- Email: [email protected]
Gastroenteropancreatic neuroendocrine tumors: Role of surgery
Annales d’Endocrinologie 80 (2019) 175–181
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Klotz communication 2019: New insights into the pathophysiology and treatment of Neuroendocrine Tumors
Gastroenteropancreatic neuroendocrine tumors: Role of surgery Tumeurs neuroendocrines gastro-entéro-pancréatiques : rôle de la chirurgie Alain Sauvanet Department of HPB surgery, pôle des maladies de l’appareil digestif (PMAD), université Paris Diderot, hôpital Beaujon, AP–HP, 100, boulevard du Général-Leclerc, 92110 Clichy, France
a r t i c l e
i n f o
Keywords: Gastroenteropancreatic neuroendocrine tumors Pancreatectomy Pancreatic insufficiency Observation
a b s t r a c t Natural history of gastroenteropancreatic (GEP) Neuroendocrine tumors (NETs) is better and better known so indications of surgery are presently selective. Surgical resection, but also endoscopic resection and observation, can be proposed for gastric NETs according to presentation, size and grade. For small bowel NETs, resection is frequently needed but should obtain the best compromise between radicality and postoperative functional disorders. Appendiceal NETs are frequently diagnosed by appendectomy for appendicitis, but some patients at high risk for lymph node metastasis and recurrence should be reoperated for radical resection. Rectal NETs are often diagnosed incidentally; the smallest (< 1 cm) can be resected endoscopically but the most aggressive need a oncological proctectomy. Pancreatic NETs represent a wide spectrum, ranging from fully benign tumors to very aggressive ones. Insulinomas are mostly benign, responsible for incapacitating symptoms despite medical treatment, and should ideally be treated by parenchyma sparing resection, mainly enucleation. Conversely, symptoms of gastrinomas are efficiently treated medically but their resection needs an oncological approach. Nonfunctioning PNETs are more and more frequently and incidentally discovered. According to their size, presentation and patient’s characteristics, they need a resection (oncological or parenchyma-sparing) or a close observation. © 2019 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Tumeurs neuroendocrine gastro-intestinales et pancréatiques Pancréatectomie Insuffisance pancréatique Surveillance
L’histoire naturelle des tumeurs neuroendocrines (TNE) gastro-entéro-pancréatiques (GEP) est de mieux en mieux connue ce qui explique le caractère actuellement sélectif des indications chirurgicales. Une résection chirurgicale, mais aussi endoscopique et une surveillance, peuvent être proposées aux TNE gastriques, selon leur présentation, leur taille et leur grade. Pour les TNE du grêle, une résection digestive est souvent nécessaire mais doit aboutir au meilleur compris entre radicalité de la résection et résultat fonctionnel. Les TNE appendiculaires sont en règle diagnostiquées sur une pièce d’appendicectomie faite en urgence, mais les patients à haut risque de métastase ganglionnaire et de récidive doivent être réopérés en vue d’une résection radicale. Les TNE rectales sont souvent diagnostiquées fortuitement : les plus petites (< 1 cm) peuvent être réséquées endoscopiquement mais les plus agressives nécessitent une proctectomie radicale. Les TNE pancréatiques constituent un spectre très large, allant des tumeurs tout à fait bénignes à d’autres très agressives. Les insulinomes sont principalement bénins, mais responsables de symptômes très gênants malgré le traitement médical et doivent être opérés idéalement par une résection préservant le parenchyme, principalement l’énucléation. À l’inverse, les symptômes des gastrinomes sont efficacement traités médicalement, mais leur résection nécessite un geste oncologique. Les TNE pancréatiques non fonctionnelles sont de plus en plus souvent diagnostiquées, de fac¸on fortuite. Selon leur taille, leur présentation et les caractéristiques du patient, elles justifient une résection (oncologique ou préservant du parenchyme), ou une surveillance rapprochée. ´ ´ es. © 2019 Elsevier Masson SAS. Tous droits reserv
E-mail address: [email protected] https://doi.org/10.1016/j.ando.2019.04.009 0003-4266/© 2019 Elsevier Masson SAS. All rights reserved.
176
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
Abbreviations
TNM PNET CP EN ENETS UICC PD DP PSP WHO GEP LN
Tumor node metastasis staging system pancreatic neuro-endocrine tumor central pancreatectomy enucleation European Neuroendocrine Tumor Society Union Internationale Contre le Cancer pancreaticoduodenectomy distal pancreatectomy parenchyma sparing pancreatectomy World Health Organization gastroenteropancreatic lymph nodes
1. Introduction Gastroenteropancreatic (GEP) neuroendocrine neoplasms can be present on any part of the digestive tract. Some locations are very rare (oesophagus, colon). Gastric, pancreaticoduodenal, small bowel, appendiceal and rectal localizations are more frequent and frequently need surgical resection, even when associated with limited metastatic (“oligometastatic”) involvement. However, surgery should be proposed on an individual basis, taking into account age, general condition, tumor location, tumor extent, and grade.
pathologic examination. These tumors can be associated with mesenteric LN metastases but the risk of LN is related to several pathological characteristics [1]. This risk is nil and there is no need to reoperation in patients with tumors < 1 cm, with tumor-free margins, and no appendiceal perforation. Conversely, reoperation for right hemicolectomy and LN mesenteric dissection is indicated in patients with tumors > 2 cm or tumors including both endocrine and exocrine components. Between these two thresholds, reoperation for right hemicolectomy or closed follow-up should be proposed according to age, general condition, grade and margins on the appendectomy specimen [1]. 5. Rectal NET Rectal NET are frequent and often diagnosed incidentally after a colonoscopy with resection of a small (< 1 to 2 cm) yellowish rectal “polyp”. Due to the submucosal origin of rectal PNET, endoscopic resection of incidental tumors is frequently not radical (R1). For tumors < 1 cm, local endoscopic resection is curative provided a radical (R0) resection is obtained thus no reoperation is needed. For tumors > 2 cm, the risk of LN metastases is high and reoperation for proctectomy with mesorectal resection (to obtain adequate LN dissection and tumor-free margins) is indicated. Between these 2 thresholds, the choice between reoperation through a trans-anal approach and proctectomy with mesorectal resection should be determined according to age, location, lymph node staging (MRI and/or endoscopic ultrasound [EUS]) and grade [1].
2. Gastric NET 6. Pancreatic neuro-endocrine tumors These tumors include 3 types: Type 1 and Type 2 gastric NET are small, multiple, and low-grade (G1-low G2) NET developed on enterochromaffin-like cells (ECL), due to hypergastrinemia induced by atrophic gastritis and Zollinger Ellison syndrome, respectively. Both entities usually do not justify surgical resection. Only ECLomas > 10 mm or invading muscularis layer or harbouring lymph node metastases can justify either an atypical local resection or an antrectomy [1]. Type 3 gastric NET are usually sporadic, large, high grade (high G2 or even G3) and node positive; an oncological gastrectomy, either partial or total, including a lymph node (LN) dissection, is usually indicated [1]. 3. Small Bowel NET These tumors are mostly ileal, low grade (G1, low G2), associated with mesenteric LN metastases (responsible for retractile mesenteritis in 20% of cases at diagnosis), metastatic to the liver (40%) and can be revealed by acute intestinal obstruction (20%) [1–3]. Mesenteric extension is responsible for vascular encasement, so complete tumor resection (possibly including also the right colon) can result in extended bowel resection with the risk of secondary short bowel syndrome. Extent of bowel and mesenteric resection should be determined to obtain the best compromise between radicality of surgery and postoperative functional disorders. Complete tumor resection allows a 75% to 85% 5 years survival but follow-up should be prolonged at least 10 years due to the very slow natural history of these tumors [1–3]. Patients operated on an emergency basis have frequently a non-radical initial resection but can benefit from delayed reoperation to perform a radical resection including the appropriate mesenteric LN dissection [2,3]. 4. Appendiceal NET Appendiceal NETs are usually revealed by an appendicular syndrome, operated on a emergency basis, and diagnosed by routine
Pancreatic neuro-endocrine tumors (PNETs) have an overall good prognosis. However, their biological behaviour is very heterogeneous (functioning or non functioning) and their prognostic spectrum is also wide, from fully benign tumors to very aggressive ones. Overall, complete surgical resection is the only curative treatment which should be proposed whenever feasible with a low immediate risk and few long term functional disorders. Practically, indications of resection should be tailored according to clinical presentation (incidental or symptomatic tumor, sporadic or genetic predisposition), the presence or not of a hormonal syndrome (functioning or non functioning PNET), the type of hormonal secretion (the most frequent are insulin and gastrin), histo-prognostic factors (including tumor stage and grade), and the general condition of the patient (age, comorbidities). 6.1. Functioning PNET 6.1.1. Insulinoma Insulinomas are usually small (usually 1–2 cm), resulting in frequent difficulty for localization, and have a benign behavior in 95% of cases with a very low (5%) risk of recurrence after resection. After an appropriate clinico-biological diagnosis (fasting test demonstrating hypoglycemia and inappropriate insulin and peptide C serum levels), the tumor should be located by CT scan, MRI and/or EUS . These 3 procedures when grouped can localize up to 95% of insulinomas [4]. Exceptionally, other imaging procedures (contrast enhanced EUS or GLP-1 scintigraphy) are necessary. Approximately 5% of insulinomas are associated with Multiple Endocrine Neoplasia type 1, and can be multiple or coexist with other non-functioning PNET [1]. Surgical resection is almost always proposed due to severity of symptoms, the poor long-term efficiency and tolerance of medical treatment (diazoxide), and the benignity of the disease (grade 1 is extremely frequent and LN or liver metastases are exceptional) [5].
