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Review Article | DOI: https://doi.org/10.31579/2690-1897/026
*Corresponding Author: Abdelkader Boukerrouche, Department of Digestive Surgery, Hospital of Beni-Messous, University of Algiers, Algiers, Algeria,
Citation: Boukerrouche A. (2020) Updated Surgical Management of Pancreatic Neuroendocrine Tumors. Journal of Surgical Case Reports and Images, 3(3): Doi: 10.31579/2690-1897/026
Copyright: © 2020. : Abdelkader Boukerrouche. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 05 May 2020 | Accepted: 15 May 2020 | Published: 18 June 2020
Keywords: pancreatic neuroendocrine tumor; surgical management; pancreatic surgery; sparing parenchyma resection; follow-up
The incidence of pancreatic neuroendocrine tumors (PNETs) is growing, related in part to increased incidental diagnosis of small asymptomatic non-functionnal tumors. Arised from uncontrolled proliferation of neuroendocrine cell with genetic alterations inducing hormone secretion, the PNETs are majorly sporadic, non-functional, and associated with genetic syndromes, mainly Multiple Endocrines Neoplasm type 1 (MEN1) in up to 5%–10% of cases. Because of the very high heterogeneity, optimizing management and standardizing therapeutic strategies for PNETs remains a challenge for surgeons, requiring a multidisciplinary collaboration. Surgery for PNETs has evolved varying from radical resection to parenchyma sparing surgery and even now a selective conservative management. This review work aims to provide an update regarding the surgical treatment for PNETs, in the light of recent published reports.
Pancreatic neuroendocrine tumors (PNETs) is an uncontrolled proliferation of neuroendocrine cell associated with further genetic alterations and induced hormonal secretion including glucagon/insulin/gastrin/VIP.The significant increase in PNETs incidence during the past decades is in part related to the widespread use of cross-sectional imaging resulting in increased diagnosis of small asymptomatic non-functionnal PNETs or ‘’ incidentalomas’’ [1].Currently, the PNETs represent approximately 3%–5% of all diagnosed pancreatic tumors with annual incidence of 0.8 per 100.000 persons [1,2]. In addition, however, the vast majority of the PNETs are sporadic. Optimal management with standardized therapeutic strategies remains difficult because of the very high heterogeneity of PNETs .Surgery for PNETs has evolved varying from extended radical surgery to parenchyma sparing resection and even now a conservative management or “wait-and-see” strategy [3, 4, 5, 6] .This review work aims to provide an update regarding the surgical treatment for PNETs, in the light of recent published reports.
Physiopathology
Physiopathology Developed from uncontrolled proliferation of neuroendocrine cell, up to 5%–10% of PNETs frequently arise from genetic syndromes including multiple endocrine neoplasm type 1 (MEN-1); Von Hippel–Lindau syndrome (VHL); neurofibromatosis type I (NF1). About 70%–80% of patients with MEN-1 will develop PNETs [7, 8], so, MEN-1 is the most common genetic syndrome associated with PNETs. Non-functional (NF)-PNETs represent 60%–85% of PNETs [9]. PNETs vary from indolent well-differentiated to poorly differentiated tumors with biological and molecular heterogeneity [10]. Understanding of disease and pathogenesis of PENTs have been well improved [11]. Genetic alterations have been identified leading to defining a subset of patients with more aggressive tumors and poor oncological outcomes [12-14].
Clinical and biological diagnostic
Mostly small and indolent, the diagnosis of PNETs is usually delayed and up to 50% of PNETs are discovered incidentally in surgical series [15]. Approximately, metastasises are present in half of patients at the time of diagnosis [16]. Majorly non-functional (80%–90%), the clinical pattern of non-functional PNETs (NF-PNETs) is poor with unspecific symptoms such as abdominal pains or bowel disorder. Depending on location, the NF-PNETs can be revealed by jaundice (17%–50%), acute pancreatitis (45%), weight loss (20%–35%), or palpable mass related to a locally advanced disease [17]. Instead of NF-PNETs, the clinical symptoms of functional PNETs (F-PNETs) are related to specific hormone hypersecretion. In decreasing order insulin, glucagon, gastrin, VIP, and somatostatin are the most frequent secreted hormones. Mainly sporadic, Insulinomas account for 30%–40% of F-PNETs. Also, gastrinomas are the most frequent F-PNETs in MEN-1 syndrome (54%) [18]. Biologically, about 80% of PNETs have an increased plasma chromogranin A (CgA) level, and CgA is widely used as a biomarker for PNETs, and it correlated to tumor burden and liver metastasis, specifically in well-differentiated tumor [19]. However, many clinical conditions may be associated with increased CgA including Helicobacter pylori infection, Biermer’s disease, atrophic gastritis, drugs, etc. CgA is a useful biological marker for response and recurrence after treatment, and it also has a prognostic value. However, a high level of CgA should be taken into consideration only with a normal plasmatic gastrin level. Specific hormones as insulin, gastrin, glucagon, VIP, should be only performed according to the clinical symptoms.
