Jie Wu 1, Wentao Fang 2, Gang Chen 1. Introduction

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1 Review Article The enlightenments from ITMIG Consensus on WHO histologicl clssifiction of thymom nd thymic crcinom: refined definitions, histologicl criteri, nd reporting Jie Wu 1, Wento Fng 2, Gng Chen 1 1 Deprtment of Pthology, Zhongshn Hospitl, Fudn University, Shnghi , Chin; 2 Deprtment of Thorcic Surgery, Shnghi Chest Hospitl, School of Medicine, Shnghi Jio Tong University, Shnghi , Chin Contributions: (I) Conception nd design: G Chen, W Fng; (II) Administrtive support: W Fng; (III) Provision of study mterils or ptients: All uthors; (IV) Collection nd ssembly of dt: J Wu; (V) Dt nlysis nd interprettion: All uthors; (VI) Mnuscript writing: All uthors; (VII) Finl pprovl of mnuscript: All uthors. Correspondence to: Gng Chen. Deprtment of Pthology, Zhongshn Hospitl, Fudn University, 180 Fenglin Rod, Shnghi , Chin. Emil: chestpthology@126.com. Abstrct: The World Helth Orgniztion (WHO) histologicl clssifiction of the thymom nd thymic crcinom (TC) hs been criticized for poor interobserver reproducibility or inconsistencies in the routine pthologicl dignosis. The Interntionl Thymic Mlignncy Interest Group (ITMIG) pnel chieved n greement to mintin the widely ccepted WHO frmework but to refine historic definitions nd histologicl criteri, nd further introduce some new terms with the im to improve interobserver reproducibility. This review ddresses the enlightenments we cn get from the ITMIG consensus on the WHO histologicl clssifiction of the thymom nd TC, which my be helpful for most pthologists. Keywords: Thymic epithelil tumor (TET); histology; reporting Submitted Oct 05, Accepted for publiction Nov 10, doi: /jtd View this rticle t: Introduction The World Helth Orgniztion (WHO) clssifiction is the most widely used histologicl clssifiction of thymoms nd thymic crcinoms (TCs). However, the WHO clssifiction hs been criticized for poor interobserver reproducibility or inconsistencies in the routine dignosis (1-3), when encountering some certin cses: (I) thymoms with fetures intermedite between prototypic subtypes (borderlnd cses); (II) tumors with typi, high mitotic ctivity, nd necrosis; (III) tumors showing more thn one histologicl pttern. To ddress these issues t n interdisciplinry conference orgnized by the Interntionl Thymic Mlignncy Interest Group (ITMIG) in New York, in Mrch 2011, the prticipnts including 18 pthologists, two surgeons, nd one oncologist reviewed prototypic nd difficult-to-clssify thymic epithelil tumors (TETs) nd chieved the consensus to refine histologicl criteri for better mngement. The rticle bout the consensus sttement ws published on Journl of Thorcic Oncology, in My 2014 (4). The ITMIG pnel chieved n greement to mintin the widely ccepted WHO frmework but to improve historic definitions nd introduce some new terms with the im to improve interobserver reproducibility: (I) The WHO clssifiction hs been criticized for imprecise descriptions of A nd AB thymom nd for clling them benign (5-7). At the consensus workshop there ws greement tht A nd AB thymoms re tumors of low mlignnt potentil. The dt of Chinese Allince for Reserch in Thymoms (ChART), 1,930 cses of TETs from 10 hospitls from 1994 to 2012, showed tht 10-yer overll survivl of type A nd AB thymoms (ccounted for 4.4% nd 22.8%), were 92.4%

2 Journl of Thorcic Disese, Vol 8, No 4 April Percent survivl Survivl curve (WHO clssifiction) Log-rnk P< yr OS: A 92.4% AB 93.2% B1 86.3% B2 80.8% B3 83% C 51% Crcinoid 22.8% Durtion of time (months) WHO A AB B1 B2 B3 C Crcinoid A-censored AB-censored B1-censored B2-censored B3-censored C-censored Crcinoid-censored Figure 1 The 10-yer overll survivl of 1,930 cses of TETs from 10 hospitls from 1994 to nd 93.2% respectively (Figure 1); (II) Tking into ccount tht thymoms with heterogeneous histologicl fetures composed of different subtypes re very common, there ws consensus tht the term combined thymom should be bndoned. Insted, the dignosis in such tumors should follow n pproch nlogous to Gleson scoring listing ll subtypes strting with the predominnt component; minor components should be reported with 10% increments. Of note, AB thymom is distinct entity for