Mass-like Lesions Causing Compression of Large Vessels in Granulomatosis with Polyangiitis

Abstract

A 69-year-old woman with a history of otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitis who had been receiving corticosteroid monotherapy presented with shortness of breath. The otitis media had been alleviated, but she had saddle nose. Chest enhanced computed tomography showed stenoses of the bronchi and large vessels surrounded by mass-like lesions in the mediastinum. These manifestations indicated an active state of granulomatosis with polyangiitis (GPA). After she was started on high-dose corticosteroids and intravenous cyclophosphamide, the mass-like lesions disappeared with improvements of the stenoses. Ameliorating mass-like lesions resulting from GPA requires therapeutic intervention using corticosteroids and immunosuppressants.

Introduction

Granulomatosis with polyangiitis (GPA), a disorder characterized by small-vessel vasculitis, involves the respiratory tract and kidney (1). Patients with GPA, however, can present with mass-like lesions in various organs, including the brain, orbit, skin, genitalia, retroperitoneum, and mediastinum, making a diagnosis difficult (2).

GPA is one form of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Two major ANCAs, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, are associated with the pathogenesis. Half of Japanese patients with GPA are positive for MPO-ANCA (3). Otitis media is an early symptom of AAV. Patients with otitis media with AAV (OMAAV), which can develop systemic inflammation, rarely meet the diagnostic criteria of systemic AAV, such as GPA at the initial visit (4). Notably, OMAAV can frequently relapse, causing complete deafness or the involvement of organs, such as the nervous, respiratory, and renal systems (5).

We herein report a patient with OMAAV who developed GPA and presented with mass-like lesions in the mediastinum.

Case Report

A 69-year-old woman presented with increasing shortness of breath with Hugh-Jones degree 3 for several months. She had been diagnosed with OMAAV three years ago, based on refractory otitis media in both ears and elevated levels of MPO-ANCA. At that time, she had been started on induction therapy consisting of prednisolone 30 mg/day (0.8 mg/kg/day). Her mixed hearing loss caused by OMAAV recovered. Subsequently, she received maintenance therapy consisting of methylprednisolone and azathioprine but had intolerance due to adverse effects of azathioprine causing liver damage. The dosage of methylprednisolone was gradually decreased to 10 mg/day.

At the current admission, she did not have a relapse of otitis media but did present with saddle nose. Blood tests showed elevated concentrations of C-reactive protein (CRP; 7.6 mg/dL) and brain natriuretic peptide (BNP; 135 pg/mL) and normal levels of MPO-ANCA and PR3-ANCA. Although her serum creatinine concentration was normal (0.43 mg/dL), urinalyses showed red blood cell sediment.

An electrocardiogram showed right ventricular stress. An echocardiogram showed a markedly enlarged right ventricle with systolic ballooning of the mid-ventricular wall as well as a tricuspid regurgitation pressure gradient (TRPG) of 38 mmHg with pericardial effusion. Chest enhanced computed tomography (CT) on the pulmonary window setting showed circumferential bronchial wall thickening of the carina of the trachea, right main bronchus, and the right segmental bronchi (Fig. 1A). Chest enhanced CT further showed that the mediastinum contained mass-like lesions compressing the right pulmonary artery, the main pulmonary veins, and the superior vena cava with stenosis (Fig. 1B).

Figure 1.

Results of a radiographic evaluation showing improvement of pulmonary lesions. (A) Chest computed tomography (CT) on pulmonary window setting showing circumferential bronchial wall thickening of the carina of the trachea and right main bronchus (red arrowheads). (B) Chest enhanced CT showing mass-like lesions surrounding the superior vena cava (yellow arrowheads), as well as the pulmonary artery and vein. (C) Lesions in remission after the start of treatment with high-dose corticosteroids and cyclophosphamide. (D) Absence of thromboembolism from the pulmonary arteries.