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
Intraoperatively, tumor localization can be determined more precisely with intraoperative ultrasound. Insulinomas located more than 1–2 mm far from the main pancreatic duct are amenable to enucleation, if possible through a laparoscopic approach, with a high risk of postoperative non-lethal complications (“pure” pancreatic fistula) but no risk of long-term pancreatic insufficiency since no parenchyma is resected [5–8]. Conversely, due to anatomical reasons (vicinity of insulinoma with the main pancreatic duct), approximately one third of patients need a “standard” pancreatectomy (distal or cephalic) resulting in a low but real risk of mortality (1 to 3%) and a 20 to 30% risk of long-term surgery-induced diabetes [5–8]. The rate of patients definitively cured by surgery ranges from 90 to 95% [1,5]. In patients with high operative risk, ablative therapy (EUS guided radio-frequency ablation) is an alternative to enucleation [9]. For insulinomas developed on MEN-1, multiple enucleations or distal pancreatectomy with cephalic enucleations can be proposed. In summary, surgical treatment of insulinoma is mainly a technical issue, since prolonged medical treatment is usually not possible and the tumoral disease has a benign behavior. Resection of insulinoma needs precise pre and intraoperative tumor localization and should include parenchyma preservation as often as possible. 6.1.2. Gastrinoma Gastrinomas are responsible for the typical Zollinger Ellison syndrome (ZES) but also upper GI-bleeding or perforated gastroduodenal ulcer as possible inaugural complications. Diagnosis can be evoked when symptoms are corrected by proton pump inhibitors, especially when high doses are necessary, and confirmed by upper GI endoscopy (when demonstrating consequences of acid hypersecretion on oeso-gastro-duodenal mucosa), CT scan and somatostatin receptor scintigraphy (SRS). Although gastrinomas are almost always located in the duodenopancreatic area, cross sectional imaging frequently fails to localize gastrinomas and their extension, due to their small size (< 1 cm), their duodenal site in 2/3 of cases, their multiplicity in 10–20% of cases (even when sporadic), and the presence of nodal metastases in 60% of cases. Due to these characteristics, EUS and or PET Ga 68 are often necessary [1,10,11]. Also, 20 to 25% of patients with gastrinoma have NEM-1, which should be routinely screened. Gastrinomas have mostly a malignant behavior, even if tumor progression is usually slow due to high prevalence of grade 1 and low grade 2. LN and liver are the most frequent metastatic sites, suggesting that liver MRI with diffusionweighted sequences should be routinely performed [12,13]. Once ZES is diagnosed (or even highly suspected), the priority is PPI treatment to inhibit completely acid hypersecretion, using high doses if necessary. Surgery should be discussed once symptoms have disappeared and after a complete work-up. The main aim of surgery is to prevent occurrence of liver metastases, which is the main prognostic factor [10]. In patients with sporadic gastrinoma, surgery is mainly indicated in patients without distant metastases and should include resection of the primary (through duodenotomy for duodenal localizations; or by enucleation or pancreatectomy for pancreatic localizations) [10] associated with systematic LN dissection [14]. Intraoperatively, routine pancreatic ultrasound and duodenotomy are useful to improve tumor detection and localization. Surgery seems able to improve overall survival (comparatively to non operated patients) [10] but definitive cure of gastrin hypersecretion is more rarely observed, probably due to some undiagnosed small primaries left in place or persisting LN metastases [15]. Surgery for metastatic gastrinomas, resecting both primary, metastatic LN and liver metastases is rarely performed in very selected patients. In patients with MEN-1, the multiplicity of secreting tumors does not allow “local” surgery (including tumorectomy + LN
177
dissection) to treat efficiently gastrin hypersecretion. For this purpose, pancreaticoduodenectomy (PD) is more efficient but several authors are reluctant to perform it due to its high early and long-term morbidity [1]. The risk of malignancy is considered only in patients with pancreatic PNET > 2 cm so surgery is usually indicated only in this subset of MEN-1 patients [1]. In summary, surgical treatment of gastrinoms is mainly an oncological issue, since acid hypersecretion is easily controlled by PPI provided sufficient doses are used. Even though the majority of gastrinomas have a malignant behaviour (60% of LN metastases at diagnosis), tumor progression is usually slow. Radical operation (particularly PD) is rarely performed and most authors prefer a more limited surgery (tumorectomy + LN dissection) to limit the risk of distant metastatic progression with few postoperative complications and functional disorders. 6.1.3. Other functional PNET This group mainly includes VIPoma, glucagonoma, and somatostatinoma, which are usually large and malignant [1]. In patients with VIPoma, the priority is to treat consequences of hypersecretion (diarrhea with hypokaliemia) usually with somatostatin analogs. When resectable, these tumors usually need a radical pancreatectomy with LN dissection. 6.2. Non-functioning PNET and incidentalomas Incidence of non-functioning PNET (NF-PNET) has dramatically increased during the last 20 years since it raised from 1.7/105 in 1973–1977 to 4.3/105 in 2003–2007 [16]. This increase is particularly marked for small NF-PNET, the incidence of which increased by 700% during 20 years, due to the widespread diffusion of cross-sectional imaging which detects more and more NF-PNET incidentally [17], particularly for small (≤ 2 cm) PNET. In recent series, incidentally diagnosed NF-PNET represent up to 50% of operated patients [18,19]. Conversely, symptomatic NF-PNET are revealed by pain or compression symptoms, can be large, locally advanced or even metastatic [20,21]. Histo-prognostic characteristics of NF-PNET are highly varying. They were determined in surgical series, which included mainly patients with non-metastatic disease, with a possible bias at least by limitation the number of G3 tumors. Histo-prognostic characteristics are mainly related to tumor size. In Table 1, are exposed the rate of LN metastases and prevalence of G2/G3 tumors in tumors ≤ and > 2 cm in diameter, respectively. Indeed, this 2 cm threshold is frequently used in the literature because: • it represents the limit between T1 and T2 tumors in the TNM classification proposed by the UICC and the ENETS; • it is clinically relevant due to its prognostic value [22–24]; • and it is close to the mean diameter of resected NF-PNET since average half (30 to 65%) of NF-PNET have a diameter ≤ 2 cm [18,19,24]. According to these surgical series, it is possible to estimate the rate of LN metastases (as a surrogate marker of the tumor “aggressiveness”) close to 10% and the probability of a G2/G3 grade to 15–20% for NF-PNET ≤ 2 cm. However this size, when measured by gross examination, can be less than the one measured by imaging probably due to loss of arterial hypervascularization after resection [30]. Otherwise, 2 series have shown that absence of symptoms (incidental diagnosis) were associated with a higher risk of “benign behaviour” and a better prognosis [18,24]. Lastly, in a collective study, absence of ductal dilatation (biliary and/or pancreatic) was an independent factor associated with a better disease free survival [29].
178
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
Table 1 rate of lymph node metastases and grade 2/3 tumors according to tumor size (≤ 2 cm ou > 2 cm) in NF-PNET. Authors, year [ref]
Haynes, 2011 [19] Bettini, 2011 [24] Cherif, 2012 [25] Cherefant, 2013 [26] Toste, 2013 [27] Ellison, 2014 [22] Fischer, 2014 [28] Sallinen, 2016 [29]a a
Lymph node metastases (N+)
Grade G2/G3
≤ 2 cm
> 2 cm
≤ 2 cm
> 2 cm
3/37 (8%) 13/90 (14%) 5/50 (10%) 4/53 (8%) 3/35 (8%) 6/69 (9%) 6/51 (12%) 14/132 (11%)
36/100 (36%) 30/87 (34%) 16/38 (42%) 27/75 (36%) 30/81 (37%) 133/249 (53%) – –
– 13/90 (14%) – 10/53 (19%) 14/35 (40%) – 8/61 (13%) 38/210 (19%)
– 40/87 (46%) – 16/75 (21%) 46/81 (57%) – – –
Multicentric series; 132/210 patients had examined lymph nodes on specimen.
6.3. Pancreatic surgery for NF-PNET 6.3.1. Principles Historically, NF-PNETs were treated by “radical” pancreatectomies including parenchymal resection and LN dissection: PD or distal pancreatectomy (DP), with or without splenectomy. Nowadays, these procedures are performed with low mortality (2 to 5% following PD, 1 to 3% following DP) in high-volume institutions but with an early morbidity ranging from 30 to 50% [31–33]. Longterm results of these procedures are characterized by a risk of de novo diabetes ranging from 10 to 20% following PD and 10 to 35% following DP [25,34,35]. The risk of de novo exocrine insufficiency needing enzyme supplementation is higher after PD than after DP (on average 60% versus 10%, respectively) [36]. Long-term pancreatic function has become an important issue in the decision to resect a low-grade NF-PNET, particularly in patients with an incidentaloma. For this reason, parenchymasparing pancreatectomies (PSP), mainly enucleation (EN) and central pancreatectomy (PC), were proposed to limit the loss of pancreatic function induced by surgery. Indeed, the risk of de novo diabetes is close to zero following EN and at the most 16% after CP, according to characteristics of parenchyma and extent of resection [32,35]. After CP, the risk of exocrine insufficiency is less than 10% that is clearly lower than observed after PD [36]. The risk of exocrine insufficiency following EN is close to zero [7,35]. However, PSP have two limitations: • a not nil mortality after both EN [7,35] or CP [32,37] due to surgical or medical complications; • and an early morbidity at least equivalent, even higher, than observed after “radical” pancreatectomies [7,32,35,37]. Indeed, the average morbidity rates are around 60% and 45% following CP and EN, versus 50% and 30% following PD and DP, respectively [7,32,35,37]. This morbidity is mainly due to pancreatic fistula, which occurs more frequently due to vicinity of main pancreatic duct during EN [6,8] and the presence of two pancreatic cut surfaces in CP [32,37]. 6.3.2. Which operation for NF-PNET? 6.3.2.1. Technical and functional aspects. Regarding technical aspects, tumor location is important. Tumors located far (> 2 mm) from the main pancreatic duct are amenable to EN [6,8]. Conversely, when the tumor is closer or even in contact with the main pancreatic duct, the risk of ductal damage and postoperative fistula argue against EN and therefore for a resection including a parenchymal resection (PD, DP or CP). Location in the pancreatic parenchyma (cephalic, central or distal) should be taken into account according to age and general condition. Particularly, PD and CP can be considered as a major
procedure in high-risk patents (aged or with comorbidities) and, conversely, DP is better tolerated [31,32]. Regarding long-term functional results, the better results of PSP should be evaluated comparatively to their higher early morbidity, particularly for CP the alternative of which is DP. Thus, patients undergoing PSP should be fit enough to overcome the higher early morbidity of PSP [25]. Also, young patients with a long life expectancy are more likely to benefit from PSP than aged patients. Overall, evaluation of the balance between benefits and risks of these operations for NF-PNETs, should take into account all these technical aspects but also age and general condition [25,27]. As an exemple, a small (< 2 cm) cephalic tumor far (> 2 mm) from the main pancreatic duct should ideally be enucleated to avoid drawbacks of PD, particularly in a high-risk patient. Conversely, a small (< 2 cm) tumor in contact to the main pancreatic duct is not amenable to EN and can be resected by a short DP when localized in the tail, or by CP when centrally located.
