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Sporadic nonfunctioning pancreatic neuroendocrine tumors: Prognostic significance of incidental diagnosis

  • David Jérémie Birnbaum
    Affiliations
    Department of Hepato-Pancreato-Biliary Surgery - Pôle des Maladies de l'Appareil Digestif (PMAD), AP-HP, hôpital Beaujon, Clichy, France
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  • Sébastien Gaujoux
    Affiliations
    Department of Hepato-Pancreato-Biliary Surgery - Pôle des Maladies de l'Appareil Digestif (PMAD), AP-HP, hôpital Beaujon, Clichy, France

    Université Paris Diderot, Paris, France

    Centre de Recherche Biomédicale Bichat Beaujon (CRB3)/INSERM U773, Institut National de la Santé et de la Recherche Médicale, Paris, France
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  • Rim Cherif
    Affiliations
    Department of Hepato-Pancreato-Biliary Surgery - Pôle des Maladies de l'Appareil Digestif (PMAD), AP-HP, hôpital Beaujon, Clichy, France
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  • Safi Dokmak
    Affiliations
    Department of Hepato-Pancreato-Biliary Surgery - Pôle des Maladies de l'Appareil Digestif (PMAD), AP-HP, hôpital Beaujon, Clichy, France
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  • David Fuks
    Affiliations
    Department of Hepato-Pancreato-Biliary Surgery - Pôle des Maladies de l'Appareil Digestif (PMAD), AP-HP, hôpital Beaujon, Clichy, France

    Université Paris Diderot, Paris, France
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  • Anne Couvelard
    Affiliations
    Université Paris Diderot, Paris, France

    Centre de Recherche Biomédicale Bichat Beaujon (CRB3)/INSERM U773, Institut National de la Santé et de la Recherche Médicale, Paris, France

    Département of Pathology, AP-HP, hôpital Beaujon, Clichy, France
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  • Marie-Pierre Vullierme
    Affiliations
    Department of Radiology, AP-HP, hôpital Beaujon, Clichy, France
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  • Maxime Ronot
    Affiliations
    Université Paris Diderot, Paris, France

    Département of Pathology, AP-HP, hôpital Beaujon, Clichy, France

    Department of Radiology, AP-HP, hôpital Beaujon, Clichy, France
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  • Philippe Ruszniewski
    Affiliations
    Université Paris Diderot, Paris, France

    Centre de Recherche Biomédicale Bichat Beaujon (CRB3)/INSERM U773, Institut National de la Santé et de la Recherche Médicale, Paris, France

    Department of Gastroenterology, Pôle des Maladies de l'Appareil Digestif (PMAD), AP-HP, hôpital Beaujon, Clichy, France
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  • Jacques Belghiti
    Affiliations
    Department of Hepato-Pancreato-Biliary Surgery - Pôle des Maladies de l'Appareil Digestif (PMAD), AP-HP, hôpital Beaujon, Clichy, France

    Université Paris Diderot, Paris, France
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  • Alain Sauvanet
    Correspondence
    Reprint requests: Dr Alain Sauvanet, MD, Department of Hepatobiliary and Pancreatic Surgery - Hospital Beaujon, 100, Bd du Général Leclerc - 92110 Clichy, France.
    Affiliations
    Department of Hepato-Pancreato-Biliary Surgery - Pôle des Maladies de l'Appareil Digestif (PMAD), AP-HP, hôpital Beaujon, Clichy, France

    Université Paris Diderot, Paris, France
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Published:November 14, 2013DOI:https://doi.org/10.1016/j.surg.2013.08.007

      Background

      Sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed as incidentalomas, and their resection is usually recommended. The prognostic significance of this diagnosis feature is poorly studied, and management of these tumors remains controversial. Clinical, pathologic characteristics and outcome of resected incidentally diagnosed NF-PNET (Inc) were compared with resected symptomatic NF-PNET (Symp) to better assess their biologic behavior and tailor their management.

      Methods

      From 1994 to 2010, 108 patients underwent resection for sporadic nonmetastatic NF-PNET. Diagnosis was considered as incidental in patients with no abdominal symptoms or symptoms unlikely to be related to tumor mass. Patients with Inc were compared with patients with Symp, regarding demographics, postoperative course, pathology, and disease-free survival (DFS).

      Results

      Of the 108 patients, 65 (61%) had incidentally diagnosed tumors. Pancreas-sparing pancreatectomies (enucleation/central pancreatectomy) were performed more frequently in Inc (62% vs 30%, P = .001). Inc tumors were more frequently <20 mm (65% vs 42%, P = .019), staged T1 (62% vs 33%, P = .0001), node negative (85% vs 60%; P = .005), and grade 1 (66% vs 33%, P = .0001). One postoperative death occurred in the Inc group, and postoperative morbidity was similar between the two groups (60% vs 65%, P = .59). DFS was substantially better in the Inc group (5-year DFS = 92% vs 82%, P = .0016).

