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1 Protocol for the Exmintion of Specimens From Ptients With Neuroendocrine Tumors (Crcinoid Tumors) of the Colon nd Rectum 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 14, 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 K. 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 COLON AND RECTUM This protocol pplies to well-differentited neuroendocrine tumors of the lrge bowel nd rectum. 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 colon of the Americn Joint Committee on Cncer (AJCC) nd the Interntionl Union Aginst Cncer (UICC) is recommended. SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST) Colon nd Rectum: Resection, Including Trnsnl Disk Excision of Rectl Neoplsms (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) Lrge intestine Cecum Ascending colon Trnsverse colon Descending colon Sigmoid colon Rectum Anus Terminl ileum Appendix 176 Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Colon nd Rectum Wshington et l

2 Procedure Right hemicolectomy Trnsverse colectomy Left hemicolectomy Sigmoidectomy Rectl/rectosigmoid resection (low nterior resection) Totl bdominl colectomy Abdominoperinel resection Trnsnl disk excision (locl excision) *Specimen Size (pplicble to trnsnl disk excision) *Specify: (length) 3 3 cm Tumor Site (select ll tht pply) (note B) Lrge bowel Cecum Ascending colon Heptic flexure Trnsverse colon Splenic flexure Left (descending) colon Sigmoid colon Rectum 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 neuroendocrine crcinoms, the College of Americn Pthologists (CAP) checklist for crcinom of the colon nd rectum 1 should be used. Mitotic Rte 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 through the musculris propri into the subserosl dipose tissue or the nonperitonelized pericolic or perirectl soft tissues but does not extend to the serosl surfce (viscerl peritoneum) Tumor penetrtes seros (viscerl peritoneum) Tumor directly invdes djcent structures Tumor penetrtes to the surfce of the viscerl peritoneum (seros) nd directly invdes djcent structures (specify: ) Mrgins Proximl Mrgin Distl Mrgin Circumferentil (Rdil) Mrgin (note F) Not pplicble 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 pt1: Tumor invdes lmin propri or submucos nd size 2 cm or less Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Colon nd Rectum Wshington et l 177

3 Site of Origin of Gstrointestinl Neuroendocrine Tumors Foregut Tumors Midgut Tumors Hindgut Tumors Site Stomch, proximl duodenum Jejunum, ileum, ppendix, Distl colon, rectum proximl colon Immunohistochemistry, % + Chromogrnin A NSE Synptophysin Serotonin 33 13, , ,5,6,14 Other immunohistochemicl mrkers Rrely, + for pncretic polypeptide, histmine, Prosttic cid phosphtse + in 20% 40% of cses 13,14 Prosttic cid phosphtse + in 20% 82% of cses 3,5,6,14 gstrin, VIP, or ACTH Crcinoid syndrome, % Rre ,7 Rre Abbrevitions: ACTH, drenocorticotropic hormone; NSE, neuron-specific enolse; VIP, vsoctive intestinl peptide; +, positive. pt1: Tumor size less thn 1 cm in gretest dimension pt1b: Tumor size 1 to 2 cm in gretest dimension pt2: Tumor invdes musculris propri or size more thn 2 cm with invsion of lmin propri or submucos pt3: Tumor invdes through the musculris propri into the subseros, or into nonperitonelized pericolic or perirectl tissues pt4: Tumor invdes peritoneum or other orgns Regionl Lymph Nodes (pn) pn0: No regionl lymph node metstsis pn1: Regionl lymph node metstsis 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) * Tumor necrosis *Comment(s): EXPLANATORY NOTES A: Appliction nd Tumor Loction. This protocol pplies to low- nd intermedite-grde neuroendocrine neoplsms (crcinoid tumors) of the colon nd rectum. 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). In generl, the distribution pttern long the gstrointestinl (GI) trct prllels tht of the progenitor cell type, nd the ntomic site of origin of GI neuroendocrine tumors is n importnt predictor of clinicl behvior. 