Richter's Syndrome manifested as diffuse large B-cell lymphoma of the mandible with lytic lesions and hypercalcemic crisis

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Case report/Kazuistyka

Richter's Syndrome manifested as diffuse large B-cell lymphoma of the mandible with lytic lesions and hypercalcemic crisis

Zespó ł Richtera objawiaj ący si ę jako ch łoniak rozlany żuchwy z du żych komórek B ze zmianami litycznymi i prze łomem hiperkalcemicznym

Katarzyna Wiśniewska-Piąty, Grzegorz Helbig *, Krzysztof Woźniczka,

Andrzej Frankiewicz, Joanna Dziaczkowska-Suszek, S ławomira Kyrcz-Krzemie ń

DepartmentofHematologyandBoneMarrowTransplantation,SilesianMedicalUniversity,Katowice,Poland actahaematologicapolonica 44(2013) 409–412

article info

Articlehistory:

Received:01.01.2013 Accepted:16.01.2013 Availableonline:21.03.2013

Keywords:

Chroniclymphocyticleukemia

Richter'sSyndrome

DiffuselargeB-celllymphoma

Hypercalcemia

Outcome

Słowakluczowe:

przewlekłabiałaczkalimfatyczna

zespółRichtera

chłoniakrozlanyzdużych komórekB

hiperkalcemia

przeżycie

abstract

Richter's Syndrome (RS)is a transformation from chronic lymphocytic leukemia (CLL) into more aggressive lymphoma. RSoccurs in about 5% of patients with CLL and its clinicaloutcomeispoor.ExtranodalinvolvementsofRSmaybepresentinupto40%of patientsandcentralnervoussystemmanifestationwasfoundtobethemostcommon.

MandibularlocalizationofRShasnotbeenreportedsofar.Thereisnoestablishedstan- dardtreatment for RS.The improvement ofsurvivalin RSpatientsis achievable with intensiveanti-lymphomachemotherapyandsubsequentallogeneicstemcelltransplan- tation(alloHSCT)performedincompleteremission.HereinwereportafemalewithRSof therightmandibleandhypercalcemiawasitsﬁrstclinicalmanifestation.

*Corresponding author at: Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland,Dabrowskistreet25.Tel.:+48322591281;fax:+48322554985.

E-mailaddress:ghelbig@o2.pl(G.Helbig).

ContentslistsavailableatSciVerseScienceDirect

Acta Haematologica Polonica

journalhomepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2013.01.001

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Introduction

Richter'sSyndrome (RS)known asRichter's transformation (RT) remains a rare complication of chronic lymphocytic leukemia(CLL)ofanystage[1]. RSoccursin5%of patients with CLL and its clinical outcome is poor with a median overall survivalof about 8months [2]. Extranodal involve- ments of RSmay bepresent inup to 40% of patientsand centralnervous systemmanifestation was foundtobethe most common in a large study cohort. Bone localization remains extremely rare and RS of the mandible has not been reported so far. The clinical outcome is poor with amedianoverallsurvivalof 5monthsfrom thetimeof RS diagnosis [3]. Herein we report a female with a 3-year historyofCLLwhodevelopedRSinitiallymanifestedaslytic lesionintherightmandiblewithhypercalcemiccrisis.

Case report

A 45-year-old previously healthy female was admitted to ourDepartmentinJanuary2009withasuspicionofchronic lymphocytic leukemia (CLL). She complained of protracted respiratorytractinfection.On admissionphysicalexamina- tion revealedtheenlargement of cervical,axillarand ingu- inal lymph nodes. The abdominal ultrasound examination revealed hepatosplenomegaly and enlarged para-aortic lymphnodes. White bloodcell (WBC)count was 2110⁹/L withan increased lymphocyte count (13.2510⁹/L). Hemo- globin (Hgb) concentration and platelet (PLT) count were normal. Biochemistry disclosed elevated serum lactate dehydrogenase (LDH=253IU/L; normal range: 91–180IU/L) and b2-microglobulin (b2M=8.59mg/L; normal range: 1.5–

