Secondary Precursor T-Cell Lymphoblastic Lymphoma Following Precursor B-cell Acute Lymphoblastic Leukemia: A Case Report and Review of the Literature

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1 Journl of Cncer Reserch Updtes, 2014, 3, Secondry Precursor T-Cell Lympholstic Lymphom Following Precursor B-cell Acute Lympholstic Leukemi: A Cse Report nd Review of the Literture Jenny L. Smith 1, Alert Kherdpour 2, Crig W. Zuppn 1, Jun Wng 1, Rhett P. Ketterling 3 nd Edwrd H. Rowsell 1,* 1 Deprtments of Pthology nd Lortory Medicine, nd 2 Peditric Hemtology nd Oncology, Lom Lind University Medicl Center, Lom Lind, CA 92354, USA; 3 Deprtment of Pthology nd Lortory Medicine, Myo Clinic College of Medicine, Rochester, MN 55905, USA Astrct: Although relpse of lymphom/leukemi is not uncommon, sequentil development of second lymphom/leukemi of different cell linege is rre. We report the cse of 3-yer-old girl who initilly presented with precursor B-cell cute lympholstic leukemi (B-ALL), chrcterized y cryptic t(12;21) with ssocited ETV6/RUNX1 fusion, n 11q (MLL) deletion, nd lnced inv(2)(q31q37). She ws successfully treted ut five yers lter developedthymicprecursor T-cell lympholstic lymphom (T-LBL) expressing completely different phenotypic profile. Fluorescence in situ hyridiztion testing identified MLL rerrngement ut indicted no ETV6/RUNX1 fusion. Although the mrrow ws uninvolved, spirtes evluted y chromosome studies reveled the sme inv(2q), suggesting constitutionl normlity distinct from the somtic ltertions ssocited with her B-ALL nd T-LBL. This risesthe possiilityof potentil tumor suppressor gene or proto-oncogene residing in the region of the inversion rekpoints which could contriute to predisposition to the development of lympholstic leukemis/lymphoms. While secondry leukemi my emerge s therpy-relted process nd the presence of n MLL rerrngement in the T-LBL represents n interesting normlity in this regrd,thymicpresenttion would e exceedingly unusul. To our knowledge, this is the first reported cse of B-ALL followed y n pprently geneticlly unreltedt-lbl. Keywords: Secondry mlignncy, cute lympholstic leukemi, cute lympholstic lymphom, peditrics, linege difference. INTRODUCTION Although relpse of cute leukemi is not infrequent, second mlignncies fter childhood cute leukemi re uncommon occurrences. The most frequent secondry mlignncy is cute myeloid leukemi (AML). Secondry cute lympholstic leukemi/lymphom (sall) is distinctly uncommon nd studies on etiology nd tretment re limited. Herein, we report cse of precursor B-cell cute lympholstic leukemi in 3-yer-old girl followed 5 yers lter y precursor T-cell cute lympholstic lymphom (T-LBL), nd discuss existing theories on the etiology of sall. CASE REPORT A 3-yer-old girl presented with hedche, intermittent fever for severl weeks, rhinorrhe nd phryngitis with tchypne nd susequent tchycrdi. A complete lood count demonstrted pncytopeni with 12% circulting lsts, hemogloin 3.0 g/l, pltelets 3.0 x 10 9 /L, nd white cell count 2.58 *Address correspondence to this uthor t the Deprtment of Pthology nd Lortory Medicine, Lom Lind University Medicl Center, Room 2516, Anderson Street, Lom Lind, CA 92354, USA; Tel: (909) ; Fx: (909) ; E-mil: erowsell@llu.edu ISSN: / E-ISSN: /14 x 10 9 /L. Her lctte dehydrogense ws elevted t 499 U/L. Chest rdiogrphs reveled telectsis ut no other intrthorcic normlities. A one mrrow iopsy nd spirtion demonstrted lsts in the mrrow similr to those seen in the peripherl lood. With supporting ncillry tests (see Pthologic nd Genetic Findings) dignosis of precursor B-cell cute lympholstic leukemi (B-ALL) ws mde, nd she ws strted on COG protocol AALL0331. After finishing the induction phse of therpy nd strting consolidtion, repet one mrrow exmintions were negtive for mlignncy. Complictions of her hospitl course included reversile posterior leukoencephlopthy with new-onset seizure ctivity, ilterl intrretinl hemorrhges, infection t the site of her one mrrow iopsy, nd hypertension. A complete nd stle remission of her leukemi ws otined with therpy. Five yers lter, she presented to the emergency deprtment complining of left shoulder pin. On dmission, complete lood count showed hemogloin of 13.7 g/l, pltelets 396 x 10 9 /L, nd white cell count 9.01 x 10 9 /L. Her lctte dehydrogense ws gin elevted, t 447 U/L. A chest x-ry demonstrted lrge left-sided pleurl effusion with complete loss of visuliztion of the left hert order. CT scn of the chest reveled new 11 x 10 x 9 cm nterior 2014 Lifescience Glol

