BURNHAM, JA

DEMETRIS, AJ

HARTLE, K

JAFFE, R

LOCKER, J

MAKOWKA, L

NALESNIK, MA

STARZL, TE

PubMed

Nalesnik, MA

Locker, J

Jaffe, R

Demetris, AJ

Hartle, K

Burnham, JA

Makowka, L

Starzl, TE

Name not available

Clonal characteristics of posttransplant lymphoproliferative disorders

D-Scholarship@Pitt

-., Clonal Characteristics of Posttransplant Llmphoproliferathe Disorders M.A. Nalesmk J Locker R Jaffe. A.J. Demetrls. K. Hartle. J.A. Burnham. L Makowka. and T.E. Starzl Cioob~q MODELS of neoplasia indi-cate a stepwise serie5 of events as the usual mechanism b~ which normal cells become neoplastic cells. I However, ca ncer clinically presents as a full~ malignant lesion capable of causing the death of the host. For this reason, it is presently not possible to trace the entire process that led to this conditIon. The occurrence of lymph0proliferativc dis-orders in immunosuppressed transplant recip-ients holds significant promise that a model of the early stages of neopbsia might exist in humans. These lesions. originally interpreted as .non-Hodgkin's lymphomas. occur in asso-ciation with Epstein- Barr virus infection in most cases." Both pol~clonal and monoclonal forms have been described_D~ We previously observed that a significant number of posttransplant Iymphoproliferative disorders (PTLDs) seen in association with cyclosporine A(CsA )-steroid immunosup-pression were capable of regression after a reduction of immunosuppression. H Our continuing studies are designed to explore the limits of this phenomenon and define the host:tumor factors that are opera-tive within this system. The present report describes a retrospective clonal analysis of tumor tissues by using recombinant D'A From Ihe Depanf?1tnlJ of Palhologl and Slirge'.I. fresbl'lerran ["nin'rslt! HMplla.'. PlflJnu'f!n. and Ihc Departmnl1 of POlholot., Children'.' Hosrllal of PillS-blJrgh Supported in parI by American Cancer Sociel} InSli-IlJliofUJl Granll .... --58X IM.A .... I .-4ddrtss rtprinl r~qli~slp 10 M.A Sale.lnil-.. MD. Departmt'fII of POlhology. VI'I era n.s AdminrSlralior. Mt'dical Cenur. Vnhersin Dri>e C. PlIlJnlirgh. fA 15240. C 1988 by Grunt' & Slra1l0n. Inc 0041-J 345/88;2001-1 10}$03.00/0 probes ~recific for the immunoglobulin h chain reg.ion. MATERIALS AND METHODS FOrl,·four patient~ in the millsburgh·aen~er pi3n, '>ene;. recwed diagnO'>e;. of PTLD, be:"ee; 19S(1 and March I9g7 Clonal desrgna:ior. "'as . orll!;ngjj~ on the re~ultI of fmmunopero~_ida;Ke ~ya:~:;" c~ 10p12SmlC Immu nc)globulim In paraffin·embed~eC sue> The 3\·idin·blc)tln melh:x! of Hsu et ai' "as bined ... it~I pronase dl~esyion Antibodies of , • immunogic)bul,n light chams .. ere obtained frorr . Corp ISant;: Ba;bara. CA) T ... ent~-three pallents ... hose lesions "ere SlUCee ~ th" l~chn"lue al,c' had suffiCient !Issue 3\allab.c !fIr clona! anaIY;'I" of B celb bl using recombinant (J,,,, me: hEldolog~ D' A purlflCati.:m and Ie'>lrlction end(,nucie<;" t. Southern blot analyses ... ere performed In ~cc£>rtD·I_ ",ith protocols pre"iously described from our laboralOl'). Frozen tissue specimens ..... ere pulverized in df) iq, freeze-dried. and solubilized in standard lysing solutioa before routine purification' High-molecular "elPi D"A was digested .,nth BamHI ...... hlch optimal!