Primary cavitary sarcoidosis: A case report, systematic review, and proposal of new diagnostic criteria.

Primary cavitary sarcoidosis (PCS) is a rare form of pulmonary sarcoidosis. In this report, we present a case of a 47-year-old male patient with PCS who was initially treated as pulmonary tuberculosis. We also systematically review the literature on PCS and propose a new classification for this entity.

INTRODUCTION

Pulmonary sarcoidosis most commonly presents with symmetric hilar and mediastinal adenopathy.[1] Other radiologic manifestations include peribronchovascular nodules, nonresolving consolidation, and fibrocystic lesions.[2] Bullous lesions, cysts, cavities, and traction bronchiectasis are commonly encountered in chronic pulmonary sarcoidosis. However, cavitation as the presenting manifestation of pulmonary sarcoidosis, termed as primary cavitary sarcoidosis (PCS), is extremely rare.[3] Herein, we report a case of PCS and systematically review the literature for this rare form of pulmonary sarcoidosis.

CASE REPORT

A 47-year-old man presented with complaints of cough and progressive breathlessness of 2 months’ duration. There was fever, malaise, anorexia, and weight loss. Auscultation revealed crackles in the right mammary region. Rest of the physical examination was unremarkable. Complete blood count, fasting plasma glucose, liver and renal function tests were all within normal limits. Chest radiograph showed bilateral hilar enlargement and nonhomogenous opacities in the mid and lower zones of both lungs along with cavitation in the right middle zone. Sputum examination for acid-fast bacilli performed on 3 consecutive days was negative. The patient received empiric antituberculosis treatment with isoniazid, rifampicin, ethambutol, and pyrazinamide for a period of 2 months, followed by isoniazid and rifampicin for 4 months. Despite good compliance with treatment, cough and dyspnea worsened over the course of treatment. Chest radiograph after 6 months of therapy showed bilateral hilar adenopathy, reticulonodular opacities in both upper zones, bilateral perihilar consolidation, and a cavity in the right middle lobe [Figure 1A]. The patient was referred to us with a suspicion of drug-resistant tuberculosis.

Figure 1

Chest radiograph showing cavitation in the right middle zone and perihilar reticulonodular opacities with bilateral hilar enlargement (Panel A). Panel B shows the computed tomography of the chest with cavitation in the right lower lobe and left lower lobe measuring 6 cm × 5 cm × 4 cm and 3 cm × 2 cm × 2 cm, respectively. Note the extensive peribronchovascular nodules and subpleural nodules seen around the areas of cavitation. Computed tomography of the chest after treatment showing clearing of perihilar consolidation and peribronchovascular nodules and obliteration of the cavity in the left side while a thin-walled cavity persists in the right lower lobe (Panel C)

Computed tomography (CT) of the chest showed enlarged intrathoracic lymph nodes with bilateral perihilar consolidation and cavitation in both the lower lobes [Figure 1B]. There were extensive peribronchovascular nodules and subpleural nodules. Tuberculin skin test performed with 5 tuberculin units was negative and serum angiotensin-converting enzyme levels were 110 U/L (normal 8–65 U/L). Spirometry showed moderate restrictive defect (forced vital capacity [FVC], 50% predicted). Diffusion capacity for carbon monoxide was decreased (2.74 mmol/min/kPa; 32% predicted). Flexible bronchoscopy revealed widespread fine nodularity in the entire bronchial tree. Transbronchial lung biopsy and endobronchial biopsy showed compact noncaseating epitheloid granulomas; stain for acid-fast bacilli or fungi revealed no organisms. Bronchoalveolar lavage fluid was negative for fungus, Mycobacterium tuberculosis (culture and nucleic acid amplification assay) and malignant cells. A diagnosis of PCS was made.

The patient was treated with oral glucocorticoids for 9 months. There was improvement in dyspnea and exercise capacity. CT performed 1 year after stopping treatment showed clearing of perihilar consolidation and peribronchovascular nodules. Furthermore, there was resolution of the cavity on the left side; however, a thin-walled cavity persisted in the right lower lobe [Figure 1C]. There was improvement in lung function (FVC, 65% predicted) and diffusion capacity (68% predicted). The patient remains stable on follow-up without any relapse or complication.

DISCUSSION

Cavitation in sarcoidosis is uncommon. In a study involving 1254 patients from 10 centers, cavitary lesions were reported in only 3 (1.3%) of the 235 patients.[4] In another study involving 200 patients, cavities were reported 11.8% of cases.[5] In a recent large series of 1060 cases of sarcoidosis, the prevalence of cavitary lung lesions was 2.2%.[11] Seventeen of the 23 cases with cavitary sarcoidosis were found to be chronic fibrocystic sarcoidosis. PCS was diagnosed in only six cases, suggesting a prevalence of PCS of only 0.56%.[11] Several theories have been proposed to explain the occurrence of cavities in sarcoidosis. These include bullae formation (secondary to airway obstruction or traction due to fibrosis), intercurrent infections with bacterial, mycobacterial, or fungal agents, extrusion of necrotic hyaline material from conglomerate areas of fibrosis, and development of cystic bronchiectasis.[6] De novo cavitation due to sarcoidosis, results from ischemic necrosis of conglomerate granulomatous lesions.[7] Granulomatous angiitis that occurs in about 70% of patients with sarcoidosis may also contribute to the ischemic necrosis, the so-called necrotizing sarcoid granulomatosis (NSG) or sarcoidosis with NSG pattern.[89] Release of tumor necrosis factor-α from macrophages and lymphocytes in active granulomatous lesions incites cellular damage and necrosis, resulting in cavitation.[10]

