G.G., a 5 yo girl who has been followed-up from birth due to genetically proven Nijmegen syndrome. Last blood test before leukemia onset had been in September, 2016: WBC 4.7, ly 43%, minimal thrombocytopenia (176, age norm 189-394), low T4 cells (0.27, age norm 0.5-2.4), low IgG (2.72 g/L, age norm 5-15). Everything else OK.  
06.12.16. After a short prodrome she developed fever, hepatosplenomegaly (liver +5cm, spleen +6cm) with multiple small mesentric nodes. Blood showed leukocytosis up to 90.000 with>90% atypical cells (photos marked d00…), anemia and thrombocytopenia, LDH 2,000.  
There were medium-sized atypical pleomorphic cells with partial maturation. Flow showed mature T phenotype: cytCD3+, CD7++, mCD3++, CD45++, TdT-, CD34-, CD5++, CD2+, CD1a-, CD99-, CD10-, CD8++, CD4 very weak, TCRab+, CD56-. CD38++, CD25 weak, CD16+, CD45RA-, HLA-DR weak.  
Cytogenetics showed a mixture of multiple hyperploid clones.  
TCR/IG clonality was performed in Lithuania; no clonal TCRB, TCRG, TCRD rearrangements detected, polyclonal background also absent. IGH - a limited diversity of polyclonal/oligoclonal pattern, IGK, and IGL in germline status.  
Marrow was totally infiltrated by phenotipically the same cells, Granzyme B was negative.  
The initial tentative diagnosis was mature T-ALL. Reduced ALL BFM protocol (50% dose at the beginning, later increased to 75%) commenced; therapy was tolerated well. Clinical status improved with some decrease in hepatosplenomegaly and LDH. Only partial remission was achieved at control points (see marrows at day 33 and day 78).  
EBV antibodies were negative, there had been documented CMV infection earlier. CMV copy number rose during treatment: December 16 – 510, - December 21 – 8950 (therapy with IVIG+Acyclovir), December 28 - 537, January 4, 17, 31 - negative.  
After some consulting the case was considered to be the systemic T-cell lymphoproliferative disease of childhood, but CMV-driven in immunodeficiency setting.  
On January, 30 at admission for the next course: substantial hepatosplenomegaly, multiple 15-20mm intraabdominal nodes, PLT decreased from previously normal range and LDH increased to 1055 U/l.  
Marrow from February, 3 (photos marked 4…). Incomplete remission of T-LPD. In addition, there is massive myeloid hyperplasia with eosinophilia, disorganised, but with more or less preserved maturation and no blasts. Increased atypical megas, including microforms. Deep reduction of erythropoiesis.  
There have always been problems with marrow cytology (prominent hemodilution), probably due to prominent myelopathy; trephines were much more sensitive for MRD. The aspirate taken simultaneously with the last trephine was deeply hypocellular, too, but WBC were higher than in blood (4.000 vs 0.8), there was some atypia - see photos marked cyt... I am particularly proud of finding a micromegakaryocyte.  
Blood values at the moment: WBC 0.79, NEU 0.4, LYM 0.3, HGB 9.4 (after transfusions), MCV 88.1 (N < 85), MCH 28.7 (N < 28.6), normoblasts 1.3%, PLT 71 (after transfusions).  
I've never seen such regeneration in ALL kids. Taking into account Nijmegen's fragile genome, could it be a secondary MDS?

tzankov 2017-02-22 07:06	very difficult case, indeed! is there some cytogenetic evidence showing typical myeloid aberrations? though the T-cells look blastic, is it possible for you to stain them for TCL1? I am not aware of the diagnosis of CMV LPD of childhood. CMV can promote (oligo-) clonal T-cell responces that are per se CMV-; but this LPD behaves like a tumor (organ involvement, leukocytosis) and has a mature, yet abnormal flow profile. mature T-ALL is the best wokring hypothesis I think.     considering the suspect MDS - indeed I see some micormegacaryocytes, but this is still not enough to cass the case MDS shortly after a chemo ha been administed... is there a BM smear to look for dysplasia in the other lineages?
SergeyN 2017-02-22 09:32	Dear Alex, thank you for the comments.   1. We treat her as ALL, but not very successfully so far. The problem with initial diagnosis is that there is not a single precursor marker. The only thing that reminds of blasts is bright CD7. Membrane CD3 ir very bright, CD4 coexpression is more imaginary than real and so on. Blasts often lack CD45RA, but it could be a feature of high activation (HLA-DR is positive), and its positivity was modulated during treatment. Mature T-ALL should be at least CD99 positive... And no, we don't have TCL1.   2. CMV instead of EBV in this setting was suggested by an outside consultant, and we really couldn't reject it for 2 reasons. First, the patient has primary immune deficiency and fragile chromosomes as a part of her syndrome, nobody really knows how persistent CMV behaves in this setting. Second, the cells have partly cytotoxic phenotype (CD3+, CD8++, CD16+, CD56-) with activation (CD25+, CD38++, HLA-DR+, CD45RA-) that would look nice in EBV-driven LPD of childhood.   Such a mess...   I will add blood values to text and marrow smear to photos, sorry, my omission.
SergeyN 2017-02-23 11:13	As for myeloid origin, the cells were CD45++ and negative for MPO, CD13, CD33, CD123. There was no CD15 or CD68 positivity on histology.
SergeyN 2017-02-23 16:00	cytology of the last biopsy uploaded
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