The lymphoid variant of hypereosinophilic syndrome: study of 21 patients with CD3-CD4+ aberrant T-cell phenotype

Abstract

The CD3-CD4+ aberrant T-cell phenotype is the most described in the lymphoid variant of hypereosinophilic syndrome (L-HES), a rare form of HES. Only a few cases have been reported, and data for these patients are scarce. To describe characteristics and outcome of CD3-CD4+ L-HES patients, we conducted a national multicentric retrospective study in the French Eosinophil Network. All patients who met the recent criteria of hypereosinophilia (HE) or HES and who had a persistent CD3-CD4+ T-cell subset on blood T-cell phenotyping were included. Clinical and laboratory data were retrospectively collected by chart review. CD3-CD4+ L-HES was diagnosed in 21 patients (13 females, median age 42 years [range, 5-75 yr]). Half (48%) had a history of atopic manifestations. Clinical manifestations were dermatologic (81%), superficial adenopathy (62%), rheumatologic (29%), gastrointestinal (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). The median absolute CD3-CD4+ T-cell count was 0.35 G/L (range, 0.01-28.3), with a clonal TCRγδ rearrangement in 76% of patients. The mean follow-up duration after HES diagnosis was 6.9 ± 5.1 years. All patients treated with oral corticosteroids (CS) (n = 18) obtained remission, but 16 required CS-sparing treatments. One patient had a T-cell lymphoma 8 years after diagnosis, and 3 deaths occurred during follow-up.In conclusion, clinical manifestations related to CD3-CD4+ T cell-associated L-HES are not limited to skin, and can involve all tissue or organs affected in other types of HE. Contrary to FIP1L1-PDGFRA chronic eosinophilic leukemia patients, CS are always effective in these patients, but CS-sparing treatments are frequently needed. The occurrence of T-cell lymphoma, although rare in our cohort, remains a major concern during follow-up.

FIGURE 1

Clinical manifestations of CD3-CD4+ L-HES patients in the French Eosinophil Network. (CNS = central nervous system.).

FIGURE 2

Fifty-one-year-old woman with CD3-CD4+ L-HES, skin lesions and peripheral enlarged lymph nodes (Patient 5). Skin lesions were pruritic maculo-papulous and predominated in the inframammary folds and abdomen, the folds of the elbows and the wrists (A). On histologic examination, the dermis was infiltrated by numerous eosinophils and some lymphocytes without epidermotropism (B). Laboratory investigations found a high (4.6 G/L) and persistent (peak 5 G/L) eosinophils count and a CD3-CD4+ aberrant T-cell subset on T-cell phenotyping (88% of total lymphocytes, 4.3 G/L) (C).

FIGURE 3

Thirty-one-year-old woman with CD3-CD4+ L-HES and articular involvement (Patient 6). She presented a bilateral extensor digitorum tenosynovitis confirmed by a magnetic resonance imaging (here 3D water selective fluid scan or 3D-WATS-f sequences) (A). Synovial biopsy showed an infiltration by eosinophils. T-cell phenotyping showed a circulating CD3-CD4+ aberrant T-cell subset (25% of total lymphocytes, 0.7 G/L) (B), which decreased with low-dose corticosteroids until the last evaluation more than 3 years after diagnosis (6.8% of total lymphocytes, 0.12 G/L) (C).

FIGURE 4

Seventeen-year-old woman with CD3-CD4+ L-HES and pulmonary involvement (Patient 20). Computed-tomography scan (A) showed multiple bilateral alveolar condensations. Repeated T-cell phenotyping (gated on total lymphocytes) on diagnosis in April 2010 (B), in November 2011 (C), June 2012 (D), and December 2012 (E) showed a small but persistent CD3-CD4+ aberrant T-cell subset.

FIGURE 5

Thirty-six-year-old man with CD3-CD4+ L-HES and diplopia revealing a neuro-meningeal involvement. Cerebrospinal fluid analysis found 22 atypical lymphocytes per microliters but no eosinophil, and brain magnetic resonance imaging (MRI) showed multiple punctate signal abnormalities on subcortical white matter in the fronto-temporal and parietal lobes on T2-weighted fluid-attenuated inversion recovery (FLAIR) images (A). T-cells phenotyping found a large circulating CD3-CD4+ T-cell subset (79% of total lymphocytes count, 3.5 G/L) (B).

FIGURE 6

Efficiency of second-line treatments in association with corticosteroids. ALEM = alemtuzumab, CSA = cyclosporin A, HU = hydroxycarbamide, IFNα = interferon α or peg-interferon α, IM = imatinib, MEPO = mepolizumab, MTX = methotrexate.