7.3.2.2. Oncological aspects. PSP do not include systematic LN dissection but a LN sampling (“picking”) is possible. Indeed, in one retrospective study, LN were analyzed in 25% of PSP versus 97% of standard pancreatectomies [27]. In our experience, these rates were 61% after PSP versus 95% after standard pancreatectomies [25]. So, the oncologic value of PSP is very debated and these procedures are only justified for small (< 2 cm) and low-grade TNEP resulting in a low risk of unanticipated LN metastases and a high expected probability of cure. Histoprognostic factors of NF-PNET ≤ 2 cm suggest that, for this subset of tumors, PSP are adequate and that, on the opposite, a radical pancreatectomy is an “over treatment” in around 90% of patients. It seems possible to propose a PSP for every NFPNET ≤ 2 cm with a favorable presentation (no symptoms, no ductal dilatation, no detectable metastases in LN and on the liver). Some authors have suggested a lower threshold in size, between 1 cm and 1.7 cm [38–41]. There is probably not a single discriminant threshold in size and other criteria, including grade if available, are important. But the general concept is to avoid a surgical over treatment in asymptomatic patients, who are often more than 60 years old [42], and particularly in case of cephalic localization.
6.3.3. Survival after resection of NF-PNET Survival should be evaluated with a sufficient follow-up to take into account the very slow natural history of PNET. Ten-year overall survival and 5-year disease free survival are the most frequently evaluated. However, reported series are most often retrospective and biased. The most frequent bias is the choice of the extent of surgery according to the supposed aggressiveness of the disease and the expected prognosis.
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
Old series have included mainly symptomatic large NF-PNET and reported overall 5-year survivals around 70% for localized (nonmetastatic) tumors [43,44]. Recently, presentation of NF-PNET has changed and survival has become better with 5-year DFS around 90% [45] and an overall 10 year survival around 50% [25,46]. Main prognostic factors are LN involvement and tumor grade [26–28,39]. Conversely, microscopic involvement of resection margins, which is frequent following EN, has no significant influence [21,22,47]. NF-PNET treated by PSP have a more favorable presentation than that treated by radical resection [25], that explains why survival after PSP is at least equivalent to that observed after radical resection, with a 5-year DFS up to 90–95% after adequate selection of indications [18,24,25,27,45,48]. Local recurrences are rare after PSP and LN and distant recurrences are more frequent [24,25,48,49]. Follow-up should be prolonged since most recurrences occur 5 to 10 years after resection [24,25].
6.4. Observation as an alternative to resection is small NF-PNET Due to the early risks and long-term consequences of pancreatectomies, the paradigm of routine resection for every NF-PNET was recently reconsidered, particularly for small and asymptomatic ones (incidentalomas). However this approach needs an precise characterization of the tumor, and an accurate evaluation of the benefit-risk balance, taking into account tumor localization and general condition. A diameter ≤ 2 even 3 cm is the threshold adopted by the majority of authors who evaluated this approach [27,50–52]. A 3-cm threshold could be justified by the frequent decrease in size from imaging to gross examination after resection [30]. However, some authors chose a lower size threshold ranging from 1 to 1.7 cm [38,40,41]. Diagnosis of PNET should be firmly established by a EUSguided biopsies [53] or a positive functional imaging [51], to avoid to observe lesions mimicking PNET (solid cystadenoma, accessory spleen) [50]. Ideally, the PNET should have a low-grade (G1 or low G2), although it can be difficult to determine the grade on a single EUS-guided biopsy [53] with a functional imaging consistent with this diagnosis (SRS or Ga68 positive, and 18 FDG negative) [54,55]. Modalities of follow-up (which examination? which periodicity?) are poorly defined. Overall, with a follow-up ranging from 34 to 44 months, tumor progression leading to subsequent resection was reported in 0% to 13% of observed patients [50–52]. No metastatic progressions were reported under observation. However, comparatively with the natural history of PNET, the follow up of available observational studies is too short to draw definitive conclusions. Presently, observation seems mainly indicated in aged patients, with some comorbidities or with a cephalic PNET requiring a PD, because in this subset of patients, the gain in survival offered by resection is probably low or even nil [56].
7. Extended resection for locally advanced tumors Gastric or mostly pancreatic NF-PNET can be large and can invade surrounding organs. Particularly they can encase surrounding vessels or be responsible for endovascular extension resulting in tumoral thrombus. Criteria of resectability of NF-PNET are less restrictive than those for adenocarcinoma so upfront resection can be frequently attempted for these locally advanced tumors [57]. Survival after resection is not altered by microscopic involvement of resection margins [28,47] and 5-year survival is around 50% after extended radical resection of locally advanced PNET [57]. The role of neoadjuvant treatment, using systemic chemotherapy or peptide receptor radionuclide therapy [58], is still under evaluation.
179
8. Surgery for GEP NET with liver metastases Surgery has also been considered as a “gold-standard” to be proposed whenever possible to patients with metastatic PNET [1]. This approach was justified by the results of large monocentric retrospective studies [59] or large multicentric databases [60], which reported a better survival after resection of the primary, or liver metastases when feasible, or both. When no extended hepatectomy is needed, resection of liver metastases can be performed during the same step than primary resection otherwise during a second step [61]. Liver surgery can be facilitated by the use of ablative techniques (radiofrequency ablation, microwave) for deep lesions < 3 cm [62]. This approach can be done with a less than 5% mortality, a 80% 5-year overall survival, but a 50% risk of liver recurrence due to unrecognized microscopic involvement at the time of surgery [61,63]. To limit the risk of recurrence, preoperative assessment of hepatic and extra-hepatic extension should use MRI with diffusion weighted sequences [13] and probably Pet Ga 68 [11]. It is also important to limit indications of hepatectomy to well differentiated and low grade (G1 and low G2) tumors. The role of neoadjuvant treatment by systemic chemotherapy is under evaluation [64]. When liver disease is not resectable, some authors have suggested to resect the primary to improve survival [58,59], to avoid long-term complications related to the primary and subsequently to focus on the treatment of liver disease. This approach is very debated since no prospective comparative studies are available [65]. However, it is frequently used for small bowel primaries, which can be complicated by obstruction in up to 25% of cases, or more rarely for distal pancreatic primaries [65]. For cephalic pancreatic primaries, to perform a PD usually precludes a simultaneous extended hepatic resection and also increases the septic complications of any subsequent liver-directed therapy (resection, ablation or embolization) due to bacterial contamination of the biliary tree above the hepatico-jejunostomy [66]. Exceptionally, diffuse bilobar liver metastases from GEP NET can be treated by total hepatectomy and liver transplantation. The most favorable long-term results are obtained in young patients with low grade primary from a previously resected small bowel primary, and a limited tumor burden resulting in a moderate hepatomegaly [67]. 9. Conclusions The management of GEP NET includes a wide spectrum of attitudes ranging from simple observation to resection of the primary followed by liver transplantation. However, despite their very variable localization and presentation, GEP-NET are very frequent indications for surgical resection which allows very high rates of definitive cure but, due to their favorable natural history and prognosis, the balance between benefits and risks of surgery should be carefully evaluated. This is particularly true for tumors with limited initial presentation, particularly when incidentally diagnosed or, on the opposite for patients with extended disease not amenable to complete resection with an acceptable risk. Disclosure of interest The author declares that he has no competing interest. References [1] O’Toole D, Kianmanesh R, Caplin M. ENETS 2016 Consensus guidelines for the management of patients with digestive neuroendocrine tumors. Neuroendocrinology 2016;103:117–8. [2] Landry CS, Lin HY, Phan A, et al. Resection of at-risk mesenteric lymph nodes is associated with improved survival in patients with small bowel neuroendocrine tumors. World J Surg 2013;37:1695–700.