2 118 Journl of Cncer Reserch Updtes, 2014, Vol. 3, No. 2 Smith et l. medistinl mss (Figure 1). Biopsies of this mss showed findings consistent with precursor T-cell lympholstic lymphom. A peripherl lood smer nd one mrrow iopsy to evlute for systemic involvement were negtive. She ws treted per protocol AALL0434. hemodilution, the cells present were nerly ll lympholsts (Figure 2). The hemtoxlin nd eosinstined one mrrow sections from the first iopsy t ge 3 demonstrted hyperplstic mrrow lmost entirely replced y sheets of lympholsts with high nucler to cytoplsmic rtios nd scnt sophilic, grnulr cytoplsm. By flow cytometry, the lstic popultion expressed CD10, CD19, CD20, CD34, CD45, CD79, nd TdT ut did not express CD22, CD3, CD4, CD7, or CD8 (Tle 1). There ws lso errnt myeloid ntigen CD13 expression. The morphologic nd immunophenotypic findings were most consistent with B-ALL. Bone mrrow chromosome studies demonstrted n inv (2) (q31q37) in ll 20 metphses nd deletion (11q) in 9 metphses. FISH studies confirmed the 11q deletion y demonstrting loss of the MLL gene (t 11q23) nd reveled ETV6/RUNX1 fusion, indicting cryptic t (12;21) (p13;q22). Figure 1: CT scn showing lrge medistinl mss with ccompnying left pleurl effusion t the time of second presenttion. As of this writing, four yers fter completing COG protocol AALL0331 chemotherpy for B-ALL, she remins in remission. One yer fter inititing protocol AALL0434 for T-LBL, she is on mintennce chemotherpy nd cliniclly stle. The only sequele she hs encountered re nxiety nd memory deficits, possily relted to neuropsychologicl issues ssocited with her medicl dignosis. PATHOLOGIC AND GENETIC FINDINGS Although the mrrow spirte smer ws extremely puci-cellulr due to dry tp nd mrked Figure 2: Precursor B-cell cute lympholstic leukemi: initil mrrow spirte (Wrigth-Giems stin, originl mgnifiction x 600). Histologicl exmintion of the susequent medistinl mss iopsy t ge 8 showed homogeneous popultion of smll lstic lymphoid cells with slight nucler irregulrity, smll nucleoli, nd moderte mitotic ctivity (Figure 3A). By flow Tle 1: Summry of Tumor Phenotype Flow Cytometric Mrkers (Blst Popultion) Positive Negtive Initil B-ALL CD10, CD20, CD34, CD45, CD79, TdT c, CD13 CD3, CD4, CD7, CD8 Susequent T-LBL CD3, CD4, CD7, CD8, CD34, CD45, CD10 CD19, CD20, CD13 B-cell cute lympholstic leukemi. T-cell cute lympholstic lymphom. c Terminl deoxynucleotidyltrnsferse.

3 Secondry Precursor T-Cell Lympholstic Lymphom Journl of Cncer Reserch Updtes, 2014, Vol. 3, No Tle 2: Summry of Somtic Genetic Altertions MLL Initil B-ALL Susequent T-LBL c d ETV6/RUNX1 fusion Deletion Present Rerrngement with unknown fusion prtner Not identified B-cell cute lympholstic leukemi. T-cell cute lympholstic lymphom. Mixed linege leukemi. d Ets vrint 6; runt-relted trnscription fctor 1. c cytometry, these tumor cells expressed CD7, CD8, CD3, CD4, CD10, CD34, nd CD45; ut did not express CD19, CD20, or CD13 (Tle 2). Immunohistochemicl stins on tissue sections demonstrted positivity for TdT nd CD3 (Figures 3B nd 3C) ut negtivity for PAX5, CD20, CD15, nd CD30. These morphologic nd immunophenotypic findings were most comptile with T-LBL. While the one mrrow ws morphologiclly uninvolved y the T-LBL, cytogenetic studies were performed on ilterl one mrrow specimens nd demonstrted the inv (2)(q31q37) in ll 20 metphses from ech one mrrow chromosome study. FISH ws performed on the T-LBL medistinl mss specimen nd demonstrted n MLL rerrngement in 41% of the nuclei without evidence of trnsloction to ny of A B C Figure 3: Precursor T-cell cute lympholstic leukemi/lymphom: A. Medistinl mss (H&E, originl mgnifiction x200). B. Lympholsts expressing terminl. deoxynucleotidyltrnsferse on immunohistochemistry (originl mgnifiction x200). C. Demonstrtion of CD3 positivity of the lsts (originl mgnifiction x200).

