Early Gastroenteropancreatic Neuroendocrine Tumors: Endoscopic Therapy and Surveillance

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1 Review Article DOI: / Pulished online: Octoer 10, 2017 Erly Gstroenteropncretic Neuroendocrine Tumors: Endoscopic Therpy nd Surveillnce Hns Scherül Guillume Cdiot Deprtments of Gstroenterology, Gstrointestinl Oncology nd Infectious Diseses, Vivntes Klinikum Am Urn, Berlin, Germny; Service d Hépto-Gstroentérologie, Hôpitl Roert Deré, Reims, Frnce Keywords Neuroendocrine tumor, NET Crcinoid Stomch Duodenum Pncres Gut Appendix Rectum Smll size Prognosis Tretment Endoscopy Endoscopic mucosl resection, EMR Endoscopic sumucosl dissection, ESD Summry Neuroendocrine neoplsis (NEN) of the stomch, duodenum, pncres, ppendix, or rectum tht re 1 cm in size s well s well-differentited with World Helth Orgniztion grde 1 (G1) cn e considered erly neuroendocrine tumors; they hve very good prognosis. Regrding prognosis, neuroendocrine tumors (NET) G1 must e distinguished from well-differentited NET G2 nd poorly differentited neuroendocrine crcinoms (NEC) G3. NET re incresing, with rise in the ge-djusted incidence in the USA y out 700% in the lst 40 yers. Erlier dignosis of NET is one of the min epidemiologicl chnges of cliniclly detected NEN. The generl vilility of high-resolution endoscopy nd dvnced rdiologicl imging techniques hs contriuted to shift in the discovery to smllersized ( 10 mm) gstrointestinl nd pncretic NET nd erlier tumor stges t dignosis. Thus, screening colonoscopy is effective in the erly dignosis not only of colorectl denoms nd denocrcinoms ut lso of rectl NET. Endoscopic resection is the tretment of choice in NET G1 of the stomch, duodenum (despite gstrinom), nd rectum tht re 10 mm in size, do not infiltrte the musculris propri (T1), nd do not show ngioinvsion (V0, L0). Similrly, histologiclly proven, erly pncretic NET G1 ( 10 mm) my e mnged conservtively y regulr surveillnce. In con- trst, smll ( 1 cm) NET G1 of the jejunum or ileum re not erly tumors nd hve to e resected surgiclly with lymph node dissection. Introduction 2017 S. Krger GmH, Freiurg The clssifiction of the World Helth Orgniztion (WHO) strtifies gstrointestinl neuroendocrine neoplsis (NEN) into three groups: neuroendocrine tumors (NET) tht re well differentited nd grded ccording to their prolifertive ctivity into G1 or G2, nd neuroendocrine crcinoms (NEC) tht re poorly differentited nd grded s NEC G3. The ltter re further divided into smll cell nd lrge cell neoplsms. Some well-differentited pncretic NET (pnet) show discordntly high prolifertive ctivity of >20% nd re clssified s pnet G3 in the recent WHO clssifiction of mlignnt tumors [1]. Gstrointestinl NET re on the rise [2]. In the USA, the prevlence nd the incidence of gstroenteropncretic NET/crcinoids ws clculted to e 35/100,000 nd 5/100,000, respectively [3], reveling sevenfold increse in the lst 40 yers. Similr chnges hve een reported for Englnd [4], Norwy [5], nd Germny [6]. The most ovious resons for this phenomenon re etter wreness of nd improved dignostic fcilities for NEN s well s n incresed nd more widespred use of gstrointestinl, high-resolution endoscopy nd dvnced rdiologicl imging [4, 5, 7 11]. The overll 5-yer survivl rte for ptients with gstrointestinl NET/crcinoids hs improved y more thn 20% in the lst 40 yers [12 14]. This chievement is due to oth erly detection nd etter therpeutic strtegies of NET. Tody, gstrointestinl NET/ crcinoids re often dignosed t n erly symptomtic stge [3], Fx Informtion@Krger.com S. Krger GmH, Freiurg Accessile online t: Prof. Dr. med. Hns Scherül Klinik für Innere Medizin Gstroenterologie, Gstrointestinle Onkologie und Infektiologie Vivntes-Klinikum Am Urn, Akdemisches Lehrkrnkenhus der Chrité Dieffenchstrße 1, Berlin, Germny vivntes.de