A systematic review of the PubMed database using the free text terms: Sarcoidosis AND cavit* yielded 311 references of which 17 citations [25 cases, Table 1] were that of PCS.[611121314151617181920212223242526] The cases have been reported from across the globe including areas with high tuberculosis prevalence,[2324] further exemplified by the index case. The patients with PCS are usually young (mean age, 32.4 [range, 12-63] years), show no gender predilection (M:F; 14:11) and can be asymptomatic. As in the index case, cavities can be detected at the time of diagnosis or may develop weeks to months later, either spontaneously or during therapy.[22] The cavities are generally small, round and thin walled. However, it is not uncommon to find cavities of varying shape with thick irregular walls. Generally single, occasionally they may be multiple.[11151722] Majority of the patients (n = 16) had symptoms of chronic cough and dyspnea; only three patients were asymptomatic and were diagnosed by abnormal chest radiographs.[121619]. PCS has a good prognosis and majority of the patients improve with treatment. Of the 25 patients, 12 (48%) had complete resolution with treatment while in 11 (44%) thin walled cavities persisted for months to years [Table 1]. The followup information was not available in two cases. Our patient had excellent clinical and radiological response with glucocorticoids. A few complications have been reported in patients with PCS including hemoptysis in three patients,[1113] pneumothorax in two cases,[1215] aspergilloma in one case,[24] and bronchopneumonia leading to respiratory failure and death in one case.[15]

Table 1

Primary cavitary sarcoidosis cases (n=25) reported in literature

The pathology of PCS is characterized by noncaseating granulomas with minimal fibrosis in the cavity walls in contrast to dense fibrous tissue with few hyalinized granulomas seen in bullae and cystic bronchiectasis due to chronic sarcoidosis. In the present case, there were classical findings of active sarcoidosis without any granulomatous angiitis or ischemic necrosis in bronchoscopic lung biopsy. Based on the clinical and biopsy findings, we propose a new classification for PCS [Table 2]. In sarcoidosis, the initial two years following diagnosis are considered to be ’“acute stage”, and cavitation developing beyond this period is likely to be secondary to chronic fibrocystic sarcoidosis. Hence, we have used two years as the cutoff for diagnosing PCS. According to our classification, nodular sarcoidosis with cavitation or sarcoidosis with NSG pattern and cavities would all be classified under PCS as the occurrence of granulomatous angiitis is not specific for NSG but could also be encountered in classical sarcoidosis.[9]

Table 2

Classification of primary cavitary sarcoidosis

The index case had bilateral cavities in the right and left lower lobes and the cavity in the right lower lobe was larger at 6 cm × 5 cm × 4 cm size. Lung biopsy revealed noncaseating granulomas without any granulomatous angiitis or ischemic necrosis. Tests for the presence of mycobacteria and fungi were negative. The patient responded to corticosteroid treatment. Thus, a diagnosis of probable PCS was tenable. To our knowledge, there has been a single case of PCS reported from India, while PCS does not find mention in several case series from India.[12728] It is likely that the overwhelming presence of tuberculosis in India “drowns” the occasional cavitary sarcoidosis in primary care.[1] The index case was treated as sputum-negative pulmonary tuberculosis for 6 months before being referred as a case of suspected drug-resistant tuberculosis. The differentiation of sarcoidosis from tuberculosis poses great challenge to physicians, radiologists and pathologists, especially in countries with high prevalence of tuberculosis.[29] Most patients presenting with prolonged cough, cavitary lesions on chest radiograph, and negative sputum smear for acid-fast bacilli are diagnosed as “sputum smear-negative” pulmonary tuberculosis in high tuberculosis burden countries and are empirically treated with antituberculous treatment.[30] There are several features that can help in differentiating between cavitary lesions of sarcoidosis and tuberculosis [Table 3]. Recently, the advent of rapid cartridge-based nucleic acid amplification test such as XpertMTB/RIF has greatly helped in distinguishing pulmonary tuberculosis from pulmonary sarcoidosis.[31]

Table 3

Differentiating between cavitary lesions of sarcoidosis and tuberculosis in countries with high prevalence of tuberculosis

CONCLUSION

Active sarcoidosis can rarely present with cavitation in the lungs. This diagnosis must be considered in patients with compatible clinicoradiological presentation when microbiological investigations for bacteria, mycobacteria, and fungi are negative.

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Conflicts of interest

There are no conflicts of interest.