4 120 Journl of Cncer Reserch Updtes, 2014, Vol. 3, No. 2 Smith et l. the most common prtner gene loci (i.e. AFF1, MLLT3, MLLT4, MLLT10, ELL, or MLLT1). In ddition, FISH testing for ETV6 nd RUNX1 ws performed nd ws norml. Arry-comprtive genomic hyridiztion nlysis (CGH) ws performed on peripherl lood nd did not identify ny gins or losses t 2q31 or 2q37 t the resolution evluted with the SNP rry (pproximtely kiloses). The CGH nlysis did identify n interstitil deletion of 622 oligonucleotide proes t 16p13.3, spnning roughly 188 kiloses, involving the RBFOX1 gene (too smll to e confirmed y FISH). However, mternl CGH reveled the sme interstitil deletion, indicting mternl inheritnce to this microdeletion. Of note, the ptient s mother hs no known history of mlignncy. Further genetic evlution of the prond included sequence nlysis for dyskertosiscongenit, condition tht my predispose ffected individuls to one mrrow dysfunction, myelodysplsi, or leukemi, which ws negtive for muttions in the DKC1, TINF2, TERC, NHP2, NOP10, nd TERT genes. In ddition, DNA sequence nlysis of the TP53 gene (exons 2 through 11) did not identify muttions or sequence vrints. DISCUSSION B-ALL is one of the most common childhood mlignncies, ccounting for nerly one qurter of ll mlignncies in ptients under 15 yers of ge [1]. Identifiction nd description of genetic normlities in cute leukemis hs helped to elucidte the pthophysiology nd guide risk strtifiction nd tretment strtegies [2]. Multiple prognostic genetic sugroups hve een delineted in B-ALL with the most common recurrent trnsloction, t(12;21)(p13;q22) occurring in pproximtely 20-25% of peditric ptients [3]. Trnsloctions of the mixedlinege leukemi (MLL) gene, residing t 11q23, re prticulrly frequent in infnt leukemi, ccounting for 80% of ALL nd 60% of AML cses [3, 4]. MLL trnsloctions occur in ll cute leukemi sutypes (AML, B-ALL nd T-ALL) in the peditric ge group, nd occur with similr frequency of pproximtely 5-10%. MLL trnsloctions re generlly thought to indicte poor prognosis. However, over 100 different fusion sites hve een descried, nd studies now suggest tht the specific fusion prtner gene is of gret importnce [4, 5]. The presence of dditionl chromosoml normlities lso portends worse prognosis thn isolted MLL trnsloctions [6]. In our ptient, the initil B-ALL clone occurred t ge 3 nd ws chrcterized y ETV6/RUNX1 fusion nd n 11q deletion (MLL deletion y FISH). However, the susequent T-LBL clone occurring t ge 8 ws chrcterized y n MLL rerrngement nd lck of ETV6/RUNX1 fusion. An pprent constitutionl chromosome 2 inversion t q31 nd q37 ws identified t oth time points. Arry CGH indicted this inv (2) (q31q37) did not result in ny gin or loss of DNA t the level of resolution of pproximtely kiloses. However, possile tumor suppressor gene or proto-oncogene residing in the region of the inversion is possile which my predispose this child to develop cute lympholstic leukemi. Of interest, muttions of 2q31 (HOXD4) hve een previously descried y vn Scherpenzeel Thim, et l., in two cses of cute lympholstic leukemi; however further studies of this region re necessry efore drwing ny conclusions [7]. This child lso hd constitutionl interstitil deletion of 16p13.3 in wht is thought to e noncoding region of the RBFOX1 gene. The RBFOX1 gene regultes tissue-specific splicing y inding mrna precursors. While point muttions within this gene hve een ssocited with epilepsy, intellectul disility, nd utism [8, 9], this region on chromosome 16p13.3 is known region of polymorphic dupliction nd deletion without pprent phenotypic consequence. In ddition, since the mother shres the sme microdeletion nd hs no known mlignncies or other ovious normlities, the mternlly inherited 16p13.3 microdeletion likely represents fmilil vrition without significnt impct on phenotype. However, there still exists the possiility tht this is deleterious deletion with miniml expression in the mother or tht the deletion is not deleterious y itself, ut rther corresponding muttion in the llele on the second chromosome 16 within the deletion region in the prond could inctivte gene of interest, thus unmsking n utosoml recessive type scenrio nd generting complete loss of tumor suppressor or proto-oncogene within this region. Although secondry mlignncies re wellrecognized following tretment of primry neoplsm, secondry mlignncies following tretment of childhood cute lympholstic leukemi re uncommon. Among second mlignncies, secondry AML predomintes in peditric ptients, with myelodysplstic syndrome nd non-meningiom rin tumors lso occurring with some frequency [10]. Secondry cute lympholstic leukemi/lymphom