      Conclusion

      Incidentally diagnosed NF-PNETs are associated with less aggressive features compared with symptomatic lesions but cannot always be considered to be benign. Operative resection remains recommended for most. Incidentally diagnosed NF-PNET may be good candidates for pancreas-sparing pancreatectomies.
      Pancreatic neuroendocrine tumors (PNET) are rare, representing 1% to 2% of all pancreatic neoplasms.
      • Halfdanarson T.R.
      • Rabe K.G.
      • Rubin J.
      • Petersen G.M.
      Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival.
      They represent a heterogeneous group of tumors with an extremely variable clinical behavior mainly depending on histologic features and disease staging.
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      Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours.
      When possible, operation provides the best chance for a cure and provides 5-year overall survival exceeding 60%.
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      Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors.
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      • et al.
      Parenchyma-sparing resections for pancreatic neuroendocrine tumors.
      In recent years, PNET, particularly sporadic nonfunctioning (NF) cases, have been increasingly diagnosed,
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      Changing incidence of pancreatic neoplasms: a 16-year review of statewide tumor registry.
      often as incidentalomas, because of the widespread use of cross-sectional imaging.
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      Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors.
      Our understanding of the natural history of incidentally discovered NF-PNET is limited, but despite the lack of high-level evidence, operative resection is usually recommended. This aggressive management recently has been challenged because of the substantial morbidity of pancreatic surgery
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      • et al.
      Parenchyma-sparing resections for pancreatic neuroendocrine tumors.
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      contrasting with the favorable long-term outcome of these lesions
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      Incidental detection of pancreatic neuroendocrine tumors: an analysis of incidence and outcomes.
      —even if this remains controversial.
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      • Deshpande V.
      • Ingkakul T.
      • Vagefi P.A.
      • Szymonifka J.
      • Thayer S.P.
      • et al.
      Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes.
      To expand our knowledge regarding this increasingly frequent situation, we retrospectively analyzed our experience of pancreatectomy for sporadic nonmetastatic NF-PNET by comparing patients with tumors incidentally discovered with the remaining population.

      Patients and methods

      Data collection

      From 1994 to 2010, 108 patients underwent complete resection for sporadic, nonmetastatic, NF-PNET in the Department of Hepatobiliary and Pancreatic Surgery - Beaujon Hospital, Clichy, France. Demographic variables, clinical presentation, preoperative workup, and intraoperative data including type of resection, postoperative course, and pathology were obtained from a prospective database with additional retrospective medical record review. NF tumors were defined as lesions without symptoms related to hormonal excess. Patients with incidentally diagnosed lesions were defined as patients without any symptoms or abnormal liver tests, ie, cholestasis, and/or patients with clinical manifestations unlikely to be related to the mass.

      Preoperative work-up, operative procedures, and pathologic analysis

      Preoperative tumor staging was done by computed tomography and/or magnetic resonance, endoscopic ultrasound, or somatostatin receptor scintigraphy at the surgeon's discretion, as previously reported.
      • Cherif R.
      • Gaujoux S.
      • Couvelard A.
      • Dokmak S.
      • Vuillerme M.P.
      • Ruszniewski P.
      • et al.
      Parenchyma-sparing resections for pancreatic neuroendocrine tumors.
      All operative indications were discussed in a multidisciplinary pancreatic tumor board, including surgeons, radiologists, pathologists, oncologists, and gastroenterologists. Diagnosis of PNET was based on conventional histology and immunohistochemistry (chromogranin A, synaptophysin, and Ki67). All cases were reviewed and classified according to the 2010 World Health Organization (WHO) classification and assigned an ENETS (European Neuroendocrine Tumor Society)/TNM-based stage and grading score.
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      • Couvelard A.
      • de Herder W.W.
      • et al.
      TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.
      • Rindi G.
      • AR
      • Bosman F.T.
      • et al.
      Nomenclature and classification of neuroendocrine neoplasms of the digestive system. WHO classification of tumours of the digestive system.
      Operative procedures were preoperatively planed based on tumor localization and intraoperatively confirmed after operative exploration assisted by routine intraoperative ultrasonography for evaluation of the proximity of the tumor from the vascular structure and the main pancreatic duct. Enucleation was performed when the tumor was near to or at the surface of the head or body of the pancreas, far enough (at least 1 to 2 mm) from the main pancreatic duct. Regarding tumors of the neck and body of the pancreas, if enucleation was not possible, central pancreatectomy was performed if the remnant pancreas was at least 5–7 cm long. In this setting, the proximal remnant was overseen after elective ligation of the main pancreatic duct. Reconstruction of the distal pancreas was done by end-to-side pancreaticogastrostomy. Pancreaticoduodenectomy and distal pancreatectomy were performed as previously reported by our group.
      • Cherif R.
      • Gaujoux S.
      • Couvelard A.
      • Dokmak S.
      • Vuillerme M.P.
      • Ruszniewski P.
      • et al.
      Parenchyma-sparing resections for pancreatic neuroendocrine tumors.
      Intraoperatively, all standard resections included regional lymph node dissection. During central pancreatectomy and enucleation, all visible lymph nodes located up to 5 cm around the tumor were resected but frozen section analysis was not routinely done. At the end of the procedure, drainage was placed close to the enucleation cavity or the pancreatic anastomosis or section and removed progressively from postoperative day 5.

