Wells syndrome associated with chronic lymphocytic leukemia

Eosinophilic cellulitis or Wells syndrome is an uncommon skin condition of unknown etiology that can occur alone or associated with other conditions. Typically, it presents with recurrent pruritic, erythematous and edematous plaques, but it can also show clinical polymorphism. Besides the cutaneous lesions, patients can experience systemic manifestations like fever, malaise, arthralgia and peripheral blood eosinophilia. We describe a case of this rare syndrome that presented with polymorphic cutaneous lesions associated with a serious systemic disease, which was revealed through the investigation of the cutaneous disease.

section_content: Eosinophilic cellulitis, fi rst described by Wells in 1971 as recurrent granulomatous dermatitis with eosinophilia, also known as Wells Syndrome (WS), is a rare infl ammatory dermatosis observed in all age groups, without preference for gender and race. 1, 2 ts causes are not completely understood, but some authors believe it may be a local hypersensitivity reaction triggered by different factors such as insect bites, vaccines containing thimerosal, immunobiological medications, viral infections and parasitic infestations, among others. ] [3] [4] [5] Although it may present a polymorphic clinical picture, recurrent pruritic, erythematous and edematous plaques are typical, affecting more frequently the trunk, face, arms and neck, that tend to regress with hyperpigmentation. 6, 7 The lesions may be preceded by local pain and a burning sensation, associated with fever, malaise, arthralgia and liver function abnormalities, besides peripheral blood eosinophilia in up to 50% of cases. 2, 5, 7 boratory evaluation of patients with suspected WS should include a complete blood cell count, metabolic panel, stool examination when intestinal parasitic infestation is suspected, and a cutaneous lesion biopsy. 2, 5 he histopathological examination may show three different stages. The acute phase is characterized by edema in superfi cial and middle dermis, with dense and diffuse eosinophilic infl ammatory infi ltrate. Eventually, the papillary dermal edema may be intense enough to result in cleavage and formation of subepidermal blisters. In the subacute or granulomatous phase it is possible to identify "fl ame fi gures" in the dermis, formed by collagen fi bers covered by eosinophil granule proteins and surrounded by histiocytes and eosinophils. The regression phase exhibits gradual reduction of eosinophils, persistence of histiocytes and the appearance of giant cells around deposits of collagen, forming microgranulomas. None of the stages shows vasculitis. 3, 6
section_name: INTRODUCTION

section_content: A mestizo female 62-year-old patient, being treated for hypertension and without other comorbidities, had presented intensely pruritic lesions on the upper and lower limbs for 18 months, without identifi cation of a triggering factor. During the dermatological examination, erythematous papular plaques were observed, some of them with superposition of serohemorrhagic vesicles and erosions located on limbs and back, besides papular purpuric lesions on the lower limbs (Figures 1 to 3 ). Cervical, supraclavicular and axillary hard and adherent lymphadenopathies could also be noticed (Figure 4 ). 

The use of hydrochlorothiazide had been suspended after a prior cutaneous biopsy at another service, suggesting drug skin eruption, without improvement; prednisone 80mg per day was introduced, achieving only partial control of the clinical picture. 

The hypotheses of dermatitis herpetiformis, linear IgA bullous dermatosis, leukocytoclastic vasculitis, Sweet's syndrome and probable systemic lymphoma were considered and a cutaneous biopsy was performed for histological examination and direct immunofl uorescence (DIF). A laboratory review and interconsultation with hematology were requested and an antihistamine was started for pruritus control. 

During follow-up, the patient maintained periods of remission and exacerbation of the cutaneous clinical picture. After lymph node biopsy, the chronic lymphocytic leukemia diagnosis was confi rmed by The histopathologic examination showed hyperkeratosis, acanthosis, papillary dermal edema with cleavage and subepidermal blisters; a moderate, lymphohistiocytic and eosinophilic diffuse dermal infl ammatory infi ltrate, extending to the hypodermis, besides the typical "fl ame fi gures" in the middle and deep dermis (Figures 5 and 6 ). DIF was negative and the immunohistochemical examination ruled out neoplastic skin infi ltration. 

The clinical and pathological correlation allowed the WS diagnosis, with complete resolution of the cutaneous clinical picture after chemotherapy for leukemia treatment.
section_name: CASE REPORT

section_content: With a polymorphic clinical presentation and relative rarity, WS is a diagnostic challenge for the dermatologist. It should always be considered in cases with a diagnosis of bacterial cellulitis which do not respond to antibiotic therapy. Another important differential diagnosis is the hypereosinophilic syndrome (HES), a multisystemic disease that may be fatal and presents persistent eosinophilia in peripheral blood, in addition to the involvement of internal organs. 5 ther differential diagnoses, mainly due to the histological similarity of the infl ammatory infi ltrate rich in eosinophils, are reactions to drugs, Churg-Strauss syndrome (CSS) and bullous pemphigoid, the latter especially important in cases with subepidermal blisters. In both CSS and WS there may be eosinophilia, increased IgE levels, increased eosinophil cationic protein, in addition to "fl ame fi gures" and formation of granulomas at the histopathological examination; what differentiates the two syndromes histologically is necrotizing vasculitis of small and middle vessels present in CSS, besides clinical fi ndings such as sinusitis, asthma, mononeuritis and pulmonary infi ltration. Some authors believe that WS, CSS and HES are part of the spectrum of eosinophilic disorders; therefore, they suggest that patients with WS be investigated and periodically monitored due to the risk of developing CSS and HES. 3, 8 he histopathologic fi nding of "fl ame fi gures" is typical of the disease, although unspecifi c. They can be observed in arthropod bites, parasitic infestations and drug reactions. Leiferman et al consider their presence mandatory for a WS diagnosis. 9 t is believed that this syndrome is a local hypersensitivity reaction triggered by different factors. Although the pathogenesis is still not completely understood, there is evidence that interleukin 5 production is increased, which would be responsible for migration of eosinophils from the bone marrow to the skin and their degranulation, resulting in tissue damage. The activated eosinophils apparently also secrete eosinophil cationic protein, a ribonuclease that is toxic for bacteria and helminths, which might contribute to the skin lesion. 

In view of the diversity of triggering factors and possible association with severe diseases like lymphoproliferative disorders, systemic vasculitides and neoplasms, a thorough clinical evaluation of the patients becomes mandatory. 3, 7, 10 n general corticotherapy allows good control of cases of isolated syndrome 1 with prednisone in a 10-60mg/day dose, but the cases associated with other conditions are most often resolved only with treatment for the basic disease. Other treatments described are ciclosporin, azatioprin, dapsone and tacrolimus. ❑
section_name: DISCUSSION

section_content: How to cite this article: Stuhr PMOD, Vale ECS. Wells syndrome associated with chronic lymphocytic leukemia. An Bras Dermatol. 2015;90(4):571-4