3.0mg/L). The bone marrow was infiltrated by small lymphocytes in 90%. The immunophenotyping of peripheral blood lymphocytes by flow cytometrywas consistent with a diagnosis of CLL. Theexpression of CD38 and ZAP70on lymphocytes was strongly positive. Fluorescence in situ hybridization (FISH) revealeddeletion of 11q chromosome, no other abnormalities were detected. Disease stage was established to be II according to Rai. Nine cycles of CC regimen(Cyclophosphamide,Cladribine)wereintroducedas first line therapy. Patient's lymphocyte count returned to normal, sheresolved peripheral lymphadenopathy but the enlarged lymph nodes were still present in her abdomen.

Due to this ﬁnding she was started R-CHOP regimen (Rituximab, Cyclophosphamide, Adriamycin, Vincristine, Prednisone)with noresponseafter 7 cycles.Thesuspicion of Richter's transformation prompted abdominal lymph node biopsy. The histopathologic examination was consis- tentwith primarydiagnosis of CLL. Patientwas proceeded to subsequent lines of chemotherapy including: R-ESHAP (Rituximab, Etoposide, Cisplatin, Cytarabine and Methyl- prednisolone) and FMD (Fludarabine, Mitoxantrone, Dexa- methasone) followed by palliativeradiotherapy (30 Grey in 10 fractions on upper-mesentery lymph nodes). She achieved only minor decrease of tumor mass. Finally, she received RB regimen (Rituximab Benadmustine) but the treatmentwas complicated byVaricella Zoster Virus(VZV)

infection. Subsequent cycles of chemotherapy were post- poned.Afewweekslatershewasurgentlyadmittedtoour Department due to worsening of overall condition with markedconfusion. Therewasrecenthistoryoftoothextrac- tion.Physicalexaminationrevealedswellingoftherightside ofthefacewithunilateralguminﬁltration.Bloodcountswere following:WBCcount:9.210⁹/Lwith37%oflymphoidcells in differential, Hgb concentration: 12.9g/dl and PLT count:

1810⁹/L.Bonemarrowbiopsyshowed100%inﬁltrationwith lymphoidcellsandimmunophenotypingwastypicalforCLL.

There were increased serum calcium (4.43mmol/L; normal range: 2.10–2.55mmol/L)and creatinine(225mmol/L; normal range:37–96mmol/L)levelsonbiochemistry.TheX-rayskele- talsurveyshoweddestructionoftherightjawwithlargelytic lesionanddisseminatedlyticlesionsinscull,righthumerus, scapulaandribs(Fig.1).Shedevelopeddiplopiaandptosison the right. Magnetic Resonance Imaging (MRI) of the head revealedpathologicalinﬁltration ofintracranialcaves,bones and right carotid artery (Fig. 2). Histological examination of the biopsied gum was consistent with the diagnosis of DLBCL.Shewasstartedanintensivetreatmentforhypercal- cemiccrisisandCHOPtreatmentwasintroducedasasalvage regimen.Thechemotherapyresultedintransitionalimprove- mentofoverallconditionbutthesymptomsofhypercalcemia recurred with subsequent fatal outcome despite intensive supportive care.The autopsy showedlymphoid inﬁltrations present in lymph nodes, bone marrow, spleen, pituitary gland,stomach,andkidneys.

Fig.1–SkullX-ray.Osteolyticlesionsseeninthebonesof theskull.Thelongerarrowshowsthepathologicalfracture oftherightmandible,theshorterarrowsshowosteolytic lesionsinskull)