2 Tle 1. Clinicopthologicl chrcteristics nd prognosis of neuroendocrine neoplsis of the stomch [9, 12, 16, 18, 19] Gstric NET G1 (crcinoids) nd NET G2 type 1 type 2 type 3 Poorly differentited NE gstric cncer (type 4): gstric NEC G3 Reltive frequency, % Fetures mostly smll ( 1 cm) mostly smll ( 1 cm) often >2 cm, solitry mostly >2 cm, solitry nd multiple nd multiple Associted conditions CAG MEN1/ZES no no Histology well-differentited G1/G2 well-differentited G1/G2 well/modertely differentited G1/G2 Serum gstrin (very) high (very) high norml (mostly) norml Gstric ph ncidic hypercidic norml (mostly) norml Metstses, % < Tumor-relted deths, % no < >50 G3 Most type 1 nd type 2 gstric NET G2 show Ki-67 expression of 5%. Some type 3 gstric NET, though well-differentited, show Ki-67 index of >20% (NET G3). CAG = Chronic trophic gstritis; MEN1 = multiple endocrine neoplsi type 1; ZES = Zollinger-Ellison syndrome; MEN1/ZES = ZES ssocited with MEN1; G1 nd G2 = well-differentited; G3 = poorly differentited (Ki-67 index of 0 2%: G1; Ki-67 index of 3 20%: G2; Ki-67 index of >20%: G3); NE = neuroendocrine; NET = neuroendocrine tumor; NEC = neuroendocrine crcinom. notly G1 tumors with size elow 10 mm. Retrospective dt from lrge ntionl registries nd lrge hospitl series, minly from Jpn, Kore, Europe, nd the USA, rgue for conservtive mngement of these erly gstroenteropncretic NET G1/crcinoids of the stomch, duodenum, pncres, nd rectum. Tle 2. Impct of endoscopic screening on the size of rectl neuroendocrine neoplsms (modified from [10]) Size of primry NET, mm Without screening, % Endoscopic screening, % < > Histologicl Grding of Neuroendocrine Neoplsms The risk of metsttic disese of gstrointestinl NEN correltes with histologicl differentition (well or poorly differentited) of the primry, prolifertive ctivity (G1 G3), tumor size, depth of tumor infiltrtion, nd ngioinvsion. The histologicl grding of gstrointestinl NEN (G1 G3) ccording to the WHO clssifiction is of mjor prognostic nd therpeutic relevnce [1]. Tle 3. Min fctors predicting metstses in ptients with rectl neuroendocrine tumors [30] Predictive fctor Odds rtio 95% CI Tumor size >14 mm ,002.6 Mitotic index 2/10 HPF ,295.8 Lymphovsculr invsion ,846.7 Musculris propri invsion HPF = High-power field; CI = confidence intervl. Prognosis of Gstric Neuroendocrine Tumors/Crcinoids At present, the most common form of gstric NET, i.e. type 1 (tle 1), is generlly dignosed t n erly stge, with 80 90% of them eing 1 cm in dimeter [9]. These smll, well-differentited tumors only rrely cuse specific symptoms; in most instnces, they re incidentlly found during gstroscopy eing performed for resons such s nemi or non-specific dominl symptoms. Type 2 gstric NET, similr to type 1 (tle 1), re usully detected t n erly stge, nd generlly hve good prognosis. For ll gstric crcinoids the prognosis hs much improved [2, 12, 15 17], with the proportion of dvnced tumor stges t dignosis decresing from 23.8% in the 1950s nd 1960s to % in the 1990s, suggesting tht erly dignosis is contriuting to the ptients improved survivl. In Jpn, the rte of dvnced stges t dignosis is s low s 5.1% tody [15]. The 5-yer survivl rte of ptients with gstric NEN hs improved from 51% in the 1970s nd 1980s to 63% in the 1990s [2, 15 17]. According to n nlysis of the SEER dt y Lndry et l. [16], the 5-yer survivl is out 71%. Smll ( 1cm), well-differentited NET G1/crcinoids of the stomch without either infiltrtion of the musculris propri or ngioinvsion hve een shown to hve very low risk of distnt metsttic spred [18, 19] or crcinoid-relted deth; they re considered erly NET G1 (crcinoids) of the stomch. The 5-yer survivl of type 1 gstric crcinoids pproches 98%. Prognosis of Neuroendocrine Tumors/Crcinoids of the Smll Bowel In the smll owel, NET/crcinoids re most frequently found in the ileum (>70%), especilly the distl ileum, ut recent dt Endoscopic Therpy nd Surveillnce 333