5 Secondry Precursor T-Cell Lympholstic Lymphom Journl of Cncer Reserch Updtes, 2014, Vol. 3, No (sall) is distinctly uncommon. Becuse of the rrity of sall, little is known out its etiology ut numer of pthogenic theories hve een proposed. One theory suggests tht sall ctully represents relpse or persistence of minor component in n initil iphenotypic/iclonl neoplsm, originting from common progenitor cell, in which minor supopultion initilly goes undetected [11]. Susequently, this supopultion my then emerge s n pprent second mlignncy. Theoreticlly, the residul tumor cells could possily dedifferente, redifferentite, nd then clonlly expnd, mnifesting s new mlignncy [12]. Still nother potentil mechnism of secondry mlignncy is tht of genetic dmge from cytotoxic tretment protocols [10-11, 13-15].Genetic predisposition to the development of cncer or gene-environment interctions my contriute to true second mlignncies [13]. The development of secondry ALL fter tretment of cute leukemi my e misinterpreted s relpse y the unwry, nd therefore under-reported. To clrify the true incidence of sall, Zun, et l., nlyzed children with cliniclly relpsed ALL following tretment with Berlin-Frnkfurt-Munster-sed protocols in four Europen centers. Of the 366 cses investigted, five cses (1.5% of those nlyzed) showed no clonl reltionship etween the initil nd recurrent disese, representing possile rel secondry mlignncy, either from pre-leukemic progenitor cell or novel pthwy, rther thn relpse. Two of those cses (0.5% of those nlyzed) fulfilled their criteri of pure sall (Tle 3) [11]. One cse ws tht of 5.1-yerold girl initilly dignosed with B-ALL. She relpsed once, then susequently developed T-ALL with new MLL rerrngement nd fusion to MAML2 t 11q21. She hd received rdition, etoposide, dunoruicin, nd cyclophosphmide/ifosfmide prior to cquiring T- ALL. The second cse ws 5.8-yer-old oy first found to hve B-ALL with ETV6/RUNX1 fusion. After tretment with etoposide, dunoruicin, nd cyclophosphmide/ifosfmide, he developed T-ALL [10]. Our ptient fulfilled Zun s criteri for pure sall since cytogenetic normlities nd fusion genes differed from the first presenttion to the second, nd were ccompnied y cler immunophenotypic linege switch. Secondry neoplsms fter tretment of n initil ALL re even more rre thn sall following other mlignncies [13]. This finding my e t lest prtilly due to the lower risk of tretment protocols for ALL compred to those used for other childhood cncers (e.g. smll round lue cell tumors, srcoms, Hodgkin s disese, etc) [14]. Tretment relted AML (t-aml) hs een reported not infrequently following tretment with rdition, epipodophyllotoxins, or topoisomerse II (topo-ii) chemotherpies. A proportion of cses, especilly those ssocited with topo-ii chemotherpies, show lnced trnsloctions involving the MLL gene t chromosome nd 11q23 [15]. Similrly, MLL rerrngements hve een reported in tretment-relted ALL (t-all), ut the incidence is fr lower [16]. In our cse, the ptient did not receive rdition, epipodophyllotoxins, or topo-ii chemotherpies fter the initil B-ALL. Additionlly, solid medistinl lympholstic lymphom hs not een descried s tretment-relted second mlignncy to our knowledge. For these resons, the thymict-lbl in our ptient ppers reltively unlikely to e relted to prior tretment, despite the presence of n MLL seprtion. CONCLUSION Secondry mlignncy following precursor B-cell cute lympholstic lymphom is rre. In our ptient, the divergent immunophenotypes of the tumor cells in ssocition with disprte genetic ltertions rgue for true secondry mlignncy, rther thn relpse. Although there re two other cse reports of T-ALL following tretment of B-ALL, these ptients hd received rdition nd/or topo-ii chemotherpy. To our knowledge, this ptient represents the first reported cse of solid (medistinl) T-LBL following B-ALL. The potentil ssocition with the constitutionl inversion, inv(2)(q31q37), or less likely the interstitil microdeletion t 16p13.3, is intriguing nd rises the considertion of possile proto-oncogene or tumor suppressor gene t or ner the inversion junctions or Tle 3: Criteri for Pure Secondry ALL, Proposed y Zun et l. No clonl reltionship etween dignosis nd recurrence (Ig/TCR, fusion genes t DNA level, cytogenetic mrker). -AND- Significnt immunophenotypic shift (i.e. linege switch), OR significnt cytogenetic shift, OR gin or loss of fusion gene Acute lympholstic leukemi. Immunogloulin/T-cell receptor.