To examine the mass-like lesions in the mediastinum, bronchoscopy was performed. Bronchoscopy revealed swollen mucous membranes of the trachea and the right bronchi with stenosis (Fig. 2A, 2B). A biopsy from the ostium of the right upper lobe bronchus showed neither granulomatous inflammation nor malignant cells. In the bronchial lavage fluid from the right upper lobe, neither mycobacterium tuberculosis nor other bacteria was cultured. We could not make a pathological diagnosis of the mass-like lesion. Positron emission tomography with CT which might have help guide the biopsy but was unavailable. These manifestations observed in this patient could not rule out the possibility that the mass-like lesion and systemic inflammation had been caused by a progressive state of GPA.

Figure 2.

Bronchoscopic findings. Bronchoscopy showing swollen mucous membranes of the (A) trachea and (B) right bronchi.

To release the stenoses of the superior vena cava and bronchi, therapeutic intervention was started before the diagnosis was confirmed. The patient was started on high-dose corticosteroids, consisting of methylprednisolone 24 mg/day, followed by 6 cycles of monthly intravenous cyclophosphamide (IVCY) (Fig. 3). After 2 cycles of IVCY, her shortness of breath was alleviated, resulting in Hugh-Jones degree 2. Her CRP and BNP levels decreased to 2 mg/dL and 36 pg/mL, respectively. Sequentially, both the circumferential bronchial wall thickening and mass-like lesions in the mediastinum disappeared with improvements of stenosis in the bronchi and vessels (Fig. 1C). This effective response to the administration of IVCY suggested that the mass-like lesions had been caused by the active state of GPA.

Figure 3.

Clinical course of granulomatosis with polyangiitis. High-dose corticosteroids and intravenous cyclophosphamide (IVCY) alleviated her shortness of breath and decreased the C-reactive protein (CRP) levels and tricuspid regurgitation pressure gradient (TRPG) values. These values then increased again during cessation of IVCY, but her shortness of breath remained alleviated. The patient has not experienced any recurrences of mass-like lesions after two cycles of IVCY. SOB: shortness of breath

We tried to continue the induction therapy using IVCY for remission of GPA, but the third cycle of IVCY was postponed due to its adverse effect of vomiting. Her CRP level increased to 4 mg/dL, and the level of TRPG was elevated to 53 mmHg. Determining her pulmonary artery pressure (PAP) precisely required right heart catheterization (RHC), which demonstrated an elevated mean PAP (31 mmHg) and pulmonary artery wedge pressure (PAWP; 20 mmHg). We speculated that the pulmonary artery hypertension (PAH) was associated with the active state of GPA.

To suppress the progression of GPA, we suggested that the patient receive rituximab (RTX) as an alternative induction therapy. However, she refused this therapy because of anxiety about its side effects. She was therefore restarted on methylprednisolone 32 mg/day and IVCY with a more effective prophylaxis against nausea. The dosage of corticosteroids was gradually decreased. Her shortness of breath and hearing loss remained alleviated. However, although an echocardiogram showed no evidence of pericardial effusion, the right ventricular stress and high levels of TRPG (45-55 mmHg) remained after treatment. The patient has not experienced any recurrences of mass-like lesions around the vessels or other organs for 12 months while continuing to receive corticosteroid monotherapy.

Discussion

The present patient with OMAAV developed stenosis in the bronchi and large vessels secondary to extrinsic compression by mass-like lesions in the mediastinum. We speculated that GPA subsequent to OMAAV presented with inflammatory mass-like lesions. Therapeutic interventions, including high-dose corticosteroids and immunosuppressants, resolved the patient's symptoms and these stenoses. However, the PAP remained slightly elevated after treatment.

Mediastinal mass-like lesions are rare manifestations in GPA. Patients with GPA are more likely to have mass-like lesions than those with other systemic vasculitis (2). In a single-center cohort, 3 of 302 patients with GPA had mass-like lesions in the mediastinum (6). Only two reports have shown that those lesions could compress organs in the mediastinum, such as the trachea (7) and venous cava (8). The present patient had shortness of breath caused by stenosis with bronchi and superior venous cava due to compression by the mediastinum mass. Mediastinal lung cancer, malignant lymphoma, and infection are likely to be considered as differential diagnoses in patients with mediastinal masses, but inflammatory masses due to GPA should also be considered in those with GPA.