3 show tht duodenl NET re more common (22%) nowdys thn previously noted [20]. Regrding prognosis, the 5-yer survivl rte hs risen from 51.9% in the 1970s nd 1980s to 60.5% in the 1990s [12]. In n nlysis of the yers , Stroserg et l. [13] reported 5-yer survivl rte of out 75% in ptients with metsttic NET/crcinoid disese of the smll intestine receiving multimodl therpy. The erlier detection of intestinl NET my hve led to improved prognosis [11, 14], since the proportion of dvnced disese of smll intestine NET (t the time of dignosis) hs decresed from 31.3% in the 1970s nd 1980s to 22.4% in the 1990s nd finlly to <18.9% etween 2002 nd 2004 [3, 12, 15, 20]. With duodenl NET/crcinoids, distnt metstses re nowdys oserved in less thn 6 10% of cses [15, 21 23]. If duodenl NET/ crcinoids re 10 mm in size, re type G1, show neither ngioinvsion nor infiltrtion of the musculris propri, nd hve no ssocited hormonl syndrome, they hve very low risk of metstsis nd cn e considered erly duodenl NET/ crcinoids. In contrst, duodenl gstrinoms (i.e. duodenl NET ssocited with the Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplsi 1 (MEN1)) s well s jejunl or ilel NET/crcinoids of only few millimeters in size my lredy hve spred to locoregionl lymph nodes nd distnt orgns. Thus, the term erly tumor is pproprite neither for jejunl nd ilel NET/crcinoids nor for duodenl gstrinoms nd should not e used. Prognosis of Rectl Neuroendocrine Tumors/Crcinoids Thnks to the introduction of ntionl colorectl cncer screening in severl countries, the vst mjority (85 95%) of rectl NET/ crcinoids is detected t n erly stge (tle 2). This shift to erlier stges hs improved the ptients 5-yer survivl rte y more thn 20% [10]. The 5-yer survivl rte of ptients with distnt metstses of rectl NET/crcinoids rnges from 15 to 30% [22, 24, 25]. For node-positive rectl crcinoid disese (without distnt metstses) the 5-yer survivl rte is 54 73% [24, 25 27]. In contrst, histologiclly, node-negtive rectl NET/crcinoids tht re 1 cm in size nd do not show ngioinvsion or infiltrtion of the musculr lyer hve n excellent 5-yer survivl rte of % [2, 22, 24, 25]. Such rectl NET G1/crcinoids 1 cm my e regrded s erly NET. Guidelines pulished y the North Americn Neuroendocrine Tumor Society (NANETS) do not recommend followup of ptients with well-differentited rectl NET G1/crcinoids 1 cm in size tht hve een completely resected nd tht hd not invded the musculris propri [28]. Yet the Europen Neuroendocrine Tumor Society (ENETS) recommends further surveillnce of these ptients in cse of ngioinvsion, invsion of the musculr lyer (T2), or G2 grding [29]. A recent literture nlysis showed tht independent fctors for the development of metstses were tumor size >14 mm, mitotic index 2/10 high-power field, lymphovsculr invsion, nd invsion of the musculris propri (tle 3) [30]. There re very few dt on the Ki-67 prolifertion index in rectl NET, nd most dt rely on the mitotic index. Fig. 1. Endoscopic imges of erly gstrointestinl neuroendocrine tumors (NET) G1/crcinoids. Multiple, smll (<1 cm), type 1 gstric NET G1/crcinoids ssocited with utoimmune chronic trophic gstritis nd pernicious nemi; NET G1/crcinoid of the rectum mesuring 7 mm; c NET G1/crcinoid of the rectum mesuring 10 mm (modified from [10]). Prognosis of