hipereosinofilia 2

8/13/2019 Hipereosinofilia 2

1/4

Persistent hypereosinophilia with Wells syndrome

J. Powell, M. Kaur, R. Muc, P. Colloby and A. SalimDepartments of Dermatology and Histopathology, Solihull Hospital, Heart of England NHS Foundation Trust, Birmingham, UK

doi:10.1111/j.1365-2230.2012.04370.x

Summary Since Wells and Smith rst described cases of eosinophilic cellulitis (Wells syndrome;WS) in 1979, it has been noted that some but not all patients with WS present witheosinophilia. In the face of idiopathic persistent eosinophilia patients will also then fallwithin the hypereosinophilic syndrome (HES), which represents a multifariousspectrum of disorders of varying severity, causes and outcomes. In this article wepropose that patients who present within the HES spectrum with cutaneous ndingsof WS and with no extracutaneous disease be classied as having persistenthypereosinophilia with Wells syndrome (PHEWS).

In 1979, Wells and Smith described cases of eosinophiliccellulitis (also known as Wells syndrome; WS). Sincethen, it has been noted that some patients with WSpresent with eosinophilia. In the face of idiopathicpersistent eosinophilia, patients may also then fallwithin the description of hypereosinophilic syndrome(HES) which represents a multifarious spectrum of disorders of varying severity, causes and outcomes.We present the case of a patient with WS who also fallswithin the HES but with no extracutaneous manifesta-tions and propose a new term and diagnostic criteria forthis condition.

Report

A 64-year-old woman presented with a 6-year historyof a pruritic skin eruption. Individual lesions persistedfor several weeks before fading, leaving postinamma-tory hyperpigmentation, but crops of new lesionscontinued to arise. The patient remained systemicallywell throughout.

On physical examination, red papules, nodules and

urticarial-like lesions were present on the patientstrunk and limbs (Fig. 1a).

On histological examination, the epidermis wasnormalin appearance. Perivascular and interstitial inltrateswere seen within the supercial dermis, containingnumerous eosinophils and occasional ame gures(Fig. 1b).

Laboratory investigations identied hypereosinophil-ia, which had been present throughout the illness,peaking at 4.12 10 9 eosinophils per litre (normalrange 00.4 10 9 L), and being persistently above1.5 10 9 L for 5 years. Full blood count, renal andliver function tests, autoimmune prole, and measure-ment of erythrocyte sedimentation rate, C-reactiveprotein, serum IgE and tryptase levels gave normalresults. Tests for larial, schistosomal and strongyloidesserology were negative. No abnormalities were seen onchest radiographs. Cytogenetic and molecular studiesdid not identify any clonal haematological abnormality,including FIP1L1 PDGFRA (family-interacting protein1-like 1 platelet-derived growth factor receptor- a ) genefusion.

Three years previously, a short course of oral steroidshad brought about a near-complete clinical remission

and had markedly improved the eosinophil count, but afull relapse occurred shortly after the steroids werestopped.

In this case, a clinicopathological diagnosis of WScould be made, however, we noted that the patient alsofalls within the HES spectrum.

In their paper, Wells and Smith 1 described thecharacteristic clinocopathological features of WS. Clas-sically and in its most severe form, WS presents initially

Correspondence : Dr James Powell, Department of Dermatology, Worces-tershire Royal Hospital, Worcester WR5 1DD, UKE-mail: [email protected]

Conict of interest: none declared.

Accepted for publication 16 January 2012

Clinical dermatology Concise report CEDClinical and Experimental Dermatology

The Author(s)40 CED 2012 British Association of Dermatologists Clinical and Experimental Dermatology , 38 , 4043


2/4

with an acute pseudocellulitis, which may extend toaffect the greater part of a limb. Areas are red andoedematous, and may blister, but the affected skin doesnot have a raised temperature on palpation, and isunresponsive to antibiotics. Lesions then become inl-trated, rm and granulomatous, with green-blue dis-coloration, resolving over several weeks, during whichlesions may resemble morphoea. 1

Wells and Smith then described other, less severe,

cutaneous presentations of WS, namely those withurticaria-like, bullous, papular, nodular, annular andplaque-like lesions, which are often pruritic. In the casesthey presented, peripheral blood eosinophilia was notalways present, and no comment was made on howlong any eosinophilia (if present) persisted, or if thisrecurred in the future.