180
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
[3] Motz BM, Lorimer PD, Boselli D, et al. Optimal lymphadenectomy in small bowel neuroendocrine tumors: analysis of the NCDB. J Gastrointest Surg 2018;22:117–23. [4] Gouya H, Vignaux O, Augui J, Dousset B, Palazzo L, Louvel A, et al. CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. AJR Am J Roentgenol 2003;181:987–92. [5] Nikfarjam M, Warshaw AL, Axelrod L, Deshpande V, Thayer SP, Ferrone CR, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg 2008;247:165–72. [6] Brient C, Regenet N, Sulpice L, et al. Risk factors for postoperative pancreatic fistulization subsequent to enucleation. J Gastrointest Surg 2012;16:1883–7. [7] Faitot F, Gaujoux S, Barbier L, et al. Reappraisal of pancreatic enucleations: a single-center experience of 126 procedures. Surgery 2015;158:201–10. [8] Heeger K, Falconi M, Partelli S, et al. Increased rate of clinically relevant pancreatic fistula after deep enucleation of small pancreatic tumors. Langenbecks Arch Surg 2014;399:315–21. [9] Barthet M, Giovannini M, Lesavre N, Boustiere C, Napoleon B, Koch S, et al. Endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine tumors and pancreatic cystic neoplasms: a prospective multicenter study. Endoscopy 2019, http://dx.doi.org/10.1055/a-0824-7067 [Epub ahead of print]. [10] Norton JA, Fraker DL, Alexander HR, Gibril F, Liewehr DJ, Venzon DJ, et al. Surgery increases survival in patients with gastrinoma. Ann Surg 2006;244:410–9. [11] Partelli S, Rinzivillo M, Maurizi A, et al. The role of combined Ga-DOTANOC and (18)FDG PET/CT in the management of patients with pancreatic neuroendocrine tumors. Neuroendocrinology 2014;100:293–9. [12] Vinault S, Mariet AS, Le Bras M, Mirallié E, Cardot-Bauters C, Pattou F, et al. Metastatic potential and survival of duodenal and pancreatic tumors in multiple endocrine neoplasia type 1: a GTE and AFCE cohort study. Ann Surg 2018, http://dx.doi.org/10.1097/SLA.0000000000003162 [Epub ahead of print]. [13] d’Assignies G, Couvelard A, Bahrami S, et al. Pancreatic endocrine tumors: tumor blood flow assessed with perfusion CT reflects angiogenesis and correlates with prognostic factors. Radiology 2009;250:407–16. [14] Bartsch D, Waldmann J, Fendrich V, Boninsegna L, Lopez C, Partelli S. Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma. Br J Surg 2012;99:1234–40. [15] Maire F, Sauvanet A, Couvelard A, Rebours V, Vullierme MP, Lebtahi R, et al. Recurrence after surgical resection of gastrinoma: who, when, where and why? Eur J Gastroenterol Hepatol 2012;24:368–74. [16] Lawrence B, Gustafsson B, Chan A, et al. The epidemiology of gastroentero-pancreatic neuro endocrine tumors. Endocrinol Metab Clin North Am 2011;40:1–18 [vii]. [17] Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol 2013;20:2815–21. [18] Birnbaum DJ, Gaujoux S, Cherif R, et al. Sporadic nonfunctioning pancreatic neuroendocrine tumors: prognostic significance of incidental diagnosis. Surgery 2014;155:13–21. [19] Haynes A, Deshpande V, Ingkakul T, et al. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes. Arch Surg 2011;146:534–8. [20] Bilimoria KY, Talamaonti MS, Tomlinson JS, et al. Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg 2008;247:490–500. [21] Fischer L, Bergmann F, Schimmack S, et al. Outcome of surgery for pancreatic neuroendocrine neoplasms. Br J Surg 2014;101:1405–12. [22] Ellison TA, Wolfgang CL, Shi C, et al. A single institution’s 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann Surg 2014;259:204–12. [23] Scarpa A, Mantovani W, Capelli P, et al. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 2010;23:824–33. [24] Bettini R, Partelli S, Boninsegna L, et al. Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 2011;150:75–82. [25] Cherif R, Gaujoux S, Couvelard A, et al. Parenchyma-sparing resections for pancreatic neuroendocrine tumors. J Gastrointest Surg 2012;16:2045–55. [26] Cherenfant J, Stocker SJ, Gage MK, et al. Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. Surgery 2013;154:785–91. [27] Toste PA, Kadera BE, Tatishchev SF, Dawson DW, et al. Nonfunctional pancreatic neuroendocrine tumors < 2 cm on preoperative imaging are associated with a low incidence of nodal metastasis and an excellent overall survival. J Gastrointest Surg 2013;17:2105–13. [28] Fischer L, Bergmann F, Schimmack S, Hinz U, Priess B, et al. Outcome of surgery for pancreatic neuroendocrine neoplasms. Br J Surg 2014;101:1405–12. [29] Sallinen V, Le Large T, Tieftrunk E, et al. Prognosis of sporadic resected small (≤ 2 cm) nonfunctional pancreatic neuroendocrine tumor — A multiinstitutional analysis. HPB (Oxford) 2018;20:251–9. [30] Partelli S, Gaujoux S, Boninsegna L, et al. Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs). JAMA Surg 2013;148:932–9. [31] Farges O, Bendersky N, Truant S, Delpero JR, Pruvot FR, Sauvanet A. The theory and practice of pancreatic surgery in France. Ann Surg 2017;266:797–804. [32] Iacono C, Verlato G, Ruzzenente A, et al. Systematic review of central pancreatectomy and meta-analysis of central versus distal pancreatectomy. Br J Surg 2013;100:873–85.
[33] Meguid RA, Ahuja N, Chang DC. What constitutes a “high-volume” hospital for pancreatic resection? J Am Coll Surg 2008;206:622e1–9. [34] Falconi M, Mantovani W, Crippa S, et al. Pancreatic insufficiency after different resections for benign tumours. Br J Surg 2008;95:85–91. [35] Hüttner FJ, Koessler-Ebs J, Hackert T, et al. Meta-analysis of surgical outcome after enucleation versus standard resection for pancreatic neoplasms. Br J Surg 2015;102:1026–36. [36] Sabater L, Ausania F, Bakker O, et al. Evidence-based guidelines for the management of exocrine pancreatic insufficiency after pancreatic surgery. Ann Surg 2016;264:949–58. [37] Goudard Y, Gaujoux S, Dokmak S, et al. Reappraisal of central pancreatectomy a 12-year single-center experience. JAMA Surg 2014;149:356–63. [38] Curran T, Pockaj BA, Gray RJ, et al. Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection. J Gastrointest Surg 2015;19:152–60. [39] Hashim YM, Trinkaus KM, Linehan DC, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg 2014;259:197–203. [40] Regenet N, Carrere N, Boulanger G, et al. Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: a French multicenter study. Surgery 2016;159:901–7. [41] Kishi Y, Shimada K, Nara S, et al. Basing treatment strategy for nonfunctional pancreatic neuroendocrine tumors on tumor size. Ann Surg Oncol 2014;21:2882–8. [42] Halfdanarson TR, Rabe KG, Rubin J, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol 2008;19:1727–33. [43] Kouvaraki MA, Solorzano CC, Shapiro SE, et al. Surgical treatment of nonfunctioning pancreatic islet cell tumors. J Surg Oncol 2005;89:170–85. [44] Phan GQ, Yeo CJ, Cameron JL, et al. Pancreaticoduodenectomy for selected periampullary neuroendocrine tumors: fifty patients. Surgery 1997;122:989–96. [45] Pitt SC, Pitt HA, Baker MS, et al. Small pancreatic and periampullary neuroendocrine tumors: resect or enucleate? J Gastrointest Surg 2009;13:1692–8. [46] Hill JS, McPhee JT, McDade TP, et al. Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer 2009;115:741–51. [47] Pomianowska E, Gladhaug IP, Grzyb K, et al. Survival following resection of pancreatic endocrine tumors: importance of R-status and the WHO and TNM classification systems. Scand J Gastroenterol 2010;45:971–9. [48] Casadei R, Ricci C, Rega D, et al. Pancreatic endocrine tumors less than 4 cm in diameter: resect or enucleate? A single-center experience. Pancreas 2010;39:825–8. [49] Falconi M, Zerbi A, Crippa S, et al. Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors. Ann Surg Oncol 2010;17:1621–7. [50] Lee LC, Grant CS, Salomao DR, et al. Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management. Surgery 2012;152:965–74. [51] Gaujoux S, Partelli S, Maire F, et al. Observational study of natural history of small sporadic nonfunctioning pancreatic neuroendocrine tumors. J Clin Endocrinol Metab 2013;98:4784–9. [52] Sadot E, Reidy-Lagunes DL, Tang LH, et al. Observation versus resection for small asymptomatic pancreatic neuroendocrine tumors: a matched case-control study. Ann Surg Oncol 2016;23:1361–70. [53] Rebours V, Cordova J, Couvelard A, et al. Can pancreatic neuroendocrine tumour biopsy accurately determine pathological characteristics? Dig Liver Dis 2015;47:973–7. [54] Garin E, Le Jeune F, Devillers A, et al. Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors. J Nucl Med 2009;50:858–64. [55] Chan DL, Pavlakis N, Schembri GP, et al. Dual somatostatin receptor/FDG PET/CT imaging in metastatic neuroendocrine tumours: proposal for a novel grading scheme with prognostic significance. Theranostics 2017;7:1149–58. [56] Hill JS, McPhee JT, McDade TP, Zhou Z, Sullivan ME, Whalen GF, et al. Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer 2009;115:741–51. [57] Birnbaum DJ, Turrini O, Vigano L, Russolillo N, Autret A, Moutardier V, et al. Surgical management of advanced pancreatic neuroendocrine tumors: shortterm and long-term results from an international multi-institutional study. Ann Surg Oncol 2015;22:1000–7. [58] Partelli S, Bertani E, Bartolomei M, Perali C, Muffatti F, Grana CM, et al. Peptide receptor radionuclide therapy as neoadjuvant therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms. Surgery 2018;163:761–7. [59] Hüttner FJ, Schneider L, Tarantino I, et al. Palliative resection of the primary tumor in 442 metastasized neuroendocrine tumors of the pancreas: a population-based, propensity score-matched survival analysis. Langenbecks Arch Surg 2015;400:715–23. [60] Franko J, Feng W, Yip L, et al. Non-functional neuroendocrine carcinoma of the pancreas: incidence, tumor biology, and outcomes in 2158 patients. J Gastrointest Surg 2010;14:541–8. [61] Kianmanesh R, Sauvanet A, Hentic O, et al. Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors: a safe approach for radical resection. Ann Surg 2008;247:659–65. [62] Elias D, Goéré D, Leroux G, et al. Combined liver surgery and RFA for patients with gastroenteropancreatic endocrine tumors presenting with more than 15 metastases to the liver. Eur J Surg Oncol 2009;35:1092–7.
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181 [63] Mayo SC, de Jong MC, Pulitano C, Clary BM, Reddy SK, Gamblin TC, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol 2010;17:3129–36. [64] Cloyd JM, Omichi K, Mizuno T, et al. Preoperative fluorouracil, doxorubicin, and streptozocin for the treatment of pancreatic neuroendocrine liver metastases. Ann Surg Oncol 2018;25:1709–15. [65] Partelli S, Cirocchi R, Rancoita PMV, Muffatti F, Andreasi V, Crippa S, et al. A Systematic review and meta-analysis on the role of palliative primary resection
181
for pancreatic neuro-endocrine neoplasm with liver metastases. HPB (Oxford) 2018;20:197–203. [66] De Jong MC, Farnell MB, Sclabas G, et al. Liver-directed therapy for hepatic metastases in patients undergoing pancreaticoduodenectomy: a dual-center analysis. Ann Surg 2010;252:142–8. [67] Treut YP, Grégoire E, Klempnauer J, et al. Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study. Ann Surg 2013;257:807–15.