Appendicel Neuroendocrine Tumors G1 V0 L0 R0 Appendicel NEN re usully NET G1/crcinoids tht re incidentlly found in ptients undergoing ppendectomy for suspected cute ppendicitis. The term erly ppendicel NET/crcinoid my e considered for tumors tht re G1, mesure 10 mm, show no ngioinvsion, re confined oth to the tip of the ppendix nd to the wll (without invsion of the mesoppendix), nd hve een completely (R0) removed y ppendectomy. Such erly ppendicel crcinoids hve very low risk of distnt metsttic spred. Neither ENETS nor NANETS recommend further surveillnce of ptients with these erly ppendicel NET tht hve een R0-resected [31, 32]. Prognosis of Spordic Pncretic Neuroendocrine Tumors G1 An interntionl Europen study group evluted the clinicopthologicl chrcteristics of 926 NEN of the pncres nd correlted clinicl outcome with tumor size nd histologicl grding [33]. 334 Scherül/Cdiot

4 Tle 4. Therpy of gstric neuroendocrine neoplsis (types 1 4) NET G1 without risk fctors (for metsttic disese) Risk fctors Size 1 cm 1 2 cm mostly >2 cm Type 1 EMR EMR/ESD surgery Type 2 EMR EMR/ESD surgery Type 3 EMR/ESD or surgery surgery surgery Type 4 surgery Risk fctors for metsttic disese re ngioinvsion, G2 G3 histologicl grding, infiltrtion of the musculris propri, enlrged regionl lymph nodes, or tumor size 2 cm. EMR my e considered for gstric NET G2 1 cm, when Ki-67 is 5%. Ptients mnged y EMR/ESD should e surveilled every 12 months. Type 4 gstric NEN re never enign; they re neuroendocrine crcinoms (NEC). EMR = Endoscopic mucosl resection; ESD = endoscopic sumucosl dissection; NET = neuroendocrine tumors. In this lrge retrospective nlysis, no tumor-relted deths were oserved in ptients with well-differentited pnet < 2 cm in dimeter. Similrly, study from the USA compred the survivl of ptients suffering from non-functioning, symptomtic pnet < 4 cm tht were either surgiclly resected or mnged conservtively [34]. No difference in survivl ws reported. Neither distnt metstses nor tumor-relted deths were oserved in the conservtively mnged ptients with symptomtic pnet of men size of 1 cm [34]. Therefore, non-men1-relted, non-functioning nd symptomtic NET G1 1 cm of the pncres cn e considered s spordic, erly pnet. Such erly ( 1 cm), histologiclly proven pnet G1 hve very low risk of distnt metsttic spred nd in prticulr of NET-relted deth. The proility of NET-relted deth in ptients with spordic, non-functioning, erly ( 1 cm) pnet G1 is certinly lower thn the current men ntionwide in-hospitl mortlity following pncretic surgery [35]. The min issue when considering conservtive mngement is to e certin of G1 grde. Biopsies re often otined vi fine needle spirtion guided y endoscopic ultrsound. Is hs een shown in series of pnet ptients mnged y pncretic surgery tht preopertive cytologicl ssessment using fine needle spirtion underestimted the tumor grde, especilly in cystic lesions [36]. Thus, Tru-cut iopsies (19-guge) re recommended for relile histologicl grding of pnet. Dignosis of Erly Neuroendocrine Tumors G1 of the Stomch, Duodenum or Rectum Both endoscopic screening nd the incresingly widespred vilility of gstrointestinl endoscopy hve led to shift in the discovery to smller-sized ( 10 mm) gstrointestinl NET G1/crcinoids. Most of these erly tumors re symptomtic, ut occsionlly they present with dominl discomfort, gstrointestinl leeding, or ltered owel hits. If they come long with hormonl hypersecretion syndrome, i.e. with ZES in duodenl gstrinom, they re clled functionl NET. Functionl NET my lredy hve spred to the regionl lymph nodes or the liver despite smll size of 1 cm. Functionl intestinl NET re not to e considered erly tumors nd will not e