      Postoperative course and follow-up

      Postoperative mortality included all deaths occurring before hospital discharge or within 90 days. Morbidity included all complications after operation until discharge and/or readmission and was graded according to the Clavien-Dindo classification.
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      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      Postoperative pancreatic fistula, hemorrhage, and delayed gastric emptying were defined according to the International Study Group of Pancreatic Surgery.
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      • et al.
      Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS).
      Follow-up was based on clinical, radiologic, and laboratory assessments and updated upon outpatient evaluation, routine postoperative visits, and correspondence. Visits were scheduled every 6 months for the first 5 years and annually thereafter. Detection of recurrence was based on thoracoabdominal computed tomography scan and chromogranin A serum level. In case of suspected recurrence, magnetic resonance imaging or octreoscan scintigraphy were performed according to the clinical situation.

      Statistical analysis

      Values are expressed as median (range), or percentage, as appropriate. The Fisher exact test was used to compare differences in discrete or categorical variables, and the Wilcoxon rank-sum test was used for continuous variables. Overall survival (OS) was calculated from the date of surgery to the date of death or last follow-up if no event had occurred. Disease-free survival (DFS) was calculated from the date of surgery to the date of the first evidence of recurrence or last follow-up if no event had occurred. Patients who died during the postoperative course were excluded from the survival analysis to assess tumor behavior only. OS and DFS were estimated by the method of Kaplan-Meier, and the log-rank test was used to compare survival curves.
      All tests were two-sided. Data were analyzed with the STATA 12 statistical software (StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP).

      Results

      Clinical characteristics

      Among the 108 patients who underwent complete resection for sporadic, nonmetastatic, NF-PNET, 61% (n = 65) had an incidentally diagnosed tumor. These 65 pancreatic incidentalomas (Inc group) were compared with the remaining 43 patients (39%) with symptomatic (Symp group) lesions either because of abdominal pain (86%; n = 37) or jaundice (14%; n = 6). The percentage of incidentally diagnosed NF-PNET increased from 40% in the period from 1995 to 1998 to 69% in the period from 2007 to 2010.
      Patient and tumor characteristics are summarized in Table I. Briefly, patients had a median age of 58 years (range, 36–75) and most of them were women (n = 69; 64%). Tumors were mostly located in the head (n = 43; 40%) of the pancreas, with a median radiologic diameter of 20 mm (range, 9–130). When compared according to age, sex, body mass index, comorbidity, tumor size, and tumor location, no significant differences were observed between the two groups.
      Table IPatient and tumor characteristics according to circumstances of diagnosis
      OverallIncidentaloma, n = 65 (%)Symptomatic lesions, n = 43 (%)P value
      Age, y58 (36–75)57 (36–71)58 (43–75).81
      Male sex39 (36)21 (32)18 (42).31
      BMI, kg/m223 (16–42)24 (16–35)23 (17–42).58
      ASA (III/IV)4 (4)2 (3)2 (5).89
      Comorbidity
       Overall67 (62)39 (60)28 (65).59
       Diabetes mellitus7 (6)4 (6)3 (7).86
      Tumor location
       Head43 (40)24 (40)19 (44).51
       Body30 (28)19 (29)11 (26)
       Tail35 (32)22 (34)13 (30)
      ASA, American Society of Anaesthesiology; BMI, body mass index.

      Operation and postoperative course

      Operative procedures and postoperative course are summarized in Table II. Briefly, 27 patients (25%) underwent pancreaticoduodenectomy, 28 (26%) distal pancreatectomy with splenectomy in 23 (21%), 53 (49%) pancreatic sparing resection including enucleation in 34 (31%), and central pancreatectomy in 19 (18%). In eight patients (7%) vein resection was required. Overall, pancreatic sparing resections were more frequently performed for incidentally diagnosed lesions (62% vs 30%; P = .001).
      Table IIOperative procedure and postoperative complications in the two groups
      OverallIncidentaloma, n = 65Symptomatic lesion, n = 43P value
      Operative resection
       Standard pancreatectomies55 (51)25 (38)30 (60).001
      Statistically significant.
       Pancreatic sparing resection53 (49)40 (62)13 (30)
       With vein resection8 (7)2 (3)6 (14).006
      Statistically significant.
      Postoperative mortality1 (1)1 (2)0 (0).41
      Morbidity (Dindo)
      Overall67 (62)39 (60)28 (65).59
       1–253 (49)33 (51)20 (47).34
       3–414 (13)6 (9)8 (19)
       Pancreatic fistula54 (50)34 (52)20 (47).55
       Hemorrhage5 (5)3 (5)2 (5).99
       Delayed gastric emptying9 (8)3 (5)6 (14).08
      Operative time, minutes240 (40–720)195 (40–560)240 (120–720)<.001
      Statistically significant.
      Blood loss, mL200 (30–3,000)200 (30–1,000)300 (50–3,000).001
      Statistically significant.
      Red blood cells transfusions14 (13)5 (8)9 (21).04
      Statistically significant.
      Hospital stay, days18 (6–70)19 (6–70)17 (7–66).65
      De novo diabetes13 (12)5 (8)8 (19).09
      De novo exocrine insufficiency14 (13)8 (13)6 (14).80
      Statistically significant.
      Overall mortality was 1% (n = 1) because of pulmonary embolism on postoperative day nine in a 68-year-old woman with an incidentally diagnosed lesion operated by central pancreatectomy. Overall morbidity was 62% (n = 67), including severe complications (Clavien-Dindo grade 3–4) in 13% of patients (n = 14). Pancreatic fistula occurred in 50% of patients (n = 54), 29% (n = 31) having a clinically significant one (ie, grade B or C). Hemorrhage occurred in 5% (n = 5), leading to the only four reoperations. Five patients (5%) required radiologic percutaneous drainage. Operative time, intraoperative blood loss, and perioperative transfusions were less important in Inc patients, and in patients who underwent parenchyma-sparing surgery. In contrast, no substantial differences were observed regarding mortality, overall morbidity, severe morbidity, reoperation rate, and length of stay between both groups.
      When we compared standard resection and pancreas-sparing pancreatectomies (PSPs), clinically significant (grade B/C) pancreatic fistula were more frequent in PSP (38%, n = 20 vs 20%, n = 11; P = .048); overall morbidity was not significantly more frequent in PSP (70% (n = 37) vs 55% (n = 30); P = .102); whereas major morbidity was not significantly different (13%, n = 7 vs 13%, n = 7; P = .941).

