radical resection of GBC. Materials and methods There is a case series study of patients undergoing laparoscopic radical resection for primary and incidental GBC, between the years 2009 and 2016 in two Chilean centers: the Hospital Clinico of the Pontificia Universidad Cato´lica de Chile and Talca Regional Hospital, Chile. The inclusion criteria for the laparoscopic approach were incidental cases (T1b-2 and T3 selected; N0-1; M0) and patients with suspected GBC whose frozen biopsy was confirmed with invasion beyond the mucosa and without other signs of hepatic and peritoneal spread in the diagnostic laparoscopy (T1b-2 and T3 selected; N0-1; M0). The exclusion criteria were preoperative suspected of invasion of the biliary tract. Patients in whom biopsy did not confirm cancer or para-aortic lymph node sampling was positive for cancer (Tx; N2; M0) were excluded from analysis. A database was designed to analyze demographic, clinical, pathological and surgical variables; postoperative complications (stratified according to Clavien–Dindo [18] classification), mortality and survival. All patients gave their informed consent for laparoscopic RC prior to surgery. Preoperative considerations for laparoscopic RC in incidentally discovered GBC When evaluating a patient with incidental GBC, some considerations should be taken in relation with details of the cholecystectomy and the histopathological study. In first place, it is necessary to know whether the gallbladder was perforated during the cholecystectomy and a bile spillage occurred, because directed and careful exploration of Morrison’s space should be performed. In second place, it must be known if the gallbladder was removed inside a protective bag (a recommendation for all laparoscopic cholecystectomy in high incidence area for incidental GBC like Chile) because in cases when it was not removed in a bag, port site resection including the parietal peritoneum should be made at the end of the surgery. The histopathological study should include a complete sampling of the gallbladder for proper staging of the depth of invasion of the tumor after the initial diagnosis [19]. In our approach, we try to perform the laparoscopic radical resection in a time lower than 1 month after cholecystectomy, but sometimes this time could be higher in referred patients. If the time from cholecystectomy to evaluation for a resection is longer than our protocols, a multidisciplinary team evaluate whether a new surgery is necessary after a complete staging. Surgical technique Patient is placed supine with reverse Trendelenburg’s position keeping the legs apart. Surgeon stands between legs of patient. Closed pneumoperitoneum is created using a Veress needle, and usually 5 trocars are used. The first step is to carefully inspect peritoneal cavity for signs of unresectable disease as peritoneal carcinomatosis. Attention must include the left subphrenic and right subphrenic spaces, recto-vesical pouch and both paracolic gutters. It is important to explore Morrison’s pouch, because sometimes the accidental perforation of the gallbladder during cholecystectomy can let tumor cells reach this area. Lymph node sampling at para-aortic space must be done systematically. The purpose of this lymph node sampling is to have a frozen section examination, since there is no benefit of RC for the patient if there is involvement at this level [8]. The hepatoduodenal ligament must be sectioned, and the duodenum mobilized medially in order to expose the retroperitoneal space. At this stage, it is useful for the complete liberation of the third part of the duodenum, to ease the lymphadenectomy. The limits of the lymph node sampling are the infrarenal inferior cava vein at right and the aorta at left, and the upper limit is the left renal vein. The depth of dissection must be the anterior longitudinal ligament of the vertebral column. During the para-aortic lymphadenectomy, the right gonadal veins must be treated carefully since their position, anterior to the cava vein, can be a source of bleeding during the dissection and in the postoperative period (Fig. 1). The lymphadenectomy of the hepatic pedicle and the celiac trunk must accomplish the same principles of the open surgery. The recommendation of the Expert Consensus of the AHPBA for the treatment of GBC is that adequate staging requires the retrieval of a minimum of 6 lymph nodes [9]. The retrieval of more lymph nodes depends on the anatomic variations of each patient, and the only certainty of a complete lymphadenectomy is to perform a complete dissection of all the structures of the hepatic pedicle [10, 12]. Anatomic variations found either on arterial vessels or on bile ducts may represent an additional technical difficulty at the lymphadenectomy and must be taken in consideration to avoid causing iatrogenic injuries during the dissection. This stage may be challenging and requires advanced laparoscopic abilities not only to complete the dissection, but also to control any bleeding from hepatic arteries or portal vein. After the para-aortic sampling, the lymphadenectomy continues with the retropancreatic group located right behind the pancreas head, previously mobilized with the Kocher maneuver. The lesser omentum is sectioned in the pars flaccida to resect the common hepatic artery lymph node; after that, the dissection follows the splenic artery until the celiac trunk with en-block lymph node resection. The surgery continues with the lymphadenectomy of the proper hepatic artery, bile duct and the portal vein. At this stage, the cystic duct is sectioned at the junction with the common bile duct. The margin of the cystic duct