\ dD-pla~ed hea\'\-chain gene rearran~ements The :~mboK nant D'A probe for the JOining region of the Imm~oogl<i­builn hean-chain gene U,I "a~ bndl~ s:;pplreG bl Dr Phdlr Leder. Hanard L "Iyerpil~ 10 -RESULTS PatienT Population The group of 44 patients was composed of 30 males and 14 females (2.1:1). Ages at transplant ranged from 1 to S~ years. with a mean age of 23 years. There were 24 li'er. ;~ . kidne~K 5 heart. and 3 heart/lung recipientsir. the popula tion who accounted for 2.2Sf. gKl~K 1.8s(. and 4.6S( of the respective organ allo-graft subpopulations. Two patients jnitiall~ received non-CsA-<:ontaining immunosur-pressive regimens. Tumors in these patgent~ occurred at 68 and 162 months posttrPn~­plant. In the remainder of the population CsA was part of the original immunosuppressive 280 Transplanlatlon Proceedings Vol XX. No 1. Suppl 1 (February!. '988: pp 280-283 ttransplaot orders '-Iartle, JAB . . urnh am. ,;'cnts "Dh~e Ie,,) had ' . en, ... erc SUffICient 11"ue a R cell<. b\ U' . ,lng rccomblTlaJll "- and restrIction d en 'lnu \ ~es ... ere ~rformed in 01;;/;' deSCribed fr Om our la .Imens were puh'c . ed . )/ u bil ized in sta ndarJd1 I .In fi r VSlOg " IClItion" High- . , molecular "1111 BamHI. which icne rearrangements The Ihe Jotnlng region of Ihe i _cne (J.J "as k,nd/.\ supplied C l n"'cfS";' I. RESULTS 44 . patlent~ Was composed 4 remale~ (., "J) A - . ges d from , to S~ years. witll ears. There were "4 r nd 3 h . - lVer, eartl lung recipients ho accounted for 2.1%. I )f the respective organ Ions. Two patients in '\--<:ontaining immunos , Tumors in these pa lnd 16') months ,- POSit f~det of the population lrJglnal immunosun .... rArr;_ . " 1 (F&bruaryJ. 1988, pp in thi~ subgroup of 42 at time inten'als ranging I month up 10 26 monlhs .".n . f t The mean tlme 0 tumor Mn~e r was 6.2 months. ,rou .. r reported. the majority 0 I'dence of either primary or cv ..' II Epstein-Barr vIrus Infection. "ration latian of PTLD was localized to and neck region in 14 patients Theis often manifested as a mononucl~-,-_.Ar-r,rnr with marked tonsillar hyper-a cervical mass. Eleven patients predominant in or localized to the tract. A third category of .d solid organ involvement. In many . lOIid organ presentation. the allograft invohed by the process. A su bca te-patients in this group presented .... ith multIsystem disease. Eight other presented with a variety of findings rrom vague constit utional disorders to may exist predominantly as tumor-infiltrative processes. In typical cases inant cell has features of a B -,,,,,'L<; All histological stages of Iympho-maturation may be seen. a condition to as polymorphous or pleomorphic . . a monomorphous appearance in all cells appear identical to each other be seen. The lesions often sho" extensive of necrosis and may contain large atypi-ring I:-mphoid cells. using a combination of immunocyto-I and recombinant D!'.:A methodolo-we have concluded that tumors were 1anf~1KDyn"l in 12 patients. polyclonal in 15 ts, and both monoclonal and polyclonal _DCOlntIgUCus) in four patients. One patient a polyclonal tumor that later evolved into 281 a pr~~bgble munoclonal tumor. Clonal stalu~ has n\.11 ~Cf been ap~lgned in 11 C;gse~K Ir 2.' CP~t:~ both Immunopcro,idase studic~ and immun,1globulln heav)-chain gene rear-rangement studle~ were performed A repre-sentati\c autoradiogram is shown in Fig I. Five case~ '>'-ere categorized as monoclonal by immunocytochemical stain All five were also shown to be monoclonal by Dl"A analy-sis. In contrast, ten cases demonstrated a polyclonal phenotype by immunoperoxidase By using a~A analysis two of these cases were s.ho" n to contain a monoclonal element. Six other cases" ere inconclusive on the basis kb 23.1-9.4-6.6-4.4-a: w > ...J ..... 