Large granular lymphocyte disorders


Clonal vs reactive increases to NK cells

The number of circulating large granular lymphocytes is normally around 0.25×109/L, but may be increased in a range of conditions. However, reactive counts do not usually exceed 0.4x109/L. Where counts approach 2x109/L and are sustained (more than 6 months in the absence of a clear cause) an LGL disorder is likely. Even with lower counts, LGL disorders should be considered where there are cytopenias, or in the context of rheumatoid disease.

The non-aggressive LGL disorders comprise two forms:

  • T-cell large granular lymphocytic leukaemia (>85% of cases)
  • Chronic lymphoproliferative disorder of NK cells (around 10% of cases)

Generally, both are indolent disorders that affect older individuals. Patients may be asymptomatic, or may present with cytopenias, recurrent infections or fatigue. Splenic enlargement is frequent and LGL cells are usually increased in the bone marrow (>10%). These disorders are more frequent in Asia.

The term LGL lymphocytosis – may be used when clonality is not confirmed, but there are clinical features related to LGL excess (such as neutropenia or anaemia). Persistent polyclonal forms may be seen post-splenectomy or after transplant of BM or solid organs.



The morphology is similar for both types of disorder:

  • The count of abnormal cells should be greater than 2 x109/L
  • The cells are of medium to large size with abundant cytoplasm
  • Cytoplasm generally contains azurophilic granules, but these will be sparse and may occasionally be absent
  • Nucleus is most often round or kidney-shaped, while chromatin is often soft and indistinct

Note some cases have atypical appearance and may be mistaken for other LPD so immunophenotype may be more sensitive for diagnosis in some instances


CD16, CD56 and CD57 are useful in detecting both T cell and NK cell forms although aberrant features should be expected. The immunophenotype will generally allow distinction between T cell and NK cell forms.


LGL lymphocytosis

Recognising LGL cells generally requires the typical sparse granules within cytoplasm to be present (the upper of the two LGL cells). However, granules may sometimes be very sparse or absent (the lower cell). In those cases look for the other typical features - pale blue cytoplasm that often appears to "flow" against adjacent red cells, as well as an angular nucleus (reminiscent of some cases of CLL) with very indistinct chromatin pattern that may contain a subtle nucleolus. Other features related to the autoimmune effects associated with LGL lymphocytosis may be found - look particularly for neutropenia.



Clonal chromosomal abnormalities may be seen but are not frequent.

Genetic testing

TCR gene studies can be used to confirm clonality of T cell LGL cell, and targeted NGS may confirm STAT3 mutations (present in 30-40% of cases). It is difficult to assess the clonality of NK-LGL because these cells do not express TCR; also STAT3 tends not to be mutated.

BM trephine

May show intrasinusoidal infiltrates with expression of TIA-1 in T-cell forms