Management of early gastrointestinal neuroendocrine neoplasms

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1 Online Submissions: doi: /wjge.v3.i7.133 World J Gstrointest Endosc 2011 July 16; 3(7): ISSN (online) 2011 Bishideng. All rights reserved. Mngement of erly gstrointestinl neuroendocrine neoplsms EDITORIAL Hns Scherübl, Robert T Jensen, Guillume Cdiot, Ulrich Stölzel, Günter Klöppel Hns Scherübl, Deprtments of Gstroenterology, Gstrointestinl Oncology nd Infectious Diseses, Vivntes Klinikum Am Urbn, Berlin 10967, Germny Robert T Jensen, Digestive Diseses Brnch, NIH, Bethesd, MD 20892, United Sttes Guillume Cdiot, Service d Hépto-Gstroentérologie, Hôpitl Robert Debré, Reims 51092, Frnce Ulrich Stölzel, Deprtments of Gstroenterology nd Gstrointestinl Oncology, Klinikum Chemnitz, Chemnitz 09116, Germny Günter Klöppel, Deprtment of Pthology, Technicl University München, Klinikum rechts der Isr, München 81675, Germny Author contributions: Scherübl H performed dt quisition, mnuscript conception nd writing; Jensen RT performed clinicl interprettion nd writing; Cdiot G performed clinicl interprettion nd writing; Stölzel U performed clinicl interprettion nd writing; Klöppel G performed clinicl interprettion, mnuscript conception nd writing. Correspondence to: Hns Scherübl, MD, Professor, Klinik für Innere Medizin - Gstroenterologie, Gstrointestinle Onkologie und Infektiologie, Vivntes-Klinikum Am Urbn, Akdemisches Lehrkrnkenhus der Chrité, Dieffenbchstrsse 1, Berlin 10967, Germny. hns.scheruebl@vivntes.de Telephone: Fx: Received: Jnury 15, 2011 Revised: My 4, 2011 Accepted: My 18, 2011 Published online: July 16, 2011 Abstrct Neuroendocrine neoplsms (NENs) of the stomch, duodenum, ppendix or rectum tht re smll ( 1 cm) nd well differentited cn be considered erly tumors, since they generlly hve (very) good prognosis. In the new WHO clssifiction of 2010, these neoplsms re clled neuroendocrine tumors/ crcinoids (NETs), grde (G) 1 or 2, nd distinguished from poorly differentited neuroendocrine crcinoms (NECs), G3. NETs re incresing, with rise in the ge-djusted incidence in the U.S.A. by bout 700 % in the lst 35 yers. Improved erly detection seems to be the min reson for these epidemiologicl chnges. Both the better generl vilbility of endoscopy, nd imging techniques, hve led to shift in the discovery of smller-sized ( mm) intestinl NETs/crcinoids nd erlier tumor stges t dignosis. Endoscopic screening is therefore effective in the erly dignosis, not only of colorectl denocrcinoms, but lso of NETs/crcinoids. Endoscopic removl, followed up with endoscopic surveillnce is the tretment of choice in NETs/crcinoids of the stomch, duodenum nd rectum tht re 10 mm in size, hve low prolifertive ctivity (G1), do not infiltrte the musculr lyer nd show no ngioinvsion. In ll the other intestinl NENs, optiml tretment generlly needs surgery nd/or medicl therpy depending on type, biology nd stge of the tumor, s well s the individul sitution of the ptient Bishideng. All rights reserved. Key words: Neuroendocrine tumor; Crcinoid; Stomch; Duodenum; Gut; Appendix; Rectum; Smll size; Prognosis; Tretment Peer reviewers: Vrut Lohsiriwt, MD, Deprtment of Surgery, Fculty of Medicine Sirirj Hospitl, Mhidol University, Bngkok 10700, Thilnd Scherübl H, Jensen RT, Cdiot G, Stölzel U, Klöppel G. Mngement of erly gstrointestinl neuroendocrine neoplsms. World J Gstrointest Endosc 2011; 3(7): Avilble from: URL: DOI: INTRODUCTION Gstrointestinl neuroendocrine neoplsms (NENs) hve received much ttention in recent yers with regrd to their dignosis, clssifiction, incidence, prognosis nd tretment [1-3]. The most recent chievement is the new WHO clssifiction, which ppered in the second hlf of July 16, 2011 Volume 3 Issue 7