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Klotz communication 2019: New insights into the pathophysiology and treatment of Neuroendocrine Tumors
Gastroenteropancreatic neuroendocrine tumors: Role of surgery Tumeurs neuroendocrines gastro-entéro-pancréatiques : rôle de la chirurgie Alain Sauvanet Department of HPB surgery, pôle des maladies de l’appareil digestif (PMAD), université Paris Diderot, hôpital Beaujon, AP–HP, 100, boulevard du Général-Leclerc, 92110 Clichy, France
a r t i c l e
i n f o
Keywords: Gastroenteropancreatic neuroendocrine tumors Pancreatectomy Pancreatic insufficiency Observation
a b s t r a c t Natural history of gastroenteropancreatic (GEP) Neuroendocrine tumors (NETs) is better and better known so indications of surgery are presently selective. Surgical resection, but also endoscopic resection and observation, can be proposed for gastric NETs according to presentation, size and grade. For small bowel NETs, resection is frequently needed but should obtain the best compromise between radicality and postoperative functional disorders. Appendiceal NETs are frequently diagnosed by appendectomy for appendicitis, but some patients at high risk for lymph node metastasis and recurrence should be reoperated for radical resection. Rectal NETs are often diagnosed incidentally; the smallest (< 1 cm) can be resected endoscopically but the most aggressive need a oncological proctectomy. Pancreatic NETs represent a wide spectrum, ranging from fully benign tumors to very aggressive ones. Insulinomas are mostly benign, responsible for incapacitating symptoms despite medical treatment, and should ideally be treated by parenchyma sparing resection, mainly enucleation. Conversely, symptoms of gastrinomas are efficiently treated medically but their resection needs an oncological approach. Nonfunctioning PNETs are more and more frequently and incidentally discovered. According to their size, presentation and patient’s characteristics, they need a resection (oncological or parenchyma-sparing) or a close observation. © 2019 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Tumeurs neuroendocrine gastro-intestinales et pancréatiques Pancréatectomie Insuffisance pancréatique Surveillance
L’histoire naturelle des tumeurs neuroendocrines (TNE) gastro-entéro-pancréatiques (GEP) est de mieux en mieux connue ce qui explique le caractère actuellement sélectif des indications chirurgicales. Une résection chirurgicale, mais aussi endoscopique et une surveillance, peuvent être proposées aux TNE gastriques, selon leur présentation, leur taille et leur grade. Pour les TNE du grêle, une résection digestive est souvent nécessaire mais doit aboutir au meilleur compris entre radicalité de la résection et résultat fonctionnel. Les TNE appendiculaires sont en règle diagnostiquées sur une pièce d’appendicectomie faite en urgence, mais les patients à haut risque de métastase ganglionnaire et de récidive doivent être réopérés en vue d’une résection radicale. Les TNE rectales sont souvent diagnostiquées fortuitement : les plus petites (< 1 cm) peuvent être réséquées endoscopiquement mais les plus agressives nécessitent une proctectomie radicale. Les TNE pancréatiques constituent un spectre très large, allant des tumeurs tout à fait bénignes à d’autres très agressives. Les insulinomes sont principalement bénins, mais responsables de symptômes très gênants malgré le traitement médical et doivent être opérés idéalement par une résection préservant le parenchyme, principalement l’énucléation. À l’inverse, les symptômes des gastrinomes sont efficacement traités médicalement, mais leur résection nécessite un geste oncologique. Les TNE pancréatiques non fonctionnelles sont de plus en plus souvent diagnostiquées, de fac¸on fortuite. Selon leur taille, leur présentation et les caractéristiques du patient, elles justifient une résection (oncologique ou préservant du parenchyme), ou une surveillance rapprochée. ´ ´ es. © 2019 Elsevier Masson SAS. Tous droits reserv
E-mail address: [email protected] https://doi.org/10.1016/j.ando.2019.04.009 0003-4266/© 2019 Elsevier Masson SAS. All rights reserved.
176
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
Abbreviations
TNM PNET CP EN ENETS UICC PD DP PSP WHO GEP LN
Tumor node metastasis staging system pancreatic neuro-endocrine tumor central pancreatectomy enucleation European Neuroendocrine Tumor Society Union Internationale Contre le Cancer pancreaticoduodenectomy distal pancreatectomy parenchyma sparing pancreatectomy World Health Organization gastroenteropancreatic lymph nodes
1. Introduction Gastroenteropancreatic (GEP) neuroendocrine neoplasms can be present on any part of the digestive tract. Some locations are very rare (oesophagus, colon). Gastric, pancreaticoduodenal, small bowel, appendiceal and rectal localizations are more frequent and frequently need surgical resection, even when associated with limited metastatic (“oligometastatic”) involvement. However, surgery should be proposed on an individual basis, taking into account age, general condition, tumor location, tumor extent, and grade.
pathologic examination. These tumors can be associated with mesenteric LN metastases but the risk of LN is related to several pathological characteristics [1]. This risk is nil and there is no need to reoperation in patients with tumors < 1 cm, with tumor-free margins, and no appendiceal perforation. Conversely, reoperation for right hemicolectomy and LN mesenteric dissection is indicated in patients with tumors > 2 cm or tumors including both endocrine and exocrine components. Between these two thresholds, reoperation for right hemicolectomy or closed follow-up should be proposed according to age, general condition, grade and margins on the appendectomy specimen [1]. 5. Rectal NET Rectal NET are frequent and often diagnosed incidentally after a colonoscopy with resection of a small (< 1 to 2 cm) yellowish rectal “polyp”. Due to the submucosal origin of rectal PNET, endoscopic resection of incidental tumors is frequently not radical (R1). For tumors < 1 cm, local endoscopic resection is curative provided a radical (R0) resection is obtained thus no reoperation is needed. For tumors > 2 cm, the risk of LN metastases is high and reoperation for proctectomy with mesorectal resection (to obtain adequate LN dissection and tumor-free margins) is indicated. Between these 2 thresholds, the choice between reoperation through a trans-anal approach and proctectomy with mesorectal resection should be determined according to age, location, lymph node staging (MRI and/or endoscopic ultrasound [EUS]) and grade [1].
2. Gastric NET 6. Pancreatic neuro-endocrine tumors These tumors include 3 types: Type 1 and Type 2 gastric NET are small, multiple, and low-grade (G1-low G2) NET developed on enterochromaffin-like cells (ECL), due to hypergastrinemia induced by atrophic gastritis and Zollinger Ellison syndrome, respectively. Both entities usually do not justify surgical resection. Only ECLomas > 10 mm or invading muscularis layer or harbouring lymph node metastases can justify either an atypical local resection or an antrectomy [1]. Type 3 gastric NET are usually sporadic, large, high grade (high G2 or even G3) and node positive; an oncological gastrectomy, either partial or total, including a lymph node (LN) dissection, is usually indicated [1]. 3. Small Bowel NET These tumors are mostly ileal, low grade (G1, low G2), associated with mesenteric LN metastases (responsible for retractile mesenteritis in 20% of cases at diagnosis), metastatic to the liver (40%) and can be revealed by acute intestinal obstruction (20%) [1–3]. Mesenteric extension is responsible for vascular encasement, so complete tumor resection (possibly including also the right colon) can result in extended bowel resection with the risk of secondary short bowel syndrome. Extent of bowel and mesenteric resection should be determined to obtain the best compromise between radicality of surgery and postoperative functional disorders. Complete tumor resection allows a 75% to 85% 5 years survival but follow-up should be prolonged at least 10 years due to the very slow natural history of these tumors [1–3]. Patients operated on an emergency basis have frequently a non-radical initial resection but can benefit from delayed reoperation to perform a radical resection including the appropriate mesenteric LN dissection [2,3]. 4. Appendiceal NET Appendiceal NETs are usually revealed by an appendicular syndrome, operated on a emergency basis, and diagnosed by routine
Pancreatic neuro-endocrine tumors (PNETs) have an overall good prognosis. However, their biological behaviour is very heterogeneous (functioning or non functioning) and their prognostic spectrum is also wide, from fully benign tumors to very aggressive ones. Overall, complete surgical resection is the only curative treatment which should be proposed whenever feasible with a low immediate risk and few long term functional disorders. Practically, indications of resection should be tailored according to clinical presentation (incidental or symptomatic tumor, sporadic or genetic predisposition), the presence or not of a hormonal syndrome (functioning or non functioning PNET), the type of hormonal secretion (the most frequent are insulin and gastrin), histo-prognostic factors (including tumor stage and grade), and the general condition of the patient (age, comorbidities). 6.1. Functioning PNET 6.1.1. Insulinoma Insulinomas are usually small (usually 1–2 cm), resulting in frequent difficulty for localization, and have a benign behavior in 95% of cases with a very low (5%) risk of recurrence after resection. After an appropriate clinico-biological diagnosis (fasting test demonstrating hypoglycemia and inappropriate insulin and peptide C serum levels), the tumor should be located by CT scan, MRI and/or EUS . These 3 procedures when grouped can localize up to 95% of insulinomas [4]. Exceptionally, other imaging procedures (contrast enhanced EUS or GLP-1 scintigraphy) are necessary. Approximately 5% of insulinomas are associated with Multiple Endocrine Neoplasia type 1, and can be multiple or coexist with other non-functioning PNET [1]. Surgical resection is almost always proposed due to severity of symptoms, the poor long-term efficiency and tolerance of medical treatment (diazoxide), and the benignity of the disease (grade 1 is extremely frequent and LN or liver metastases are exceptional) [5].