can be sent to frozen biopsy, in cases that bile duct involvement is suspected, in order to proceed to a bile duct resection (Fig. 2). The hepatic mobilization to complete the resection must be evaluated according to the liver anatomy. In some patients, lateral segment of liver presents with a prominent III segment and with the pneumoperitoneum it falls over the IVB segment making the hepatic pedicle lymphadenectomy more difficult in an early stage; in these cases, the round ligament and the falciform ligament section allows a better sight. Almost always, this is the only procedure required to mobilize the liver. To control the hepatic pedicle and achieve the Pringle maneuver if needed, we use a tape with a piece of polyurethane left prepared for traction. Liver resection in RC has two main objectives of the intervention: a tumor-free liver margin and resects preventively local parenchyma to avoid locoregional recurrence. In the choice of type of resection (non-anatomic wedge resection of the gallbladder bed versus a formal segment IVb/V resection), the location of tumor and first surgeon criteria were considered (neck, body or fundus) for an appropriate surgical margin at that level (over than 2 cms), and the oncological prognosis does not get compromised. For liver transection, we used laparoscopic ultrasonic dissectors and bipolar forceps, associated with saline solution pulses and aspiration (Fig. 3). If there is any concern about the extraction of the gallbladder or when it has been explicitly drawn through the port without protection, we perform complete port site resection. This resection should include the entire wall (including the parietal peritoneum). Adjuvant therapy Patients who had a T2 tumor plus perivascular, perineural or perilymphatic invasion, a T3 tumor or residual disease at second-time resection were submitted to an oncological meeting for adjuvant therapies evaluation. Follow-up program The routine follow-up program consisted of physical examinations and laboratory test every three months for the first three years and then biannually for the next two years. Abdominopelvic CT was also performed as part of the routine protocol every 6 months for the first two years and then annually for the next 3 years. Statistical analysis SPSS 22 software (SPSS Inc., Chicago, IL) was used. For the description of continuous variables, the median, minimum and maximum values were used. Descriptions of categorical variables were performed using absolute frequencies and percentages. Kaplan–Meier survival analysis was performed. Results Eighteen patients were operated, 14 of them (77.8%) were female, and the median age was 60.5 years (32–71). The most frequent ASA category was II in 13 patients (72.2%), followed by category I in 5 (27.8%). Preoperative jaundice occurred in one patient (5.6%). Within preoperative imaging, abdominal ultrasound was performed in 16 patients (88.9%), computed tomography (CT) in 14 (77.8%), magnetic resonance imaging in 2 (11.1%) and positron emission tomography in 2 (11.1%). Porcelain gallbladder was found in one case (5.6%) and cholelithiasis in 16 cases (88.9%). In 16 patients (88.9%), a previous cholecystectomy had been performed and the cancer finding was incidental. Of these patients, cholecystectomy was laparoscopic in 15 cases (93.7%) and open in one case (6.3%). All these patients underwent a second radical surgery; the median time between both procedures was 77 days (60–455). The remaining 2 patients (11.1%) had a primary GBC; they underwent radical surgery at one time, along with cholecystectomy. The histopathological results are detailed in Table 1. The median operative time and blood loss were 490 min (400–550) and 125 mL (50–200), respectively. No conversion to open surgery occurred. A Pringle maneuver was performed in 14 patients (77.8%), with a median time of 24 min ( 15–30 ). All the patients achieved a R0 resection. Postoperative complications occurred in 2 patients (11.1%); one patient had an intra-abdominal abscess classified as Clavien–Dindo grade II, which required broadspectrum antibiotic treatment, with favorable evolution. The other patient had a biloma that required CT-guided percutaneous drainage and broad-spectrum antibiotic treatment, with favorable evolution. It was classified as Clavien–Dindo grade IIIA. There was no mortality in this study. The postoperative results are detailed in Table 2. One of incidental GBCs (6.25%), a lymphatic retroportal residual disease, was found. Seven patients (38.9%) received adjuvant therapy. The most frequent treatment was chemotherapy regimen based on gemcitabine plus cisplatin in 5 patients (27.8%). Two patients (11.1%) received adjuvant chemoradiotherapy with fluorouracil. After a median follow-up of 59 months ( 7–92 ), two patients (11.1%) had a local recurrence. One of them had a peritoneal recurrence 6 months after the radical surgery; he had the antecedent of gallbladder perforation with bile spillage in his primary surgery (laparoscopic cholecystectomy) and died 8 months after the RC. The other patient had hepatic recurrence 15 months after radical surgery. She received adjuvant chemotherapy; then presented pulmonary metastases; and finally died 44 months after RC. The 5-year survival was 80.7% as shown in Fig. 4. Discussion In the current study, 18 patients underwent RC for GBC with low morbidity, no mortality and excellent five-year survival rate. Optimum surgical management of GBC remains controversial, in a first instance; laparoscopy represented an absolute contraindication for GBC surgery because pneumoperitoneum could have a spread (‘‘spray’’) effect on a tumoral gallbladder, with