2 Scherübl H et l. Mngement of erly gstrointestinl NENs Tble 1 Comprison of the WHO clssifiction 2010 for gstroenteropncretic neuroendocrine neoplsms with previous WHO clssifictions WHO 1980 WHO 2000 WHO 2010 Ⅰ Crcinoid WDET NET G1 (crcinoid) G2 WDEC PDEC MEEC NEC G3 Lrge cell or smll cell type MANEC Ⅱ Pseudotumour lesions TLL Hyperplstic nd preneoplstic lesions G: Grde (for definition, see text nd tble 2); In cse tht the Ki67 prolifertion rte exceeds 20%, this NET my be grded G3. WHO: World Helth Orgniztion; WDET: Well-differentited endocrine tumor; WDEC: Well-differentited endocrine crcinom; MEEC: Mixed exocrineendocrine crcinom; TLL: Tumour-like lesions; NET: Neuroendocrine tumor; NEC: Neuroendocrine crcinom; MANEC: Mixed denoneuroendocrine crcinom. Tble 2 Grding of gstrointestinl neuroendocrine neoplsms ccording to prolifertive ctivity Grde Ki-67 index (%) b G1 2 G G3 > 20 Modified ccording to reference [4,5,19] ; b MIB1 ntibody, % of 100 tumor cells in res of highest nucler lbeling. In essence, this clssifiction strtifies the pure gstroenteropncretic (GEP)-NENs into three groups (Tble 1): neuroendocrine tumors (NETs, equivlent to crcinoids) tht re well differentited nd grded ccording to their prolifertive ctivity into G1 or G2 (Tble 2), nd neuroendocrine crcinoms (NECs) tht re poorly differentited nd grded s G3. The poorly differentited NECs re divided into smll cell nd lrge cell neoplsms. Stging of tumor extension ccording to the vilble TNM clssifictions of ENETS [4,5] nd AJCC/UICC [6] leds to further strtifiction of NETs nd NECs. The neoplsms tht show non-endocrine components (usully denocrcinom structures) in ddition to considerble number of neuroendocrine cells (exceeding t lest 30% of ll tumor cells), re distinguished from the pure neuroendocrine neoplsms, nd clled mixed deno-neuroendocrine crcinoms (MANEC). Gstrointestinl NETs/crcinoids re on the rise [3]. In the U.S.A., the prevlence nd the incidence of gstrointestinl NETs/crcinoids hs recently been clculted to be 35/ nd 5/ , respectively [7], reveling 7-fold increse in the lst 35 yers. Similr observtions hve been reported from Englnd [8] nd Norwy [9]. The most obvious reson for this phenomenon is better wreness of, nd improved dignostic strtegies, for NENs, nd n incresed nd more widespred use of gstrointestinl endoscopy [8-15]. The overll 5-yer-survivl rte for ptients with gstrointestinl NETs/crcinoids hs improved by lmost 20% in the lst 35 yers [16-18]. This chievement is lrgely due to erly detection, s gstrointestinl NETs/crcinoids re nowdys more frequently dignosed t n erly symptomtic stge [7], notbly tumors with size below 10 mm nd G1 differentition. Due to lck of controlled prospective studies the mngement of these erly gstrointestinl NETs/crcinoids hs been mtter of debte. Here we review the retrospective dt from lrge ntionl registries nd lrge hospitl series, minly from Jpn, the U.S.A. nd Kore. RISK STRATIFICATION AND PROGNOSIS OF GASTROINTESTINAL NEN DISEASE The risk of metsttic disese of gstrointestinl NENs correltes with histologicl differentition (well or poorly differentited), prolifertive ctivity (G1-3, Tble 2), tumor size, depth of tumor infiltrtion nd ngioinvsion. The recently introduced nd generlly ccepted histologicl grding of gstrointestinl NENs (G1-G3) by the WHO is of mjor prognostic nd therpeutic relevnce (Tble 2). Prognosis of gstric NETs/crcinoids At present, the most common of the gstric NENs, the type 1 (Tble 3), is mostly dignosed t n erly stge, with 80%-90% of them being 1 cm in dimeter [13]. These smll tumors only rrely cuse specific symptoms; in most instnces they re found incidentlly during gstroscopy being performed for nother reson, such s nemi, reflux symptoms or other non-specific bdominl symptoms. Type 2 gstric NENs, similr to type 1 (Tble 3) re usully detected t n erly stge, nd thus hve n excellent long term prognosis. For ll gstric crcinoids the prognosis hs much improved [3,16,20-22], with the proportion with dvnced tumor stges t dignosis decresing from 23.8% in the 1950s nd 1960s to 6.5%-7.9% in the 1990s, suggesting tht erly