      Pathologic findings

      Results of pathologic analysis are summarized in Table III. In brief, median tumor size was 20 mm (range, 9–140 mm) and tumor-free margins (R0) were obtained for all but six patients (5.5%). Overall, most tumors were classified as T1 (n = 54; 50%) or T2 (n = 34; 31%) according to ENETS TNM classification. According to ENETS/TNM classification, 51 (47%) tumors were classified as stage I, 29 (27%) as stage II, and 28 (26%) as stage III.
      Table IIIPathologic characteristics
      OverallIncidentaloma (n = 65) (%)Symptomatic lesion (n = 43) (%)P value
      Tumor size, mm20 (9–140)18 (9–100)25 (9–140).02
      Statistically significant.
       <2060 (55)42 (65)18 (42).02
      Statistically significant.
      TNM classification
       T1 (<2 cm)54 (50)40 (62)14 (33)<.001
      Statistically significant.
       T2 (2–4 cm)34 (31)18 (28)16 (37)
       T3 (>4 cm)18 (17)7 (11)11 (26)
       T4 (invading adjacent organs)2 (2)0 (0)2 (5)
      Nodal status
       N0/Nx81 (75)55 (85)26 (60).005
      Statistically significant.
       N127 (25)10 (15)17 (40)
      ENETS stage
       Stage I (T1N0M0)51 (47)38 (59)13 (30)<.001
      Statistically significant.
       Stage II (T2 or T3, N0M0)29 (27)17 (26)12 (28)
       Stage III (T4N0M0 or any T, N1M0)28 (26)10 (15)18 (42)
       Stage IV (any T, any N, M1)000
      Resection margin
       R0102 (94)63 (97)39 (9).17
       R16 (6)2 (3)4 (9)
      Tumor grade
       G157 (53)43 (66)14 (33)<.001
      Statistically significant.
       G251 (47)22 (34)29 (67)
      Microangio invasion33 (31)15 (23)18 (42).04
      Statistically significant.
      Perineural invasion23 (21)8 (12)15 (35).005
      Statistically significant.
      Mitotic count (/10 HPF)1 (0–12)1 (0–5)2 (0–12)<.001
      Statistically significant.
       >2 mitosis/10 HPF24 (22)7 (11)17 (40)<.001
      Statistically significant.
      Ki671 (1–25)1 (1–12)4 (1–25)<.001
      Statistically significant.
       >2%40 (37)15 (23)25 (58)<.001
      Statistically significant.
      HPF, High-power field.
      Statistically significant.
      Overall, symptomatic tumors were diagnosed at a more advanced stage and showed more aggressive features than incidentally diagnosed lesions. Stage I tumors were more frequent in the Inc group (P = .0001). In 23 patients (21%), no nodes were present in the pathologic specimen (Nx), 83% (n = 19) of them after PSPs, ie, 19 of the 53 patients having their lesion resected by PSP (36%). When present, an average of three (two to six) nodes and up to 16 were harvested after PSP versus 12 (7–20) and up to 39 after standard resection (P < .001). Metastatic regional lymph nodes were found in 27 patients (25%) and were found more frequently in the Symp group (n = 17, 40% vs n = 10, 15%; P = .005). If we considered N0, N1, and Nx separately, the difference between Inc and Symp group remained significant (P = .018). During the 10 patients with incidentally diagnosed lesions and positive lymph nodes, only three were less than 2 cm in size. When comparing incidentally diagnosed lesions according to their lymph nodes status, lymph node positive tumors had a significantly greater tumor size than lymph node negative tumors (27 mm [22–40] vs 17 [12–25]; P = .005). Of the 13 NF-PNETs less than 10 mm in size, 11 had lymph node sampling, and none were metastatic.
      Regarding WHO grading classification, 57 tumors (53%) were classified as grade 1 and 51 (47%) as grade 2. Inc patients had more frequent tumors ≤20 mm (65%, n = 42, vs 42%, n = 18, P = .019), staged as T1 (n = 40, 62% vs n = 14, 33%; P = .0001), and N0 (N0/Nx = 55, 85% vs n = 26, 60%; P = .005) than Symp patients. Additionally, microangioinvasion (23% vs 42%; P = .038), perineural invasion (12% vs 35%; P = .005), mitotic count (1 vs 2; P = .0002), and Ki67 index (1 vs 4; P = .0004) were lower in incidentally diagnosed cases than in Symp tumors.

