Abstract
Simple SummaryLarge granular lymphocyte leukemia (LGLL) is a chronic disorder of either mature T or NK lymphocytes. As clonal expansions of the immune system cells, difficulties in the distinction between a true neoplasia and a physiological reactive process have been common since its description. We review here the different conditions associated with persistent clonal LGL expansions and discuss their potential origin and whether they can modulate the clinical features.Large granular lymphocyte leukemia (LGLL) is a chronic disease of either mature phenotype cytotoxic CD3+ T lymphocytes or CD3- NK cells. LGLL diagnosis is hampered by the fact that reactive persistent clonal LGL expansions may fulfill the current criteria for LGLL diagnoses. In addition to the presence of characteristic clinical and hematological signs such as anemia or neutropenia, LGLL/LGL clonal expansions have been associated with an array of conditions/disorders. We review here the presence of these persistent clonal expansions in autoimmune, hematological disorders and solid neoplasms and after hematopoietic stem cell transplantation. These associations are a unique translational research framework to discern whether these persistently expanded LGL clones are causes or consequences of the concomitant clinical settings and, more importantly, when they should be targeted.
Highlights
Large granular lymphocyte leukemia (LGLL) is defined as an abnormal clonal expansion of mature LGLs that remain long-term competent [1]
LGLL diagnosis is hampered by the fact that reactive persistent clonal LGL expansions may fulfill the current criteria for LGLL diagnoses
This hypothesis gains even more strength when considering the following observations: (1) STAT3 mutational status is closely associated with the presence of rheumatoid arthritis (RA) in patients with LGLL; (2) STAT3 mutations, revealing “hidden” cases of LGLL, have been detected in 6 out of 14 (43%) subjects with prior diagnosis of Felty’s syndrome (FS), as reported by Savola et al [40]; and (3) “aleukemic” forms of T-LGLL, with severe neutropenia and splenomegaly, some of them previously misdiagnosed with FS, have been recently reported by Gorodetskiy et al LGL infiltration and clonal TCR rearrangement were detectable in splenic tissue in all patients, and STAT3 was mutated in 3 (30%) of them
Summary
Large granular lymphocyte leukemia (LGLL) is defined as an abnormal clonal expansion of mature LGLs that remain long-term competent [1]. The presence of an acquired mutation in the JAK/STAT pathway seemed to definitely separate neoplastic from reactive cases. The diagnosis of LGLL, according to the 2016 classification of the World Health Organization (WHO), is based on a persistent (>6 months) increase in the number of LGL cells in peripheral blood (PB), usually 2–20 × 109/L, without an identifiable cause. Loughran first comprehensively compiled the different conditions associated with LGLL, and reviewed them under the soubriquet of “the root of many evils” [7]. We revisit here those evils, more described since, and a few associations related to good outcomes. We have kept the definition used by each author, even though many of the “LGL clonal expansions” may fulfill current WHO-defined LGLL criteria
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