dignosis is contributing to ptients improved survivl. In Jpn, the rte of dvnced stges t dignosis tody is s low s 5.1% [20]. The 5-yer-survivl rte of ptients with gstric NENs hs improved from 51% in the 1970s nd 1980s to 63% in the 1990s [3,20-22]. According to recent nlysis of the SEER dt by Lndry et l [21], the 5- yer-survivl is now up to 71%. Smll ( 1cm), well-differentited (G1) crcinoids/ NETs of the stomch tht do not infiltrte the musculris propri nd do not show ngioinvsion hve been shown to hve very low risk of distnt metsttic spred or crcinoid-relted deth; they re considered erly NETs/ crcinoids of the stomch. Prognosis of NETs/crcinoids of the smll bowel In the smll bowel, ilel NETs/crcinoids re most frequently found (> 70%), but recent dt show tht the NE- 134 July 16, 2011 Volume 3 Issue 7

3 Scherübl H et l. Mngement of erly gstrointestinl NENs Tble 3 Clinicopthologicl chrcteristics of gstric neuroendocrine neoplsms [4,23-26] Gstric NETs/crcinoids Gstric NECs (poorly differentited NENs) Type 1 Type 2 Type 3 Type 4 Reltive frequency 70%-80% 5%-6% 14%-25% 6%-8% Fetures Mostly smll (< 1-2 cm) nd multiple Mostly smll (< 1-2 cm) nd multiple Solitry often > 2 cm Solitry mostly exulcerted, > 2 cm Associted conditions CAG MEN1/ZES No No Histology Well differentited Well differentited Well/moderte differentited* Poorly differentited G1 G1 G2 G3 Serum gstrin (Very) high (Very) high Norml (Mostly) norml Gstric ph Ancidic Hypercidic Norml (Mostly) norml Metstses < 10% 10%-30% 50%-100% 80%-100% Tumor-relted deths no < 10% 25%-30% 50% NET: Neuroendocrine tumor; NEC: Neuroendocrine crcinom; CAG: Chronic trophic gstritis, due to pernicious nemi or Helicobcter pylori infection; MEN1: Multiple endocrine neoplsi type1; ZES: Zollinger-Ellison syndrome; MEN1/ZES: ZES ssocited with MEN1; G1-3 histologicl differentition: see Tble 2; ENETS nd NANETS nomenclture re identicl for G1 nd G3 grding: G1: Well differentited; G3: Poorly differentited. For G2 grding ENETS nd NANETS nomenclture differ: *ENETS-nomenclture: G2: Well-differentited; NANETS-nomenclture: G2: Moderte differentited (modified from Scherübl et l [13] ) Ts of the duodenum re nowdys more common (22%) thn previously noted [27]. Regrding prognosis, the 5-yer survivl rte hs risen from 51.9% in the 1970s nd 1980s to 60.5% in the 1990s [16]. In n nlysis of the yers , Strosberg et l reported 5-yer survivl rte of bout 75% in ptients with metsttic NET/crcinoid disese of the smll intestine, receiving multimodl therpy [17]. An erlier detection of ll NETs of the smll bowel my hve led to improved prognosis [15,18], since the proportion of dvnced disese of smll intestine NETs (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% in the yers between [7,16,20,27]. With duodenl NETs/crcinoids, distnt metstses re nowdys observed in less thn 6%- 10% of the cses [19,20,28,29,30]. If duodenl NETs/crcinoids re 10 mm in size, re G1, show neither ngioinvsion nor infiltrtion of the musculr lyer, nd hve no ssocited hormonl syndrome, they hve very low metsttic potentil nd cn be considered erly duodenl NETs/ crcinoids. In contrst, duodenl gstrinoms (i.e. duodenl NETs/crcinoids ssocited with Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplsi 1) s well s jejunl/ilel NETs/crcinoids of only few millimeters in size, my lredy hve spred to locoregionl lymph nodes nd/or distnt orgns such s the liver. Thus, neither for jejunl/ilel NETs/crcinoids nor for duodenl ZES/gstrinoms, is the term erly pproprite, nd should not be used. Tble 4 Impct of endoscopic screening on the size of detected rectl NENs/crcinoids [14] Size of the primry Without screening (%) Endoscopic screening (%) < 10 mm mm > 20 mm Prognosis of rectl NETs/crcinoids Becuse of the introduction of colorectl cncer screening, the vst mjority (85%-100%) of rectl NETs/crcinoids re nowdys detected t n erly stge (Tble 4). This hs improved ptients 5-yer-survivl rte by more thn 