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Discussion

Richter's Syndrome remains a rare complication of CLL or SLL.PathogenesisofRSremainsunknown.Itwaspostulated that transformation into aggressive lymphoma may be triggered byviral infection, especiallyEBV [1]. RT ismani- fested predominantly as diffuse large B-cell lymphoma (DLBCL), but presentations as Hodgkin lymphoma[4], lym- phoblasticlymphoma[5]orhairycellleukemia[6]werealso reported. The extranodal manifestations in testis, central nervoussystem,skinorgastrointestinaltractwerefoundto be the most common [3, 7–10]. To our best knowledge a patientwith mandibular localizationof RShas notbeen describedintheliterature sofar.However,thereare single cases of DLBCL localized in the mandible [11, 12]. It was demonstrated that RS may occur at both early and late phases of CLL and prompt diagnosis is crucial for clinical outcome[1,13].Hypercalcemiaastheﬁrstmanifestationof RS has been rarely reported so far [3,14, 15]. All patients presented with hypercalcemia-associatedRS had prior CLL and osteopenia with lytic lesions were found in X-ray survey.Twomechanismsofhypercalcemiawerepostulated.

Firstitmayresultsfromanincreasedboneresorptionwhich is due to secretion of osteoclast-stimulating factors by tumorcells.InadditionanoverproductionofinterleukinIL- 6and tumornecrosis factor TNF-aseems toplay arole in the developmentof hypercalcemiain singlecases. Despite initial responsetotherapy withbone resorption inhibitors, the outcome was eventually fatal [14]. The same was also observed in our patient. Other study demonstrated that

patients with hypercalcemia-associated DLBCL had shorter survival if compared to those with normal serum calcium level[16].SeveralfactorsmaypredictthedevelopmentofRS andtheydifferfromthoseforCLLprogression.Amultivariate analysis including biologicalandclinical variablesidentiﬁed lymph node size 3cm and the lack of deletion 13q14 as predictorsofRichter'stransformation[13].Itwasalsodemon- stratedthatsomegeneticabnormalitieswerecrucialforthe development of RS and they had higher complexity and heterogeneity if compared to CLL. A detailed molecular characterizationof 86patientswith RShasfound thatTP53 disruption and c-MYC rearrangements were themost common genetic alterations. Moreover, the absence of TP53 disruption was associated with an improved survival. This studyrevealedthreepredictorsofRSsurvivalandtheywere following: 1) TP53 status, 2) response to treatment and 3) ECOGperformance[17].Diseaseoutcomeintermsofclinical course and response to therapy was variable. There is no established standard treatment for RS. In a large study including352patientswithprobableorprovenRS,anoverall response was 39% and there was no difference between chemotherapy and chemoimmunotherapy. Most common therapeutic schema included purine analog-based therapy, Hyper-CVAD (cyclophosphamide, doxorubicin, vincristine, dexamethasone)orCHOP+/ anti-CD20monoclonalantibody.

Itwasalsodemonstratedthatallogeneichematopoieticstem celltransplantation (alloHSCT)usedasremissionconsolida- tion may prolong survival in this patient cohort [2]. In summary, bone damage by lymphoma cells resulting in resistanthypercalcemiamaybetheﬁrstmanifestationofRS.

The prognosis remains fatal despite aggressive chemotherapy.Basedoncurrentexperiencetheimprovementofsurvi- val in RS patients is achievable with intensive anti- lymphomaregimensandsubsequentalloHSCTperformedin completeremission[2].

Authors' contributions/Wkład autorów

KWP – study design, data collection and interpretation, manuscript preparation, literature search. GH – study design, data interpretation, manuscript preparation. JDS – studydesign.KW,AF–datacollection.GH–datainterpreta- tion,manuscriptpreparation.SKK–manuscriptpreparation.

Financial support/Finansowanie

Nonedeclared.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

Ethics/Etyka

Thework describedinthisarticlehavebeen carriedoutin accordance with The Code of Ethics of the World Medical Fig.2–MRIscanofthehead.Lymphomainfiltrationofthe

mandible

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Association(Declaration of Helsinki)for experimentsinvol- ving humans; EU Directive 2010/63/EU for animal experi- ments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.

When submitting article with own research on people/

animals,theresearchwereconductedaccordingtotheGood ClinicalPracticeguidelines, allpatientsagreedinwritingto participation and these researches wereaccepted by local BioethicsCommittee.

references/pi smiennictwo

[1] TsimberidouAM,KeatingMJ.Richtersyndrome:biology, incidenceandtherapeuticstrategies.Cancer2005;103:

216–228.

