AJHE2407 - CME/CMLE - How I diagnose large granular lymphocytic leukemia-How I diagnose large granular lymphocytic leukemia

How I diagnose large granular lymphocytic leukemia
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The review article discusses the diagnosis of Large Granular Lymphocytic Leukemia (LGLL), a rare clonal expansion of mature cytotoxic T cells or natural killer (NK) cells.<br /><br />**Key Points:**<br />- LGLL leads to cytopenia or hepatosplenomegaly.<br />- It shares similarities with reactive processes and uncertain T-cell and NK cell clones.<br />- Diagnosing LGLL requires an integrated approach, including morphology, immunophenotype, clonality, bone marrow, and genetic mutations.<br /><br />**Background:**<br />LGLL involves chronic proliferation of cytotoxic lymphocytes with granular morphology, divided into T-cell LGLL (T-LGLL) and NK-cell LGLL (NK-LGLL). It often presents diagnostic challenges due to overlaps with reactive conditions.<br /><br />**Clinical Features:**<br />- LGLL affects mostly adults (~60 years), with no significant sex or ethnic predilection.<br />- Cytopenia, particularly neutropenia, is common. Anemia and thrombocytopenia may also occur.<br />- Approximately 20-30% of patients exhibit splenomegaly, 10% have hepatomegaly, and isolated lymphadenopathy is rare.<br />- Around 30% of patients have autoimmune disorders, most commonly rheumatoid arthritis.<br />- Associated clonal hematologic diseases include B-cell lymphomas and myeloid neoplasms.<br /><br />**Diagnostic Approach:**<br />- Diagnosis hinges on meeting major criteria: clonal T/NK-cell proliferation, intrasinusoidal bone marrow infiltration by cytotoxic lymphocytes, genetic mutations in STAT3, STAT5B, and TET2, and unexplained cytopenia or organomegaly.<br />- Minor criteria involve immunophenotypically aberrant T/NK cells and persistent clonal cells for at least 6 months.<br />- Diagnostic workup may include morphological analysis, immunophenotyping, clonality assessment via flow cytometry, and molecular studies.<br /><br />**Case Studies:**<br />Two detailed cases illustrate the diagnostic process and pitfalls in differentiating LGLL from other conditions. Case 1 describes a 41-year-old man with γδ T-cell LGLL and autoimmune hemolytic anemia. Case 2 involves a 70-year-old man with NK-LGLL associated with somatic TET2 gene mutations, presenting with isolated anemia and splenomegaly.<br /><br />**Challenges:**<br />The review emphasizes the complexity of diagnosing LGLL due to significant overlap with reactive lymphocyte proliferations and the necessity of comprehensive evaluation involving clinical, histological, immunophenotypic, and molecular analysis to achieve accurate diagnosis and guide treatment. The evolution in understanding genetic mutations associated with LGLL aids in diagnosis and identifying therapeutic targets.<br /><br />**Conclusion:**<br />LGLL requires an integrated diagnostic approach that combines various clinical and laboratory findings. Improving comprehension of genetic variations enhances diagnostic precision and may open up new treatment avenues for LGLL.
Keywords
Large Granular Lymphocytic Leukemia
LGLL
cytopenia
hepatosplenomegaly
T-cell LGLL
NK-cell LGLL
immunophenotyping
genetic mutations
STAT3
TET2