Such multifarious clinical ndings continue to bereported in patients diagnosed with WS, meaning that

the diagnosis will sometimes be made solely on charac-teristic cutaneous histological features. 1,2 Such featuresinclude dermal oedema with inltration of eosinophilsand macrophages between connective-tissue bundles,with scattered ame gures (clusters of eosinophils andmacrophages around a central focus of collagen coatedin granular eosinophilic material).

Wells and Smith stated originally that WS is probablya hypersensitivity reaction induced by various triggerssuch as insect bites or drug reactions. 1 Since their study,WS has been reported to occur in systemic disordersassociated with eosinophilia such as ChurgStrausssyndrome, 3 HES4 and chronic lymphocytic leukaemia. 5

It therefore seems that WS represents a cutaneousreaction pattern that can develop in any situation inwhich abnormal numbers of eosinophils are allowed toaccumulate in the skin for any, often unknown, reason.

Hypereosinophilic syndrome is a term covering a wide

range of heterogenous conditions. Since 1975, threecriteria have been used to dene HES: (i) bloodeosinophilia over 1.5 10 9 L for > 6 months or deathwithin that time, associated with signs and symptoms of hypereosinophilic disease; (ii) no secondary cause foreosinophilia found; and (iii) signs and symptoms of organ damage. 6 In HES, tissue eosinophilic inltrationand mediator release leads to variable end-organdamage, which despite aggressive treatment, may resultin severe complications and even death. 7 Such compli-cations include cardiac failure and brosis, peripheralneuropathy, and generalized central nervous systemdysfunction such as upper motor neurone signs andencephalopathy. 7 Pulmonary features (such as brosisand nonproductive cough), hypersplenism, hepatitis,hepatic-vein obstruction, eosinophilic oesophagitis, gas-tritis or colitis, and choroidal abnormalities can alloccur. 7 However, some patients with HES are asymp-tomatic or present with more benign disease, perhapslimited to the skin, and these patients may never, despitechronic hypereosinophilia, develop such complications.

Since it was rst described, the underlying aetiologiesin some cases of HES have been identied. For diagnosticpurposes, there is no longer the insistence that thehypereosinophilia be truly idiopathic, so long as

secondary causes of eosinophilia, such as drug-induced,parasitic, allergic and autoimmune causes, have beenexcluded. 7,8 For example, patients with myeloprolifera-tive (M)-HES can now be identied through molecularand genetic techniques. The commonest chromosomalmutation seen in M-HES is the deletion on chromosome4q12, causing the fusion of the FIP1L1 PDGFRA (F P)genes, leading to a protein with signicant tyrosine-kinase activity. Furthermore, using ow cytometry,

(a)

(b)

Figure 1 (a) Multiple urticated plaques on the abdomen withexcoriated areas; (b) ame gure showing clusters of eosinophilsand macrophages around a central focus of collagen, coated ingranular eosinophilic material (haematoxylin and eosin; originalmagnication 100).

The Author(s)CED 2012 British Association of Dermatologists Clinical and Experimental Dermatology , 38 , 4043 41

Persistent hypereosinophilia with Wells syndrome J. Powell et al.


3/4

lymphocytic (L)-HES has been identied, characterizedby an aberrant population of T-cells of uncertain origin,which secrete eosinophilopoietic cytokines [interleukin(IL)-3 and or IL-5] causing eosinophilia. 8,9

Owing to this ongoing aetiological uncertainty inmany cases of HES, an attempt has been made toclassify patients within the spectrum based on theirclinical and pathological features. In 2005, six subtypesof HES were proposed: 8 (i) M-HES (including F Pnegative with myeloproliferative features, F P positiveand chronic eosinophilic leukaemia with cytogeneticabnormalities); (ii) L-HES (with demonstrable clonal orphenotypically aberrant lymphocyte population); (iii)familial eosinophilia (including an autosomal dominantform mapped to chromosome 5q3133); (iv) unidenti-ed HES (idiopathic with or without symptoms, includ-ing episodic variants); (v) overlap HES (eosinophilicdisease restricted to one organ system with eosinophilia

> 1.5 109

L); and (vi) associated HES (eosinophilia> 1.5 10 9 L in the setting of another diagnosis, inwhich eosinophilia has been described as a feature in asubset of those affected). 8,9

Identication of different subtypes of HES is importantto allow treatment to be tailored and long-termoutcomes predicted in individual cases within the HESspectrum. For example, corticosteroids were initially therst-line treatment for all types of HES, but since theidentication of the F P mutation, these patients arenow treated successfully with imatinib mesylate.