6 122 Journl of Cncer Reserch Updtes, 2014, Vol. 3, No. 2 Smith et l. within the deletion region. Study of other ptients with genetic normlities involving these chromosome loctions is needed to clrify whether inversions or deletions in these regions re truly oncogenic. DISCLOSURES The uthors hve no conflicts of interest or funding to disclose. REFERENCES [1] Howlder N, Noone AM, Krpcho M, et l. SEER Cncer Sttistics Review, , Ntionl Cncer Institute. Bethesd, MD, sed on Novemer 2012 SEER dt sumission, posted to the SEER we site, April [2] Moormn A. The clinicl relevnce of chromosoml nd genomic normlities in B-cell precursor cute lympholstic leukemi. Blood Rev 2012; 26: [3] Swerdlow SH, Cmp E, Hrris NL, et l. WHO Clssifiction of Tumours of Hemtopoietic nd Lymphoid Tissues. IARC: Lyon [4] Blgoind BV, Rimondi SC, Hrott J, et l. Novel prognostic sugroups in childhood 11q23/MLL-rerrnged cute myeloid leukemi: results of n interntionl retrospective study. Blood 2009; 114: [5] Meyer C, Kowrz E, Hofmnn J, et l. New insights to the MLL recominome of cute leukemis. Leukemi 2009; 23: [6] Binto R, Meyer, C, Mcedo-Silv, ML, et l. Anlyzing cute leukemi ptients with complex MLL rerrngements y sequentil LDI-PCR pproch. Cncer Lett 2013; 338: [7] vn Scherpenzeel Thim V. Muttion nlysis of the HOX prlogous 4-13 genes in children with cute lymphoid mlignncies: Identifiction of novel germline muttion of HOXD4 leding to pritl loss-of-function. Humn Mut 2005; 25: [8] Bhll K, Phillips HA, Crwford J, et l. The de novo chromosome 16 trnsloctions of two ptients with norml phenotypes (mentl retrdtion nd epilepsy) disrupt the A2BP1 gene. J Hum Genet 2004; 49: [9] Mrtin CL, Duvll JA, Ilkin Y, et l. Cytogenetic nd moleculr chrcteriztion of A2BP1/FOX1 s cndidte gene for utism. Am J Med Genet B Neuropsychitr Genet 2007; 144B: [10] Schmiegelow K, Levinsen MF, Attrschi A, et l. Second mlignnt neoplsms fter tretment of childhood cute lympholstic leukemi. J Clin Oncol 2013; 31: [11] Zun J, Cve H, Szczepnski T, et l. Childhood secondry ALL fter ALL tretment. Leukemi 2007; 21: [12] Coled C, Jochum W, Busslinger M. Conversion of mture B cells into T cells y dedifferentition to uncommitted progenitors. Nture 2007; 449: [13] Bhti S, Sklr C. Second cncers in survivors of childhood cncer. Nt Rev Cncer 2002; 2: [14] Geeth N, SreedeviAmm N, Kusumkumry P, et l. Acute lympholstic leukemi occurring s second mlignncy: report of cse nd review of literture. Pedit Hemtol Oncol 1999; 16: [15] Thndl S, Alshri M, Green DM, et l. Therpy-relted T cell lympholstic lymphom with t(11;19)(q23;p13) nd MLL gene rerrngement. Leukemi 1999; 12: [16] Pedersen-Bjergrd J. Acute lymphoid leukemi with t(4;11)(q21;q23) following chemotherpy with cytosttic gents trgeting t DNA-topoisomerse II (editoril). Leukemi Res 1993; 16: Received on Accepted on Pulished on DOI: Smith et l.; Licensee Lifescience Glol. This is n open ccess rticle licensed under the terms of the Cretive Commons Attriution Non-Commercil License ( which permits unrestricted, non-commercil use, distriution nd reproduction in ny medium, provided the work is properly cited.