Pathological diagnostic
The confirmation of pathological diagnosis of PNETs is done if at least two markers among CgA, Synaptophysin or CD56 are expressed in immunohistochemistry. The histoprognostic classification of PNETs is based on a proliferative activity defined by the Ki67 index and the mitotic count (number of mitoses per 10 high power fields). The revised World Health Organization (WHO) classification (2017) included the following modifications, the cut-off Ki-67 raised to 3% for G2 tumors, the Grade-3 PNETs was divided into well-differentiated neuroendocrine tumor of high-grade NET-G3 and poorly differentiated NEC NEC-G3. Up to 20% of G3 tumors, was NET-G3 with a Ki-67 index varying from 20% to 50% and should be managed as a G2 tumor (Table 1).
WHO: World Health Organization; PNET: pancreatic neuroendocrine tumor; PNEC: pancreatic neuroendocrine carcinoma; MINEN: mixed neuroendocrine–nonneuroendocrine neoplasm.
The tumor– node–metastasis classification (TNM) is also recommended to defining a prognostic subset of tumor. New criteria and modifications on T-stage and M-status have been introduced in the 8th AJCC edition (2017), and asserted by the European Neuroendocrine Tumor Society (ENTS; Table 2).
AJCC: American Joint Committee on Cancer; TNM: tumor–node–metastasis; SMA: superior
Mesenteric artery; CA: celiac artery. ANon-regional lymph node, lung, ovary, peritoneum, bone, brain.
As reported by studies, this new classification is more accurate than the previous 7th AJCC edition in defining the prognosis of patients with PNETs.
Morphological imaging
Radiology
The PNETs are usually hypervascularized with the tendency of easier identification from the surrounding pancreatic parenchyma in the delayed arterial phase (30s) enhancement, and “washout” in the portal venous phase (60–90s). Therefore, multiple detector computed tomography (MDCT) scan is the first imaging modality used to detect PNETs with including delayed arterial (30s) and portal venous (60–90s) phases to increase the detection rate. The sensitivity and specificity of MDCT are 82% and 96%, respectively [20]. MDCT allows to detect F-NETs in an earlier stage with small size and to assess the local extension, vascular involvement, and distant metastases. In addition, magnetic resonance imaging (MRI) with gadolinium-enhanced and diffusion-weighted sequences is the more accurate modality to detect small tumors and liver metastases [21]. Also, it was more accurate than SRS for the detection of distant metastasis, especially small liver metastasis [22]. contrast enhanced endoscopic ultrasonography (EUS) has a higher sensitivity in detecting small tumors (< 20mm>
Nuclear medicine imaging.
The radiometabolic somatostatin analog (SA) is used to uptake the somatostatin receptor [removed]SR) that reportedly was present in about 70% of PNETs, especially in well-differentiated tumors. This functional imaging allows to assessing tumor stage, metastasis and SR expression in bite to select patients for peptide receptor radiometabolic treatment (PRRT). The somatostatin receptor scintigraphy (SRS) also called Octreoscan has a respective sensibility and specificity of 90% and 80% in diagnosing well-differentiated PNETs larger than 1cm. However, SRS has a limited diagnostic value for NF-small NET of <1>10%, fluorodeoxyglucose (FDG)-PET/TDM is more suitable with better sensitivity in this setting [24]. It can also be used as a prognostic tool.