discussed here in detil. Endoscopy is the method of choice to detect (symptomtic) gstric, duodenl or rectl NET G1/crcinoids even t n erly stge (fig. 1). Therpy of Erly Gstroenteropncretic Neuroendocrine Tumors/Crcinoids Endoscopic Techniques Used for the Resection of Superficil Digestive Tumors Conventionl polypectomy with snre for flt mucosl lesions, especilly NET/crcinoids, should e voided ecuse complete resection is often not chieved, e.g. 59% in recent review of rectl NET [30]. Insted, endoscopic mucosl resection (EMR) or endoscopic sumucosl dissection (ESD) should e preferred. In EMR, snre resection is preceded y the sumucosl injection of sline in order to rise the tumor nd cut into the sumucos elow the tumor (fig. 2). EMR cn e performed with or without cp or ligtion device [37]. ESD is preferred to EMR in cse of suspicion of limited sumucosl invsion or tumor lrger thn 2 cm [38]. After sumucosl injection of sline, the sumucos is dissected with specific knives in order to chieve endoscopic en loc resection of the whole neoplsm. ESD requires specific trining nd is usully performed in expert endoscopic centers. Considering rectl NET/crcinoids, oth EMR with cp/ligtion device nd ESD llow complete resection in out 90% [30]. The rte of perfortion is higher with ESD ut perfortions re usully closed during the endoscopic procedure. Indictions for NET/Crcinoids Smll ( 1 cm), well-differentited NET G1/crcinoids of the stomch, duodenum, or rectum tht neither infiltrte the musculris propri nor show ngioinvsion hve very low risk of metsttic spred; i.e., they re considered s erly NET/crcinoids. The tretment of choice of erly NET/crcinoids of the stomch, duodenum, or rectum is endoscopic resection (tle 4 6). Endoscopic ultrsound is excellent for determining the exct tumor size nd for excluding infiltrtion of the NET/crcinoids into the musculris propri (T2) or enlrged regionl lymph nodes. Endoscopic Therpy nd Surveillnce 335

5 Tle 5. Therpy of duodenl neuroendocrine tumors (without multiple endocrine neoplsi type 1) NET G1 without risk fctors (for metsttic disese) Risk fctors Size 1 cm 1 2 cm mostly 2 cm Spordic NET EMR, c EMR c or surgery d surgery d Spordic gstrinom (loclized) surgery d surgery d surgery d Risk fctors for metsttic disese re ngioinvsion, G2 G3 histologicl grding, infiltrtion of the musculris propri, enlrged regionl lymph nodes, or tumor size 2 cm. In the elderly, symptomtic duodenl NET G1 1 cm my just e followed up [44]. c EMR my e considered for NET G2 1 cm, when Ki-67 is 5%. Endoscopic sumucosl dissection (ESD) increses the risk of duodenl perfortion (most often mnged endoscopiclly) ut increses complete resection rte. ESD my e considered in some ptients if mnged in reference centers. d With lymph node dissection. EMR = Endoscopic mucosl resection; NET = neuroendocrine tumors. Fig. 2. Endoscopic mucosl resection (EMR) und endoscopic sumucosl dissection (ESD). EMR cn e performed without or with cp. c ESD. 336 Scherül/Cdiot

6 Tle 6. Therpy of rectl neuroendocrine tumors G1 NET G1 without risk fctors (for metsttic disese) Risk fctors Size 1 cm 1 2 cm mostly >2 cm G1 EMR/ESD EMR/ESD for NET <15 mm; surgery surgery Risk fctors for metsttic disese re ngioinvsion, G2 G3 histologicl grding, infiltrtion of the musculris propri, enlrged regionl lymph nodes, or tumor size 2 cm. EMR/ESD my e considered for NET G2 1 cm, when Ki-67 is 5% nd finl therpy will e discussed fter pthologicl nlysis of the resected specimen. EMR = Endoscopic mucosl resection; ESD = endoscopic sumucosl dissection; NET = neuroendocrine tumors. Erly NET/crcinoids of the stomch, duodenum, or rectum re generlly removed y EMR [30, 39, 40]. In erly