Subcarinal Mass: An Unusual Presentation of Granulomatosis With Polyangiitis

Introduction

Granulomatosis with polyangiitis (GPA) is a cytoplasmic-antineutrophil cytoplasmic antibody (C-ANCA) necrotizing vasculitis. The estimated prevalence of GPA ranges between 2.6 and 146 cases per million persons, making this quite a rare condition [1]. GPA typically presents with glomerulonephritis, involvement of the upper or lower respiratory tracks, and systemic vasculitis [2]. In GPA, less common manifestations include ocular findings such as scleral thinning and retro-orbital tumors; cutaneous manifestations such as purpura, necrotizing vasculitis, and skin nodules; neurological manifestations such as peripheral neuropathy, mononeuritis multiplex, and pachymeningitis; musculoskeletal manifestations such as arthralgias; and constitutional symptoms such as fever, weight loss, and malaise [3]. Mass lesions are a rather uncommon presentation of GPA [4]. While mediastinal masses have been reported, we were not able to find any reported cases of a subcarinal mass specifically as a manifestation of GPA. This makes this particular case extremely rare and unusual. Cases of GPA can range from mild cases localized to a single organ system to more severe, potentially fatal multiorgan disease. The rarity of the disease along with nonspecific presentations with varying degrees of severity often leads to diagnostic delay [5]. This diagnostic challenge became all the more significant for our patient due to an extremely rare presentation. Some of the features that can help distinguish GPA from other vasculitides include the presence of red blood cell casts on urinalysis, abnormal findings on chest radiograph, oral ulcers or nasal discharge, and necrotizing granulomatous inflammation on biopsy [2].

Case Report

A 22-year-old previously healthy White woman presented after a syncopal episode. Prior to presentation, she reported a 2-week history of fatigue, intermittent fevers with chills, anorexia, and unintentional weight loss. The episode of syncope occurred while walking through an airport. It was preceded by blurry vision, lightheadedness, and pallor. Witnesses noted that she collapsed to the ground and regained consciousness within minutes.

On examination, she appeared cachectic and ill, with a body mass index of 15 kg/m2. Vital signs were significant for tachycardia, with a maximum heartrate of 135 beats per minute that improved to the 90s after 2 liters of Lactated Ringer’s infusion. She did not have a fever. Blood pressure, respiratory rate, and oxygen saturation were normal as well. She had dry mucous membranes on oropharyngeal examination. The rest of the physical examination was unrevealing.

Initial laboratory test results revealed a microcytic anemia (hemoglobin, 9.7 g/dL), normal white blood cell count, mild microscopic hematuria, and a low albumin level, at 2.6 g/dL. Electrolyte, renal function, and liver function test results were within the reference range. High-sensitivity troponin and D-dimer levels were modestly elevated. An electrocardiogram showed sinus tachycardia without ischemic changes.

Computed tomography (CT) pulmonary angiography revealed a 4.5-cm subcarinal soft tissue mass causing significant compression and stenosis of the right main pulmonary artery (Figure 1). Multiple enlarged mediastinal lymph nodes were present, and bilateral peripheral ground-glass opacities were noted. The findings from the CT scan became the main focus of continued inpatient evaluation.

Bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of the mass and mediastinal lymph nodes was performed. Pathology revealed necrotizing granulomatous inflammation without malignant cells (Figure 2). Bacterial, fungal, and mycobacterial stains and cultures were negative. HIV, rapid plasma reagin, and interferon-gamma release assay were also negative. A transthoracic echocardiogram at the time revealed a moderate pericardial effusion. The patient was transferred to a tertiary care center where a second EBUS-TBNA was performed. Interestingly, the patient received a dose of dexamethasone peri-procedurally, which led to an improvement in her symptoms. Pathologic examination of the biopsy specimens showed necrotizing granulomatous inflammation with lymphocytes. Bacterial, fungal, and acid-fast bacilli cultures were negative, and cytology and flow cytometry results were unremarkable. These findings led to a strong suspicion that the patient had histoplasmosis, especially given that she had recently been living in the Ohio River Valley area. Therefore, she was started on oral itraconazole 200 mg every 8 hours and oral prednisone 1 mg/kg per day.

At this time, the patient also developed new dermatologic findings, including a painful, migratory urticarial eruption and a non-blanching purpuric rash on the lower extremities (Figure 3A, 3B). Urinalysis showed dysmorphic hematuria, and a 24-hour urine collection was significant for proteinuria of 1.5 g per day. Given the necrotizing granulomatous inflammation, suspicion of glomerulonephritis, new skin lesions, and improvement of symptoms after receiving dexamethasone, vasculitis was also considered as a possible etiology. Subsequent rheumatologic evaluation revealed a C-ANCA titer of 1: 320 and elevated serine proteinase-3 antibody level of 640 units. The rheumatoid factor level was also elevated. In the context of a mediastinal mass causing pulmonary artery compression, necrotizing granulomatous inflammation on pathology, microscopic hematuria on urinalysis, new cutaneous vasculitic features, and C-ANCA with elevated serine proteinase-3 antibody levels, a diagnosis of GPA was made, as the patient had more than 5 points according to the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA [6]. The patient received a total of 9 points; 5 for C-ANCA and serine proteinase-3 antibody, 2 for mass on CT chest, and 2 for granulomatous inflammation. Obtaining a renal biopsy was considered; however, given that the diagnosis was made on guideline based clinical criteria, this was ultimately not perused, with the opinion that its results would not change management and would expose the patient to procedure-related adverse events. Therefore, we were unable to definitively demonstrate vasculitis on pathology, although it was most certainly present, given renal and dermatological involvement.

