Cardiovascular Pathology 23 (2014) 363–365

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Cardiovascular Pathology

Clinical Case Report

A case of aortic and mitral valve involvement in granulomatosis

with polyangiitis

Olivier Espitia a,⁎, Laure Droy b, Sabine Pattier c, Frédérique Naudin d, Antoine Mugniot e, Arnaud Cavailles d,Mohamed Hamidou a, Patrick Bruneval f, Christian Agard a,1, Claire Toquet b,1

a Department of Internal Medicine, University Hospital of Nantes, Franceb Department of Pathology, University Hospital of Nantes, Francec Department of Cardiology, University Hospital of Nantes, Franced Department of Pulmonary Medicine, University Hospital of Nantes, Francee Department of Thoracic and Cardio-vascular Surgery, University Hospital of Nantes, Francef Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France

a b s t r a c ta r t i c l e i n f o

Conflicts of interest: The authors declare that theyFunding source: No external funding was secured f

⁎ Corresponding author. Department of Internal MHospitalier Universitaire de Nantes, 1 place Alexis RicTel.: +33 240 083 146; fax: +33 240 083 379.

E-mail address: olivier.espitia@chu-nantes.fr (O. Esp1 Christian Agard and Claire Toquet contributed equally

http://dx.doi.org/10.1016/j.carpath.2014.07.0071054-8807/© 2014 Elsevier Inc. All rights reserved.

Article history:Received 8 May 2014Received in revised form 28 July 2014Accepted 28 July 2014

Keywords:Granulomatosis with polyangiitisWegener’s granulomatosisValve diseasePolymorphous microabscessesEpithelioid granuloma

Granulomatosis with polyangiitis (GPA) (Wegener’s) is a necrotizing systemic vasculitis of the small-sizedblood vessels, affecting kidneys, lungs, upper respiratory tract and skin. Cardiac valvular involvement is anuncommon manifestation of GPA. We report the case of a 60-year-old woman with arthritis and lung nodulesdue to GPA without antineutrophil cytoplasmic antibodies (ANCA) at time of diagnosis. Remission wasobtained with cyclophosphamide and corticosteroid. Azathioprine was then prescribed for 2 years. Four yearslater, she developed severe inflammatory aortic andmitral valvular involvement characterized by GPA typicalhistopathological valvular lesions. Search for ANCA was positive at this time (anti-myeloperoxidase). Cardiacvalvular involvement is a rare and potentially fatal complication of GPA and may misleadingly suggestinfectious endocarditis. A review of literature revealed few cases of histologically well-documented cardiacvalvular involvement in GPA. Pathologists should be aware of valvular heart diseases in GPA, which usuallycomprise valvular necrotic lesions without any microbial agents.

have no conflict of interest.or this report.edicine, Hôtel-Dieu, Centre

ordeau 44093 Nantes, France.

itia).to this report as co-last author.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

Granulomatosis with polyangiitis (GPA) is a systemic necrotizingantineutrophil cytoplasmic antibodies (ANCA)-associated vasculitiswhich typically involves the upper respiratory tract, kidneys, andlungs. Cardiac manifestations are rare and might be underdiagnosedwhen typical clinical signs are lacking. Pericarditis and coronaryvasculitis are the most frequent findings of cardiac involvement inGPA (half of cases); myocarditis and conduction block are alsodescribed. In GPA, cardiac valvular disease seems to be very uncommon[1]. We report an exceptional case of dual valvular involvement duringGPA with well-documented histopathological analysis.

2. Case report

In 2005, a 60-year-oldwomanwith a history of arterial hypertension,chronic obstructive pulmonary disease, and active smoking initially

developed weight loss, dyspnea, arthritis, and inflammatory syndrome[C-reactive protein (CRP) 150 mg/l]. She had no treatment. Computedtomographic (CT) scan found multiple thoracic lung nodules withcompression of the right upper lobe bronchus. Lung nodules wereexplored by biopsywhich showed necrosis surrounded by inflammatoryinfiltrates composed of some epithelioid and giant cells, mononuclearcells, and polymorphous microabscesses without any pathogens.Blood tests including ANCA, enzyme-linked immunosorbent assay anti-myeloperoxidase (MPO) and anti-proteinase 3 (PR3) antibodies, bloodculture, mycobacterial investigations, and viral serology were negative.Electrocardiogram was normal; echocardiography found septal kineticsdisorder without valvular involvement; left ventricular ejection fraction(LVEF) was 63%. Based on these findings, ANCA-negative GPA wasdiagnosed. At diagnosis, there was neither renal (serum creatinine63 μmol/l, proteinuria 0.14 g/l, no hematuria) nor upper respiratory tractinvolvement, and Birmingham Vasculitis Activity Score (BVAS) was 13.

