CD3-CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder

Abstract

The CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3(-)CD4(+) T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome. Atypical CD4(+) T cells lymphoid infiltrates were found in 10 of 12 CD3(-)CD4(+) L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3(-)CD4(+) T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3(-)CD4(+) T cells were CD2(hi) (n=9 of 14), CD5(hi) (n=12 of 14), and CD7(-)(n=4 of 14) or CD7(low) (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3(-)CD4(+) T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative disorder, which should not be confused with angio-immunoblastic T-cell lymphoma.

Figure 1.

Skin histopathology in CD3⁻CD4⁺ L-HES. Hematoxylin and Eosin (HE) staining of these two representative skin biopsies (Patients P1 and P2) reveal dense nodular, periadnexal and perivascular infiltrates (black arrows), a hypodermis infiltrate in P2 (*). Lymphoid cells are small to medium-sized, with irregular nucleus and scarce cytoplasm. Numerous eosinophils are also observed (Δ). Cells appear to be CD3⁺CD4⁺ (A), there are no CD10, CXCL13 and PD1-positive cells (data not shown). Flow cytometry confirms the presence of CD3⁻CD4⁺ T cells in skin lesions (B). The same clonal TCRγ rearrangement is detected in skin and blood samples (C).

Figure 2.

Persistence of clonal T cells in peripheral blood and various tissues CD3⁻CD4⁺ L-HES patients. Comparison of TCR rearrangement (γI-10 and γ9–11 family genes) between the most recent peripheral blood sample and various tissues biopsies in 7 representative CD3⁻CD4⁺L-HES patients. Note the spatial dissemination of the clonal T cell in various sites, including peripheral blood, and its persistence over years in all patients. Patient P4’s samples presented here have been collected during L-HES course, before AITL diagnosis.

Figure 3.

Comparison of cytological characteristics of lymphoid cells in CD3⁻CD4⁺ L-HES and at AITL diagnosis in patient P4. In context of CD3⁻CD4⁺ L-HES (lymph node biopsy performed during follow up in 2011), lymphoid cells were monomorphic, small- to medium-sized, with irregular nucleus and scarce cytoplasm (HE: Hematoxylin & Eosin staining), and did not express CD10, CXCL13 or PD1. At AITL diagnosis in 2014, neoplastic cells were polymorphic, medium to large sized with clear nucleus and clear and large cytoplasm, and some CD10, CXCL13 and/or PD1-positive cells are found. In both cases, the same clonal TCRγ rearrangement was detected.