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1 Protocol for the Exmintion of Specimens From Ptients With Neuroendocrine Tumors (Crcinoid Tumors) of the Stomch Mry Ky Wshington, MD, PhD; Lur H. Tng, MD, PhD; Jordn Berlin, MD; Philip A. Brnton, MD; Lwrence J. Burgrt, MD; Dvid K. Crter, MD; Crolyn C. Compton, MD, PhD; Ptrick L. Fitzgibbons, MD; Wendy L. Frnkel, MD; J. Milburn Jessup, MD; Snjy Kkr, MD; Bruce Minsky, MD; Rouf E. Nkhleh, MD; for the Members of the Cncer Committee, College of Americn Pthologists Accepted for publiction October 8, From the Deprtments of Pthology (Dr Wshington) nd Medicine (Dr Berlin), Vnderbilt University Medicl Center, Nshville, Tennessee; the Deprtment of Pthology, Memoril Slon-Kettering Cncer Center, New York, New York (Dr Tng); the Deprtment of Pthology, Inov Firfx Hospitl, Flls Church, Virgini (Dr Brnton); Allin Lbortories, Abbott Northwestern Hospitl, Minnepolis, Minnesot (Dr Burgrt); Deprtment of Pthology, St Mry s/duluth Clinic Helth System, Duluth, Minnesot (Dr Crter); the Office of Biorepositories nd Biospecimen Reserch (Dr Compton) nd the Division of Cncer Tretment nd Dignosis (Dr Jessup), Ntionl Cncer Institute, Bethesd, Mrylnd; the Deprtment of Pthology, St Jude Medicl Center, Fullerton, Cliforni (Dr Fitzgibbons); the Deprtment of Pthology, Ohio Stte University Medicl Center, Columbus, Ohio (Dr Frnkel); the Deprtment of Pthology, University of Cliforni Sn Frncisco nd the Veterns Affirs Medicl Center, Sn Frncisco, Cliforni (Dr Kkr); the Deprtment of Rdition Oncology, University of Chicgo, Chicgo, Illinois (Dr Minsky); nd the Deprtment of Pthology, Myo Clinic, Jcksonville, Florid (Dr Nkhleh). The uthors hve no relevnt finncil interest in the products or compnies described in this rticle. Reprints: Mry Ky Wshington, MD, PhD, Deprtment of Pthology, C-3316 MCN, Vnderbilt University Medicl Center, Nshville, TN (e-mil: The College of Americn Pthologists offers these protocols to ssist pthologists in providing cliniclly useful nd relevnt informtion when reporting results of surgicl specimen exmintions. The College regrds the reporting elements in the Surgicl Pthology Cncer Cse Summry (Checklist) portion of the protocols s essentil elements of the pthology report. However, the mnner in which these elements re reported is t the discretion of ech specific pthologist, tking into ccount clinicin preferences, institutionl policies, nd individul prctice. The College developed these protocols s n eductionl tool to ssist pthologists in the useful reporting of relevnt informtion. It did not issue the protocols for use in litigtion, reimbursement, or other contexts. Nevertheless, the College recognizes tht the protocols might be used by hospitls, ttorneys, pyers, nd others. Indeed, effective Jnury 1, 2004, the Commission on Cncer of the Americn College of Surgeons mndted the use of the checklist elements of the protocols s prt of its Cncer Progrm Stndrds for Approved Cncer Progrms. Therefore, it becomes even more importnt for pthologists to fmilirize themselves with these documents. At the sme time, the College cutions tht use of the protocols other thn for their intended eductionl purpose my involve dditionl considertions tht re beyond the scope of these documents. PROTOCOL FOR THE EXAMINATION OF SPECIMENS FROM PATIENTS WITH NEUROENDOCRINE TUMORS (CARCINOID TUMORS) OF THE STOMACH This protocol pplies to well-differentited neuroendocrine tumors of the stomch. Crcinoms with mixed endocrine/glndulr differentition, poorly differentited crcinoms with neuroendocrine fetures, nd smll cell crcinoms re not included. The 7th edition TNM stging system for neuroendocrine tumors of the stomch of