2 B: Site-Specific Fetures. Rectl neuroendocrine tumors re common nd constitute pproximtely qurter of GI neuroendocrine tumors. 3 They re usully smll, solitry, nd cliniclly silent, most commonly occurring 4 to 13 cm from the nl verge. Mitoticlly inctive rectl neuroendocrine tumors or those smller thn 2.0 cm re lmost lwys cliniclly benign. 4 Metstses nd crcinoid syndrome re very rre. Lrge intestinl neuroendocrine tumors outside the ileocecl region nd rectum re extremely rre; most reported tumors hve been lrge (verge size, 5.0 cm) nd high grde, with poor prognosis. Mny low-grde neuroendocrine tumors involving the ileocecl vlve represent tumors rising in the terminl ileum rther thn in the lrge bowel. 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. Rectl crcinoids smller thn 1.0 cm re lmost lwys cliniclly benign, nd locl excision is generlly considered sufficient for tumors 1.0 cm or smller, s well s mny tumors between 1.0 nd 2.0 cm. More extensive procedures (eg, right hemicolectomy nd bdominoperinel resection) re usully reserved for ptients with tumors lrger thn 2.0 cm. D: Histologic Type. The World Helth Orgniztion (WHO) clssifies neuroendocrine neoplsms s welldifferentited 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. 178 Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Colon nd Rectum Wshington et l

4 All colonic neuroendocrine tumors re considered potentilly mlignnt; none re clssified s benign or low-mlignnt-potentil neuroendocrine tumors. Most re lrge, bulky, high grde, highly invsive tumors tht re metsttic t presenttion. Two-thirds rise within the cecum or right colon. Rectl neuroendocrine tumors, in contrst to colonic neuroendocrine tumors, re reltively common nd generlly behve in benign fshion. Histologic Clssifiction of Rectl Neuroendocrine Tumors, Adpted from WHO Well-Differentited Neuroendocrine Tumor Benign. Nonfunctioning cytologiclly blnd tumors confined to mucos or submucos, with no ngioinvsion, nd mesuring not more thn 2 cm in gretest dimension. Uncertin Mlignnt Potentil. Nonfunctioning cytologiclly blnd tumors confined to mucos or submucos, with ngioinvsion, less thn 2 cm in size. Well-Differentited Neuroendocrine Crcinom Nonfunctioning tumors tht re lrger thn 2 cm, or invde the musculris propri or beyond, or re metsttic. Functionl tumors ssocited with crcinoid syndrome re included in this ctegory. Histologic Ptterns Although specific histologic ptterns in well-differentited neuroendocrine neoplsms, such s trbeculr, insulr, nd glndulr, roughly correlte with tumor loction, 4 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 system bsed on mitotic ctivity hs been proposed for neuroendocrine tumors of the ileum, ppendix, colon, nd rectum 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 10 ; 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 checklist for crcinoms of the colon nd rectum 1 should be used for poorly differentited neuroendocrine crcinoms rising in these sites). F: Circumferentil (Rdil or Mesenteric) Mrgin. In ddition to ddressing the proximl nd distl mrgins, A, Mesenteric mrgin in viscus completely encsed by peritoneum (dotted line). B, Circumferentil (rdil) mrgin (dotted line) in viscus incompletely encsed by peritoneum. C, Circumferentil (rdil) mrgin (dotted line) in viscus completely unencsed by peritoneum. Reproduced with permission from Wshington et l. 1 Copyright College of Americn Pthologists. ssessment of the circumferentil (rdil) mrgin is necessry for ny segment of gstrointestinl trct, either unencsed (Figure, C) or incompletely encsed by peritoneum (Figure, B). The circumferentil mrgin represents the dventitil soft-tissue mrgin closest to the deepest penetrtion of tumor nd is creted surgiclly by blunt or shrp dissection of the retroperitonel or subperitonel spect, respectively. The distnce