Surgical Treatment
The natural history and biological behavior of the PNETs have been better studied and understood leading to substantial progress in the surgical management of PNETs during the last decade. Therefore; conservative treatment can be supported in selected patients with indolent and small tumors. In bite to define the best suitable strategy for PNETs management, treatment decision should be made after a multidisciplinary discussion.
Surgical strategy
When surgery is considered, two strategies can be discussed, including standard pancreatic resection with lymphadenectomy, and conservative surgery or parenchyma sparing surgery (PSS) with LN picking. As known, node involvement is a strong prognostic factor of survival, so, pancreaticoduodenectomy and distal pancreatectomy should be indicated for PNETs with a high risk of nodal involvement [26]. Distal pancreatectomy with spleen preservation can be considered for small left-sided PNETs with benignity presumption [27]. Parenchyma sparing surgery (PSS) includes enucleation and central pancreatectomy and can be considered for small- and low-grade tumors [28, 29]. However, LN picking should be performed to assess node invasion. Enucleation may be indicated for a small low-grade or benign PNETs located further than 2–3mm from the main pancreatic duct. So, preoperative assessment using echoendoscopy and MRI, and /or intraoperative evaluation by echography is highly recommended to refine the tumor location when the tumor is closer to the main pancreatic duct. Central pancreatectomy for tumors of the pancreatic neck and the first part of the body is associated with significant morbidity especially pancreatic fistula, and so, this surgical procedure is rarely performed for such tumor location. Regarding postoperative pancreatic function, PSSs are only associated with 5% of postoperative exocrine and endocrine insufficiency, and excellent overall and recurrence-free 5-year survival of >95% in selected PNETs. Pancreatic parenchyma sparing is associated with 5% of postoperative exocrine and endocrine insufficiency and excellent overall and recurrence-free 5-year survival (>95%) in selected PNETs.
Minimally invasive approach versus open approach
The open surgery remains the standard of care for pancreatic resection, and nowadays, indications for the minimally invasive approach are not based on clear consensus. Laparoscopic pancreaticoduodenectomy did not show any advantage over the open approach [30]. In addition, and due to increased mortality in the laparoscopic arm, a Dutch trial comparing the minimally invasive approach to open pancreaticoduodenectomy has been prematurely stopped [31]. Differently, safety and effectiveness of laparoscopic distal pancreatectomy were clearly reported by several studies and meta-analysis; also, it was associated with decreased morbidity rate and shorter length stay [30, 31]. Regarding robotic pancreatic surgery, the reported preliminary results of robot-assisted pancreatectomy are encouraging [32, 33], however, further trials are required to better evaluate the role of robotic approach in pancreatic surgery especially in pancreaticoduodenectomy that might improve the postoperative outcome
Surgical indication
The indication of surgery should be balanced with morbidity, mortality and impaired functional results after pancreatectomy. Surgery is clearly indicated for symptomatic NF-PNETs, NF-PNETs greater than 2 or 3 cm, NF-PNETs with main pancreatic duct dilatation on imaging. Also, functional PNETs including insulinomas, sporadic gastrinomas, VIPomas, somatostatinomas must be absolutely operated. Recently, a better understanding of the natural history of small sporadic NF-PNETs has led to consider surgery for this category of PNETs [34, 35]. Asymptomatic sporadic NF-PNETs <2cm>
Oncological results
The oncological results varied widely depending on multiple factors including tumor grade, size, and stages. A year disease-specific survival superior to 90% has been reported in resected patients without synchronous liver metastasis [37], and median overall survival ranging from 12years to less than one year for G1-PNETs and G3 tumors has been reported respectively by data from Surveillance, Epidemiology, and End Results (SEER) [2]. Although, overall survival remains mostly excellent, and recurrence incidence after curative surgery varies from 27% to 40% within 3 to 5years respectively [38]. A recurrence risk score (RRS) has been recently (2019) proposed to tailoring follow-up strategies [39]. This score included independent prognostic factors: tumor, size >2cm, Ki67 of 20%, and positive LN. The patients were stratified into three groups, low (0–2), moderate (3–5), and high (6–10) risk with a 2-year recurrence rate of 2%, 14%, and 33%, respectively. Postoperative exocrine and endocrine pancreatic insufficiencies vary from 9% to 30% and 5% to 25%, respectively [40]. However, it decreases below 5
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