the Americn Joint Committee on Cncer (AJCC) nd the Interntionl Union Aginst Cncer (UICC) is recommended. SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST) Stomch: Endoscopic Resection, Gstrectomy (note A) Select Single Response Unless Otherwise Indicted * Dt elements with sterisks re not required. However, these elements my be cliniclly importnt but re not yet vlidted or regulrly used in ptient mngement. Specimen (select ll tht pply) Stomch Portion of stomch Gstric body Gstric ntrum Distl esophgus Proximl duodenum Procedure Endoscopic resection Prtil gstrectomy, proximl Prtil gstrectomy, distl Prtil gstrectomy, other (specify): Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Stomch Wshington et l 187

2 Totl gstrectomy *Specimen Size (if pplicble) *Specify: (length) 3 3 cm Tumor Site (select ll tht pply) (note B) Gstric crdi Gstric fundus Gstric body Gstric ntrum Tumor Size (note C) Gretest dimension: cm (specify size of lrgest tumor if multiple tumors re present) *Additionl dimensions: 3 cm Cnnot be determined (see Comment) Tumor Foclity Unifocl Multifocl (specify number of tumors: ) Cnnot be determined Histologic Type (note D) Crcinoid tumor *Alterntive Histologic Clssifiction (note E) * Well-differentited endocrine tumor, benign behvior * Well-differentited endocrine tumor, uncertin behvior * Well-differentited endocrine crcinom *Histologic Grde (note E) * Not pplicble * GX: Cnnot be ssessed * G1: Low grde * G2: Intermedite grde For poorly differentited (high-grde) neuroendocrine crcinoms, the College of Americn Pthologists (CAP) checklist for crcinom of the stomch 1 should be used. Mitotic Rte (note E) Specify: /10 high-power fields (HPFs) Cnnot be determined Microscopic Tumor Extension No evidence of primry tumor Tumor invdes lmin propri Tumor invdes into but not through musculris mucose Tumor invdes submucos Tumor invdes musculris propri Tumor invdes subserosl tissue without involvement of viscerl peritoneum Tumor penetrtes seros (viscerl peritoneum) Tumor directly invdes djcent structures (specify: ) Tumor penetrtes to the surfce of the viscerl peritoneum (seros) nd directly invdes djcent structures (specify: ) Mrgins (select ll tht pply) Proximl Mrgin Distl Mrgin Omentl (Rdil) Mrgin (note F) Other Mrgin(s) (specify): Not pplicble If ll mrgins uninvolved by neuroendocrine tumor: Distnce of tumor from closest mrgin: mm or cm Specify mrgin: Lymph-Vsculr Invsion Not identified Present Indeterminte *Perineurl Invsion * Not identified * Present * Indeterminte Pthologic Stging (ptnm) (note G) TNM Descriptors (required only if pplicble) (select ll tht pply) m (multiple primry tumors) r (recurrent) y (posttretment) Primry Tumor (pt) ptx: Primry tumor cnnot be ssessed pt0: No evidence of primry tumor ptis: Crcinom in situ/ (tumor size less thn 0.5 mm), confined to mucos pt1: Tumor invdes lmin propri or submucos nd 1 cm or less in size pt2: Tumor invdes musculris propri or more thn 1 cm in size pt3: Tumor penetrtes subseros pt4: Tumor invdes viscerl peritoneum (serosl) or other orgns or djcent structures Regionl Lymph Nodes (pn) pn0: No regionl lymph node metstsis pn1: Metstsis in regionl lymph nodes 188 Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Stomch Wshington et l