      Survival

      Excluding the only postoperative death, after a median follow-up of 42 months (range 5–187 months), the 1-, 3-, 5-, and 10-year OS rates were 100%, 96% (90–99), 96% (90–99), and 91% (70–97), respectively, with a difference between the two groups (P = .029) in favor of incidentally diagnosed tumors. Median survival time was not reached. Four patients died during follow-up, and only one death was related to tumor or treatment. Specific survival was not different between the two groups (P = .345).
      The 1-, 3-, 5-, and 10-year DFS rates were 95% (89–98), 89% (81–94), 87% (78–93), and 62% (42–78), respectively. Five patients (5%) experienced local nodal recurrence and 14 patients (13%) a distant recurrence, mainly located in the liver (86%, n = 12); none were classified pNx. Median DFS was 130 months. DFS was better in patients with incidentally diagnosed tumors (P = .003), with a 1-, 3-, 5-, and 10-year DFS of 98% (89–99), 95 (85–98), 92 (79–97), and 92 (79–97), vs 90% (76–96), 82% (66–91), 82% (66–91), and 31% (9–57) for symptomatic diagnosed lesions (Fig).
      Figure thumbnail gr1
      FigDFS of nonmetastatic sporadic NF-PNETs according to circumstance of diagnosis (incidentaloma, red line; symptomatic, blue line).
      At multivariate analyses, including usually reported PNET prognostic factors such as tumor size, presence of positive lymph nodes, and tumor grade, in addition to circumstance of diagnosis (incidentaloma yes/no), tumor size and tumor grade were found to be the only independent prognostic factors of DFS. In the multivariate model, there was a trend (P = .055) toward a better DFS in patients with incidentally diagnosed PNET.

      Analysis of the subgroup of patients with a lesion size less than 2 cm

      When comparing incidentally diagnosed (n = 34) and symptomatic NF-PNET (n = 16) less than 2 cm in size, demographic characteristics were not different between the two groups. Nevertheless, symptomatic tumors harbored more aggressive features, including more frequent grade 2 tumors (P = .012), more frequent perineural invasion (P = .044), and a greater Ki67 (P = .020). In addition, the presence of metastatic local nodes was more frequent in symptomatic lesions (25% vs 9%; P = .19) despite an equivalent tumor size, even if the difference did not reach significance. Overall, 91% of incidentally diagnosed NF-PNET less than 2 cm in size were N0/Nx. DFS was not different between the two groups (P = .09).

