We present the cases of 4 patients with hematologic neoplasms who developed lesions with clinical and histological features reminiscent of insect bites. All 4 patients were diagnosed with eosinophilic dermatosis (ED) of hematologic malignancy. In one of these patients, the underlying disease was a cutaneous T-cell lymphoma. This type of cutaneous eruption has previously been reported in patients with B-cell lymphomas, human immunodeficiency virus (HIV), congenital agammaglobulinemia, acute monocytic leukemia, and myelofibrosis.1–6

We carried out a retrospective study of cases of ED of hematologic malignancy diagnosed in our hospital between 2009 and 2015. The clinical characteristics of the patients are summarized in Table 1. The patients were 1 woman and 3 men, aged between 53 and 86 years. Three of them were diagnosed with chronic lymphocytic leukemia (CLL) and one with mycosis fungoides (MF) CD3+, CD4–, CD7–, and CD8–. All 4 patients were referred for consultation by the Hematology Department because they had developed cutaneous lesions. The interval between diagnosis of the blood cancer and the appearance of the dermatosis varied from 2 months to 10 years. None of the 3 patients with CLL were receiving specific treatment for their hematologic disease at the time the skin lesions appeared: in case 1 because of sepsis caused by Klebsiella pneumoniae, which had led to the cessation of the third cycle of chemotherapy a few months earlier; in case 2 because the disease was in a very early stage; and in case 3 because the patient was in partial remission following 2 cycles of chemotherapy. The patient with MF had been receiving treatment with bexarotene for 2 months.

In all 4 cases, the presenting complaint was the appearance of a pruritic eruption with onset between 1 and 4 weeks earlier. Multiple palpable preauricular and cervical lymph nodes were found in Case 2 and accompanying B symptoms were observed in Case 3. The basic lesions varied:excoriated papules in Case 1 (Fig. 1A); erythematous papules in a linear pattern in case 2 (Fig. 1B); confluent papules of various sizes on the forearm in Case 3 (Fig. 2A); and poorly defined erythematous-violaceous plaques in patient 4 (Fig. 2B). The site most frequently affected was the upper limbs. In Case 1, ED developed when the patient was in hospital because of progression of her CLL. None of the patients reported any history of an insect bite.

Figure 1.

A, Excoriated papules on back. B, Erythematous papules in a linear pattern.

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Figure 2.

A, Erythematous papules of different sizes, some confluent. B, Poorly defined erythematous-violaceous plaques.

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In all 4 cases, a histologic study was performed following staining with hematoxylin-eosin. Immunofluorescence was not performed since clinically the lesions were papules or plaques consistent with insect bites. In all 4 cases, histologic examination revealed a perivascular and periadnexal interstitial inflammatory infiltrate in the superficial and deep dermis composed of polymorphonuclear lymphocytes and abundant eosinophils (Fig. 3). The presence of malignant cells in the infiltrate was ruled out using fluorescence in-situ hybridization (FISH); no monoclonal rearrangement of lymphocytes was observed.

Figure 3.

A, Hematoxylin-eosin(×50). Epidermis with mild spongiosis. Mixed inflammatory infiltrate, predominantly perivascular and periadnexal, in the superficial dermis. B, Hematoxylin-eosin (×400). Eosinophil-rich inflammatory infiltrate in the deep dermis.

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Patients 1, 2, and 4 were treated with topical corticosteroid therapy alone, with the addition of oral prednisone in patient 3. The lesions disappeared within a few weeks. In case 2, resolution coincided with the start of specific chemotherapy. The cutaneous lesions recurred in all of the patients with CLL over subsequent months. The patient in Case 1 died a few months after onset of the cutaneous symptoms and progression of CLL was observed in the other 2 patients after the diagnosis of ED. The patient with MF (Case 4) responded to topical corticosteroid therapy; ED was not associated with a worse prognosis and the patient is currently stable.

