Short- and Long-Term Outcomes of Laparoscopic Organ-Sparing Resection for Pancreatic Neuroendocrine Neoplasms

Pancreatic neuroendocrine neoplasms (PNENs) are rare neoplasms associated with a long life expectancy after resection. In this setting, patients may benefit from laparoscopic organ-sparing resection. Studies of laparoscopic organ-sparing resection for PNENs are limited. The aim of this study was to evaluate the short- and long-term outcomes of laparoscopic organ-sparing resection for PNENs. A retrospective study was performed for patients with PNENs who underwent laparoscopic organ-sparing pancreatectomy between March 2005 and May 2018. The patients’ demographic data, operative results, pathological reports, hospital courses and morbidity, mortality, and follow-up data (until August 2018) were analysed. Thirty-five patients were included in the final analysis. There were 9 male and 26 female patients, with a median age of 46 years (range 25–75 years). The mean BMI was 24.6 ± 3.3 kg/m2. Nine patients received laparoscopic enucleation (LE), 20 received laparoscopic spleen-preserving distal pancreatectomy (LSPDP), and 6 received laparoscopic central pancreatectomy. The operative time, intraoperative blood loss, transfusion rate, and postoperative hospital stay were 186.4 ± 60.2 min, 165 ± 73.0 ml, 0 days, and 9 days (range 5–23 days), respectively. The morbidity rate, grade ≥ III complication rate, and grade ≥ B pancreatic fistula rate were 34.2%, 11.4%, and 8.7%, respectively, with no mortality. The rate of follow-up was 94.3%, and the median follow-up time was 55 months (range 3–158 months). One patient developed recurrence 36 months after LE and was managed with surgical resection. The other patients survived without metastases or recurrence during the follow-up. One patient had diabetes after LSPDP, and no patients had symptoms of pancreatic exocrine insufficiency. Nineteen patients who underwent LSPDP (16 with the Kimura technique and 3 with the Warshaw technique) were followed. Normal patency of the splenic artery and vein was observed in 14 and 14 patients within 1 month of surgery and in 15 and 14 patients 6 months or more after the operation, respectively. Partial splenic infarction was observed in 3 patients within 1 month of surgery and in no patients 6 months or more after the operation. Three patients eventually developed collateral venous vessels around the gastric fundus and reserved spleen, with one case of variceal bleeding. Laparoscopic organ-sparing resection for selected cases of PNENs is safe and feasible and has favourable short- and long-term outcomes.


Abstract Background
Pancreatic neuroendocrine neoplasms (PNENs) are rare neoplasm with long life expectancy. In this setting, patients may benefit from laparoscopic organ-sparing resection. There are few reports of laparoscopic organ-sparing resection for PNENs. The aim of this study was to evaluate the Short-and long-term outcomes of laparoscopic organ-sparing resection for PNENs.

Methods
A retrospective study was performed for patients with PNENs who underwent laparoscopic organsparing pancreatectomy between March 2005 and May 2018. The patients' demographic data, operative results, pathological reports, hospital courses, morbidity and mortality, and follow-up data (including pancreatic function, till August 2018) was analyzed.

Results
Thirty-five patients were identified. There were 9 male and 26 female patients, with a median age of 46 years (range, 25-75 years). The mean BMI was 24.6±3.3kg/m 2 . Nine patients received laparoscopic enucleation, 20 received laparoscopic spleen-preserving distal pancreatectomy, and 6 received laparoscopic central pancreatectomy. The operative time, intraoperative blood loss, transfusion rate, postoperative hospital stay were 186.4±60.2min, 165±73.0ml, 0, 9d(range, 5-23d), respectively. The morbidity rate, ≥Grade III complication rate and ≥grade B pancreatic fistula rate were 34.2%, 11.4%, 8.7%, respectively, with no mortality. The rate of follow-up was 94.3%, and the median follow-up time was 55 months (range, 3-158months). One patients had diabetes after laparoscopic spleen-preserving distal pancreatectomy, no patient had symptom of pancreatic exocrine insufficiency. One patient developed recurrence 36 months after laparoscopic enucleation and was managed with surgical resection. The other patients survived without metastases or recurrence during the follow-up.