20% [14]. The 5-yer-survivl rte of rectl NETs/crcinoid ptients with distnt metstses rnges between 15%-30% [29,31,32]. For nodl-positive rectl crcinoid disese (without distnt metstses detected t the time of dignosis) the 5-yersurvivl rte is 54%-73% [31,32-34]. In contrst, histologiclly nodl-negtive rectl NETs/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 98.9%-100% [3,29,31,32]. These rectl NETs/ crcinoids my be regrded s erly tumors. The risk of lymph node metstses of rectl NETs/crcinoids is not lower thn the metsttic risk of rectl denocrcinom of the sme size [29,32,33]. Interestingly, neither is the prognosis of ptients with metsttic rectl NET/crcinoid disese better thn tht of ptients suffering from metststic rectl denocrcinom of the sme size [31-34]. The clinicl significnce of histologicl lymph node involvement in G1-G2 differentited rectl NETs/crcinoids of 1-2 cm in size is not well studied nd therefore not known, t lest not in Western countries. Current guidelines published by NANETS do not recommend follow-up of ptients with well-differentited rectl crcinoids/nets of 1-2 cm in size tht hve been completely resected nd tht hd not invded the musculr lyer [35]. Yet ENETS recommends further surveillnce of these ptients when ngioinvsion or invsion of the musculr lyer or G2 grding hve been reported [36]. DIAGNOSIS OF EARLY NETS/ CARCINOIDS OF THE STOMACH, DUODENUM OR RECTUM Endoscopic screening nd the incresingly widespred 135 July 16, 2011 Volume 3 Issue 7

4 Scherübl H et l. Mngement of erly gstrointestinl NENs A C1 B C2 Figure 1 Endoscopic imges of erly gstrointestinl NETs/crcinoids. A: Multiple smll (< 1 cm), well differentited (G1) type 2 gstric NETs/crcinoids ssocited with Zollinger-Ellison-syndrome (ZES) nd multiple endocrine neoplsi type 1 (MEN1); B: Multiple smll (< 1 cm), well differentited (G1) type 1 gstric NETs/crcinoids ssocited with utoimmune chronic trophic gstritis nd pernicious nemi; C: 8 mm mesuring NET/crcinoid in the duodenl bulb (C1). Endoscopic ultrsound shows the infiltrtion of mucos nd submucos (C2). The duodenl NET/crcinoid exhibits low echogenic pttern on EUS; D: 10 mm mesuring NET/crcinoid of the rectum (D1). 7 mm mesuring NET/crcinoid of the rectum (D2). Modified from reference [13-15]. NETs: neuroendocrine tumors; EUS: Endoscopic ultrsound. D1 D2 vilbility of gstrointestinl endoscopy hve led to shift in the discovery of smller-sized ( mm) gstrointestinl crcinoids/nets t the time of dignosis. Most of these tumors re symptomtic, but occsionlly they my present with bdominl discomfort, gstrointestinl bleeding, ltered bowel hbits or in the cse of n mpullry NET with jundice. If they present with hormonl hypersecretion syndromes, s for instnce s duodenl gstrinoms ssocited with ZES (see bove), they hve often lredy spred to the regionl lymph nodes, despite their smll size. These functionl intestinl NETs tht lmost never represent erly tumors, will not be discussed here in detil (see recent reviews). Endoscopy is the only method of choice to detect (symptomtic) gstric, duodenl or rectl NETs/crcinoids t n erly stge. So fr there re no dt vilble concerning the sensitivity nd specificity of rdiologicl nd scintigrphic imging techniques to visulize erly gstric, duodenl or rectl NETs/crcinoids (Figure 1). THERAPY OF EARLY GASTROINTESTINAL NETS/CARCINOIDS For erly NETs/crcinoids of the stomch, duodenum or rectum, the tretment of choice is endoscopic resection. For the tretment nd mngement of more dvnced NETs/crcinoids, ll the prognosticlly relevnt prmeters (see below) hve to be tken into ccount. Best pllitive therpy is required for fr dvnced tumor disese. Stomch, duodenum nd rectum Smll ( 1 cm), well-differentited (G1) NETs/crcinoids of the stomch, duodenum or rectum tht do not infiltrte the musculris propri nd do not show ngio-invsion hve very low risk of metsttic spred, i.e. they re considered erly NETs/crcinoids of the stomch, duodenum or rectum. Endoscopic ultrsound is excellent for determining exct tumor size nd to exclude infiltrtion of the NETs/crcinoids into the musculr wll (musculris 136 July 16, 2011 Volume 3 Issue 7