00""') .. "~fD -G -G Fig 1. Autoradi~ram demonstrating heavy-chain immunoglobulin gene r.arrang.ment. Banda in each Lara rapr ... nt DNA hybridized to the Labal.d J. probe. LN .. DNA ,.",as 85 • control to define unraarranged (polycionall P4nern, lanas I. D. D. and J show P4nern, obtained whan using DNA obtained from tumor .peci-men •. The extra band in Lane J indicatea tha presenca of • clone of c.n. with e singl. he.vy-chain gen. rear-rangemant. Th. other lanes show • germline band p.ttern. kb. kilobs .. ; G. germlin •. I f I j I I 282 of Immunoglobulin light-chain staim D' ..... rearrangement patterns revealed five of the~e cases to be polydonal and one to be monoclo-nal. On occasion. multiple tumors were ana-lyzed b~ one technique but not by another. Two cases categorized as polyclonal b~ pheno-type had separate tumors analyzed by DNA probes. In both cases monoclonal tumors were uncovered. The converse situation was obtained in two cases in which additional tissue was available for immunoglobulin staining. Two cases categorized as either monoclonal or polyclonal on the basis of heav~-chain gene rearrangement analysis were each show n to have had separate mono-clonal and po!yclonal tumors when separate specimens were stained for immunoglobulin light chains. Correlation of Histology and Clonality A full description of the histological aspects ofCsA-associated PTLDs is in preparation. In brief. a pleomorphic histology was associated with polyclonality in most but not all cases. Occasional pleomorphic cases contained a monoclonal component. In contrast. a monomorphous histology invariably implied a monoclonal tumor. In some cases. minimal pleomorphism was seen in association with prominent plasmacytoid features. These Ie· sions were frequently associated with mono-clonalit). Survival Seven of 12 patients with monoclonal dis-ease are alive at intervals ranging from 7 to 58 months after diagnosis. Only one of the seven received chemotherapy in the initial thera· peutic regimen. There have been two cases of recurrence in these seven patients. One case of persistently recurrent disease was subse-quently treated with chemotherapy. Another case resolved after reduction of immunosup-pression. Five of 12 patients with monoclonal tumor died. one despite the use of chemother· apy. . Resolution of pol~clonallesion!> Was sc.:. nIne of II cases. One patient required quent radiotherar~ for control of a morphologically consistent with disease. The remainder of the nine pa . responded to a reduction of immunosu sian. Two of the nine later died of other with no evidence of tumor. One patient recurrent polyclonal disease that resolved. One patient developed u '" idespread. presumably monoclonal and died of aspergillosis in aSSOCiation chemotherap) . The 5-year ~~rviyDal rat~ for the entire ~ of 44 patlents IS 63c:;.. No dIfference is SCQ when these figures are segregated aCClrt~ to donality. DISCUSSION The increased inCidence of lymphoproEfer. ative disorders in transplant patients was ~nt recognized by StaTZI in 1968. 12 Purtilc 5:s: suggested that Epstein-Barr virus might ;:00-tribute to this disQrder. 1l This was found:: be the case in studies of transplant patients a~:be Cniversity of Minnesota. 