3 Tble 1. Site of Origin of Gstrointestinl Neuroendocrine Tumors Foregut Tumors Midgut Tumors Hindgut Tumors Site Stomch, proximl duodenum Jejunum, ileum, ppendix, proximl colon Distl colon, rectum Immunohistochemistry, % + Chromogrnin A NSE Synptophysin Serotonin 33 11, , ,12 Other immunohistochemicl mrkers Rrely, + for pncretic polypeptide, histmine, gstrin, somtosttin, VIP, or ACTH Prosttic cid phosphtse + Prosttic cid phosphtse + in 20% 40% of cses 11,12 in 20% 82% of cses 3 5,12 Crcinoid syndrome, % Rre ,7 Rre Abbrevitions: ACTH, drenocorticotropic hormone; NSE, neuron-specific enolse; VIP, vsoctive intestinl peptide; +, positive. Specify: Number exmined: Number involved: Distnt Metstsis (pm) Not pplicble pm1: Distnt metstsis *Specify site(s), if known: *Ancillry Studies (select ll tht pply) (notes E nd H) * Ki-67 index * #2% *.2% to 20% *.20% * Not performed Additionl Pthologic Findings (select ll tht pply) (note I) * Atrophic gstritis * Intestinl metplsi of gstric mucos * Glndulr of gstric mucos * Endocrine cell hyperplsi * Absence of prietl cells * Tumor necrosis *Comment(s): EXPLANATORY NOTES A: Appliction nd Tumor Loction. This protocol pplies to well-differentited neuroendocrine neoplsms (crcinoid tumors) of the stomch. Poorly differentited neuroendocrine crcinoms, smll cell crcinoms, nd tumors with mixed glndulr/neuroendocrine differentition re not included. Becuse of site-specific similrities in histology, immunohistochemistry, nd histochemistry, neuroendocrine tumors of the digestive trct hve trditionlly been subdivided into those of foregut, midgut, nd hindgut origin (Tble 1). In generl, the distribution pttern long the gstrointestinl trct prllels tht of the progenitor cell type, nd the ntomic site of origin of gstrointestinl neuroendocrine tumors is n importnt predictor of clinicl behvior. 2 B: Site-Specific Fetures. Gstric neuroendocrine tumors re divided into 4 types. 3 Type 1 tumors rising in the setting of trophic gstritis with ssocited hypergstrinemi re the most common. These lesions re composed of enterochromffin-like cells nd re usully found s multiple smll nodules in the body of the stomch nd limited to mucos nd submucos. Type 1 lesions re generlly benign nd my regress following ntrectomy; lymph node metstses re very rre nd occur only when the tumors re lrge (greter thn 2 cm) nd infiltrte the musculris propri. Type 2 gstric neuroendocrine tumors re rre. These multifocl smll tumors, which re ssocited with multiple endocrine neoplsi type 1 with Zollinger-Ellison syndrome, develop in the body of the stomch, re usully smller thn 1.5 cm, nd re confined to the mucos or submucos. However, in contrst to type 1 tumors, 30% metstsize. Tumors greter thn 2 cm nd invding the musculris propri nd exhibiting vsculr invsion re more likely to metstsize. Type 3 gstric neuroendocrine tumors, the second most common neuroendocrine tumor in the stomch, re spordic solitry tumors tht re unssocited with trophic gstritis or endocrine cell hyperplsi. These tumors my occur nywhere in the stomch. Metstsis is ssocited with lrger men size, ngioinvsion, nd invsion of musculris propri. Surgicl resection is usully dvised for solitry gstric crcinoid tumors, prticulrly those lrger thn 2.0 cm, but tumors smller thn 1.0 cm hve been rrely reported to metstsize. 4 Type 4 gstric neuroendocrine tumors re rre, highgrde neuroendocrine crcinoms tht re usully bulky tumors with metstses t dignosis (the CAP cncer checklist for gstric crcinom 1 pplies). C: Tumor Size. For neuroendocrine tumors in ny prt of the gstrointestinl trct, size greter thn 2.0 cm is ssocited with higher risk of lymph node metstsis. In the stomch, types 3 nd 4 neuroendocrine tumors re significntly lrger thn type 1 tumors, 3 which usully mesure 1 cm or less 5,6 (Tble 2). Tumor size correltes with depth of invsion for gstric neuroendocrine tumors, with lrger tumors more likely to be deeply infiltrtive nd thus t higher risk for metstses. Nodules mesuring 0.5 mm or lrger re defined s neuroendocrine tumors; lesions mesuring less thn 0.5 mm re regrded s representing in situ tumor, neuroendocrine cell, or hyperplsi. D: Histologic Type. The World Helth Orgniztion (WHO) clssifies neuroendocrine neoplsms s well- Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Stomch Wshington et l 189