Conclusions
Laparoscopic organ-sparing resection for selected cases of PNENs is safe and feasible, and have favorable short-and long-term outcome.
3 Background Pancreatic neuroendocrine neoplasms (PNENs) are rare tumors that represent about 2-4% of pancreatic tumors and have an incidence of 1 per 100,000 population [1,2]. Due to availability of high-resolution medical imaging and histopathological methods, the diagnosis of PNENs has increased [3]. PNENs comprise a heterogeneous group of tumors with a very varied biological behavior.
Complete surgical resection is the curative modality for resectable PNENs with the expectancy to long-term survival [3].
Organ-sparing pancreatectomy represents a limited resection alternative to pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) for treatment of benign or low-grade malignant tumors of the pancreas [4][5][6]. This procedure is thought to be associated with minimal exocrine and/or endocrine insufficiency, better quality of life, and preservation of the spleen and its immunologic properties [4][5][6].Laparoscopic pancreatic surgery has been gaining popularity in the last decade due to recent technological developments in laparoscopic technique and instruments. So, laparoscopic organ-sparing pancreatectomy is thought to be an ideal procedure for the PNENs.
Previous study of laparoscopic pancreatectomy for PNENs has found advantages related to minimalaccess surgery and a good overall disease-specific long-term prognosis [7][8][9]. The studies of laparoscopic organ-sparing resection for PNENs are limited [9,10]. The aim of this study was to evaluate the Short-and long-term outcomes of laparoscopic organ-sparing resection for PNENs. Pancreatic fistula (PF) was assessed according to the International Study Group on Pancreatic Fistula recommendations [11]. Postoperative morbidity was graded using the Clavien-Dindo classification [12]. Graded Ⅰand Ⅱwere grouped as minor and graded Ⅲ-Ⅴ was considered as major complications [12].

Methods
Patients were followed up via out-patient examination. The final follow-up was taken in August 2018.
Recurrence or distant metastasis was diagnosed pathologically by surgical resection, biopsy, or cytology and/or radiological examination. Pancreatic endocrine insufficiency was defined as newonset diabetes and worsening diabetes [13]. Patients with diarrhea and steatorrhea, weight loss, and taking of pancreatic enzyme supplementation were considered to have pancreatic exocrine insufficiency [13].
The Institutional Review Board of Zhejiang provincial people's Hospital approved this study protocol.

Operative Technique
All indications of operation were discussed by a multidisciplinary team board. The type of pancreatic resection was based on the locations and size of the tumors. Laparoscopic enucleation(LE) was performed for the tumors located ≥ 3 mm distant from the Wirsung duct (WD) [9]. Laparoscopic central pancreatectomy(LCP) was performed for the tumors located in the neck-body of the pancreas < 3 mm from the WD and which allowed 5 cm of the tail of the pancreas to be preserved [9]. When the remaining tissue of the distal pancreas was fibrotic or atrophic or < 5 cm long, laparoscopic spleenpreserving distal pancreatectomy(LSPDP) was performed [9]. LSPDP was performed for tumors located < 3 cm from the distal end of the pancreas and < 3 mm from the WD [9].
The procedures were planned before surgery, but the final procedure was decided on during surgery based on a combination of macroscopic, intraoperative ultrasonographic findings, and intraoperative frozen section examination.
Patients were placed in supine position with the head slightly elevated. The surgeon and the second assistant who held the laparoscope stood on the right side of the patientand the first assistant stood on the left. Five trocars (three 5-mm trocars and two 10/12-mm trocars) are used; and the five trocars were arranged in a V shape [14][15][16][17][18].