This clinical entity was first described by Weed in 1965.7 It was interpreted as an exaggerated hypersensitivity to mosquito bites in patients with CLL. It was never possible to demonstrate whether or not a bite was necessary to trigger the process and, after several nomenclatures in the intervening period, it is now known as ED of hematologic malignancy, a term that covers all the malignancies in which the condition has been described.1,8 We found 34 publications under the older term exaggerated reaction to insect bites, most relating to isolated cases. Table 2 shows the most recent cases published with the new nomenclature. This is a rare condition, primarily associated with CLL,1–5,7,8 although it has also been reported in association with other B-cell hematologic malignancies6,9–14 (mantle cell lymphoma, acute lymphoblastic leukemia, large cell lymphoma, multiple myeloma), and with acute monocytic leukemia, myelofibrosis, and nonmalignant processes, such as HIV infection and congenital agammaglobulinemia.3 Although the eruption usually appears several years after the diagnosis of the malignancy, cases have also been reported in which the condition developed before or at the same time as the malignancy.1

The pathogenesis of the condition is unknown, but it has been suggested that the leukemic cells may cause an imbalance in cytokines, which leads to increased interleukin (IL)-5 and ultimately to the proliferation of eosinophils. Other authors have suggested that the patient's underlying immunodeficiency followed by an immune stimulus (an insect bite, drugs, or a virus) may trigger an altered immune response with overexpression of IL-5.1,8

The clinical presentation takes the form of pruritic papules or hive-like nodules reminiscent of arthropod bites. Cases have also been reported involving true plaques of variable size and occasionally vesiculobullous lesions.1,3 Lesions usually affect exposed and unexposed areas of the skin and occur predominantly on the limbs. In many cases, the cutaneous symptoms recur in situations in which insect bites would be unlikely.

The characteristic histologic feature is the presence of an eosinophil-rich, perivascular and periadnexal, interstitial inflammatory lymphocytic infiltrate, which occasionally extends into the subcutaneous tissue.13 The lymphocytic infiltrate is predominantly composed of T cells (CD3+, CD43+, CD45RO+)1; when B cells are present they form polyclonal aggregates. No leukemic cells are observed.1,13 One case has been described in which FISH revealed the presence of malignant cells in the infiltrate of a biopsy from a patient with CLL.15 This did not occur in our patients.

In 2001, Byrd et al. proposed the set of diagnostic criteria shown in2Table 3.

The differential diagnosis includes leukemia cutis, scabies, toxicoderma, hypersensitivity to insect bites, early stages of blistering diseases such as bullous pemphigoid and dermatitis herpetiformis, eosinophilic folliculitis, and Wells syndrome.1,8

To date, no relationship has been demonstrated between the onset of ED and the course of the underlying disease. However, a rapidly progressive course of CLL has been observed in some patients coinciding with the onset of ED.1–9,11 In our series, 3 of the 4 patients progressed to a more advanced stage of their hematologic disease, and 1 patient died due to CLL a few months after onset of ED. By contrast, in another recently reported case, a patient with CLL and recurrent ED remained stable for 45 months after initial onset of ED.10 Thus, the prognostic implications of ED in this setting are still unclear.

Many treatments have been proposed, but most are associated with partial response and frequent recurrence. Improvement has been achieved with specific chemotherapy.1,6 The condition is generally refractory to oral antihistamines and topical corticosteroids8 although in our patients the latter were the treatment of choice. The most effective and generally accepted treatment at the present time is oral corticosteroids at doses of 0.5-1 mg/kg/d.3 This regimen achieves good initial results, but relapse is common when the dose is reduced. UVB phototherapy would appear to be a good choice of therapy.2

We report 4 new cases of ED. Three were associated with CLL (the most common association reported in the literature) and the onset of ED was associated with a poor prognosis. The fourth case was associated with a cutaneous T-cell lymphoma, representing the first instance of this association reported in the literature. After 7 years of follow-up and treatment with oral bexarotene, the fourth patient has had no new outbreaks and remains stable. The cutaneous manifestation are ordinary lesions resembling insect bites. However, in the case of patients with a history of hematologic malignancy, the possibility of ED of hematologic malignancy should be considered and the patient should be closely monitored since, while the relationship is not entirely clear, the presence of ED may be an indication of progression of the underlying disease.

The authors declare that they have no conflicts of interest.