4 Tble 2. Types of Gstric Neuroendocrine Tumors Type 1 Type 2 Type 3 Type 4 Frequency 70% 80% of cses Rre 10% 15% of cses Rre Multiplicity Multifocl Multifocl Solitry Solitry Size cm,1.5 cm or less Vrible; one-third re lrger Lrge thn 2 cm Loction Corpus Corpus Anywhere in stomch Anywhere in stomch Associtions Hypergstrinemic sttes; chronic trophic gstritis, ECL cell hyperplsi, pernicious nemi MEN type 1, with hypergstrinemi or Zollinger-Ellison syndrome Spordic Spordic Clinicl behvior Demogrphic profile Usully benign 30% metstsize 71% of tumors.2 cm with musculris propri nd vsculr invsion hve lymph node metstses 70% 80% re women in their 50s nd 60s Eqully in mles nd femles; men ge, 50 y Abbrevitions: ECL, enterochromffin-like; MEN, multiple endocrine neoplsi. More common in mles; men ge, 55 y High-grde crcinom; metstses common; poor prognosis More common in mles differentited neuroendocrine tumors, well-differentited neuroendocrine crcinoms, nd poorly differentited neuroendocrine crcinoms. 5 8 Historiclly, well-differentited neuroendocrine neoplsms hve been referred to s crcinoid tumors, term which my cuse confusion becuse cliniclly crcinoid tumor is serotoninproducing tumor ssocited with functionl mnifesttions of crcinoid syndrome. Clssifiction of neuroendocrine tumors is bsed upon size, functionlity, site, nd invsion. Functioning tumors re those ssocited with clinicl mnifesttions of hormone production or secretion of mesurble mounts of ctive hormone; immunohistochemicl demonstrtion of hormone production is not equivlent to cliniclly pprent functionlity. Alterntive Clssifiction for Neuroendocrine Tumors of the Stomch, Adpted From WHO Well-Differentited Neuroendocrine Tumor Benign. Nonfunctioning cytologiclly blnd tumors confined to mucos or submucos, without ngiovsculr invsion, nd mesuring not more thn 1 cm in gretest dimension. Nodules of neuroendocrine cells tht mesure between 0.5 nd 1 cm nd re confined to the mucos re clssified by some s microneuroendocrine tumors. Uncertin Mlignnt Potentil. Nonfunctioning, cytologiclly blnd tumors confined to mucos or submucos, with or without ngioinvsion nd mesuring from 1 to 2 cm. Well-Differentited Neuroendocrine Crcinom Low-Grde Mlignnt Potentil. Nonfunctioning tumors tht invde the musculris propri or beyond, or re metsttic, or mesure greter thn 2 cm; ll spordic gstric neuroendocrine tumors (type 3 tumors) nd some type 1 nd 2 tumors. All functioning tumors of ny type, including gstrinoms. Histologic Ptterns Although specific histologic ptterns in well-differentited neuroendocrine neoplsms, such s trbeculr, insulr, nd glndulr, roughly correlte with tumor loction, these ptterns hve not been clerly shown independently to predict response to therpy or risk of nodl metstsis nd re rrely reported in clinicl prctice. E: Histologic Grde. Cytologic typi in low-grde neuroendocrine tumors hs no impct on clinicl behvior of these tumors. However, grding systems bsed on mitotic ctivity hve been shown to hve utility for foregut tumors. The following grding system is recommended 9 : Grde Mitotic Count (per 10 HPFs) Ki-67 Index, % b G1,2 #2 G2 2 to 20.2 to20 G Mitotic count should be bsed upon counting 50 high-power (340 objective) fields in the re of highest mitotic ctivity nd reported s number of mitoses per 10 HPFs. b Ki-67 index is reported s percentge of positive tumor cells in re of highest nucler lbeling. It hs been recommended tht 2000 tumor cells be counted to determine the Ki-67 index 