Key words: chronic, dermatosis, eosinophilic, hematologic, infection, leukemia, lymphocytic, malignancy, varicella, zoster
Citation: Bari O, Cohen PR. Eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection: report in a woman with chronic lymphocytic leukemia and review of the literature. Dermatol Pract Concept 2017;7(3):2. DOI: https://doi.org/10.5826/dpc.0703a02
Received: December 1, 2016; Accepted: April 29, 2017; Published: July 31, 2017
Copyright: ©2017 Bari et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Competing interests: The authors have no conflicts of interest to disclose.
All authors have contributed significantly to this publication.
Corresponding author: Philip R. Cohen, MD, Department of Dermatology, University of California San Diego, La Jolla, CA, USA. Email: email@example.com
Eosinophilic dermatosis of hematologic malignancy is a rare papulovesicular eruption that presents in patients with hematoproliferative disorders, particularly chronic lymphocytic leukemia. A 59-year-old woman with chronic lymphocytic leukemia who developed eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection is described. PubMed database was searched with the key words: chronic, dermatosis, eosinophilic, hematologic, infection, leukemia, lymphocytic, malignancy, varicella, zoster. The papers generated by the search and their references were reviewed. The patient presented, on more than 20 occasions, with a dermatomal vesicular eruption. Her oncologist, based on the clinical presentation, treated each episode as recurrent varicella zoster virus infection. A complete workup of the patient not only demonstrated negative viral studies but also revealed pathologic changes consistent with eosinophilic dermatosis of hematologic malignancy on lesional skin biopsy. The recurrence of the patient’s dermatosis was less frequent when her malignancy was under better control. Eosinophilic dermatosis of hematologic malignancy may mimic other reactive dermatoses. The morphology of our patient’s recurrent dermatosis resembled varicella zoster virus infection. Disseminated zoster virus infection with dermatomal and non-dermatomal distribution should be added to the clinical differential diagnosis of eosinophilic dermatosis of hematologic malignancy.
Eosinophilic dermatosis of hematologic malignancy was first reported in 1965 and thought to be a hypersensitivity reaction to insect bites in patients with chronic lymphocytic leukemia (CLL) . Subsequent reports noted that most patients failed to recall insect bites; thus, the term “insect bite-like reaction” was established . Byrd et al. later dubbed the process eosinophilic dermatosis of myeloproliferative disease , though Farber et al. favor the term eosinophilic dermatosis of hematologic malignancy to better encompass the numerous hematologic malignancies associated with this cutaneous eruption [4,5]. We describe a woman with CLL whose lesions resembled varicella zoster virus infection and review the literature on eosinophilic dermatosis of hematologic malignancy.
A 59-year-old woman with CLL presented for evaluation of vesicular eruptions thought to be recurrent varicella zoster virus infection. She was diagnosed with CLL in 2003 but experienced several recurrences of her leukemia. Shortly after the first recurrence of CLL in 2009, she developed skin lesions that appeared in a dermatomal distribution on her back. These lesions reappeared several times, and her oncologist treated her for presumptive herpes zoster virus infection with an appropriate dosage of acyclovir on more than 20 occasions. The patient had no definitive prior history of herpes zoster virus infection; varicella zoster virus infection had never been objectively confirmed with biopsy, viral culture, or PCR amplification. However, the patient did have several complete blood counts drawn. Eosinophil percentages ranged from 1-10%, though most frequently were 4-5% (normal range 0-7%); however, absolute eosinophil count never exceeded 500 cells per ml (normal range 0-500 cells per ml). Serum IgE level was assessed and found to be 2 International Units (IU) per ml (normal range 0-99 IU/ml). Her CLL therapy initially included fludarabine, cyclophosphamide, and rituximab but later included alemtuzumab, lenalidomide, venetoclax, and obinutuzumab.
She presented to the dermatologist for evaluation of a new onset of her skin lesions; these were similar to those that her oncologist had previously treated as varicella zoster virus infection outbreaks. Cutaneous examination showed dermatomal (Figure 1) and non-dermatomal (Figure 2) lesions with similar morphology on her back and flanks. Vesicles ranging from 2 mm to 5 mm, within areas of erythema, were present. Initial evaluation included viral cultures for herpes simplex virus and varicella zoster virus; vesicular fluid was sent for direct fluorescent antibody to these viruses. In addition, biopsies were performed for both routine staining and direct immunofluorescence to rule out autoimmune bullous diseases.
Figure 1. Distant views of vesicles on an erythematous base corresponding to the left T6 dermatome presenting below the breast (A), and extending to involve the upper abdomen and mid-back (B). [Copyright: ©2017 Bari et al.]
Figure 2. Distant (A) and close (B) views of an isolated, non-dermatomal, erythematous-based vesicle appears on the lower left flank. [Copyright: ©2017 Bari et al.]
The viral cultures and direct fluorescent antibody studies were negative. Microscopic examination of the skin biopsy showed an intraepidermal vesicle with eosinophils, eosinophilic spongiosis, and an accompanying diffuse and dense perivascular and periadnexal lymphocytic infiltrate with numerous eosinophils (Figure 3). Direct immunofluorescence and enzyme-linked immunosorbent assay (ELISA) studies were negative for bullous pemphigoid antigen-1 and bullous pemphigoid antigen-2.