which the 10% rule does not pply. For scientific nd sttisticl purposes, thymom components of 0% to 10% cn be neglected, nd the given tumor clssified ccording to the dominnt component. If thymic tumors comprising crcinom component should be different from the reporting of thymoms: such tumors should in the first plce be lbeled s crcinoms with listing of the proportion, differentition, nd grde, followed by the list of the thymom components; (III) In the WHO clssifiction the imprecise definition of AB thymoms ws orgnotypic thymic epithelil neoplsms composed of mixture of lymphocyte-poor type A thymom component nd more lymphocyterich type B-like component nlogous to B1 or B2 thymoms (8). Now the potentilly confusing term B-like re is replced by lymphocyte-rich component in AB thymoms, nd the criticized sttement given in the WHO clssifiction tht lymphocyte-rich res in AB thymoms hrbor polygonl tumor cells is replced: tumor cells in such res re typiclly spindly or ovl; (IV) The new concept of typicl type A thymom ws posed in the consensus sttement. Agreed criteri of typi were incresed mitotic ctivity (4 or more per 10 high power field) nd true (cogultive) tumor necrosis (in contrst to ischemic or biopsy-induced necrosis). Other criteri, such s hypercellulrity, enlrged hyperchromtic nuclei, lrge nucleoli, incresed Ki67 index, nd extent of typicl res, were difficult to quntify or could not be greed upon. Actully some of type A thymoms indeed showed overt invsiveness nd metstsis (5,6), there ws greement tht the type A thymom fmily includes smll subset of ggressive tumors. Nevertheless, further subdivision of type A thymom into different entities in nlogy to the B1, B2, nd B3 prdigm ppers to premture before relible dt vilble (9). The pnel members greed on the description of mjor (indispensble) nd minor (typicl) dignostic criteri by tbles, insted of the nrrtive style of the WHO clssifiction. As supplement, glleries of figures illustrted different-to-clssify tumors t the borderlnds between prototypic cses. On ccount of the interest in borderlnd cses with differentil dignostic vlue, 72 cses were selected for review t the consensus workshop, only 58 could finlly be fully evluted due to time restrictions. The differentil dignosis on these borderlnd cses minly focused on type A nd AB thymom, type B1 nd B2 thymom, type B3 thymom nd TC. Differentil dignosis on type A thymom Distinguishing type A thymom from AB thymom In the WHO clssifiction the description of type A thymom ws tht there ws no or only few T cells with expression of CD3 nd CD5. Immture T cells with expression of CD1 nd CD99 could lso present in type A thymom. In the consensus sttement the pnels greed to quntify the proportion of immture T cells of type A thymom. It should hrbor no or only few TdT+ T cells (esy to count) (grde 1) or moderte mount of TdT+ T cells (I could count if I hd to) (grde 2) in 10% or less of given biopsy (Tble 1). Moderte numbers of TdT+ T cells bove the rbitrry 10% threshold in vilble biopsies or ny re with bundnt (impossible to count) TdT+ T cells (grde 3) would fvor dignosis of AB thymom over type

3 740 Wu et l. Thymic epithelil tumor, histology, reporting Tble 1 Mjor nd criteri of conventionl type A thymoms Mjor criteri Spindle nd/or ovl-shped tumor cells lcking nucler typi Pucity or bsence of immture, TdT(+) thymocytes throughout the tumor Minor criteri Occurrence of rosettes nd/or subcpsulr (to be distinguished from PVS) Presence of focl glndulr formtions Pucity or bsence of PVS contrsting with presence of bundnt cpillries Lck of Hssll s corpuscles Complete or mjor encpsultion Expression of CD20 in epithelil cells; bsence of cortexspecific mrkers b, Pucity implies no (immture) lymphocyte-rich with dense, impossible-to-count TdT(+) lymphocytes; or t most 10% tumor regions with moderte immture lymphocyte; b, Bet5t, PRSS16, nd cthepsin V by IHC. PVS, perivsculr spce; IHC, immunohistochemistry. A thymom. The role of immunohistochemistry (IHC) ws emphsized in the consensus sttement: epithelil cells of AB thymoms express both corticl nd medullry mrkers in n intermingled pttern, wheres type A thymoms lck corticl mrkers (Tble 2) (10). Distinguishing type A thymom from spindle cell B3 thymom In the