[2] TsimberidouAM,O'BrienS,KhouriI,GilesFJ,Kantarjian HM,ChamplinR,etal.Clinicaloutcomesandprognostic factorsinpatientswithRichter'sSyndrometreatedwith chemotherapyorchemoimmunotherapywithorwithout stem-celltransplantation.JournalofClinicalOncology 2006;24:2343–2351.

[3] RobertsonLE,PughW,O'BrienS,KantarjianH,Hirsch- GinsbergC,CorkA,etal.Richter'sSyndrome:areporton39 patients.JournalofClinicalOncology1993;11:1985–1989.

[4] BrecherM,BanksPM.Hodgkin'sdiseasevariantofRichter's Syndrome.Reportofeightcases.AmericanJournalof ClinicalPathology1990;93:333–339.

[5] PistoiaV,RoncellaS,DiCellePF,SessaregoM,CutronaG, CerrutiG,etal.EmergenceofaB-celllymphoblastic lymphomainapatientwithB-cellchroniclymphocytic leukemia:evidenceforthesingle-celloriginofthetwo tumors.Blood1991;78:797–804.

[6] DuchayneE,DelsolG,KuhleinE,KleinB,ZhangXG,AttalM, etal.HairycelltransformationofaB-cellchronic

lymphocyticleukemia:amorphological,cytochemical, phenotypicandmolecularstudy.Leukemia1991;5:

150–155.

[7] HoudeletteP,DumotierJ,HautevilleD,PierreC,BerthodN.

Richter'ssyndromewithtesticularlocalization.Journalof Urology1989;95:507–508.

[8] O'NeillBP,HabermannTM,BanksPM,O'FallonJR,EarleJD.

Primarycentralnervoussystemlymphomaasavariantof Richter'ssyndromeintwopatientswithchronic

lymphocyticleukemia.Cancer1989;64:1296–1300.

[9] YuL,BandhlishA,FullenDR,SuLD,MaL.Cutaneous Richtersyndrome:reportof3casesfromoneinstitution.

JournaloftheAmericanAcademyofDermatology 2012;67:187–193.

[10] ParrensM,SawanB,DubusP,LacombeF,MaritG,VergierB, etal.PrimarydigestiveRichter'sSyndrome.Modern Pathology2001;14:452–457.

[11] KiniR,SahaA,NaikV.DiffuselargeB-celllymphomaof mandible:acasereport.MedicinaOralPatologiaOraly CirugiaBucal2009;14:421–424.

[12] SomeyaM,SakataK,NagakuraH,ItouK,NakataK,Oouchi A,etal.ThreecasesofdiffuselargeB-celllymphomaofthe mandibletreatedwithradiotherapyandchemotherapy.

RadiationMedicine2005;23:296–302.

[13] RossiD,CerriM,CapelloD,DeambrogiC,RossiFM, ZucchettoA,etal.Biologicalandclinicalriskfactorsof chroniclymphocyticleukaemiatransformationtoRichter syndrome.BritishJournalofHaematology2008;142:

202–215.

[14] BeaudreuilJ,LortholaryO,MartinA,FeuillardJ,GuillevinL, LortholaryP,etal.HypercalcemiamayindicateRichter's Syndrome:reportoffourcasesandreview.Cancer 1997;79:1211–1215.

[15] BrionesJ,CervantesF,MontserratE,RozmanC.

Hypercalcemiainapatientwithchroniclymphocytic leukemiaevolvingintoRichter'sSyndrome.Leukemiaand Lymphoma1996;21:521–523.

[16] MajumdarG.Incidenceandprognosticsigniﬁcanceof hypercalcaemiainB-cellnon-Hodgkin'slymphoma.

JournalofClinicalPathology2002;55:637–638.

[17] RossiD,SpinaV,DeambrogiC,RasiS,LaurentiL, StamatopoulosK,etal.ThegeneticsofRichterSyndrome revealsdiseaseheterogeneityandpredictssurvivalpost- transformation.Blood2011;117:3391–3401.

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