Figure 3. Microscopic examination of a low magnification view showing a large vesicle (A). Intermediate magnification views (B and C) of the lateral aspects of the vesicle demonstrating that it is intraepidermal and contains serosanguinous fluid with eosinophils. The base of the blister shows eosinophilic spongiosis (D); the spaces between keratinocytes are filled with eosinophils. In the underlying dermis, there is edema and a dense infiltrate that is not only diffuse but also perivascular and periadnexal; the infiltrate consists of lymphocytes and numerous eosinophils (D and E) (hematoxylin and eosin; a = x4; b = x20; c = x20; d = x20; and e = x40). [Copyright: ©2017 Bari et al.]
Correlation of the clinical history, morphology, pathologic changes, and laboratory studies established the diagnosis of eosinophilic dermatosis of hematologic malignancy. Initial management included twice daily application of betamethasone dipropionate 0.05% cream, which provided relief and eventual resolution of the lesions. Two weeks later, the patient had recurrence of her lesions (Figure 4) and another skin biopsy showed similar pathologic changes. The patient was receiving investigational systemic therapy for her CLL; oral and other systemic therapies were prohibited. She continued her topical treatment.
Figure 4. Distant (A) and closer (B and C) views of a linear presentation of erythematous-based vesicles of eosinophilic dermatosis of hematologic malignancy corresponding to the left L4 dermatome. [Copyright: ©2017 Bari et al.]
The frequency of relapsing skin lesions was markedly reduced during periods in which the patient’s hematologic malignancy was under better control. Recently, she had an exacerbation of her CLL and antineoplastic therapy was altered. Subsequently, she has had less frequent flares of her dermatosis after being placed on obinutuzumab.
Patients with CLL usually present with eosinophilic dermatosis of hematologic malignancy between 40 to 60 years of age . Table 1 offers a review of this condition [1-25]. The eruption often occurs concurrently with or months to years after the diagnosis of the associated hematologic malignancy. However, the condition has also been reported to present prior to the cancer diagnosis .
Table 1. Summary of eosinophilic dermatosis of hematologic malignancy. [Copyright: ©2017 Bari et al.]
Eosinophilic dermatosis of hematologic malignancy occurs most often with CLL. It has also been associated with acute lymphoblastic leukemia, acute monocytic leukemia, large cell lymphoma, mantle cell lymphoma, multiple myeloma, and myelofibrosis [4,6,7].
Eosinophilic dermatosis of hematologic malignancy has a polymorphic presentation. The condition may manifest as erythema, papules, nodules, urticaria, or vesicles [4,9]. The eruption is usually indurated and erythematous but can also be tender . The clinical differential diagnosis includes arthropod assault, dermatitis herpetiformis, drug reaction, eosinophilic cellulitis, eosinophilic folliculitis, infection, leukemia cutis, papular urticaria, scabies, and urticarial stage of bullous pemphigoid [4,9].
Histologically, this condition displays a superficial and deep dense perivascular infiltrate of lymphocytes and eosinophils [2,4]. Vesicles or bullae may also present due to intraepidermal or subepidermal edema . Flame figures in the dermis have also been reported .
The pathogenesis of this condition is poorly understood . It has been hypothesized that there is an excess of interleukin-4 and interleukin-5; this imbalance may lead to a proliferation of neoplastic B cells, which have been considered a major driver of the eruption [3,4,9]. This hypothesis is supported by the fact that interleukin-5 is the major eosinophil-recruiting cytokine . Alternatively, it has been thought that neoplastic B cells drive a hypersensitivity reaction .
Several therapeutic options to treat eosinophilic dermatosis of hematologic malignancy have been reported. They include antibiotics, antihistamines, chemotherapy, dapsone, interferon alpha, intravenous immunoglobulin, phototherapy, and radiation [2,4,10]. Though some patients report favorable responses to therapy, overall the results have been disappointing . The poor response underscores the lack of clarity of this condition’s pathogenesis .
In regards to prognosis, eosinophilic dermatosis of hematologic malignancy may be associated with an aggressive course of CLL ; our patient lends support to this observation, given her repeat recurrences of CLL. Reported complications in patients with CLL and eosinophilic dermatosis of hematologic malignancy include Richter transformation and malignant clone expansion [2,10]. An underlying state of immunosuppression is postulated as the cause for these occurrences.
Our patient’s recurrent skin lesions of eosinophilic dermatosis of hematologic malignancy were clinically interpreted by her oncologist to be varicella zoster virus infection because they were frequently dermatomal. However, the likelihood of over 20 episodes of herpes zoster would be unique and unexpected; hence, we were prompted to evaluate her skin lesions and exclude the diagnosis of either a viral infection or autoimmune bullous disease. It is conceivable that our patient may have initially had zoster sine herpete, which manifests as radicular pain without rash . With a background of zoster sine herpete, the patient plausibly could have developed an immunocompromised zone and therefore displayed Wolf’s isotopic response, in which a new skin disorder occurs at the site of a previously healed skin disease . However, our investigation established the diagnosis of eosinophilic dermatosis of hematologic malignancy. Based on our patient’s morphologic presentation of eosinophilic dermatosis of hematologic malignancy, we add disseminated zoster infection with dermatomal and non-dermatomal distribution to the differential diagnosis of this condition.
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