WHO description Th reticulin fibers ws pplied for differentil dignosis on type A thymom nd spindle cell B3 thymom (8). In type A thymom reticulin fiber often presented round single tumor cell with expression of Lminin nd collgen IV, wheres B3 thymom lck of reticulin fibers. The consensus sttement proposed reticulin fiber did not relibly distinguish type A from spindle B3 thymoms, while the difference on morphology ws more vluble. Prominent nd bundnt perivsculr spces (PVSs) would strongly fvor dignosis of type B3 thymom, wheres uniform nuclei, bundnce of cpillry vessels, rosette formtion, cystic spces, nd epithelil expression of CD20 would fvor type A thymom. Nevertheless, distinction between typicl type A thymom nd spindle cell B3 thymom cn be more difficult becuse nucler typi is present in both, nd immunohistochemicl studies my be further required. Differentil dignosis on type B thymoms Distinguishing B1 thymoms from B2 thymoms B1 thymoms closely mimic norml thymus (NT) t both low nd high mgnifiction, with presence of prominent medullry islnds tht contin epithelil cells with or without Hssll s corpuscles; mjority of mture, TdT ( ) T cells; nd scttered CD20+ mture B cells. Medullry islnds cn lso occur in B2 thymom. PVS nd bundnt TdT+ T cells occur in both B1 nd B2 thymoms, but PVSs re often inconspicuous in B1 thymoms. The distinguishing fetures of B2 thymoms re: (I) incresed number of epithelil cells compred with NT often visible t low mgnifiction; nd (II) epithelil cell clusters (defined s t lest three contiguous epithelil cells). On immunostining, the network of epithelil cells in B2 thymom is significntly denser. In the WHO description there ws significnt difference on tumor cell size, shpe nd nucleolus between B thymoms, while the consensus chieved is tht nucler size nd typi of epithelil cells re not helpful nd relible distinguishing fetures. Distinguishing B2 thymom from B3 thymom According to the sttisticl results from ChART, the prognosis of B2 thymom ws worse thn B3 (10-yer overll survivl: 80.8% vs. 83.0%) (Figure 1). As rule of thumb H&E-stined B2 nd B3 thymoms give blue vs. pink impression, respectively, due to the prominent T cells in B2 versus B3 thymoms. In the WHO clssifiction previously described distinguishing criteri such s nucler size nd PVS re not helpful for this distinction. Differentil dignosis between thymom nd TC Distinguishing B3 thymom from thymic squmous cell crcinom (TSCC) In generl, TCs show the sme histologicl fetures s nlogous extr-tcs (Tble 3) (11-14). B3 thymoms typiclly show lobulr growth, conspicuous PVS, minor/ moderte nucler typi, lck of intercellulr bridges, presence of TdT+ immture T cells, nd lck of expression of CD5, CD117, GLUT1, nd MUC1 in neoplstic epithelil cells (15-18). Nevertheless, some following

4 Journl of Thorcic Disese, Vol 8, No 4 April Tble 2 Mjor nd minor histologicl fetures encountered in type A nd AB thymoms Fetures Type A thymom Type AB thymom Mjor criteri Biphsic pttern t low mgnifiction due to vrible lymphocyte No Common content High epithelil cell content Yes Yes Spindle or ovl epithelil cells b Yes Yes Pucity c or bsence of TdT+ T cells Yes No Medullry islnds d No Rrely present,e Minor criteri Smll lobulr growth pttern No Rre Lrge lobulr growth pttern Common Common Perivsculr spces Rrely present Rrely present CD20 expression in epithelil cells Common Common Corticl mrker expression f No Yes, these feture re minor criteri in type AB thymom; b, typi in type AB thymom hs not been ddressed so fr; c, s defined in Tble 1; d, detection of medullry islnds is usully cler-out on hemtoxylin-eosin stining but my require IHC, prticulrly when Hssll s corpuscles re missing; e, in lymphocyte-rich res, usully with lck of Hssll s corpuscles; f, Bet5t, PRSS16, nd cthepsin V (detectble by IHC in epithelil cells within lymphocyte-rich res). IHC, immunohistochemistry. Tble 3 Criteri for the histologicl dignosis of TC Mjor (indispensible) Cler-cut typi of tumor epithelil cells with the severity typicl of crcinom Exclusion of thymom with typi nd/or nplsi nd of typicl or typicl crcinoids Exclusion of metstsis to the thymus nd germ cell nd mesenchyml tumors with epithelil fetures Minor (typicl) Infiltrtive growth pttern Smll tumor