Clonal T-Large Granular Lymphocyte Proliferations in Childhood: Friend or Foe?

Background: The pathophysiology of clonal T-large granular lymphocyte (T-LGL) proliferations is not well understood; the distinction between reactive and malignant entities is not very clear given the fact that acquired STAT3 mutations can be seen with clonal T-LGL proliferations in non-malignant Felty syndrome and with frequent use of immunosuppression for the treatment of T-LGL leukemia. Historically, determination of clonality has been often seen as an indicator of T-LGL leukemia. We reviewed our experience on clonal T-LGL proliferations in children.

Material and Methods: T-LGLs were identified by CD3 and dim CD5 staining on flow cytometric analysis and observation of lymphocytes with large granular cytoplasm appearance in peripheral blood. Cases with peripheral blood lymphocyte T-LGL population greater than 10% were reviewed in patients whom had flow cytometry studies performed for different indications. Among them, ones with available T cell receptor (TCR) gene rearrangement studies were selected and 16 cases with clonal TCR rearrangement patterns were included in this study. Fifty-seven peripheral blood flow cytometric tests using 15 surface markers were analyzed in those 16 cases. Patients have been followed for up to 7 years.

Results: Sixteen cases of clonal T-LGL proliferation associated with different diseases were included in this analysis. Three patients had chronic graft versus host disease, 2 Evans syndrome, and one case each with the following conditions: common variable immunodeficiency disorder, severe combined immunodeficiency who developed CMV infection following umbilical cord blood transplantation (UCBT) and later acute EBV infection, co-existing Langerhans cell histiocytosis and primary hemophagocytic lymphohistiocytosis, autoimmune hemolytic anemia, chronic idiopathic thrombocytopenic thrombocytopenia, Hodgkin lymphoma, X-linked lymphoproliferative disorder, Rosai Dorfman disease (RDD), acute EBV infection, acute parvovirus B19 infection and paroxysmal nocturnal hemoglobinuria with history of treated severe aplastic anemia. Pathophysiological processes involved in these cases included various combinations of inherited immune deficiency in 4, acquired immune deficiency in 5, lymphoproliferation in 6, alloimmune reaction in 3, autoimmune reaction in 5, infection in 4, inflammation in 3 and malignancy in 1. One patient had three different clonal populations at different times due to maternal engraftment, CMV infection following UCBT and during an acute EBV infection after immune suppression withdrawal, respectively. The patient with RDD developed clonal T-LGL expansion when his disease flared. In some cases, clonal T-LGL proliferations disappeared with the resolution of the underlying pathological process. However, the T-LGL clone persisted and was frequently associated with relative increase over time, if the disease process continued to be active and/or progressed, even despite use of therapeutic approaches often including immunosuppression. Four clonal T-LGL proliferations in 2 patients have resolved, remaining 10 were persistent and have not been reevaluated in 4 cases. None of the cases showed a purely monoclonal pattern. The size of the clonal T-LGL population was variable with a median value of 18.6%, as high as 58.7% of the lymphocyte population. T-LGL population has positively correlated with CD3, CD8, CD57 (p<0.001) and inversely with CD19 (p=0.001) expression. There was also an overall positive correlation between the percent of T-LGL cells and absolute T-LGL count (p<0.001).

Discussion: Clonal T-LGL proliferations in childhood is a reactive process reflecting the activity of the underlying disease process, including immunodeficiency, autoimmunity, alloimmunity, infection, inflammation, lymphoproliferation and malignancy. Use of immunosuppression has been associated with relative increase in the clone size despite decrease in peripheral blood absolute lymphocyte count along with relative reduction in T and B lymphocyte compartments in patients with active disease. Presence of clonal T-LGL proliferations in a polyclonal background is not an indicator of malignant process. It is very possible that such proliferations are an effort of the immune system to control the most prominently involved immunogenic stressors.