rectl NET/crcinoids nd in prticulr in rectl NET G1 of 9 14 mm in size, ESD cn e considered [41]. ESD of duodenl NET increses the complete resection rte to lmost 100% when compred to EMR (out 50%), ut t the expense of higher perfortion rte [42]. Endoscopic therpy of duodenl NET comes with some interventionl moridity nd cn cuse mortlity prticulrly in multimorid elderly ptients [42]. The recent Germn S2k guideline does not recommend ESD for erly duodenl NET. In ny cse, the resected specimen hs to e crefully evluted regrding grde, ngioinvsion, nd infiltrtion of the deep resection mrgin. In cse of ngioinvsion, histologicl infiltrtion of the musculris propri (T2), or grde G2/G3, surgery with lymph node dissection is the therpy of choice in loclized NET disese. However, in some cses of smll ( 1 cm) type 3 gstric NET G1/G2 (Ki-67 < 5%) totlly resected (R0) y endoscopy nd in the sence of the other risk fctors for metsttic disese, endoscopic resection might e sufficient [43]. Erly ( 1 cm) ppendicel NET G1 re dequtely mnged y ppendectomy. R0-resected, erly ( 1 cm) NET G1 of the ppendix do not require follow-up. Spordic, non-functioning nd symptomtic NET G1 1 cm of the pncres re found incidentlly nowdys. Due to their excellent prognosis, histologiclly proven erly pnet cn e mnged conservtively nd should e surveilled y endoscopic ultrsound or mgnetic resonnce imging every 12 months. In cse of ovious tumor growth, the ptient should e dvised for surgery. It is importnt to note tht smll ( 1 cm) NET G1 of the jejunum or ileum re y no mens erly tumors nd hve to e resected surgiclly with systemtic lymph node dissection. The risk of regionl lymph node metstsis is high even in smll ( 1 cm) NET G1 of the jejunum or ileum. Conclusion High-resolution endoscopy nd dvnced rdiologicl imging techniques cn detect gstroenteropncretic NET G1/crcinoids even when very smll. The generl widespred use nd vilility of gstrointestinl endoscopy hs led to shift in the discovery towrds smller-sized ( 10 mm) gstrointestinl NET/crcinoids. In the lst 40 yers, the 5-yer survivl rte of ptients with gstroenteropncretic NET/crcinoids disese hs incresed y more thn 20%. Most ptients with erly ( 1 cm), well-differentited NET G1/crcinoids of the stomch, duodenum, rectum, or pncres cn e mnged conservtively nd e followed up y endoscopic surveillnce. It should e noted tht ptients with (previous) NET/crcinoid disese hve 15 25% risk for second mlignncies including rest (in women), prostte (in men), colorectl, nd gstric cncer. Disclosure Sttement The uthors do not hve ny conflict of interests concerning this review pper. References 1 Brierley J, Gospodrowicz M, Wittekind C (eds): TNM Clssifiction of Mlignnt Tumours, ed 8. Hooken, NJ; Wiley-Blckwell, Modlin IM, Oerg K, Chung DC, Jensen RT, de Herder WW, Thkker RV, Cplin M, Delle Fve G, Kltss GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Slzr R, Ruszniewski P, Sundin A: Gstroenteropncretic neuroendocrine tumours. Lncet Oncol 2008; 9: Yo JC, Hssn M, Phn A, Dgohoy C, Lery C, Mres JE, Adll EK, Fleming JB, Vuthey JN, Rshid A, Evns DB: One hundred yers fter crcinoid : epidemiology of nd prognostic fctors for neuroendocrine tumors in 35,825 cses in the United Sttes. J Clin Oncol 2008; 26: Ellis L, Shle MJ, Colemn MP: Crcinoid tumors of the gstrointestinl trct: trends in incidence in Englnd since Am J Gstroenterol 2010; 105: Huso O, Gustfsson BI, Kidd M, Wldum HL, Drozdov I, Chn AK, Modlin IM: Neuroendocrine tumor epidemiology: contrsting Norwy nd North Americ. Cncer 2008; 113: Scherül H, Streller B, Stenow R, Herst H, Höpfner M, Schwertner C, Steinerg J, Eick J, Ring W, Tiwri K, Zppe S: Cliniclly detected