Lymphoma-associated versus lymphocytic-variant hypereosinophilia

Secondary eosinophilia may be seen with various lymphoid neoplasms as a result of non-clonal expansion of normal eosinophils mediated by eosinophilopoietic growth factors/ cytokines, such as interleukin-3 (IL-3), granulocyte- macrophage colony stimulating factor (GM-CSF) and IL-5. These cytokines are normally produced by activated T-cells (IL-3 and GM-CSF by Th1 and Th2, and IL-5 by Th2 helper T cells) [1]. In contrast, clonal eosinophilia constitutes neoplastic proliferation of eosinophils from an underlying stem cell malignancy, as is the case with myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 and chronic eosinophilic leukemia, not otherwise specified (CEL-NOS).

Almost every type of lymphoma has been described with eosinophilia in the medical literature. The most well known association is with Hodgkin lymphoma, where the incidence of eosinophilia might be as high as 15% [2]. There has been a suggestion that patients with advanced stage Hodgkin lymphoma with eosinophilia have a better survival than their counterparts without eosinophilia [2]. Other lymphomas commonly associated with eosinophilia include T-cell lymphomas, including cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), adult T-cell leukemia/lymphoma, anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma, T-cell large granular lymphocyte leukemia and natural killer (NK) cell/T-cell lymphoma, nasal type [3–5]. For T-cell lymphomas, the association of blood eosinophilia suggests an unfavorable prognosis [4,5]. Eosinophilia has also been described in B-cell lymphomas, including B- lymphoblastic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma and small lymphocytic lymphoma/chronic lymphocytic leukemia [3,6–9].

In this issue of Leukemia and Lymphoma, McKelvie et al. [10] describe a middle-aged male with symptomatic hypereosinophilia identified to have an occult T-cell clone. After a lag of 2 years from the initial presentation with eosinophilia, the patient developed a nodular cutaneous lesion that upon biopsy revealed an anaplastic lymphoma kinase (ALK)-negative ALCL, with systemic involvement. At the time of diagnosis of ALCL, a new T-cell clone was identified. This patient's clinical course was further complicated by the co-occurrence of granulomatous myositis.

Abnormal T-cell clones have been described in 14–27% of patients presenting with idiopathic hypereosinophilic syndrome (HES)-like phenotype [11,12]. Such cases are currently included in the operational category of “lymphocytic variant hypereosinophilia,” which also includes patients with hypereosinophilia associated with abnormal T-cell immunophenotype. Overt lymphoma is absent at the time of disease presentation, although 14–25% of patients with lymphocytic variant hypereosinophilia might progress into overt T-cell lymphoma over the course of their disease, predominantly a PTCL or CTCL type [11,12]. Patients with lymphocytic variant hypereosinophilia tend to have dominant cutaneous involvement such as erythoderma, pruritus, papulonodular rash and angioedema. Histologically, skin biopsies demonstrate epidermal and dermal edema with inflammatory infiltrates [11]. These inflammatory lesions can be infiltrated with atypical CD30-positive lymphoid cells, making the distinction from CD30-positive lymphomas, such as ALCL, difficult [13].

The significance of finding an occult T-cell clone in the work-up of patients with eosinophilia is not entirely clear for the treating clinician. Are all of them a harbinger of an eventual T-cell malignancy? Do they signify a latent lymphoma or a predisposition to lymphoma development? How should they be followed? The case report described by McKelvie et al. is unique in that the T-cell clone at the time of lymphoma diagnosis was different from the one seen during the original presentation of eosinophilia. The particular observation suggests that while patients with lymphocytic variant hypereosinophilia may be predisposed to develop overt lymphoma, they do not necessarily harbor an occult lymphoma clone at presentation. In this particular case, it is possible that the occult T-cell clone was part of the manifestation of lymphoma predisposition but its phenotypic consequence was limited to secondary eosinophilia at initial presentation. Whether or not one can abrogate the development of lymphoma, in such instances, by pharmacologically suppressing the T-cell clone is unknown, and it is equally unclear whether such treatment would lower the eosinophil count. Nevertheless, a high index of suspicion for occult or overt lymphoma is warranted in patients with eosinophilia, and those with a T-cell clone must be monitored closely for the development of overt lymphoma.

Potential conflict of interest

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