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
Intraoperatively, tumor localization can be determined more precisely with intraoperative ultrasound. Insulinomas located more than 1–2 mm far from the main pancreatic duct are amenable to enucleation, if possible through a laparoscopic approach, with a high risk of postoperative non-lethal complications (“pure” pancreatic fistula) but no risk of long-term pancreatic insufficiency since no parenchyma is resected [5–8]. Conversely, due to anatomical reasons (vicinity of insulinoma with the main pancreatic duct), approximately one third of patients need a “standard” pancreatectomy (distal or cephalic) resulting in a low but real risk of mortality (1 to 3%) and a 20 to 30% risk of long-term surgery-induced diabetes [5–8]. The rate of patients definitively cured by surgery ranges from 90 to 95% [1,5]. In patients with high operative risk, ablative therapy (EUS guided radio-frequency ablation) is an alternative to enucleation [9]. For insulinomas developed on MEN-1, multiple enucleations or distal pancreatectomy with cephalic enucleations can be proposed. In summary, surgical treatment of insulinoma is mainly a technical issue, since prolonged medical treatment is usually not possible and the tumoral disease has a benign behavior. Resection of insulinoma needs precise pre and intraoperative tumor localization and should include parenchyma preservation as often as possible. 6.1.2. Gastrinoma Gastrinomas are responsible for the typical Zollinger Ellison syndrome (ZES) but also upper GI-bleeding or perforated gastroduodenal ulcer as possible inaugural complications. Diagnosis can be evoked when symptoms are corrected by proton pump inhibitors, especially when high doses are necessary, and confirmed by upper GI endoscopy (when demonstrating consequences of acid hypersecretion on oeso-gastro-duodenal mucosa), CT scan and somatostatin receptor scintigraphy (SRS). Although gastrinomas are almost always located in the duodenopancreatic area, cross sectional imaging frequently fails to localize gastrinomas and their extension, due to their small size (< 1 cm), their duodenal site in 2/3 of cases, their multiplicity in 10–20% of cases (even when sporadic), and the presence of nodal metastases in 60% of cases. Due to these characteristics, EUS and or PET Ga 68 are often necessary [1,10,11]. Also, 20 to 25% of patients with gastrinoma have NEM-1, which should be routinely screened. Gastrinomas have mostly a malignant behavior, even if tumor progression is usually slow due to high prevalence of grade 1 and low grade 2. LN and liver are the most frequent metastatic sites, suggesting that liver MRI with diffusionweighted sequences should be routinely performed [12,13]. Once ZES is diagnosed (or even highly suspected), the priority is PPI treatment to inhibit completely acid hypersecretion, using high doses if necessary. Surgery should be discussed once symptoms have disappeared and after a complete work-up. The main aim of surgery is to prevent occurrence of liver metastases, which is the main prognostic factor [10]. In patients with sporadic gastrinoma, surgery is mainly indicated in patients without distant metastases and should include resection of the primary (through duodenotomy for duodenal localizations; or by enucleation or pancreatectomy for pancreatic localizations) [10] associated with systematic LN dissection [14]. Intraoperatively, routine pancreatic ultrasound and duodenotomy are useful to improve tumor detection and localization. Surgery seems able to improve overall survival (comparatively to non operated patients) [10] but definitive cure of gastrin hypersecretion is more rarely observed, probably due to some undiagnosed small primaries left in place or persisting LN metastases [15]. Surgery for metastatic gastrinomas, resecting both primary, metastatic LN and liver metastases is rarely performed in very selected patients. In patients with MEN-1, the multiplicity of secreting tumors does not allow “local” surgery (including tumorectomy + LN
177
dissection) to treat efficiently gastrin hypersecretion. For this purpose, pancreaticoduodenectomy (PD) is more efficient but several authors are reluctant to perform it due to its high early and long-term morbidity [1]. The risk of malignancy is considered only in patients with pancreatic PNET > 2 cm so surgery is usually indicated only in this subset of MEN-1 patients [1]. In summary, surgical treatment of gastrinoms is mainly an oncological issue, since acid hypersecretion is easily controlled by PPI provided sufficient doses are used. Even though the majority of gastrinomas have a malignant behaviour (60% of LN metastases at diagnosis), tumor progression is usually slow. Radical operation (particularly PD) is rarely performed and most authors prefer a more limited surgery (tumorectomy + LN dissection) to limit the risk of distant metastatic progression with few postoperative complications and functional disorders. 6.1.3. Other functional PNET This group mainly includes VIPoma, glucagonoma, and somatostatinoma, which are usually large and malignant [1]. In patients with VIPoma, the priority is to treat consequences of hypersecretion (diarrhea with hypokaliemia) usually with somatostatin analogs. When resectable, these tumors usually need a radical pancreatectomy with LN dissection. 6.2. Non-functioning PNET and incidentalomas Incidence of non-functioning PNET (NF-PNET) has dramatically increased during the last 20 years since it raised from 1.7/105 in 1973–1977 to 4.3/105 in 2003–2007 [16]. This increase is particularly marked for small NF-PNET, the incidence of which increased by 700% during 20 years, due to the widespread diffusion of cross-sectional imaging which detects more and more NF-PNET incidentally [17], particularly for small (≤ 2 cm) PNET. In recent series, incidentally diagnosed NF-PNET represent up to 50% of operated patients [18,19]. Conversely, symptomatic NF-PNET are revealed by pain or compression symptoms, can be large, locally advanced or even metastatic [20,21]. Histo-prognostic characteristics of NF-PNET are highly varying. They were determined in surgical series, which included mainly patients with non-metastatic disease, with a possible bias at least by limitation the number of G3 tumors. Histo-prognostic characteristics are mainly related to tumor size. In Table 1, are exposed the rate of LN metastases and prevalence of G2/G3 tumors in tumors ≤ and > 2 cm in diameter, respectively. Indeed, this 2 cm threshold is frequently used in the literature because: • it represents the limit between T1 and T2 tumors in the TNM classification proposed by the UICC and the ENETS; • it is clinically relevant due to its prognostic value [22–24]; • and it is close to the mean diameter of resected NF-PNET since average half (30 to 65%) of NF-PNET have a diameter ≤ 2 cm [18,19,24]. According to these surgical series, it is possible to estimate the rate of LN metastases (as a surrogate marker of the tumor “aggressiveness”) close to 10% and the probability of a G2/G3 grade to 15–20% for NF-PNET ≤ 2 cm. However this size, when measured by gross examination, can be less than the one measured by imaging probably due to loss of arterial hypervascularization after resection [30]. Otherwise, 2 series have shown that absence of symptoms (incidental diagnosis) were associated with a higher risk of “benign behaviour” and a better prognosis [18,24]. Lastly, in a collective study, absence of ductal dilatation (biliary and/or pancreatic) was an independent factor associated with a better disease free survival [29].
178
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
Table 1 rate of lymph node metastases and grade 2/3 tumors according to tumor size (≤ 2 cm ou > 2 cm) in NF-PNET. Authors, year [ref]
Haynes, 2011 [19] Bettini, 2011 [24] Cherif, 2012 [25] Cherefant, 2013 [26] Toste, 2013 [27] Ellison, 2014 [22] Fischer, 2014 [28] Sallinen, 2016 [29]a a
Lymph node metastases (N+)
Grade G2/G3
≤ 2 cm
> 2 cm
≤ 2 cm
> 2 cm
3/37 (8%) 13/90 (14%) 5/50 (10%) 4/53 (8%) 3/35 (8%) 6/69 (9%) 6/51 (12%) 14/132 (11%)
36/100 (36%) 30/87 (34%) 16/38 (42%) 27/75 (36%) 30/81 (37%) 133/249 (53%) – –
– 13/90 (14%) – 10/53 (19%) 14/35 (40%) – 8/61 (13%) 38/210 (19%)
– 40/87 (46%) – 16/75 (21%) 46/81 (57%) – – –
Multicentric series; 132/210 patients had examined lymph nodes on specimen.
6.3. Pancreatic surgery for NF-PNET 6.3.1. Principles Historically, NF-PNETs were treated by “radical” pancreatectomies including parenchymal resection and LN dissection: PD or distal pancreatectomy (DP), with or without splenectomy. Nowadays, these procedures are performed with low mortality (2 to 5% following PD, 1 to 3% following DP) in high-volume institutions but with an early morbidity ranging from 30 to 50% [31–33]. Longterm results of these procedures are characterized by a risk of de novo diabetes ranging from 10 to 20% following PD and 10 to 35% following DP [25,34,35]. The risk of de novo exocrine insufficiency needing enzyme supplementation is higher after PD than after DP (on average 60% versus 10%, respectively) [36]. Long-term pancreatic function has become an important issue in the decision to resect a low-grade NF-PNET, particularly in patients with an incidentaloma. For this reason, parenchymasparing pancreatectomies (PSP), mainly enucleation (EN) and central pancreatectomy (PC), were proposed to limit the loss of pancreatic function induced by surgery. Indeed, the risk of de novo diabetes is close to zero following EN and at the most 16% after CP, according to characteristics of parenchyma and extent of resection [32,35]. After CP, the risk of exocrine insufficiency is less than 10% that is clearly lower than observed after PD [36]. The risk of exocrine insufficiency following EN is close to zero [7,35]. However, PSP have two limitations: • a not nil mortality after both EN [7,35] or CP [32,37] due to surgical or medical complications; • and an early morbidity at least equivalent, even higher, than observed after “radical” pancreatectomies [7,32,35,37]. Indeed, the average morbidity rates are around 60% and 45% following CP and EN, versus 50% and 30% following PD and DP, respectively [7,32,35,37]. This morbidity is mainly due to pancreatic fistula, which occurs more frequently due to vicinity of main pancreatic duct during EN [6,8] and the presence of two pancreatic cut surfaces in CP [32,37]. 6.3.2. Which operation for NF-PNET? 6.3.2.1. Technical and functional aspects. Regarding technical aspects, tumor location is important. Tumors located far (> 2 mm) from the main pancreatic duct are amenable to EN [6,8]. Conversely, when the tumor is closer or even in contact with the main pancreatic duct, the risk of ductal damage and postoperative fistula argue against EN and therefore for a resection including a parenchymal resection (PD, DP or CP). Location in the pancreatic parenchyma (cephalic, central or distal) should be taken into account according to age and general condition. Particularly, PD and CP can be considered as a major
procedure in high-risk patents (aged or with comorbidities) and, conversely, DP is better tolerated [31,32]. Regarding long-term functional results, the better results of PSP should be evaluated comparatively to their higher early morbidity, particularly for CP the alternative of which is DP. Thus, patients undergoing PSP should be fit enough to overcome the higher early morbidity of PSP [25]. Also, young patients with a long life expectancy are more likely to benefit from PSP than aged patients. Overall, evaluation of the balance between benefits and risks of these operations for NF-PNETs, should take into account all these technical aspects but also age and general condition [25,27]. As an exemple, a small (< 2 cm) cephalic tumor far (> 2 mm) from the main pancreatic duct should ideally be enucleated to avoid drawbacks of PD, particularly in a high-risk patient. Conversely, a small (< 2 cm) tumor in contact to the main pancreatic duct is not amenable to EN and can be resected by a short DP when localized in the tail, or by CP when centrally located.