5 Tble 5 Therpy of gstric NENs Tble 7 Therpy of rectl NENs No risk fctors (for metsttic disese) risk fctors No risk fctors (for metsttic disese) Risk fctors Size 1 cm 1-2 cm Type 1 Surveillnce b EMR followed by surveillnce Surgery c optionlly EMR Type 2 Surveillnce b EMR followed by surveillnce Surgery c Type 3 EMR Surgery c Surgery c Type Surgery d risk fctors for metsttic disese re ngioinvsion or G2-G3 histologicl grding or infiltrtion of the musculris propri or tumor size > 2cm; b somtosttin nlogs re being tested in ongoing clinicl trils, they should not be used except in clinicl trils; c followed by endoscopic surveillnce of the gstric remnnt. Adjuvnt (medicl) therpy is not estblished in NET/crcinoid disese; d surgery in loclized type 4 gstric/ d NEC disese (or systemic cytoreductive chemotherpy in dvnced type 4 gstric NEC disese). Type 4 gstric NECs re never benign, they re neuroendocrine crcinoms. EMR: Endoscopic mucosl resection; NENs: Neuroendocrine neoplsms. Grde/Size 1.0 cm cm Any size G1 EMR or polypectomy or ESD Surgery b (EMR or ESD in cse of surgicl risk or for crcinoids of mm in dimeter) Surgery b G2 EMR, ESD, surgery b Surgery b Surgery b G3 - - Surgery b risk fctors for metsttic disese re ngioinvsion or infiltrtion of the musculris propri, or tumor size of > 2cm; b surgery only in loclized NET/ NEC disese nd systemic medicl therpy in dvnced tumor/cncer disese. Adjuvnt medicl therpy is not estblished for curtively resected, well-differentited NETs/crcinoids of the rectum. G3 neuroendocrine neoplsms of the rectum re lwys neuroendocrine crcinoms. EMR: Endoscopic mucosl resection; ESD: endoscopic submucosl dissection; NENs: Neuroendocrine neoplsms. Tble 6 Therpy of duodenl NENs Type 1 cm 1-2 cm Any size but risk fctors b Spordic NET (no gstrinom, no MEN1 ) Spordic gstrinom Gstrinom nd MEN1 EMR Surgery (in cse of surgicl risk: EMR followed by surveillnce) Surgery Surgery c Surgery c Surgery c PPI therpy nd surveillnce (or surgery) Surgery (prticulrly if the gstrinom is growing) or PPI therpy combined with surveillnce Surgery (or PPI therpy combined with surveillnce in G1 gstrinoms nd/or surgicl risk) NEC (G3) - - Surgery or cytoreductive chemotherpy without risk fctors (for metsttic disese) such s G2-G3, ngioinvsion, infiltrtion of the musculris propri or tumor size > 2 cm; b in the presence of risk fctors for metsttic disese, surgery is generlly indicted, regrdless of tumor size; c Surgery is the therpy of choice for spordic gstrinom (without distnt metstses). In (very) elderly ptients conservtive mngement my, however, be preferred to surgery. Adjuvnt (medicl) therpy is not estblished in NET/crcinoid disese. NET: Well differentited neuroendocrine tumor; EMR: Endoscopic mucosl resection; PPI: Proton pump inhibitor; MEN1: Multiple endocrine neoplsi type 1. propri). Endoscopic ultrsound is not mndtory for NE- Ts/crcinoids mesuring less thn 1 cm, becuse those do generlly not infiltrte the musculr lyer. Erly, G1-differentited NETs/crcinoids of the stomch, duodenum or rectum should be removed by endoscopic polypectomy or by endoscopic mucosl resection (EMR). In erly rectl NETs/crcinoids endoscopic submucosl dissection (ES- D) my be considered, too. The resected specimen hs to be crefully evluted for grde, ngioinvsion, nd infiltrtion of the deep resection mrgin. In cse of ngioinvsion, histologicl infiltrtion of the musculr wll or grde G2/G3, surgery is the first line therpy. The mngement of G1 NETs/crcinoids of 1-2 cm in size is mtter of debte [16-18]. Unfortuntely, there re no controlled prospective studies vilble tht hve compred the endoscopic to the surgicl pproch for these 1-2 cm sized crcinoids/nets. Due to the prticulr tumor biology of G1 NETs/crcinoids (of 1-2 cm in size) the endoscopic pproch should be preferred to surgery in ptients with significnt comorbidities nd, in elderly ptients, (high) surgicl risk. No djuvnt therpy hs been estblished for curtively resected, G1-G2 gstrointestinl NETs/crcinoids. Anlogous to the sitution of smll cell or lrge cell neuroendocrine cncer disese of the lungs, cytoreductive chemotherpy is generlly recommended for gstrointestinl NECs (G3 neuroendocrine crcinoms). G3 NE- Ns re never erly nd lmost lwys metsttic t dignosis. The specific therpeutic strtegies for erly NETs/ crcinoids of the rectum, duodenum nd stomch re outlined in Tble 5-7. APPENDIX Appendicel NENs re usully NETs/crcinoids tht re found incidentlly in (young) ptients undergoing ppendectomy for suspected cute ppendicitis. The term erly ppendicel NET/crcinoid my be considered for the tumors tht re G1, mesure 10 mm, show no ngioinvsion, re confined both to the tip of the ppendix nd to the wll (without invsion of the mesoppendix) nd hve been completely (R0) removed. 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 tumors [38,39]. The mngement of other ppendicel crci- 137 July 16, 2011 Volume 3 Issue 7

6 noids/nets is not discussed here; we refer to recent review nd guideline ppers [38,39]. CONCLUSION New dignostic techniques hve led to incresingly erly recognition of erly gstrointestinl NETs/crcinoids. The generl widespred use nd vilbility of gstrointestinl endoscopy hs led to shift in the discovery of smllersized ( mm) gstrointestinl NETs/crcinoids t the time of dignosis. In the lst 35 yers, the overll 5-yersurvivl rte of ptients with gstrointestinl crcinoid/ NEN disese hs incresed by lmost 20%. Most ptients with erly, well differentited (G1) NETs/crcinoids of the stomch, duodenum nd rectum cn be treted conservtively, nd be followed-up by endoscopic surveillnce. It should be noted tht ptients with (previous) NET/crcinoid disese hve 15%-25% risk for second mlignncies including brest, prostte, colorectl or gstric cncer. REFERENCES 1 Klöppel G, Rindi G, Anluf M, Perren A, Komminoth P. Sitespecific biology nd pthology of gstroenteropncretic neuroendocrine tumors. 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7 TJ, Rinke A, Arnold R, Berndt U, Plöckinger U, Wiedenmnn B, Moch H, Heitz PU, Komminoth P, Perren A, Klöppel G. Somtosttin-producing neuroendocrine tumors of the duodenum nd pncres: incidence, types, biologicl behvior, ssocition with inherited syndromes, nd functionl ctivity. Endocr Relt Cncer 2008; 15: Modlin I, Drozdov I, Gustfsson B, Öberg K, Kidd M. Rectl neuroendocrine tumors - Dignosis nd tretment. In: Modlin I, Öberg K, eds. A century of dvnces in neuroendocrine tumor biology nd tretment. Germny: Felsenstein CCCP; p Konishi T, Wtnbe 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, Wtnbe T, Muto T, Kotke K, Ngw H. Risk fctors for lymph node nd distnt metstsis in colorectl crcinoids: An nlysis of ntionwide registry in Jpn over 15 yers. J Clin Oncol 2006; 24: Konishi T, Wtnbe T, Ngw H, Oy M, Ueno M, Kuroyngi H, Fujimoto Y, Akiyoshi T, Ymguchi T, Muto T. Tretment of colorectl crcinoids: A new prdigm. World J Gstrointest Surg 2010; 2: Anthony LB, Strosberg JR, Klimstr DS, Mples WJ, O Dorisio TM, Wrner RR, Wisemn GA, Benson AB, Pommier RF. The NANETS consensus guidelines for the dignosis nd mn- gement 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: Prk CH, Cheon JH, Kim JO, Shin JE, Jng BI, Shin SJ, Jeen YT, Lee SH, Ji JS, Hn DS, Jung SA, Prk DI, Bek IH, Kim SH, Chng DK. Criteri for decision mking fter endoscopic resection of well-differentited rectl crcinoids with regrd to potentil lymphtic spred. Endoscopy 2011 Epub hed of print 38 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 goblet 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, Appendix, nd Cecum. Pncres 2010; 39: S- Editor Zhng HN L- Editor Herholdt A E- Editor Zhng L 139 July 16, 2011 Volume 3 Issue 7