Histopathological Data
Histopathological data, such as tumor size, tumor location, margin status, lymph node status, were also analyzed. Tumors were reviewed and graded based on mitotic count and Ki-67 index, according to the World Health Organization(WHO) classification [19] and the European Neuroendocrine Tumor Society(ENETS) TNM classification [20].

Statistical analysis
Continuous clinicopathological data were expressed as mean ± standard deviation or median (range) as appropriate. Categorical variables were reported as number and percentage. All statistical analyses were performed using SPSS version 19.0.  Table 1. There were 9 male and 26 female patients, with a median age of 46 years (range, 25-75 years). The mean BMI was 24.6 ± 3.3 kg/m2. Four patients underwent previous laparotomy: two with cholecystectomy, one appendectomy, and one partial gastrectomy. Of the 35 patients, 10 cases (28.6%) were functional tumors. All of them were insulinoma. The remaining 25 patients (71.4%) were nonfunctional tumors.   The histopathological data are given in Table 3. The mean tumor diameter was 2.2 ± 1.5 cm.

Results
According to the WHO classification [18], 24 patients(68.6%) were graded G1, 11 patients(31.4%) G2, and no G3. According to ENETS TNM classification [19], 20 patients(57.1%)were stage I, 13 patients(37.1%) IIA, 2 patients(5.8%)IIIA. ALL patients had an R0 status. A total of 33 patients (follow-up rate 94.3%) were followed up via out-patient examination. The median follow-up period was 55 months (range 3-158 months). One patient developed recurrence 36 months after LE and was managed with surgical resection. The other patients survived without metastases or recurrence during the follow-up. One patient experienced intestinal obstruction 2 years after LSPDP. One patient developed new-onset diabetes treated with oral drug after LSPDP. No patient had symptom of pancreatic exocrine insufficiency.