      Discussion

      NF-PNET are more and more frequently diagnosed as incidentaloma because of the widespread use of cross-sectional imaging,
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      • McGrath D.J.
      • Lauwers G.Y.
      • Thayer S.P.
      • et al.
      Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005.
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      • et al.
      Nonfunctioning pancreatic endocrine tumors: a multicenter clinical study.
      The management of small sporadic NF-PNET is controversial, and the benefit of resection regarding OS and DFS has not been clearly established for lesions below 2 cm.
      • Bettini R.
      • Partelli S.
      • Boninsegna L.
      • Capelli P.
      • Crippa S.
      • Pederzoli P.
      • et al.
      Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor.
      • Falconi M.
      • Bartsch D.K.
      • Eriksson B.
      • Kloppel G.
      • Lopes J.M.
      • O'Connor J.M.
      • et al.
      ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors.
      We have shown here that sporadic incidentally diagnosed NF-PNET are associated with less aggressive features than symptomatic lesions but cannot be considered to be benign tumors. If operative resection should remain recommended for most of them, incidentally diagnosed NF-PNET frequently are amenable to pancreas-sparing pancreatectomies with an excellent long-term DFS.
      • Cherif R.
      • Gaujoux S.
      • Couvelard A.
      • Dokmak S.
      • Vuillerme M.P.
      • Ruszniewski P.
      • et al.
      Parenchyma-sparing resections for pancreatic neuroendocrine tumors.
      Identification of a subgroup of patients with indolent lesion amenable to a “wait-and-see” policy will be the next challenge for the medical and surgical community.
      Our understanding of the natural history of incidentally diagnosed PNET is limited, and because NF-PNET are traditionally associated with aggressive behavior, most institutions have recommended their systematic operative resection.
      • Fitzgerald T.L.
      • Smith A.J.
      • Ryan M.
      • Atri M.
      • Wright F.C.
      • Law C.H.
      • et al.
      Surgical treatment of incidentally identified pancreatic masses.
      • Fendrich V.
      • Waldmann J.
      • Bartsch D.K.
      • Langer P.
      Surgical management of pancreatic endocrine tumors.
      • Clark O.H.
      • Benson 3rd, A.B.
      • Berlin J.D.
      • Choti M.A.
      • Doherty G.M.
      • Engstrom P.F.
      • et al.
      NCCN Clinical Practice Guidelines in Oncology: neuroendocrine tumors.
      • Kulke M.H.
      • Anthony L.B.
      • Bushnell D.L.
      • de Herder W.W.
      • Goldsmith S.J.
      • Klimstra D.S.
      • et al.
      NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas.
      Recently, few series have focused on the management of incidentally diagnosed PNET with conflicting results.
      • Cheema A.
      • Weber J.
      • Strosberg J.R.
      Incidental detection of pancreatic neuroendocrine tumors: an analysis of incidence and outcomes.
      • Haynes A.B.
      • Deshpande V.
      • Ingkakul T.
      • Vagefi P.A.
      • Szymonifka J.
      • Thayer S.P.
      • et al.
      Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes.
      Some suggested that compared with symptomatic NF-PNET, incidentally diagnosed lesions had a better DFS after resection, this diagnostic feature being an independent prognostic factor. Although operative resection is curative in most cases, they suggested that clinical and radiographic surveillance might be an appropriate alternative for highly selected patients with asymptomatic and small tumors.
      • Bettini R.
      • Boninsegna L.
      • Mantovani W.
      • Capelli P.
      • Bassi C.
      • Pederzoli P.
      • et al.
      Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours.
      In contrast, the Massachusetts General Hospital group reported that incidentally diagnosed PNET can sometimes display aggressive behavior, even when small, and should undergo resection and careful postoperative surveillance, even when operative and pathologic findings suggest benign disease.
      • Haynes A.B.
      • Deshpande V.
      • Ingkakul T.
      • Vagefi P.A.
      • Szymonifka J.
      • Thayer S.P.
      • et al.
      Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes.
      These studies underline the difficulty in assessing the biological behavior of NF-PNET. Regarding small lesions, ie, those less than 2 cm in size, they usually carry excellent long-term OS and DFS, but up to 10% are node-positive.
      • Cherif R.
      • Gaujoux S.
      • Couvelard A.
      • Dokmak S.
      • Vuillerme M.P.
      • Ruszniewski P.
      • et al.
      Parenchyma-sparing resections for pancreatic neuroendocrine tumors.
      • Haynes A.B.
      • Deshpande V.
      • Ingkakul T.
      • Vagefi P.A.
      • Szymonifka J.
      • Thayer S.P.
      • et al.
      Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes.
      • Bettini R.
      • Partelli S.
      • Boninsegna L.
      • Capelli P.
      • Crippa S.
      • Pederzoli P.
      • et al.
      Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor.
      Even if the prognosis significance of node positivity is debatable, this low probability of distant disease justifies operative resection for most of these lesions. Not surprisingly, the number of lymph nodes present in the specimen after standard resection was greater than the one after PSP. Nevertheless, the extent of lymph node sampling can be tailored to the primary tumor size. As an example, this concept of a limited resection of the primary tumor with wide lymph node dissection is the standard procedure for sporadic gastrinomas.
      • Norton J.A.
      • Fraker D.L.
      • Alexander H.R.
      • Gibril F.
      • Liewehr D.J.
      • Venzon D.J.
      • et al.
      Surgery increases survival in patients with gastrinoma.
      It remains theoretically possible that LN positivity in limited resections is underestimated, even if none of the 19 patients with Nx status after PSP recurred.
      Prognostic factors for PNET have been widely studied based on institutional review of operative patients
      • Schurr P.G.
      • Strate T.
      • Rese K.
      • Kaifi J.T.
      • Reichelt U.
      • Petri S.
      • et al.
      Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience.
      • Vagefi P.A.
      • Razo O.
      • Deshpande V.
      • McGrath D.J.
