CD3-Negative CD4+ T-Cells: A Useful Diagnostic Tool with High Specificity in Angioimmunoblastic Lymphadenopathy (AILD)-Type T-Cell Lymphoma

Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma is one of the common T cell lymphomas in Western countries. Many patients present with symptoms of a systemic disease and diagnosis can often be challenging. Particularly in cases in which histological confirmation cannot be easily achieved flowcytometry of peripheral blood can give important clues for the differential diagnosis of AILD. We have previously reported that CD4-negative CD3+ T-cells in peripheral blood are a characteristic immunophenotypic finding in AILD patients. Gene scan analysis for the TCR gamma chain and intracellular CD3 expression clearly showed that these CD3-negative CD4+ cells are of T cell origin. In this study we further evaluated the phenotype of the CD4− CD3+ T cells and we compared their frequency in AILD patients with the frequency in patients with other histologically confirmed leukemic T cell lymphomas. 14 patients with AILD (clinical stage III/IV) were compared with 26 patients with other subtypes of leukemic T cell lymphomas (6 T-large granular lymphocyte leukemias (T-LGL), 4 T-chronic lymphocytic leukemias/prolymphocytic leukemias (T-CLL/PLL), 5 anaplastic large cell lymphomas (ALCL), 1 adult T-cell leukemia/lymphoma (ATLL), 1 mycosis fungoides and 9 peripheral T-cell lymphomas. Flowcytometric analysis of peripheral blood was performed in a lymphocyte gate using fluorochrome-labeled antibodies against CD3, CD2, CD4, CD5, CD7, CD8, CD16, CD56, CD57 and TCR. In 14/14 AILD patients a small but distinct population of CD3-negative CD4+ T cells was found (mean percentage of CD3-negative CD4+ T cells in the gate: 12,0 ± 17,6 %, range 0,05 – 51,8 %). In contrast, CD3-negative CD4+ T cells could be detected in only 1/26 patients with other leukemic T cell lymphomas. This patient had been diagnosed with mycosis fungoides. Further immunophenotypic analysis showed that the aberrant T cells in AILD also express pan T cell markers, such as CD2, CD5 and partially CD7, surface TCR expression could not be detected. In conclusion our comparative study shows that flowcytometric detection of CD3-negative CD4+ T cells in peripheral blood is a characteristic feature of AILD with a high specificity. Therefore, flowcytometry is particulary useful in the differential diagnosis of AILD, even if the aberrant T cell population has a very low frequency. Although AILD is mostly CD3+ on immunohistochemistry, the presence of low numbers of CD3-negative CD4+ T cells in peripheral blood appears to be a typical feature of AILD. Cytoplasmic CD3-expression is one possible explanation for this discrepancy. Since complete or partial loss of pan T cell antigens is a characteristic feature of many T cell lymphomas, the aberrant CD3-negative CD4+ T cells might also represent just a subfraction of lymphoma cells in AILD. Further biological characterization of this subpopulation should be performed.