7.3.2.2. Oncological aspects. PSP do not include systematic LN dissection but a LN sampling (“picking”) is possible. Indeed, in one retrospective study, LN were analyzed in 25% of PSP versus 97% of standard pancreatectomies [27]. In our experience, these rates were 61% after PSP versus 95% after standard pancreatectomies [25]. So, the oncologic value of PSP is very debated and these procedures are only justified for small (< 2 cm) and low-grade TNEP resulting in a low risk of unanticipated LN metastases and a high expected probability of cure. Histoprognostic factors of NF-PNET ≤ 2 cm suggest that, for this subset of tumors, PSP are adequate and that, on the opposite, a radical pancreatectomy is an “over treatment” in around 90% of patients. It seems possible to propose a PSP for every NFPNET ≤ 2 cm with a favorable presentation (no symptoms, no ductal dilatation, no detectable metastases in LN and on the liver). Some authors have suggested a lower threshold in size, between 1 cm and 1.7 cm [38–41]. There is probably not a single discriminant threshold in size and other criteria, including grade if available, are important. But the general concept is to avoid a surgical over treatment in asymptomatic patients, who are often more than 60 years old [42], and particularly in case of cephalic localization.
6.3.3. Survival after resection of NF-PNET Survival should be evaluated with a sufficient follow-up to take into account the very slow natural history of PNET. Ten-year overall survival and 5-year disease free survival are the most frequently evaluated. However, reported series are most often retrospective and biased. The most frequent bias is the choice of the extent of surgery according to the supposed aggressiveness of the disease and the expected prognosis.
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
Old series have included mainly symptomatic large NF-PNET and reported overall 5-year survivals around 70% for localized (nonmetastatic) tumors [43,44]. Recently, presentation of NF-PNET has changed and survival has become better with 5-year DFS around 90% [45] and an overall 10 year survival around 50% [25,46]. Main prognostic factors are LN involvement and tumor grade [26–28,39]. Conversely, microscopic involvement of resection margins, which is frequent following EN, has no significant influence [21,22,47]. NF-PNET treated by PSP have a more favorable presentation than that treated by radical resection [25], that explains why survival after PSP is at least equivalent to that observed after radical resection, with a 5-year DFS up to 90–95% after adequate selection of indications [18,24,25,27,45,48]. Local recurrences are rare after PSP and LN and distant recurrences are more frequent [24,25,48,49]. Follow-up should be prolonged since most recurrences occur 5 to 10 years after resection [24,25].
6.4. Observation as an alternative to resection is small NF-PNET Due to the early risks and long-term consequences of pancreatectomies, the paradigm of routine resection for every NF-PNET was recently reconsidered, particularly for small and asymptomatic ones (incidentalomas). However this approach needs an precise characterization of the tumor, and an accurate evaluation of the benefit-risk balance, taking into account tumor localization and general condition. A diameter ≤ 2 even 3 cm is the threshold adopted by the majority of authors who evaluated this approach [27,50–52]. A 3-cm threshold could be justified by the frequent decrease in size from imaging to gross examination after resection [30]. However, some authors chose a lower size threshold ranging from 1 to 1.7 cm [38,40,41]. Diagnosis of PNET should be firmly established by a EUSguided biopsies [53] or a positive functional imaging [51], to avoid to observe lesions mimicking PNET (solid cystadenoma, accessory spleen) [50]. Ideally, the PNET should have a low-grade (G1 or low G2), although it can be difficult to determine the grade on a single EUS-guided biopsy [53] with a functional imaging consistent with this diagnosis (SRS or Ga68 positive, and 18 FDG negative) [54,55]. Modalities of follow-up (which examination? which periodicity?) are poorly defined. Overall, with a follow-up ranging from 34 to 44 months, tumor progression leading to subsequent resection was reported in 0% to 13% of observed patients [50–52]. No metastatic progressions were reported under observation. However, comparatively with the natural history of PNET, the follow up of available observational studies is too short to draw definitive conclusions. Presently, observation seems mainly indicated in aged patients, with some comorbidities or with a cephalic PNET requiring a PD, because in this subset of patients, the gain in survival offered by resection is probably low or even nil [56].
7. Extended resection for locally advanced tumors Gastric or mostly pancreatic NF-PNET can be large and can invade surrounding organs. Particularly they can encase surrounding vessels or be responsible for endovascular extension resulting in tumoral thrombus. Criteria of resectability of NF-PNET are less restrictive than those for adenocarcinoma so upfront resection can be frequently attempted for these locally advanced tumors [57]. Survival after resection is not altered by microscopic involvement of resection margins [28,47] and 5-year survival is around 50% after extended radical resection of locally advanced PNET [57]. The role of neoadjuvant treatment, using systemic chemotherapy or peptide receptor radionuclide therapy [58], is still under evaluation.
179
8. Surgery for GEP NET with liver metastases Surgery has also been considered as a “gold-standard” to be proposed whenever possible to patients with metastatic PNET [1]. This approach was justified by the results of large monocentric retrospective studies [59] or large multicentric databases [60], which reported a better survival after resection of the primary, or liver metastases when feasible, or both. When no extended hepatectomy is needed, resection of liver metastases can be performed during the same step than primary resection otherwise during a second step [61]. Liver surgery can be facilitated by the use of ablative techniques (radiofrequency ablation, microwave) for deep lesions < 3 cm [62]. This approach can be done with a less than 5% mortality, a 80% 5-year overall survival, but a 50% risk of liver recurrence due to unrecognized microscopic involvement at the time of surgery [61,63]. To limit the risk of recurrence, preoperative assessment of hepatic and extra-hepatic extension should use MRI with diffusion weighted sequences [13] and probably Pet Ga 68 [11]. It is also important to limit indications of hepatectomy to well differentiated and low grade (G1 and low G2) tumors. The role of neoadjuvant treatment by systemic chemotherapy is under evaluation [64]. When liver disease is not resectable, some authors have suggested to resect the primary to improve survival [58,59], to avoid long-term complications related to the primary and subsequently to focus on the treatment of liver disease. This approach is very debated since no prospective comparative studies are available [65]. However, it is frequently used for small bowel primaries, which can be complicated by obstruction in up to 25% of cases, or more rarely for distal pancreatic primaries [65]. For cephalic pancreatic primaries, to perform a PD usually precludes a simultaneous extended hepatic resection and also increases the septic complications of any subsequent liver-directed therapy (resection, ablation or embolization) due to bacterial contamination of the biliary tree above the hepatico-jejunostomy [66]. Exceptionally, diffuse bilobar liver metastases from GEP NET can be treated by total hepatectomy and liver transplantation. The most favorable long-term results are obtained in young patients with low grade primary from a previously resected small bowel primary, and a limited tumor burden resulting in a moderate hepatomegaly [67]. 9. Conclusions The management of GEP NET includes a wide spectrum of attitudes ranging from simple observation to resection of the primary followed by liver transplantation. However, despite their very variable localization and presentation, GEP-NET are very frequent indications for surgical resection which allows very high rates of definitive cure but, due to their favorable natural history and prognosis, the balance between benefits and risks of surgery should be carefully evaluated. This is particularly true for tumors with limited initial presentation, particularly when incidentally diagnosed or, on the opposite for patients with extended disease not amenable to complete resection with an acceptable risk. Disclosure of interest The author declares that he has no competing interest. References [1] O’Toole D, Kianmanesh R, Caplin M. ENETS 2016 Consensus guidelines for the management of patients with digestive neuroendocrine tumors. Neuroendocrinology 2016;103:117–8. [2] Landry CS, Lin HY, Phan A, et al. Resection of at-risk mesenteric lymph nodes is associated with improved survival in patients with small bowel neuroendocrine tumors. World J Surg 2013;37:1695–700.