She was treated with six cyclophosphamide (CYC) monthly pulses(600 mg/m2) followed by oral azathioprine (100 mg daily) associatedwith corticosteroids (prednisone 1 mg/kg/d). Remission was achieved,and treatmentwas discontinued after 2 years; oral corticosteroidswerereplaced by inhaled corticosteroids. The patient was followed every6 months; CRP remained normal and ANCA negative.

Four years later, she complained of isolated progressive dyspneaand pulmonary edema due to aortic andmitral regurgitation. CRP was

364 O. Espitia et al. / Cardiovascular Pathology 23 (2014) 363–365

92 mg/l. She had no other systemic symptoms. Search for p-ANCAwaspositive (perinuclear pattern) with ANCA anti-MPO (35 UI/ml).Thoracic CT scan found no active lesion. Echocardiography showedan aortic regurgitation (4/4), a restrictive mitral regurgitation (2/4), a50% LVEF, and a dilated left atrium (27 cm2). Transesophagealechocardiography showed thickening of aortic annulus, thickeningof anterior mitral valve, and restriction of posterior mitral valve; novegetationwas present on the valves. Coronary angiography showed avery irregular, calcified, and dominant right coronary artery with anold occlusion in proximal segment. Aortic and mitral valve replace-ments associated with coronary artery bypass were performed.Macroscopically, aortic valve was tricuspid; cups appeared diffuselythickened. Mitral valve’s leaflet appeared also thickened; chordaetendineae displayed no abnormalities. A few calcified deposits wereobserved closed to the mitral annulus. No vegetations were seen.

Fig. 1.Mitral and aortic valves. (A, B)Mitral valve: Involvement of (A) the leaflet (central layer) andmagnification ×20). (C) Aortic valve: thickening of the valve; diffuse inflammatory infiltrate, and “

(D)Eosinophilic and “dirty”necrosis surroundedbygranulomatous infiltratewithpalissadingminfiltrate with giant cells (arrows) with polymorphous microabscesses (*) (HES; magnification

Blood and valves cultures were negative. Histopathological analysis ofthe aortic and mitral valve specimens showed extensive typicallesions of GPA, namely, a granulomatous inflammation and polymor-phonuclear microabscesses with minute and remarkable geographicnecrosis (Fig. 1). This necrosis was sometimes referred to as “dirtynecrosis” because it contained cellular debris and dead polymorpho-nuclear cells, or “eosinophilic necrosis”when it was devoid of cellulardebris. The necrosis was surrounded by a granulomatous infiltratecomposed of macrophages, giant cells, lymphocytes, and plasma cells.This infiltrate, mainly deeply located in the central layer of the valve,could also be observed superficially underlying an intact endotheliallayer. This endothelial layer could be focally interrupted, and surfaceerosions could be observed. However, neither vegetation nor fibrindeposit was seen. Areas of fibrosis were observed. There werenumerous vessels surrounded by the inflammatory infiltrate. Very

(B) the chordae tendineae by the inflammatory infiltrate (hematoxylin eosin staining [HES];geographic” necrosis involving the different layers of the valve (*) (HES;magnification ×20).acrophages, lymphocytes, andplasmacells (HES;magnification×200). (E)Granulomatous×200). (F) “Dirty” necrosis within fibrosis’ areas (HES; magnification ×200).

365O. Espitia et al. / Cardiovascular Pathology 23 (2014) 363–365

rare lymphocytes could infiltrate their wall, but it was considered as anonspecific finding. Stains (periodic acid–Schiff, Gram–Weigert, andZiehl) for fungi, bacteria, or other organisms were negative.

The patient felt better after surgery and did not receive any specifictreatment of necrotizing vasculitis (BVAS 6). Seven months later, shepresented with right eye papillitis, inflammatory syndrome, arterialhypertension, increase in serum creatinine 92 μmol/l, proteinuria0.05 g/d, no hematuria, wheezing, and arthralgia arising with anti-MPO ANCA persistence (24UI/ml). Considered as a relapse of GPA(BVAS 19), she received three new courses of CYC with prednisone1 mg/kg/d followed by rituximab as a maintenance therapy, withclinical remission and ANCA decrease (5.6 UI/ml).

3. Discussion

We report a rare case of dual valvular involvement during GPAwith well-documented histopathological analysis. The diagnosis wasbased on clinical history, histopathological findings, and rise of ANCA.

Although GPA is a systemic disorder, clinical evidence of cardiacinvolvement is uncommon. In a large cohort of 595 patients withperiarteritis nodosa, microscopic polyangiitis, and eosinophilic granu-lomatosis with polyangiitis (Churg–Strauss syndrome), 14% of patientshad congestive cardiac failure at diagnosis [2]. Frequency of heartinvolvement in GPA is about 25% in autopsy study and 8% in clinicalstudy. Half of patients with GPA heart involvement had pericarditis;25%, myocarditis; 21%, valvular involvement; 17%, conduction block;and 11%,myocardial infarction. In a series of 21 patients with GPA heartvalve involvement, aortic valve was involved in 57.1% of case; mitralvalve, 14.3%; and both aortic and mitral valves, 28.6%. Aorticregurgitation is the main manifestation; other manifestations arerare: mitral regurgitation, aortic stenosis, valvular vegetations, massinvolving a mitral leaflet, and multiple atrial masses [3]. In the cases ofGPA-specific valvular involvement, 50% of valvular lesionswere presentat diagnosis, and 19% were observed after the first year of the vasculitisdiagnosis [3].