9 ; however, this prctice my not be prcticl for routine clinicl purposes, nd it is cceptble to estimte the lbeling index. G1 nd G2 re well-differentited tumors with diffuse intense chromogrnin/synptophysin positivity. Punctte necrosis is more typicl of G2 tumors. G3 tumors re highgrde neuroendocrine crcinoms (the CAP crcinom checklist for crcinoms of the stomch 1 pplies). F: Circumferentil (Rdil) Mrgin. For surgicl resection specimens, mrgins include the proximl, distl, nd rdil mrgins. The rdil mrgins represent the nonperitonelized soft-tissue mrgins closest to the deepest penetrtion of tumor. In the stomch, the lesser omentl (heptoduodenl nd heptogstric ligments) nd greter omentl resection mrgins re the only rdil mrgins. For endoscopic resection specimens, mrgins include mucosl mrgins nd the deep mrgin of resection. It my be helpful to mrk the mrgin(s) closest to the tumor with ink. Mrgins mrked by ink should be designted in the mcroscopic description. G: TNM nd Antomic Stge/Prognostic Groupings. The TNM stging system for gstric neuroendocrine tumors of the AJCC nd the UICC is recommended Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Stomch Wshington et l

5 By AJCC/UICC convention, the designtion T refers to primry tumor tht hs not been previously treted. The symbol p refers to the pthologic clssifiction of the TNM, s opposed to the clinicl clssifiction, nd is bsed on gross nd microscopic exmintion. pt entils resection of the primry tumor or biopsy dequte to evlute the highest pt ctegory, pn entils removl of nodes dequte to vlidte lymph node metstsis, nd pm implies microscopic exmintion of distnt lesions. Clinicl clssifiction (ctnm) is usully crried out by the referring physicin before tretment during initil evlution of the ptient or when pthologic clssifiction is not possible. Pthologic stging is usully performed fter surgicl resection of the primry tumor. Pthologic stging depends on pthologic documenttion of the ntomic extent of disese, whether or not the primry tumor hs been completely removed. If biopsied tumor is not resected for ny reson (eg, when techniclly unfesible) nd if the highest T nd N ctegories or the M1 ctegory of the tumor cn be confirmed microscopiclly, the criteri for pthologic clssifiction nd stging hve been stisfied without totl removl of the primry cncer. TNM Descriptors For identifiction of specil cses of TNM or ptnm clssifictions, the m suffix nd y, r, nd prefixes re used. Although they do not ffect the stge grouping, they indicte cses needing seprte nlysis. The m suffix indictes the presence of multiple primry tumors in single site nd is recorded in prentheses: pt(m)nm. The y prefix indictes those cses in which clssifiction is performed during or fter initil multimodlity therpy (ie, neodjuvnt chemotherpy, rdition therpy, or both chemotherpy nd rdition therpy). The ctnm or ptnm ctegory is identified by y prefix. The yctnm or yptnm ctegorizes the extent of tumor ctully present t the time of tht exmintion. The y ctegoriztion is not n estimte of tumor before multimodlity therpy (ie, before initition of neodjuvnt therpy). The r prefix indictes recurrent tumor when stged fter documented disese-free intervl nd is identified by the r prefix: rtnm. The prefix designtes the stge determined t utopsy: TNM. N Ctegory Considertions The specific nodl res of the stomch re listed below Greter curvture of stomch: greter curvture, greter omentl, gstroduodenl, gstroepiploic, pyloric, nd pncreticoduodenl 2. Pncretic nd splenic re: pncreticolienl, peripncretic, splenic 3. Lesser curvture of stomch: lesser curvture, lesser omentl, left gstric, crdioesophgel, common heptic, celic, nd heptoduodenl Involvement of other intr-bdominl lymph nodes, such s heptoduodenl, retropncretic, mesenteric, nd pr-ortic, is clssified s distnt metstsis. 