gstroenteropncretic neuroendocrine tumors re on the rise: epidemiologicl chnges in Germny. World J Gstroenterol 2013; 19: Kminski M, Polkowski M, Regul J: Prevlence nd endoscopic fetures of rectl neuroendocrine tumors (crcinoids) mong 50,148 prticipnts of the Polish colorectl-cncer screening progrmme. Gut 2007; 56(suppl III):A Hosokw O, Miyng T, Kizki Y, Httori M, Dohden K, Oht K, Itou Y, Aoygi H: Decresed deth from gstric cncer y endoscopic screening: ssocition with popultion-sed cncer registry. Scnd J Gstroenterol 2008; 43: Scherül H, Cdiot G, Jensen RT, Rösch T, Stölzel U, Klöppel G: Neuroendocrine tumors of the stomch (gstric crcinoids) re on the rise: smll tumors, smll prolems? Endoscopy 2010; 42: Endoscopic Therpy nd Surveillnce 337

7 10 Scherül H: Rectl crcinoids re on the rise: erly detection y screening endoscopy. Endoscopy 2009; 41: Scherül H, Jensen RT, Cdiot G, Stölzel U, Klöppel G: Neuroendocrine tumors of the smll owels re on the rise: erly spects nd mngement. World J Gstrointest Endosc 2010; 2: Modlin IM, Lye KD, Kidd M: A 5-decde nlysis of 13,715 crcinoid tumors. Cncer 2003; 97: Stroserg J, Grdner N, Kvols L: Survivl nd prognostic fctor nlysis of 146 metsttic neuroendocrine tumors of the midgut. Neuroendocrinology 2009; 89: Zr N, Grmo H, Holmerg L, Rstd J, Hellmn P: Long-term survivl of ptients with smll intestinl crcinoid tumors. World J Surg 2004; 28: Ito T, Tnk M, Ssno H, Osmur YR, Sski I, Kimur W, Tkno K, Or T, Ishishi M, Nko K, Doi R, Shimtsu A, Nishid T, Komoto I, Hirt Y, Immur M, Kwe K, Nkmur K: Preliminry results of Jpnese ntionwide survey of neuroendocrine gstrointestinl tumors. J Gstroenterol 2007; 42: Lndry CS, Brock G, Scoggins CR, McMsters KM, Mrtin RC: A proposed stging system for gstric crcinoid tumors sed on n nlysis of 1,543 ptients. Ann Surg Oncol 2009; 16: Modlin IM, Lye KD, Kidd M: A 50-yer nlysis of 562 gstric crcinoids: smll tumor or lrger prolem? Am J Gstroenterol 2004; 99: Klöppel G, Clemens A: The iologicl relevnce of gstric neuroendocrine tumors. Yle J Biol Med 1996; 69: Ruszniewski P, Delle Fve G, Cdiot G, Komminoth P, Chung D, Kos-Kudl B, Kinmnesh R, Hochhuser D, Arnold R, Ahlmn H, Puwels S, Kwekkeoom DJ, Rindi G: Well-differentited gstric tumors/crcinoms. Neuroendocrinology 2006; 84: Bilimori KY, Bentrem DJ, Wyne JD, Ko CY, Bennett CL, Tlmonti MS: Smll owel cncer in the United Sttes: chnges in epidemiology, tretment, nd survivl over the lst 20 yers. Ann Surg 2009; 249: Sog J: Endocrinocrcinoms (crcinoids nd their vrints) of the duodenum. An evlution of 927 cses. J Exp Clin Cncer Res 2003; 22: Sog J: Erly-stge crcinoids of the gstrointestinl trct: n nlysis of 1914 reported cses. Cncer 2005; 103: Grrecht N, Anluf M, Schmitt A, et l: Somtosttinproducing neuroendocrine tumors of the duodenum nd pncres: incidence, types, iologicl ehvior, ssocition with inherited syndromes, nd functionl ctivity. Endocr Relt Cncer 2008; 15: Modlin I, Drozdov I, Gustfsson B, Öerg K, Kidd M: Rectl neuroendocrine tumors dignosis nd tretment; in Modlin I, Öerg K (eds): A Century of Advnces in Neuroendocrine Tumor Biology nd Tretment. Felsenstein, CCCP, 2007, pp Konishi T, Wtne T, Kishimoto J, Kotke K, Muto T, Ngw H: Prognosis nd risk fctors of metstsis in colorectl crcinoids: results of ntionwide registry over 15 yers. Gut 2007; 56: Konishi T, Wtne T, Muto T, Kotke K, Ngw H: Risk fctors for lymph node nd distnt metstsis in colorectl crcinoids: n nlysis of ntionwide registry in Jpn over 15 yers. J Clin Oncol 2006; 24: Konishi T, Wtne T, Ngw H, Oy M, Ueno M, Kuroyngi H, Fujimoto Y, Akiyoshi T, Ymguchi T, Muto T: Tretment of colorectl crcinoids: new prdigm. World J Gstrointest Surg 2010; 2: Anthony