Discussion
Laparoscopic organ-sparing resection for PNENs was initially described by Gagner in 1996 [21].The patient underwent LE of an insulinoma of the anterior body of the pancreas in 3 hours, and the hospital stay was 4 days. No recurrence was seen in follow-up. Owing to complicated operation and low prevalence of PNENs, papers about laparoscopic organ-sparing resection for PNENs reported in the literature are limited [9,10]. Cienfuegos et al [9]documented the effectiveness of laparoscopic organ-sparing resection in selected cases of PNENs. However, there study also included 11 cases of Laparoscopic radical distal pancreatosplenectomy for PNENs [9]. Moekotte et al [10] performed 87 cases of LSPDP for PNENs with feasible short-term outcome. However, there study also included 142 cases of LSPDP for pathologies other than PNENs and without long-term outcome [10]. To the best of our knowledge, this study was just focused on laparoscopic organ-sparing resection for PNENs. Our study demonstrated that laparoscopic organ-sparing resection for selected cases of PNENs is safe and feasible, and have favorable short-and long-term outcome.
The morbidity rates of laparoscopic pancreatectomy for PNENs reported in literatures varied greatly from 21.5-50% [8,9].PF was the most frequent complication after laparoscopic pancreatectomy for PNENs. The PF rates varied greatly from 21.5-36.1% [8,9].These studies included both laparoscopic organ-sparing resection and standard resection. Cherif et al [22] reported that high rate of morbidity (76%) and PF (grades B and C) (42%) after open parenchyma-sparing resection for PNENs. The present study revealed that the postoperative complications occurred in 12 patients (34.2%) and PF in 3 patients (8.7%,Grade B). Because the present study used the new version of International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula [11]. Our pilot studies showed that the morbidity rates and PF rates of LE ,LSPDP and LCP were similar to open surgery [14,15,16,18].Therefore, we believe that it is not the type of the techniques (Laparoscopic or Open), but the patient's condition and operation's difficulty level were associated with PF formation. The methods of PD or DP, sacrificed the pancreatic parenchyma and spleen, leads to the endocrine and exocrine deficiency and possibility of overwhelming post-splenectomy infection (OPSI) and potential increased risk of malignancy. Hence, organ-sparing pancreatectomy has increasingly become an option to treat benign or low-grade malignant tumors in order to preserve pancreatic parenchyma and spleen as much as possible. Zhang et al [14 15 18]reported LE ,LSPDP and LCP are safe and feasible for benign or borderline malignant lesions with faster recovery. LCP is associated with better quality of life [18].Song et al [23]reported that 2 (8%) and 10 (38.5%)patients were associated with new-onset diabetes and weight loss, respectively. New-onset diabetes was less frequent after LCP than after Extended LDP (8% vs. 30.8%,p = 0.037) [23]. Cienfuegos et al [9] reported that none of the patients with early stages PNENs treated with laparoscopic organ-sparing techniques presented recurrence during mean follow-up of 51 months. In our study, only one patient developed recurrence 36 months after LE. The other patients survived without metastases or recurrence during the follow-up. Only one patient developed new-onset diabetes treated with oral drug after LSPDP. No patient had symptom of pancreatic exocrine insufficiency. So laparoscopic organ-sparing pancreatectomy for PNENs has advantages related to minimal-access and functionpreserving surgery.
Compared to standard resection, laparoscopic organ-sparing pancreatectomy was nonoptimal oncologic resection with limited margin and nonstandard lymphadenectomy. Cherif et al [22] regarded that parenchyma-sparing pancreatectomy should be considered for low grade tumor which was suspected in nonsecreting tumor below 2 cm in size or insulinoma in the absence of distant or lymph node metastasis on preoperative assessment. Cienfuegos et al [9] regarded that tumors with no vascular invasion (stages I (T1N0M0) ,IIA(T2N0M0) and IIB (T3N0M0) established by the ENETS) seem to be the best candidate for laparoscopic organ-sparing pancreatectomy. In our study, all of functional tumors were insulinoma. All of tumors were graded G1 or G2, no G3. And 20 patients(57.1%)were stage I, 13 patients(37.1%) IIA, 2 patients(5.8%)IIIA. Most patients carry an overall excellent prognosis. So which part of the advanced stages of PNENs were suitable for laparoscopic organsparing pancreatectomy need more cases to evaluation.
In our study, the mean tumor diameter was 2.2 ± 1.5 cm. Most tumors were less than 2 cm. The challenge was to locate the tumor and make the decision of surgical approach. The planned surgical approach is governed largely by the findings in preoperative localization studies, but may commonly change in accordance with intraoperative findings. During the operation, ultrasonic examination of the pancreas is used to locate neoplasms which were deep in the parenchyma and make sure the distance between neoplasm and the main pancreatic duct.
The limitations of this study were its retrospective design with relatively small number of cases. The ideal study would be a large, prospective randomized trial, which was difficult to accomplish owing to the infrequent diagnosis of patients with PNENs that were suitable for laparoscopic organ-sparing pancreatectomy. Despite these limitations, we believe that this study could provide valuable evidence in clinical practice.

Conclusions
Laparoscopic organ-sparing resection for selected cases of PNENs is safe and feasible, and have favorable short-and long-term outcome. The Institutional Review Board of Zhejiang provincial people's Hospital approved this study. The written informed consent was obtained from the patients before inclusion in the study.

Consent for publication
All the authors express the consent for publication on World Journal of Surgical Oncology.

Availability of data and materials
All data generated or analysed during this study are included in this published article.

Competing interests
Ren-Chao Zhang, Jun Ma, Yi-Ping Mou, Yu-Cheng Zhou, Wei-Wei Jin, and Chao Lu have no conflict of interest or financial ties to disclose.

Funding
There were no funding contributions to this study.

Authors' contributions
ZRC and MYP conceived and designed the study. ZRC, MYP and ZYC performed the operation. MJ, JWW and LC collected and analyzed data. ZRC drafted the manuscript. MYP revised the manuscript. All authors read and approved the final manuscript.