Cutaneous involvement is present in 4560% of patients with HES, and pruritus, erythematous papules,nodules, urticara-like lesions and angio-oedema have allbeen described. 7,10,11 Diagnoses of WS occurring insuch patients with HES continue to occur, and includethe case we describe above. 4 Wells and Smith 1 recog-nized this overlap in 1979, and regarded those affectedas being at the benign end of the HES spectrum(benign here indicating no extracutaneous complica-tions resulting from eosinophilia). However, time hasshown that the term benign is misleading, as somepatients with chronic eosinophilia can and will developinternal organ disease as detailed above, includingtransformation to leukaemia or lymphoma. 7

Using current classication schemes, those with WSand persistent idiopathic eosinophilia but no extracuta-neous organ involvement do not t happily into anysingle subtype of HES. Furthermore, eosinophilia,although often present, is not needed to make adiagnosis of WS, and therefore patients should not beregarded as having solely WS, especially if the eosin-ophilia is persistent. It is important to be able to identify

and classify such patients on clinicopathologicalgrounds, so that the aetiology, treatments and outcomesin such cases can be dened.

We have therefore set out the case for distinguishingpatients with WS from those with WS plus persistentidiopathic eosinophilia with no extracutaneous organinvolvement. Such cases are a readily identiablesubgroup of patients within the HES spectrum. Cur-rently no classication system adequately identies suchpatients, and thus we propose a new classication of persistent hypereosinophilia with Wells syndrome:PHEWS, using the following diagnostic criteria: (i)idiopathic persistent hypereosinophilia > 1.5 10 9 L;(ii) clinicopathological features of WS; and (iii) noeosinophilia-mediated extracutaneous organ involve-ment.

Idiopathic here means that any causes of M-HES andsecondary eosinophilia have been excluded. This will

include referral for a haematological assessment, inclu-ding measurement of serum tryptase levels, FIP1L1 PDGFRA analysis, and possibly bone-marrow biopsywith cytogenetic, molecular, histochemical andimmunophenotypic studies. 11 We have used the cut-off point of > 1.5 10 9 L for > 6 months, as used inthe HES diagnostic criteria established by Chusid et al.6

in 1975, to dene persistent hypereosinophilia. Whencarrying out investigations for any extracutaneouscomplications of persistent hypereosinophilia, physi-cians can be guided by clinical ndings and symptoms,with a low threshold of suspicion for cardiac andpulmonary involvement.

Treatment in cases of conrmed PHEWS will largelybe aimed at symptomatic relief, and for now remains asfor WS, with systemic corticosteroids used initially,and dose adjustments according to response. Topicalcorticosteroids alone may be sufcient. Antihistamines,dapsone, ciclosporin, azathioprine, griseofulvin, tetra-cyclines and interferon- a 2a have also been reported tobe effective and useful as steroid-sparing agents inpatients needing long-term treatment. 12 Currently, aswith many issues around HES, patient outcome, treat-ment goals and disease progression are largely uncer-tain in PHEWS. Monitoring such patients with

persistent hypereosinophilia on a long-term basis tosome degree seems currently sensible, as it is not yetpossible to predict what, if any, damage such persistenthypereosinophilia may cause or whether a haemato-logical malignancy will develop in the future. We hopethat with the establishment of PHEWS as a distinctsyndrome, such questions will be answered in thefuture.

The Author(s)42 CED 2012 British Association of Dermatologists Clinical and Experimental Dermatology , 38 , 4043

Persistent hypereosinophilia with Wells syndrome J. Powell et al.


4/4

hipereosinofilia 2

Documents