The patient was treated with intravenous methylprednisolone 250 mg daily for 3 days followed by a prednisone taper and 2 doses of rituximab 1g, spaced 2 weeks apart. She received the first rituximab dose in the hospital. At the time of discharge, considerable clinical improvement was noted. She followed up with outpatient rheumatology for the second rituximab dose. Testing done at that time showed that her sedimentation rate, which had been 80 mm/h on admission, had normalized to 21 mm/h. Over the ensuing weeks, she continued to improve, and a follow-up CT chest at 3 months demonstrated resolution of the subcarinal mass and pericardial effusion. By this time, her prednisone dose had been tapered to 10 mg daily, and she was maintained on this dose. She received her third and last planned dose of rituximab 6 months after her hospital stay. During this follow-up period, she did not have any further flares. She has been able to return to a normal life with continuing follow-up and management by rheumatology in the outpatient setting.

Discussion

GPA is an autoimmune small-to-medium vasculitis characterized by necrotizing granulomatous inflammation. GPA commonly involves the upper and lower respiratory tracts and kidneys, but any organ system can be involved. GPA is a rare disease with an estimated prevalence ranging between 2.6 and 146 cases per million [1].

GPA typically presents with nonspecific symptoms such as fatigue, fever, and weight loss, followed by organ-specific manifestations localizing to the respiratory tract and kidneys, including sinusitis/epistaxis, cough, and hematuria. Pulmonary findings can include nodules, masses, infiltrates, and potentially alveolar hemorrhage, while renal involvement presents with anything from microscopic hematuria to rapidly progressive glomerulonephritis.

In the 1950s, the diagnostic criteria for GPA were initially developed and included evidence of necrotizing granulomatous inflammation in the upper airways and glomerulonephritis [7]. The criteria for diagnosis have since broadened, now indicating a diagnosis in patients with a clinical suspicion for vasculitis, histologic findings of granulomatous inflammation, as well as positive antibody serology testing. Specifically, C-ANCA with autoantibodies directed against proteinase 3 antibodies help confirm the diagnosis, as it is seen in 80% to 90% of GPA cases [5,8]. Treatment of GPA begins with induction therapy with steroids and either rituximab or cyclophosphamide to induce remission. Maintenance therapy is then continued with rituximab or other immunomodulating therapies [9].

This patient’s presenting syncope is hypothesized to be from the mediastinal mass effect on the pulmonary artery resulting in high-grade stenosis. This could further explain the presenting tachycardia; however, her poor oral intake, dehydration, or underlying inflammation may have played a role as well. Aside from granulomatous inflammation found in the tissue sample of the mass, there was no vessel biopsy completed, which would have aided in making a diagnosis.

In this patient, GPA manifested with a subcarinal mass. In our literature search, we did not find any such cases. Having said that, mediastinal masses have been reported with GPA. This includes a case report by Hanzawa et al that caused large vessel compression, much as in our case [10]. However, in contrast to our case, this particular patient presented with dyspnea. In another case, reported by Song et al, a mediastinal mass secondary to GPA had invaded the tracheal wall [11].

The diagnostic workup in the present case was challenging, considering necrotizing granulomas are nonspecific, and without an alternative malignant or infectious cause, there was a high suspicion for histoplasmosis given the patient’s geographic exposure. However, multiple rounds of biopsies yielded negative cultures, and the skin findings were consistent with palpable purpura. Evidence of glomerulonephritis, mediastinal mass, and positive antibody serologies confirmed the GPA diagnosis.

Conclusions

This case highlights an unusual presentation of GPA as a subcarinal mediastinal mass causing right pulmonary artery compression and syncope. Such vascular involvement is rare in GPA and more often seen with large vessel vasculitis. When patients present with mediastinal masses, malignancies, such as lymphoma or metastatic disease, autoimmune conditions, such as sarcoidosis, and infections, such as histoplasmosis and tuberculosis, are the most likely etiologies, and, naturally, diagnostic workup is focused on these conditions. This case suggests clinicians should also consider GPA in the differential diagnosis of necrotizing mediastinal granulomas and mediastinal masses, especially when more common etiologies are excluded. At a minimum, testing for serologic markers associated with GPA, which is readily available at most tertiary care centers, should be performed as early as possible. Early recognition is critical because prompt immunosuppressive therapy can prevent irreversible organ damage and improve long-term outcomes.