between the tumor nd circumferentil (rdil) mrgin should be reported. The circumferentil (rdil) mrgin is considered negtive if the tumor is more thn 1 mm from the inked nonperitonelized surfce but should be recorded s positive if the tumor is locted 1 mm or less from the nonperitonelized surfce. This ssessment includes tumor within lymph node s well s direct tumor extension, but if circumferentil (rdil) mrgin positivity is bsed solely on intrnodl tumor, this should be so stted. The mesenteric resection mrgin is the only relevnt circumferentil mrgin in segments completely encsed by peritoneum (eg, trnsverse colon) (Figure, A). Involvement of this mrgin should be reported even if tumor does not penetrte the serosl surfce. G: TNM nd Antomic Stge/Prognostic Groupings. The TNM stging system for neuroendocrine tumors of the colon nd rectum of the AJCC nd the UICC is recommended. 11 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. Arch Pthol Lb Med Vol 134, Februry 2010 Checklist for Neuroendocrine Tumors of the Colon nd Rectum Wshington et l 179

5 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 regionl lymph nodes of the colon nd rectum re s follows. 1. Cecum: Pericolic, nterior cecl, posterior cecl, ileocolic, right colic 2. Ascending colon: Pericolic, ileocolic, right colic, middle colic 3. Heptic flexure: Pericolic, middle colic, right colic 4. Trnsverse colon: Pericolic, middle colic 5. Splenic flexure: Pericolic, middle colic, left colic, inferior mesenteric 6. Descending colon: Pericolic, left colic, inferior mesenteric, sigmoid 7. Sigmoid colon: Pericolic, inferior mesenteric, superior rectl (hemorrhoidl), sigmoidl, sigmoid mesenteric 8. Rectosigmoid: Pericolic, perirectl, left colic, sigmoid mesenteric, sigmoidl, inferior mesenteric, superior rectl (hemorrhoidl), middle rectl (hemorrhoidl) 9. Rectum: Perirectl, sigmoid mesenteric, inferior mesenteric, lterl scrl, prescrl, internl ilic, scrl promontory (Gerot s), internl ilic, superior rectl (hemorrhoidl), middle rectl (hemorrhoidl), inferior rectl (hemorrhoidl) TNM Antomic Stge/Prognostic Groupings 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. 7 Becuse of their reltive sensitivity nd specificity, chromogrnin A nd synptophysin re recommended. It should be noted tht hindgut neuroendocrine tumors often do not express pprecible mounts of chromogrnin A. Rectl neuroendocrine tumors express prosttic cid phosphtse, potentil dignostic pitfll for tumors rising in mle ptients. 12 Immunohistochemistry for Ki-67 my be useful in estblishing tumor grde (note E) nd prognosis 12 but is not currently considered stndrd of cre. 7 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. Cogultive tumor necrosis, usully punctte, my indicte more ggressive behvior 10 nd should be reported. References 1. Wshington MK, Berlin J, Brnton PA, et l. Protocol for the exmintion of specimens from ptients with primry crcinoms of the colon nd rectum. Arch Pthol Lb Med. 2009;33(10): Rorstd O. Prognostic indictors for crcinoid neuroendocrine tumors of the gstrointestinl trct. J Surg Oncol. 2005;89(3): Modlin IM, Lye KD, Kidd M. A 5-decde nlysis of 13,715 crcinoid tumors. Cncer. 2003;97(4): Sog J. Crcinoids of the colon nd ileocecl region: sttisticl evlution of 363 cses collected from the literture. J Exp Clin Cncer Res. 1998;17(2): 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: 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; 2000: 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: Rindi G, Klöppel G, Couvelrd A, et l. TNM stging of midgut nd hindgut (neuro) endocrine tumors: consensus proposl including grding system. Virchows Arch. 2007;451(4): 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; Sobin LH, Hjermstd BM, Sesterhenn IA, Helwig EB. Prosttic cid phosphtse ctivity in crcinoid tumors. Cncer. 1986;58(1): 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 Colon nd Rectum Wshington et l