2 These prior studies were based on patients receiving conventional immunosuppress,on Differences in tumor localization. tumor M~ time. and reyersibilit~ of tumors are ~rK when CsA-containing immunosuppres,;\e regimens are used. IO The present studies indicate that bott monoclonal and polyclonal tumors OCCLr it association with CsA immunosuppres,jo:: Analysis of immunoglobulin genes is shOll;) ~c be a more sensitive indicator of clonal S:2tus than is analysis of cytoplasmic immunogicbu-lin expression. It is important to emphasize that dona. status alone does not constitute the dividing line between benign and malignant lesior:$ ir these cases. In our experience modulation of immunosuppression results in resolution of most polydonal lesions and some monocluna: lesions. The lack of response in some cases :DM1~clonal lesion~ ~as stet! One patient r~tK;ired Dr~ for conlrol of a consi!-tent with Hod 13 i noer of t he nine eduction of immu line later died of other ca of tumor. One patient lonal disease that 'jent de\'eloped unres ·umabg~ monoclonal :rgillosis in association ,j\al rate for the entire 63C:C, '0 difference is e~ are segregated a )ISCUSSION incidence of Iymphop transplant patients was :arzl in 1968. 1: Purtilo pstein-Barr virus might ~rderKfF This was found to 5 of transplant patients at 1nesota.2 Jdies were based on llional immunosu nor localization. tumor .ibility of tumors are aining I 1< ! to emphasize that not constitute the di gn and malignant lesions jf experience modulation In results in resolution :sions and some of response in some , Ni LYMPHOMAS :~ 283 -I-D~K reRee! the fact that lherar~ ~as started majority of ca!De~ ~ill respond to a c;Heful , ""'\Jle 111 the Cl1urse of the dl~e;gse Indeed. reduction of i~munosurrrc<;Dion ~ ith contrul , -. r.s ~lDre aslikel) 10 die from iter~ helm· of local complicalion~I Aggrcs~:yDe chern other· , ~yclE1nal disease as frl)m oyerwhel~lfng ary in these immunosuppressed patient~ ~fonai disea~e (Starzl et a1. unpubhshed should only be used In those rare cases in ........- ~hich tumor cannot be controlled by other <~y distinct minorit:- of cases it is likel) means. ,:,;tT- the tumor had progressed to a stage that The ultimate lessons of these lesions ha\'e . " .. I~ it beyond the ,reach of host control not yet been realized. It is likely thaI con· -~nismsI Prospectl\e studies are under tinued studies of PTLDs will reveal important " to identify additional factors that contrib- underlying mechanisms of immunosurveil-::: 10 the fully developed malignant pheno- lance and tumor progression in the human, >. in these tumors, Thus the importance of PTLDs ma) be far in "D~Dfbc clinician caring for a transplant patient excess of their sporadic occurrence in this K:;~ this syndrome should be aware that the highly select group of patients, - ,(" REFERENCES I:~;t :;,"" l.eIIOir G"i. Bvrnkamm GW: Ad" Cancer o~ 1987 Sacmundser. AK. Purtilo DT. Salamalo K. el al: oes41:4O~TI19U1 . .1 Frizzera G. Hanw DW. Gajl·Peclalska KJ. CI J1 .•. !?~ Res 414262. 1981 ........ SUrzi TE. Sale,nlk "iA. Poner KA, et al Lancet Jjll. 1984 - Clean ~fiK Sklar J: Lancet 1489. 1984 N.les'nik "iA. Starzl TE. Porter KA. el al: Trans· __ buK~n4PR9OK 1987 Hsu SM. Raine L. Fanger H J Hlslochem Cj1o-"' •• -.; ...... - 29:577.1981 8. Kunnalh L. Locker J: Suc1eic Acids Res 1038-;. 19U~ 9. Graham DE: Anal Bllxhcm 85:609.19'111 10 Ra-etch JV. Sicbcnhs' C. horsme~er SJ. et a! Cell 27583. 1981 II. Ho M. \iiller G ...... tchlwn R \0\, cl al J Infect DIS 152:876.198< 12 Starzl TE Ann Surg 168:416. 1968 13. Purtilo DT: Lab Invest SU73. 1984 14. Penn I qran~planlalion 4332. 1987 

CLONAL CHARACTERISTICS OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS

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CLONAL CHARACTERISTICS OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS

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