10 TNM Antomic Stge/Prognostic Groupings Stge 0 Tis N0 M0 Stge I T1 N0 M0 Stge IIA T2 N0 M0 Stge IIB T3 N0 M0 Stge IIIA T4 N0 M0 Stge IIIB Any T N1 M0 Stge IV Any T Any N M1 M0 is defined s no distnt metstsis. H: Ancillry Studies. Immunohistochemistry nd other ncillry techniques re generlly not required to dignose well-differentited neuroendocrine tumors. Specific mrkers tht my be used to estblish neuroendocrine differentition include chromogrnin A, neuron-specific enolse, synptophysin, nd CD56. 6 Becuse of their reltive sensitivity nd specificity, chromogrnin A nd synptophysin re recommended. Immunohistochemistry for Ki-67 my be useful in estblishing tumor grde (note E) nd prognosis 8 but is not currently considered stndrd of cre. 6 Immunohistochemistry for specific hormone products, such s glucgon, gstrin, nd somtosttin, my be of interest in some cses. However, immunohistochemicl demonstrtion of hormone production does not equte with clinicl functionlity of the tumor. I: Additionl Pthologic Findings. Most gstric neuroendocrine tumors rise in the setting of chronic trophic gstritis (see note B). Atrophic gstritis my be ssocited with glndulr, nd in rre cses, gstric denocrcinom. Cogultive tumor necrosis, usully punctte, my indicte more ggressive behvior 9 nd should be reported. References 1. Wshington K, Berlin J, Brnton P, et l. Protocol for the exmintion of specimens from ptients with crcinom of the stomch. In: Reporting on Cncer Specimens: Cse Summries nd Bckground Documenttion. Northfield, IL: College of Americn Pthologists; Rorstd O. Prognostic indictors for crcinoid neuroendocrine tumors of the gstrointestinl trct. J Surg Oncol. 2005;89(3): Borch K, Ahren B, Ahlmn H, Flkmer S, Grnerus G, Grimelius L. Gstric crcinoids: biologic behvior nd prognosis fter differentited tretment in reltion to type. Ann Surg. 2005;242(1): Xie SD, Wng LB, Song XY, Pn T. Minute gstric crcinoid with regionl lymph node metstsis: cse report nd review of the literture. World J Gstroenterol. 2004;10(16): Greme-Cook F. Neuroendocrine tumors of the GI trct nd ppendix. In: Odze RD, Goldblum JR, Crwford JM, eds. Surgicl Pthology of the GI Trct, Liver, Biliry Trct, nd Pncres. Phildelphi, PA: WB Sunders; 2004: Willims GT. Endocrine tumours of the gstrointestinl trct: selected topics. Histopthology. 2007;50(1): Klöppel G, Perren A, Heitz PU. The gstroenteropncretic neuroendocrine cell system nd its tumors: the WHO clssifiction. Ann N Y Acd Sci. 2004; 1014: Solci E, Klöppel G, Sobin LH, et l. Histologicl typing of endocrine tumours. In: Solci E, Klöppel G, Sobin LH, eds. World Helth Orgniztion Interntionl Histologicl Clssifiction of Tumours. 2nd ed. New York, NY: Springer; Rindi G, Klöppel G, Alhmn H, et l; nd ll other Frscti Consensus Conference prticipnts; Europen Neuroendocrine Tumor Society (ENETS). TNM stging of foregut (neuro)endocrine tumors: consensus proposl including grding system. Virchows Arch. 2006;449(4): Edge SB, Byrd DR, Crducci MA, Compton CC, eds. AJCC Cncer Stging Mnul. 7th ed. New York, NY: Springer; 2009: Kimur N, Ssno N. Prostte-specific cid phosphtse in crcinoid tumors. Virchows Arch A Pthol Ant Histopthol. 1986;410(3): Nsh SV, Sid JW. Gstroenteropncretic neuroendocrine tumors: histochemicl nd immunohistochemicl study of epithelil (kertin proteins, crcinoembryonic ntigen) nd neuroendocrine (neuron-specific enolse, bombesin nd chromogrnin) mrkers in foregut, midgut, nd hindgut tumors. Am J Clin Pthol. 1986;86(2): Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Stomch Wshington et l 191