TCR gamma/delta LGL proliferation causing recurrent episodes of neutropenia proceeding into fatal hepatosplenic T-cell lymphoma in an adolescent girl 5 years after renal transplantation Mejstříková Ester, Sumerauer David, Froňková Eva, Mužíková Kateřina, Seeman Tomáš, Zemanová Zuzana, Čapková Linda, Kodet Roman, Edita Kabíčková, Ondřej Hrušák Departments of Pediatric Hematology and Oncology, Pediatrics, Pathology 2nd Faculty of Medicine, University Hospital Motol Center of Tumor Cytogenetics, First Faculty of Medicine, General University Hospital Charles University Prague

absolute neutrophil count 02/2005 – 10/ /2006 neutropenia, marrow aspirate normal, stomatitis 10/ january 2007 january - february 2007 atypical "monocytes" in blood time 16-years old female 5-years after kidney transplantation for end stage renal failure (Fanconi nephronopthisis) combined immunosuppression (prednisone, tacrolimus, mycophenolate)

Immunophenotype of "atypical monocytes" Forward scatter Side scatter CD3 CD5 CD7 CD7dimCD5negTCRgamma/delta+CD3bright+ proven clonality in TCR genes VgI-JG1.3 Dd2-Jd1-3 cytogenetic including FISH no abnormality

Other findings transient hepatosplenomegaly by ultrasound transient hepatosplenomegaly by ultrasound anemia, transient trombocytopenia anemia, transient trombocytopenia increased triacylglycerols (up to14.28 mmol/L , ferritin not analysed) increased triacylglycerols (up to14.28 mmol/L , ferritin not analysed) retrospectivelly extremely increased sCD25 (incipient organ rejection, marker of T cell proliferations) retrospectivelly extremely increased sCD25 (incipient organ rejection, marker of T cell proliferations) Interim diagnosis Proliferation of clonal atypical T  cells morphologically appearing as monocytes = previously described posttransplant non malignant chronic condition (Tαβ more frequent) Treatment started 6- mercaptopurin, continued G-CSF

May 2007, 3 months after beginning of treatment with 6-mercaptopurin Since 5/2007 febrile, pancytopenia, abdominal distension (ascites, organomegaly). WBC: Leu 6.0, Ery 2.29, Hb 70, hct 0.205, tr 10, atypical cells 62%, LDH (IFCC) 27.02, ferritin FACS (blood): same immunophenotype as in January, increased SG2M fraction (>20%) in bone marrow and peripheral blood

Change of clinical behaviour = hepatosplenic T– NHL rare type of extranodal lymphoma young adults (median age, 35 years) typical B-symptoms, organomegaly splenomegaly + hepatomegaly, lymphadenopathy usually not present often pancytopenia also identified in patients treated with immunosuppression (after organ transplants or after TNF-alfa inhibitors) what‘s known:

Prednisone 60 mg/m 2 /d Fludarabin 30 mg/m 2 /d1-3 MabCampath 3,10,3x30mg VCR 1.5 mg/m 2 Daunorubicin 30 mg/m 2 Asparaginase U/m 2 days of therapy WBCx 10 9 /L Therapy (day 1-13) WBC x 10 9 /l no response, death 13 days since diagnosis

Change of biological behaviour cytogenetics 6/2007 – newly identified isochromosome 7, abnormality often identified with hepatosplenic lymphoma

Retrospective analysis of clonal atypical T cells march 06 normal WBC neutropenia

Conclusions prelymphoma cells found in patient more than 1 year before lymphoma manifestation Isochromosome found as a late change during the lymphomagenesis hepatosplenic lymphoma after solid organ transplantation: very rare, very poor outcome, no therapeutic approach established

Conclusions appendix - T a NK cell PTLD - SH Swerdlow, AJCP, 2007, review 130 publ. případů