      • Lauwers G.Y.
      • Thayer S.P.
      • et al.
      Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005.
      • Fischer L.
      • Kleeff J.
      • Esposito I.
      • Hinz U.
      • Zimmermann A.
      • Friess H.
      • et al.
      Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas.
      • Chung J.C.
      • Choi D.W.
      • Jo S.H.
      • Heo J.S.
      • Choi S.H.
      • Kim Y.I.
      Malignant nonfunctioning endocrine tumors of the pancreas: predictive factors for survival after surgical treatment.
      and several have been proposed,
      • Bilimoria K.Y.
      • Talamonti M.S.
      • Tomlinson J.S.
      • Stewart A.K.
      • Winchester D.P.
      • Ko C.Y.
      • et al.
      Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients.
      • Chu Q.D.
      • Hill H.C.
      • Douglass Jr., H.O.
      • Driscoll D.
      • Smith J.L.
      • Nava H.R.
      • et al.
      Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas.
      • Hochwald S.N.
      • Zee S.
      • Conlon K.C.
      • Colleoni R.
      • Louie O.
      • Brennan M.F.
      • et al.
      Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups.
      including clinical parameters (age, functional status, presence of distant metastases), classification (TNM staging, WHO classification), or pathologic characteristics (macroscopically radical resection, tumor size, lymph node metastases, or angiolymphatic invasion).
      • Schurr P.G.
      • Strate T.
      • Rese K.
      • Kaifi J.T.
      • Reichelt U.
      • Petri S.
      • et al.
      Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience.
      • Bilimoria K.Y.
      • Talamonti M.S.
      • Tomlinson J.S.
      • Stewart A.K.
      • Winchester D.P.
      • Ko C.Y.
      • et al.
      Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients.
      • Chu Q.D.
      • Hill H.C.
      • Douglass Jr., H.O.
      • Driscoll D.
      • Smith J.L.
      • Nava H.R.
      • et al.
      Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas.
      • Bahra M.
      • Jacob D.
      • Pascher A.
      • Plockinger U.
      • Kristiansen G.
      • Neuhaus P.
      • et al.
      Surgical strategies and predictors of outcome for malignant neuroendocrine tumors of the pancreas.
      • Bonney G.K.
      • Gomez D.
      • Rahman S.H.
      • Verbeke C.S.
      • Prasad K.R.
      • Toogood G.J.
      • et al.
      Results following surgical resection for malignant pancreatic neuroendocrine tumours. A single institutional experience.
      • Kazanjian K.K.
      • Reber H.A.
      • Hines O.J.
      Resection of pancreatic neuroendocrine tumors: results of 70 cases.
      To the best of our knowledge, we studied one of the largest single institution series evaluating incidentally diagnosed sporadic NF-PNET with specific attention paid to overall and DFS. Our study confirmed that asymptomatic NF-PNET less than 2 cm are more likely to be benign, ie, without long-term recurrence than larger and symptomatic lesions. Patients with incidental tumors smaller than 2 cm were more often staged T1, node negative, and graded 1, with a low rate of vascular and perineural invasion, pain, low mitotic count, and Ki67 than tumors measuring 2 cm or more. Interestingly, vascular and perineural invasion could explain symptoms in patients with abdominal pain. In addition, tumor grade and tumor size were the only independent prognostic factors of DFS in multivariate analyses, as reported by others
      • Ferrone C.R.
      • Tang L.H.
      • Tomlinson J.
      • Gonen M.
      • Hochwald S.N.
      • Brennan M.F.
      • et al.
      Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified?.
      • Scarpa A.
      • Mantovani W.
      • Capelli P.
      • Beghelli S.
      • Boninsegna L.
      • Bettini R.
      • et al.
      Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients.
      but incidental diagnosis was a nearly substantial prognostic factor (P = .05). In our series, DFS was 95%, 89%, 87%, and 62% at 1-, 3-, 5-, and 10-year, respectively, and was better in patients with incidentally diagnosed PNET. It now seems likely that incidentally diagnosed NF-PNET, especially small ones, harbor a better prognosis and less aggressive features than their symptomatic counterparts. What remains controversial is the clinical implication of this finding because a fraction of these patients will present at diagnosis with positive lymph nodes anyway, and will consequently be exposed to recurrences or distant metastasis. As in our study, most reports agree that a lymph node-positive disease does not preclude resection and does not dramatically affect overall survival,
      • Fischer L.
      • Kleeff J.
      • Esposito I.
      • Hinz U.
      • Zimmermann A.
      • Friess H.
      • et al.
      Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas.
      • Chung J.C.
      • Choi D.W.
      • Jo S.H.
      • Heo J.S.
      • Choi S.H.
      • Kim Y.I.
      Malignant nonfunctioning endocrine tumors of the pancreas: predictive factors for survival after surgical treatment.
      • Bahra M.
      • Jacob D.
      • Pascher A.
      • Plockinger U.
      • Kristiansen G.
      • Neuhaus P.
      • et al.
      Surgical strategies and predictors of outcome for malignant neuroendocrine tumors of the pancreas.
      • Bonney G.K.
      • Gomez D.
      • Rahman S.H.
      • Verbeke C.S.
      • Prasad K.R.
      • Toogood G.J.
      • et al.
      Results following surgical resection for malignant pancreatic neuroendocrine tumours. A single institutional experience.
      • Kazanjian K.K.
      • Reber H.A.
      • Hines O.J.
      Resection of pancreatic neuroendocrine tumors: results of 70 cases.
      most of recurrences being local, late, and amendable to re-resection. Association between size and PNET biologic behavior also has been clearly reported,
      • Rindi G.
      • Kloppel G.
      • Alhman H.
      • Caplin M.
      • Couvelard A.
      • de Herder W.W.
      • et al.
      TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.
      • Hochwald S.N.
      • Zee S.
      • Conlon K.C.
      • Colleoni R.
      • Louie O.
      • Brennan M.F.
      • et al.
      Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups.
      • Scarpa A.
      • Mantovani W.
      • Capelli P.
      • Beghelli S.
      • Boninsegna L.
      • Bettini R.
      • et al.
      Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients.
      • Ekeblad S.