180
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181
[3] Motz BM, Lorimer PD, Boselli D, et al. Optimal lymphadenectomy in small bowel neuroendocrine tumors: analysis of the NCDB. J Gastrointest Surg 2018;22:117–23. [4] Gouya H, Vignaux O, Augui J, Dousset B, Palazzo L, Louvel A, et al. CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. AJR Am J Roentgenol 2003;181:987–92. [5] Nikfarjam M, Warshaw AL, Axelrod L, Deshpande V, Thayer SP, Ferrone CR, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg 2008;247:165–72. [6] Brient C, Regenet N, Sulpice L, et al. Risk factors for postoperative pancreatic fistulization subsequent to enucleation. J Gastrointest Surg 2012;16:1883–7. [7] Faitot F, Gaujoux S, Barbier L, et al. Reappraisal of pancreatic enucleations: a single-center experience of 126 procedures. Surgery 2015;158:201–10. [8] Heeger K, Falconi M, Partelli S, et al. Increased rate of clinically relevant pancreatic fistula after deep enucleation of small pancreatic tumors. Langenbecks Arch Surg 2014;399:315–21. [9] Barthet M, Giovannini M, Lesavre N, Boustiere C, Napoleon B, Koch S, et al. Endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine tumors and pancreatic cystic neoplasms: a prospective multicenter study. Endoscopy 2019, http://dx.doi.org/10.1055/a-0824-7067 [Epub ahead of print]. [10] Norton JA, Fraker DL, Alexander HR, Gibril F, Liewehr DJ, Venzon DJ, et al. Surgery increases survival in patients with gastrinoma. Ann Surg 2006;244:410–9. [11] Partelli S, Rinzivillo M, Maurizi A, et al. The role of combined Ga-DOTANOC and (18)FDG PET/CT in the management of patients with pancreatic neuroendocrine tumors. Neuroendocrinology 2014;100:293–9. [12] Vinault S, Mariet AS, Le Bras M, Mirallié E, Cardot-Bauters C, Pattou F, et al. Metastatic potential and survival of duodenal and pancreatic tumors in multiple endocrine neoplasia type 1: a GTE and AFCE cohort study. Ann Surg 2018, http://dx.doi.org/10.1097/SLA.0000000000003162 [Epub ahead of print]. [13] d’Assignies G, Couvelard A, Bahrami S, et al. Pancreatic endocrine tumors: tumor blood flow assessed with perfusion CT reflects angiogenesis and correlates with prognostic factors. Radiology 2009;250:407–16. [14] Bartsch D, Waldmann J, Fendrich V, Boninsegna L, Lopez C, Partelli S. Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma. Br J Surg 2012;99:1234–40. [15] Maire F, Sauvanet A, Couvelard A, Rebours V, Vullierme MP, Lebtahi R, et al. Recurrence after surgical resection of gastrinoma: who, when, where and why? Eur J Gastroenterol Hepatol 2012;24:368–74. [16] Lawrence B, Gustafsson B, Chan A, et al. The epidemiology of gastroentero-pancreatic neuro endocrine tumors. Endocrinol Metab Clin North Am 2011;40:1–18 [vii]. [17] Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol 2013;20:2815–21. [18] Birnbaum DJ, Gaujoux S, Cherif R, et al. Sporadic nonfunctioning pancreatic neuroendocrine tumors: prognostic significance of incidental diagnosis. Surgery 2014;155:13–21. [19] Haynes A, Deshpande V, Ingkakul T, et al. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes. Arch Surg 2011;146:534–8. [20] Bilimoria KY, Talamaonti MS, Tomlinson JS, et al. Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg 2008;247:490–500. [21] Fischer L, Bergmann F, Schimmack S, et al. Outcome of surgery for pancreatic neuroendocrine neoplasms. Br J Surg 2014;101:1405–12. [22] Ellison TA, Wolfgang CL, Shi C, et al. A single institution’s 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann Surg 2014;259:204–12. [23] Scarpa A, Mantovani W, Capelli P, et al. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 2010;23:824–33. [24] Bettini R, Partelli S, Boninsegna L, et al. Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 2011;150:75–82. [25] Cherif R, Gaujoux S, Couvelard A, et al. Parenchyma-sparing resections for pancreatic neuroendocrine tumors. J Gastrointest Surg 2012;16:2045–55. [26] Cherenfant J, Stocker SJ, Gage MK, et al. Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. Surgery 2013;154:785–91. [27] Toste PA, Kadera BE, Tatishchev SF, Dawson DW, et al. Nonfunctional pancreatic neuroendocrine tumors < 2 cm on preoperative imaging are associated with a low incidence of nodal metastasis and an excellent overall survival. J Gastrointest Surg 2013;17:2105–13. [28] Fischer L, Bergmann F, Schimmack S, Hinz U, Priess B, et al. Outcome of surgery for pancreatic neuroendocrine neoplasms. Br J Surg 2014;101:1405–12. [29] Sallinen V, Le Large T, Tieftrunk E, et al. Prognosis of sporadic resected small (≤ 2 cm) nonfunctional pancreatic neuroendocrine tumor — A multiinstitutional analysis. HPB (Oxford) 2018;20:251–9. [30] Partelli S, Gaujoux S, Boninsegna L, et al. Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs). JAMA Surg 2013;148:932–9. [31] Farges O, Bendersky N, Truant S, Delpero JR, Pruvot FR, Sauvanet A. The theory and practice of pancreatic surgery in France. Ann Surg 2017;266:797–804. [32] Iacono C, Verlato G, Ruzzenente A, et al. Systematic review of central pancreatectomy and meta-analysis of central versus distal pancreatectomy. Br J Surg 2013;100:873–85.
[33] Meguid RA, Ahuja N, Chang DC. What constitutes a “high-volume” hospital for pancreatic resection? J Am Coll Surg 2008;206:622e1–9. [34] Falconi M, Mantovani W, Crippa S, et al. Pancreatic insufficiency after different resections for benign tumours. Br J Surg 2008;95:85–91. [35] Hüttner FJ, Koessler-Ebs J, Hackert T, et al. Meta-analysis of surgical outcome after enucleation versus standard resection for pancreatic neoplasms. Br J Surg 2015;102:1026–36. [36] Sabater L, Ausania F, Bakker O, et al. Evidence-based guidelines for the management of exocrine pancreatic insufficiency after pancreatic surgery. Ann Surg 2016;264:949–58. [37] Goudard Y, Gaujoux S, Dokmak S, et al. Reappraisal of central pancreatectomy a 12-year single-center experience. JAMA Surg 2014;149:356–63. [38] Curran T, Pockaj BA, Gray RJ, et al. Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection. J Gastrointest Surg 2015;19:152–60. [39] Hashim YM, Trinkaus KM, Linehan DC, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg 2014;259:197–203. [40] Regenet N, Carrere N, Boulanger G, et al. Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: a French multicenter study. Surgery 2016;159:901–7. [41] Kishi Y, Shimada K, Nara S, et al. Basing treatment strategy for nonfunctional pancreatic neuroendocrine tumors on tumor size. Ann Surg Oncol 2014;21:2882–8. [42] Halfdanarson TR, Rabe KG, Rubin J, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol 2008;19:1727–33. [43] Kouvaraki MA, Solorzano CC, Shapiro SE, et al. Surgical treatment of nonfunctioning pancreatic islet cell tumors. J Surg Oncol 2005;89:170–85. [44] Phan GQ, Yeo CJ, Cameron JL, et al. Pancreaticoduodenectomy for selected periampullary neuroendocrine tumors: fifty patients. Surgery 1997;122:989–96. [45] Pitt SC, Pitt HA, Baker MS, et al. Small pancreatic and periampullary neuroendocrine tumors: resect or enucleate? J Gastrointest Surg 2009;13:1692–8. [46] Hill JS, McPhee JT, McDade TP, et al. Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer 2009;115:741–51. [47] Pomianowska E, Gladhaug IP, Grzyb K, et al. Survival following resection of pancreatic endocrine tumors: importance of R-status and the WHO and TNM classification systems. Scand J Gastroenterol 2010;45:971–9. [48] Casadei R, Ricci C, Rega D, et al. Pancreatic endocrine tumors less than 4 cm in diameter: resect or enucleate? A single-center experience. Pancreas 2010;39:825–8. [49] Falconi M, Zerbi A, Crippa S, et al. Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors. Ann Surg Oncol 2010;17:1621–7. [50] Lee LC, Grant CS, Salomao DR, et al. Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management. Surgery 2012;152:965–74. [51] Gaujoux S, Partelli S, Maire F, et al. Observational study of natural history of small sporadic nonfunctioning pancreatic neuroendocrine tumors. J Clin Endocrinol Metab 2013;98:4784–9. [52] Sadot E, Reidy-Lagunes DL, Tang LH, et al. Observation versus resection for small asymptomatic pancreatic neuroendocrine tumors: a matched case-control study. Ann Surg Oncol 2016;23:1361–70. [53] Rebours V, Cordova J, Couvelard A, et al. Can pancreatic neuroendocrine tumour biopsy accurately determine pathological characteristics? Dig Liver Dis 2015;47:973–7. [54] Garin E, Le Jeune F, Devillers A, et al. Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors. J Nucl Med 2009;50:858–64. [55] Chan DL, Pavlakis N, Schembri GP, et al. Dual somatostatin receptor/FDG PET/CT imaging in metastatic neuroendocrine tumours: proposal for a novel grading scheme with prognostic significance. Theranostics 2017;7:1149–58. [56] Hill JS, McPhee JT, McDade TP, Zhou Z, Sullivan ME, Whalen GF, et al. Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer 2009;115:741–51. [57] Birnbaum DJ, Turrini O, Vigano L, Russolillo N, Autret A, Moutardier V, et al. Surgical management of advanced pancreatic neuroendocrine tumors: shortterm and long-term results from an international multi-institutional study. Ann Surg Oncol 2015;22:1000–7. [58] Partelli S, Bertani E, Bartolomei M, Perali C, Muffatti F, Grana CM, et al. Peptide receptor radionuclide therapy as neoadjuvant therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms. Surgery 2018;163:761–7. [59] Hüttner FJ, Schneider L, Tarantino I, et al. Palliative resection of the primary tumor in 442 metastasized neuroendocrine tumors of the pancreas: a population-based, propensity score-matched survival analysis. Langenbecks Arch Surg 2015;400:715–23. [60] Franko J, Feng W, Yip L, et al. Non-functional neuroendocrine carcinoma of the pancreas: incidence, tumor biology, and outcomes in 2158 patients. J Gastrointest Surg 2010;14:541–8. [61] Kianmanesh R, Sauvanet A, Hentic O, et al. Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors: a safe approach for radical resection. Ann Surg 2008;247:659–65. [62] Elias D, Goéré D, Leroux G, et al. Combined liver surgery and RFA for patients with gastroenteropancreatic endocrine tumors presenting with more than 15 metastases to the liver. Eur J Surg Oncol 2009;35:1092–7.
A. Sauvanet / Annales d’Endocrinologie 80 (2019) 175–181 [63] Mayo SC, de Jong MC, Pulitano C, Clary BM, Reddy SK, Gamblin TC, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol 2010;17:3129–36. [64] Cloyd JM, Omichi K, Mizuno T, et al. Preoperative fluorouracil, doxorubicin, and streptozocin for the treatment of pancreatic neuroendocrine liver metastases. Ann Surg Oncol 2018;25:1709–15. [65] Partelli S, Cirocchi R, Rancoita PMV, Muffatti F, Andreasi V, Crippa S, et al. A Systematic review and meta-analysis on the role of palliative primary resection
181
for pancreatic neuro-endocrine neoplasm with liver metastases. HPB (Oxford) 2018;20:197–203. [66] De Jong MC, Farnell MB, Sclabas G, et al. Liver-directed therapy for hepatic metastases in patients undergoing pancreaticoduodenectomy: a dual-center analysis. Ann Surg 2010;252:142–8. [67] Treut YP, Grégoire E, Klempnauer J, et al. Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study. Ann Surg 2013;257:807–15.