The correct answer is D: Chronic lymphocytic leukemia
Discussion: The skin biopsy demonstrated a dense perivascular, perifollicular, and periadnexal infiltrate composed of mature lymphocytes admixed with abundant eosinophils. There was extreme papillary dermal edema, leading to subepidermal bulla formation. Direct and indirect immunofluorescence were both negative. The dermatopathologist commented that the histologic picture was most compatible with an arthropod assault and extreme hypersensitivity reaction. Basic screening laboratory studies disclosed the following abnormalities: elevated white blood cell count (60,000/mm3), white blood cell differential consisting of 75% lymphocytes and 20% neutrophils, and hemoglobin level of 8.3 gm/dL. The picture strongly suggested chronic lymphocytic leukemia (CLL), and the patient was promptly referred to a hematologist for further evaluation and appropriate treatment. A report received several weeks later indicated that additional testing revealed a CD20+/CD5+ clonal expansion of lymphocytes in both the peripheral blood and bone marrow, an absence of detectable adenopathy or organomegaly following multimodality imaging, and a final diagnosis of CLL, Rai stage III.
Exaggerated reactions to insect bites are characteristic of patients with hemoproliferative disorders. This association is particularly true of chronic lymphocytic leukemia (CLL).[1-10] Despite a fairly strong association, this phenomenon is rare. In a large retrospective study of over 1000 B-cell CLL patients, only 1% developed an eruption which suggested exaggerated response to insect bites. Although the histology is nearly pathognomonic for an arthropod assault, patients may deny being bitten and, thus, the biopsy results can conflict with the patient's history.[2,7] On the other hand, some patients clearly associate the development of skin lesions with observed insect bites, usually due to mosquitoes.[1,3,5] In this particular case, the patient was well aware of being bitten by mosquitoes, something regularly endured in order to tend to her garden. At least one investigation demonstrated an objective hypersensitivity to pooled mosquito antigen in similar patients.
Such skin lesions usually appear weeks to years after the diagnosis of CLL has already been established. However, the eruption may rarely precede or occur coincident with the diagnosis of CLL.[5,6] In this particular case, the cutaneous manifestations directly led to the laboratory testing which established the underlying diagnosis. Nonetheless, based on the patient's history, it is certainly possible that leukemia had been present for some time before being recognized. In virtually all reported cases, the appearance of this characteristic pruritic eruption seems unrelated to laboratory findings, disease severity or course, and mode of therapy. The eruption is likely to run a chronic course and represents a therapeutic challenge. Oral prednisone(Drug information on prednisone) appears to be the most effective therapy, although oral antihistaminics and potent topical corticosteroids may also be effective.[1,6,8,10]
Individual lesions may be intensely pruritic papules, nodules or plaques, all of which have a propensity for development of a vesiculobullous component. On the other hand, in some patients, the lesions initially present as tense blisters on an inflammatory base, which closely mimic autoimmune bullous disorders such as pemphigus and pemphigoid. In fact, despite uniformly negative immunofluorescence studies in most patients, controversy remains as to whether this phenomenon is actually a paraneoplastic form of pemphigoid. Using an immunoblotting technique, one study demonstrated serum autoantibodies directed against the 180-kDa minor pemphigoid antigen in half of such cases. Nevertheless, most authorities still consider this finding an atypical response to insect bites, associated primarily with CLL, with an unknown precise pathogenesis.
Finally, it should be noted that this type of cutaneous reaction may also be associated with other hematologic and lymphoproliferative disorders, most notably mantle-cell lymphoma and natural killer cell leukemia and lymphoma.[11,12] The latter association has been described almost exclusively in Japan.
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2. Rosen LB, Frank BL, Rywlin AM. A characteristic vesiculobulous eruption in patients with chronic lymphocytic leukemia. J Am Acad Dermatol 1986;15L943-950.
3. Kolbusz RV, Micetich K, Armin A, et al. Exaggerated response to insect botes. An unusual cutaneous manifestation of chronic lymphocytic leukemia. Int J Dermatol 1989;28:186-187.
4. Pederson J, Carganello J, Van-Der Weyden MB. Exaggerated reaction to insect bites in patients with chronic lymphocytic leukemia: Clinical and histologic findings. Pathology 1990;22:141-143.
5. Davis MDP, Perniciaro C, Dahl PR, et al. Exaggerated arthropod-bite lesions in patients with chronic lymphocytic leukemia: A clinical, histopathologic, and immunopathologic study of eight patients. J Am Acad Dermatol 1998;39:27-35.
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7. Blum RR, Phelps RG, Wei H. Arthropod bites manifestingas recurrent bullae in a patient with cronic lymphocytic leukemia. J Cutan Med Surg 2001;5:312-314.
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9. Bottoni U, Cozzani E, Innocenzi D, et al. Bullous lesions in chronic lymphocytic leukaemia: Pemphigoid or insect bites? Acta Dermato-Venereol 2006;86:74-76.
10. Walker P, Long D, James C, et al. Exaggerated insect bite reaction exacerbated by a pyogenic infection in a patient with chronic lymphocytic leukaemia. Australas J Dermatol 2007;48:165-169.
11. Dodiuk-Gad RP, Dann EJ, Bergman R. Insect bite-like reaction associated with mantle cell lymphoma: a report of two cases and review of the literature. Int J Dermatol 2004;43:754-758.
12. Adachi A, Horikawa T, Kunisada M, et al. Hypersensitivity to mosquito bites in association with chronic Epstein-Barr virus infection and natural killer (NK) leukaemia/lymphoma with expansion of NK cells expressing a low level of CD56. Br J Dermatol 2002;147:1036-1037.