Our literature review found 16 cases of documented valvular GPAinvolvement [3,4]: 10 GPA aortic valve involvement, and 3 mitral and3 aortic/mitral involvements. Including this report, mean age atdiagnosis of valvular involvement was 48.3 years. ANCAwere positivein 10/12 patients: 6 patients with c-ANCA, 2 with p-ANCA, and 2 withunknown specificity. Anti-PR3 was positive in three cases and anti-MPO in two cases. Six cases of valvular involvement occurred after thediagnosis of GPA: two cases occurred without immunosuppressive(IS) treatment; two cases, under IS treatment.

In our case, microscopic examination of the valves demonstrated atypical GPA histopathological pattern based on two major histologicalcriteria: polymorphous microabscesses with minute and remarkablegeographic necrosis and a granulomatous inflammation. Neovascular-ization was present but without any obvious signs of vasculitis.Moreover, a major part of the infiltrate was located in the central layerof the valve, but it could also underlie the endothelial layer or a surfaceerosion. There were no vegetations and no fibrin deposit on the valve’s

surface. All these findings provided arguments in favor of an active GPA.However, in any cases, presence of microabscesses requires specialstainings to rule out a bacterial/ fungal valves’ secondary infection.

In all these cases, extensive valve samples are required to performthe correct diagnosis especially when the patient is under IS therapy.In a very few cases, histological lesions within valvular tissue werespecific, characterized by granulomatous inflammation with minuteor large necrosis and polymorphous microabscesses as describedabove. In most cases (12 cases on 16), pathological findings werenonspecific, without argument for active valve involvement. Thelesions included insignificant inflammatory infiltrate, myxomatouschange, or degeneration of collagen. Some other cases displayedneovascularization and fibrosis with no significant inflammatoryinfiltrate. These lesions are nonspecific but can be the onlymanifestation of underlying GPA and considered as “scarring” lesions.

Infectious diseases of cardiac valves should be mentioned becausecardiac valvular involvement in GPA is uncommon. Subacute bacterialendocarditis (SBE) has first to be ruled out based on negative bloodcultures, intracellular pathogens search (with serology and bacterialpolymerase chain reaction), and absence of microorganism onpathologist’s examination. In the present report, blood cultureswere negative and p-ANCA anti-MPO positive. However, this type ofvalvular involvement associated with ANCA may be encountered in SBE[5]. c-ANCA are most often encountered in SBE, but p-ANCA are alsodescribed. Recently, among 109 infective endocarditis cases, 18% had c- orp-ANCA, and 8% had anti-PR3 or anti-MPO [5]. This report illustrates adiagnosticdifficultybetweenSBEandspecific involvementofGPAwithnoclassical systemic symptoms. Clinical, biological, and pathological datamust be taken into account to propose final diagnosis.

To conclude, we report an exceptional case of severe GPA withaortic and mitral valves specific involvement whose diagnosis wasonly established at pathological analysis. Clinicians should be aware ofsuch involvement in GPA that may occur as a sole sign of a relapse.ANCA should be monitored regularly even in patients with initialANCA-negative GPA. Our case illustrates the need of a closecollaboration between clinicians and pathologists in order to assesssuch difficult diagnosis.

References

[1] Goodfield NE, Bhandari S, Plant WD, Morley-Davies A, Sutherland GR. Cardiacinvolvement in Wegener’s granulomatosis. Br Heart J 1995;73:110–5.

[2] Bourgarit A, Le Toumelin P, Pagnoux C, Cohen P, Mahr A, Le Guern V, et al. Deathsoccurring during the first year after treatment onset for polyarteritis nodosa,microscopic polyangiitis, and Churg–Strauss syndrome: a retrospective analysis ofcauses and factors predictive of mortality based on 595 patients. Medicine(Baltimore) 2005;84:323–30.

[3] Lacoste C, Mansencal N, M’rad M Ben, Goulon-Goeau C, Cohen P, Guillevin L, et al.Valvular involvement in ANCA-associated systemic vasculitis: a case report andliterature review. BMC Musculoskelet Disord 2011;12:50–6.

[4] Shakil O, Matyal R, Khabbaz K, Wang A, Mahmood F. Intracardiac Wegener’sgranulomatosis. Ann Thorac Surg 2012;94:e105.

[5] Mahr A, Batteux F, Tubiana S, Goulvestre C, Wolff M, Papo T, et al. Prevalence of anti-neutrophil cytoplasmic antibodies in infective endocarditis. Arthritis Rheumatol 2014;66(6):1672–7.