LB, Stroserg JR, Klimstr DS, Mples WJ, O Dorisio TM, Wrner RR, Wisemn GA, Benson AB, Pommier RF: The NANETS consensus guidelines for the dignosis nd mngement of gstrointestinl neuroendocrine tumors (NETs): well-differentited NETs of the distl colon nd rectum. Pncres 2010; 39: Rmge JK, Goretzki PE, Mnfredi R, Komminoth P, Ferone D, Hyrdel R, Kltss G, Kelestimur F, Kvols L, Scozec JY, Grci MI, Cplin ME: Consensus guidelines for the mngement of ptients with digestive neuroendocrine tumours: well-differentited colon nd rectum tumour/crcinom. Neuroendocrinology 2008; 87: de Mestier L, Brixi H, Gincul R, et l: Updting the mngement of ptients with rectl neuroendocrine tumors. Endoscopy 2013; 45: Plöckinger U, Couvelrd A, Flconi M, Sundin A, Slzr R, Christ E, de Herder WW, Gross D, Knpp WH, Knigge UP, Kulke MH, Ppe UF: Consensus guidelines for the mngement of ptients with digestive neuroendocrine tumours: well-differentited tumour/crcinom of the ppendix nd golet cell crcinom. Neuroendocrinology 2008; 87: Boudreux JP, Klimstr DS, Hssn MM, Woltering EA, Jensen RT, Goldsmith SJ, Nutting C, Bushnell DL, Cplin ME, Yo JC: The NANETS consensus guideline for the dignosis nd mngement of neuroendocrine tumors: well-differentited neuroendocrine tumors of the jejunum, ileum, ppendix, nd cecum. Pncres 2010; 39: Rindi G, Flconi M, Klersy C, et l: TNM stging of neoplsms of the endocrine pncres: results from lrge interntionl cohort study. J Ntl Cncer Inst 2012; 104: Lee L, Grnt C, Slomo D, et l: Smll, non-functioning, symptomtic pncretic neuroendocrine (PNETs): role of nonopertive mngement. Surgery 2012; 152: Nimptsch U, Krutz C, Weer G, Mnsky T, Grützmnn R: Ntionwide in-hospitl mortlity following pncretic surgery in Germny is higher thn nticipted. Ann Surgery 2016; 264: Reours V, Cordov J, Couvelrd A, Fre M, Plzzo L, Vullierme MP, Hentic O, Suvnet A, Auert A, Bedoss P, Ruszniewski P: Cn pncretic neuroendocrine tumour iopsy ccurtely determine pthologicl chrcteristics? Dig Liver Dis 2015; 47: ASGE Technology Committee; Hwng JH, Kond V, Au Dyyeh BK, Chuhn SS, Enestvedt BK, Fujii-Lu LL, Komnduri S, Mple JT, Murd FM, Pnnl R, Thosni NC, Bnerjee S: Endoscopic mucosl resection. Gstrointest Endosc 2015; 82: Pimentel-Nunes P, Dinis-Rieiro M, Ponchon T, et l: Endoscopic sumucosl dissection: Europen Society of Gstrointestinl Endoscopy (ESGE) Guideline. Endoscopy 2015; 47: Scherül H, Jensen RT, Cdiot G, Stölzel U, Klöppel G: Mngement of erly gstrointestinl neuroendocrine neoplsms. World J Gstrointest Endosc 2011; 16: Kim GH, Kim JI, Jeon SW, Moon JS, Chung IK, Jee SR, Kim HU, Seo GS, Bik GH: Endoscopic resection for duodenl crcinoid tumors: multicenter, retrospective study. J Gstroenterol Heptology 2014; 29: Yng DH, Prk Y, Prk SH, Kim KJ, Ye BD, Byeon JS, Myung SJ, Yng SK: Cp-ssisted endoscopic mucosl resection for rectl neuroendocrine tumors: comprisons with conventionl endoscopic mucosl resection nd endoscopic sumucosl dissection (with videos). Gstrointest Endosc 2016; 83: Gincul R, Ponchon T, Npoleon B, Scozec JY, Guillud O, Surin JC, Ciocirln M, Lepilliez V, Pioche M, Lefort C, Adhm M, Pilt J, Chyville JA, Wlter T: Endoscopic tretment of spordic smll duodenl nd mpullry neuroendocrine tumors. Endoscopy 2016; 48: Kwon YH, Jeon SW, Kim GH, Kim JI, Chung IK, Jee SR, Kim HU, Seo GS, Bik GH, Choi KD, Moon JS: Long-term follow up of endoscopic resection for type 3 gstric NET. World J Gstroenterol 2013; 19: Min BH, Kim ER, Lee JH, Kim KM, Min YW, Rhee PL, Kim JJ, Rhee JC: Mngement strtegy for smll duodenl crcinoid tumors: does conservtive mngement with close follow-up represent n lterntive to endoscopic tretment? Digestion 2013; 87: Scherül/Cdiot