Patients with GPA may present with mass-like lesions, making the diagnosis difficult. To differentiate them from malignancy, samples are needed. We tried collecting a sample from bronchi that might have been invaded by the mass-like lesions; however, we were unable to obtain pathological evidence of the mass-like lesions, as no lesions had infiltrated the airway surface. The current patient presented with airway involvement and saddle nose as well as a history of OMAAV. Microscopic hematuria at admission suggested potential small-vessel vasculitis of the kidneys. Based on these symptoms of the respiratory tract and kidney, this patient should have been regarded as potentially having GPA subsequent to OMAAV. The current patient showed normal levels of MPO-ANCA and PR3-ANCA at admission. The serum levels of ANCA, however, do not always reflect the relapse of AAV in organs other than kidney (9), suggesting that the fever and serum levels of CRP rather than MPO-ANCA might have reflected the disease activity of the present patient. The mass-like lesions disappeared after starting immunosuppressive therapy that included corticosteroids and IVCY, suggesting that the mass-like lesion was a sign of active GPA.

Mass-like lesions in GPA can potentially cause irreversible damages in various organs. GPA has been reported to be accompanied by severe superior vena cava stenosis due to fibrosing mediastinitis and pulmonary artery stenosis due to a fibrosing artery wall (8). Orbital masses associated with GPA have been reported to be responsible for blindness due to optic nerve compression (10). Such damages can be induced by subacute or chronic inflammatory processes, requiring surgical intervention. The present patient had been diagnosed with OMAAV, indicating that organ involvement was initially limited to the middle ear. However, a nationwide survey of patients with OMAAV in Japan showed that the frequency of involvement of the lungs and kidneys was 38% and 26%, respectively (4), suggesting that patients with OMAAV may be complicated by systemic AAV. One literature review showed that 8 of 28 GPA patients with mass-like lesions presented with otitis media, suggesting that patients without OMAAV may be more likely to have mass-like lesions than those with OMAAV (2). Nevertheless, the present patient may have had subsequent systemic inflammation, resulting in the appearance of the mass-like lesions. Although our patient received induction and maintenance therapy for OMAAV using corticosteroids alone due to her advanced age and intolerance to immunosuppressants, preventing persistent or refractory inflammation would require optimal interventions with immunosuppressants during the early stage of the disease.

Although high-dose corticosteroids and IVCY ameliorated the clinical symptoms and attenuated the disease activity in our patient, right ventricular stress remained. Although RHC showed that she had PAH, the examination did not reveal the exact pathology of the PAH. Her high level of PAWP implied that left-side heart disease had resulted in the PAH, but she had a normal ejection fraction and mild valvular dysfunction that was disproportionate to the right ventricular stress. PAH associated with AAV is rare, but some cases have been described in the literature (11). We speculated that the current patient's lungs might have had small-vessel occlusions resulting from AAV at a microscopic level and that the disease activity might not have been adequately controlled. Thus, the cumulative dose of corticosteroids has been increased. Notably, induction therapy with high-dose corticosteroids and immunosuppressants is not always effective for GPA patients with mass-like lesions, who experience residual mass-like lesions or refractory disease in a high proportion of cases (12). RTX, which is beneficial in patients with refractory AAV, has been reported to suppress GPA with mass lesions (13). Although the present patient did not receive induction therapy using RTX due to her refusal, it should have been started in order to achieve remission of GPA.

The clinical manifestations in this patient suggest that patients with OMAAV can develop GPA and have mass-like lesions. The optimal therapy for such cases should be determined.

Appropriate written informed consent was obtained for the publication of this case report and accompanying images.

The authors state that they have no Conflict of Interest (COI).