an even higher risk of spread if there was a gallbladder perforation. We currently know that the risk of developing implants during surgery is low if precautions are taken in the surgery [20, 21]. Laparoscopic simple cholecystectomy alone is now widely accepted treatment for Tis and T1a GBC [22, 23]. Laparoscopic approach to a patient with suspected resectable GBC has several advantages. In first place, it allows to keep the minimally invasive management in benign pathologies that could mimic cancers like xanthogranulomatous cholecystitis, gallbladder adenomyomatosis and adenomatous polyps, given that the positive predictive value of CT for diagnosing GBC in patients with vesicular masses is approximately 80% [24]. Moreover, laparoscopic approach of a patient with gallbladder wall thickening or mass has the advantage of avoiding an unnecessary laparotomy in cases of peritoneal carcinomatosis or unsuspected liver metastasis. The extension of liver resection in RC has been discussed in relation to size and kind, and the evidence is limited in define when a IVb-V bi-segmentectomy is better than a wedge bed resection for early GBC. The main of liver resection is a tumor-free liver margin and resect preventively local parenchyma to avoid locoregional recurrence. In 2010, Goetze et al. [11] published the results of analysis of prospective The German Registry of GBC; in this study, patients with a radical reresection were treated according to the S3 Guidelines in Germany. Over 624 patients with incidental GBC, the study shows how the wedge resection combined with lymph node dissection may be the surgical strategy of choice in T1 tumor cases, while for T2 tumors a IVb/V resection plus lymph node dissection of the hepatoduodenal ligament appears to be better than wedge resection. Japanese Biliary Tract Cancer Registry published a comparative study of non-anatomic resection of the gallbladder bed versus a formal segment IVb/V resection for T2 GBC and did not found significant differences in outcomes between the two procedures [7]. In 2010, Cho et al. [16] reported a series of patients with GBC (Tis-T2 lesions) treated by laparoscopic surgery. In this study, frozen section examination was made to determine the presence of cancer. The confirmed cases underwent lymphadenectomy without hepatic bisegmentectomy. Of the 36 cases with intention to treat, 18 presented frozen section examination positive for cancer and the lymphadenectomy was completed. Two patients (11%) presented intraoperative complications during the lymph node dissection: one patient had left hepatic duct injury repaired with T-insertion and one a portal injury that required conversion to open surgery. Probably, the lymph node dissection of hepatic pedicles and celiac trunk is the most technical difficult step in this procedure. More recently, other authors have reported short[14, 15, 17] and long-term [13, 25, 26] results in patients undergoing RC for GBC. Most of these studies have fewer than 25 patients with laparoscopic radical resections. Palanisamy et al. [25] published 14 cases of laparoscopic RC in patients with preoperative suspicion of GBC, without conversion. Twelve presented pathological diagnosis of GBC, and 11 were stage I or II according to the TNM 7th edition. Morbidity was 14.28% and mainly given by biliary fistula. The mean of resected lymph nodes was 8 ( 4–14 ). The median follow-up was 51 months with a 5-year survival of 68.75%. Like in our experience, the median of lymph node harvesting in a dissection is similar to open classical approach and complies with recommendation [9]. Shirobe et al. [26] reported 11 patients that underwent laparoscopic RC (4 incidentally discovered and 7 with frozen section examination). Two patients underwent bile duct resection with biliary tract reconstruction. Nine patients were staged as I or II according to the 7th edition TNM classification. One patient presented a surgical site infection in relation to the mini-laparotomy done for the bile duct reconstruction. This study did not present surgical mortality. The 5-year survival was 100% for T1b and 83.3% for T2 tumors. Finally, Agarwal et al. [13] present the larger study with 24 patients that underwent laparoscopic RC (4 incidentally discovered and 20 with parietal thickening). Thirteen were stage I or II according to the TNM 7th edition. The postoperative morbidity was 12.5%. The median lymph nodes yield was 10 ( 4–31 ). The survival was 95.8% with a median follow-up of 18 months. In summary, this study demonstrates the technical feasibility of laparoscopic radical resection of GBC with the same principles of radicalism as classical open surgery. It appears that long-term oncological findings would also be similar at least in the group of less advanced lesions. Larger and ideally randomized control trials are required to obtain categorical conclusions, but to our knowledge, this study represents the longest median follow-up of these minimally invasive techniques using this approach previous to RC. 1. Eslick GD ( 2010 ) Epidemiology of gallbladder cancer . Gastroenterol Clin North Am 39 : 307 - 330 2. Roa I , Ibacache G , Mun˜oz S, De Aretxabala X ( 2014 ) Gallbladder cancer in Chile: pathologic characteristics of survival and prognostic factors: analysis of 1,366 cases . Am J Clin Pathol 141 ( 5 ): 675 - 682 3. 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César Muñoz Castro, Sergio Pacheco Santibañez, Tomás Contreras Rivas, Nicolás Jarufe Cassis. Totally Laparoscopic Radical Resection of Gallbladder Cancer: Technical Aspects and Long-Term Results, World Journal of Surgery, 2018, 1-7, DOI: 10.1007/s00268-018-4490-4