cell nests within desmoplstic strom Absence of immture, TdT+ T cells (with rre exceptions) IHC: epithelil expression of CD5, CD117; extensive expression of GLUT1, MUC1 Fetures comptible b with the dignosis of TC Invsion with pushing borders Occurrence of perivsculr spces Occurrence of Hssll-like epidermoid whorls nd/or of myoid cells Occurrence of (usully rre) immture, TdT+ cells, CD5, CD117, GLUT1, nd MUC1 re expressed by mny nonthymic cncers; b, lthough most of these fetures re orgnotypic, tht is, chrcteristic of thymom, their presence does not exclude dignosis of TC if mjor dignostic criteri of TC re fulfilled. IHC, immunohistochemistry; TC, thymic crcinom. equivocl situtions still needed clrifiction. If tumors tht lck TdT+ T cells in the vilble histologicl mteril but otherwise show fetures of typicl B3 thymoms nd CD5/ CD117 negtivity should be clled B3 thymoms. Despite the expression of CD5, CD117, MUC1, or GLUT1 in n otherwise typicl B3 thymom, we should not chnge the dignosis to TC (Tble 4). If tumors with bsence of two fetures of thymic squmous cell crcinom (TSCC) (cler-

5 742 Wu et l. Thymic epithelil tumor, histology, reporting Tble 4 Mjor nd minor histologicl feture of type B1 versus B2 thymoms Fetures Type B1 thymom Type B2 thymom Mjor criteri Thymus-like pttern throughout Consistently present Rrely present Medullry islnds (+/ Hssl s corpuscles) Consistently present Occsionlly present Confluence of epithelil cells in corticl res b No (like in the NT) Yes Absence of type A res (even if <10%) Yes Yes Minor criteri Smll lobulr growth pttern Rre Common Lrge lobulr growth pttern Common Rre Perivsculr spces Commonly present Commonly present Kertin+ c network like in NT Yes Denser thn in NT, These fetures re, therefore, minor criteri of type B2 thymoms; b, defined s t lest three contiguous epithelil cells; c, on immunostining. NT, norml thymus. cut nucler typi nd intercellulr bridges) nd lck of n importnt feture of B3 thymoms (TdT+ T cells), they were tenttively lbeled s B3/TSCC borderline TETs. Distinguishing typicl type A thymom from spindle cell TC As to this borderlnd, the pnel members thought there were no efficient pproches to differentil dignosis. Anlysis of TdT is not helpful, s bsence of TdT+ thymocytes does not exclude dignosis of typicl type A thymom. Morphologiclly clssicl type A thymoms should not be reclssified s TC only on the bsis of CD117 nd CD5 expression. New subtype-specific mrkers re needed to study this unresolved borderlnd. The sttisticl dt of ChART reveled tht TC ptients hd lowest prognosis, with 51% 10-yer overll survivl. As new subtype, whether the prognosis of typicl A thymom is worse or not, need more dt to verify tht (Figure 1). Conclusions The consensus chieved by the pnel of ITMIG on refined definitions nd histologicl criteri is helpful for interobserver reproducibility. The borderlnd cses often occurred in spectrum of type A nd AB thymom, type B thymom, nd TC. The tbles tht list mjor nd minor dignosis criteri nd the glleries of figures tht illustrte different-to-clssify TETs mke pthologists esy to grsp nd prctice on dignosis. The proposl of new concepts of typicl type A thymom nd B3/TSCC borderline TETs further supplement the WHO clssifiction. IHC ply n importnt role in differentil dignosis, especilly on thymoms nd TCs, while s n uxiliry pproch, the pnelists still emphsize the morphology fetures, including nucler typi, mitotic ctivity, nd tumor necrosis, when encountering the borderlnd cses. Acknowledgements Funding: This study ws supported by the Shnghi Science nd Technique Committee ( ). Footnote Conflicts of Interest: The uthors hve no conflicts of interest to declre. References 1. Suster S, Morn CA. Problem res nd inconsistencies in the WHO clssifiction of thymom. Semin Dign Pthol 2005;22: Rieker RJ, Hoegel J, Morresi-Huf A, et l. Histologic clssifiction of thymic epithelil tumors: comprison of estblished clssifiction schemes. Int J Cncer 2002;98: Verghese ET, den Bkker MA, Cmpbell A, et l. Interobserver vrition in the clssifiction of thymic tumours-- multicentre study using the WHO clssifiction system. Histopthology 2008;53: Mrx A, Ströbel P, Bdve SS, et l. ITMIG consensus

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