      • Skogseid B.
      • Dunder K.
      • Oberg K.
      • Eriksson B.
      Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution.
      • La Rosa S.
      • Sessa F.
      • Capella C.
      • Riva C.
      • Leone B.E.
      • Klersy C.
      • et al.
      Prognostic criteria in nonfunctioning pancreatic endocrine tumours.
      and overall, knowing the substantial morbidity and mortality of standard pancreatectomies, this favors a less-aggressive management from pancreas-sparing resection to even observation for a subset of patients with small indolent tumors, even if up to now, no high level evidence could support a “wait-and-see” policy.
      The type and extent of operative resection for PNET remain controversial because of our inability to accurately predict which tumors are benign and which are malignant. Enucleation is now a standard of care for insulinoma because their benignity can be assumed most of the time.
      • Crippa S.
      • Bassi C.
      • Salvia R.
      • Falconi M.
      • Butturini G.
      • Pederzoli P.
      Enucleation of pancreatic neoplasms.
      • Nikfarjam M.
      • Warshaw A.L.
      • Axelrod L.
      • Deshpande V.
      • Thayer S.P.
      • Ferrone C.R.
      • et al.
      Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital.
      Conversely, it is unclear whether pancreas-sparing pancreatectomies can be applied to small, sporadic NF-PNET because they are not optimal oncologic resections – with limited margins and no formal lymphadenectomy. Standard pancreatic resections ie, pancreaticoduodenectomy and distal pancreatectomy, are associated, even in experienced hands, with a significant postoperative morbidity and mortality and disappointing long-term functional results.
      • Falconi M.
      • Mantovani W.
      • Crippa S.
      • Mascetta G.
      • Salvia R.
      • Pederzoli P.
      Pancreatic insufficiency after different resections for benign tumours.
      The up to 30% reported rates of de novo diabetes following standard pancreatic resection
      • Falconi M.
      • Mantovani W.
      • Crippa S.
      • Mascetta G.
      • Salvia R.
      • Pederzoli P.
      Pancreatic insufficiency after different resections for benign tumours.
      • DiNorcia J.
      • Ahmed L.
      • Lee M.K.
      • Reavey P.L.
      • Yakaitis E.A.
      • Lee J.A.
      • et al.
      Better preservation of endocrine function after central versus distal pancreatectomy for mid-gland lesions.
      are no longer acceptable in the setting of asymptomatic patients with long life expectancy. Consequently, in our opinion standard pancreatic resections should be limited to large (>2 cm in diameter) and aggressive tumors requiring extensive lymphadenectomy. Conversely, parenchyma-sparing procedures could be offered to less aggressive PNET,
      • Falconi M.
      • Zerbi A.
      • Crippa S.
      • Balzano G.
      • Boninsegna L.
      • Capitanio V.
      • et al.
      Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors.
      • Pitt S.C.
      • Pitt H.A.
      • Baker M.S.
      • Christians K.
      • Touzios J.G.
      • Kiely J.M.
      • et al.
      Small pancreatic and periampullary neuroendocrine tumors: resect or enucleate?.
      this includes NF-PNET less than 2 cm, especially when incidentally-discovered.
      • Aranha G.V.
      • Shoup M.
      Nonstandard pancreatic resections for unusual lesions.
      In our experience, about two-thirds of patients with incidentally diagnosed lesion underwent PSP, ie, every time than their anatomical location allowed it. With adequate patient selection, DFS is excellent, up to 90% at 5 years,
      • Sperti C.
      • Beltrame V.
      • Milanetto A.C.
      • Moro M.
      • Pedrazzoli S.
      Parenchyma-sparing pancreatectomies for benign or border-line tumors of the pancreas.
      • Adham M.
      • Giunippero A.
      • Hervieu V.
      • Courbiere M.
      • Partensky C.
      Central pancreatectomy: single-center experience of 50 cases.
      • Crippa S.
      • Bassi C.
      • Warshaw A.L.
      • Falconi M.
      • Partelli S.
      • Thayer S.P.
      • et al.
      Middle pancreatectomy: indications, short- and long-term operative outcomes.
      and in a recent study, when incidental small tumors were considered, only 6% were malignant and no patients died of disease.
      • Bettini R.
      • Partelli S.
      • Boninsegna L.
      • Capelli P.
      • Crippa S.
      • Pederzoli P.
      • et al.
      Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor.
      Interestingly, as previously reported,
      • Cherif R.
      • Gaujoux S.
      • Couvelard A.
      • Dokmak S.
      • Vuillerme M.P.
      • Ruszniewski P.
      • et al.
      Parenchyma-sparing resections for pancreatic neuroendocrine tumors.
      PSP carry a greater overall morbidity, especially regarding pancreatic fistula, but without significantly different severe morbidity or mortality.
      The benefit of watchful surveillance can be discussed in the subgroup of patients with the smallest lesions, or in patients whose general condition precludes a safe operative resection. Extending this logic further, some authors suggested that for PNET less than 2 cm, a nonoperative management could be considered.
      • Lee L.C.
      • Grant C.S.
      • Salomao D.R.
      • Fletcher J.G.
      • Takahashi N.
      • Fidler J.L.
      • et al.
      Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management.
      Our results could support this strategy. Indeed, most of the small incidentally diagnosed lesions were N0 and about 80% were grade 1, ie, nonaggressive neoplasms. A more accurate preoperative patient selection, using, for example, fine-needle aspiration to assess tumor grade, might be needed before extending a “wait-and-see” policy for small PNET. Until then, parenchyma-sparing surgery could represent an alternative for small incidentally diagnosed sporadic NF-PNET.
      In conclusion, incidentally diagnosed NF-PNET is an increasing clinical situation now accounting for the majority of newly diagnosed patients. These tumors have more favorable histopathological characteristics than their symptomatic counterparts. Our results favor a less aggressive management of small incidentally diagnosed NF-PNET. In this setting, the value of PSP should be considered in these asymptomatic patients, who, ideally should remain asymptomatic, ie, as they were before operation.

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