Review of research on pulmonary cysts in sjögren’s syndrome

Abstract

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease mainly involving exocrine glands and particularly affecting the salivary glands and lacrimal glands, thus inducing a dry mouth and dry eyes. Extraglandular organs are also involved in SS, and this results in damage to multiple systems. Among these, lung damage is more common, with high morbidity and mortality rates, and the lack of typical symptoms in the early stages makes it challenging to identify it. The main pulmonary manifestations of SS are bronchitis, pulmonary hypertension, pulmonary cysts, pulmonary amyloidosis, interstitial pneumonia, and pulmonary fibrosis. Cystic lung disease affects about 4–46.2% of patients with SS. The imaging characteristics of pulmonary cysts in SS, including the size, number, morphology, and distribution, as well as differential diagnosis, mechanisms underlying the formation of pulmonary cysts, and current treatment strategies, are presented in this review.

Introduction

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease mainly involving the exocrine glands. It is categorized as primary SS, which occurs independently, and secondary SS, which refers to SS secondary to another well-diagnosed connective tissue disease. Up to 10% of patients with primary SS present with pulmonary cysts, defined as thin-walled sacs embedded within normal lung tissue and typically measuring less than 3 mm. Pulmonary cysts are rare in other immune disorders and serve as a characteristic manifestation of SS [1, 2]. SS is also an important consideration in the differential diagnosis of cystic lung diseases.

In this review, the imaging features of pulmonary cysts in SS, including the size, number, morphology, and distribution, as well as the differential diagnosis, mechanisms of formation of pulmonary cysts, and current treatment strategies, are presented.

Imaging features of pulmonary cysts in sjögren’s syndrome

SS is a diffuse connective tissue disease characterized by a significant infiltration of lymphocytes, particularly affecting exocrine glands such as the lacrimal glands and salivary glands. Its immune-inflammatory response is mainly manifested in the epithelial cells of the exocrine glands. The primary clinical manifestations are keratoconjunctivitis sicca, xerostomia, and symptoms of multisystem damage due to involvement of exocrine glands and extraglandular organs, including nose bleeding, hoarseness, and a dry cough, among others. Although patients with SS often present with typical dryness symptoms, some patients develop systemic symptoms such as fatigue and neuropathy.

In patients with SS, the impaired function of the exocrine glands within the respiratory tract results in dryness of the trachea and compromised ciliary function on the mucosal surfaces. This predisposes patients to a dry cough and can lead to the development of interstitial lung lesions. In addition, existing literature highlights that SS is often complicated by cystic lung disease. Pulmonary cysts can develop independently or as a secondary condition to other pulmonary complications associated with SS, including lymphocytic interstitial pneumonia (LIP), follicular bronchiolitis, and pulmonary amyloidosis [2].

Patients with SS complicated with pulmonary cysts do not have typical clinical manifestations, and these cysts are usually found on imaging examinations. The diameter of pulmonary cysts varies from 3 mm to 52 mm, with an average of 16 mm. They may present in various shapes, including oval, round, or irregular forms. In a study comprising 84 patients with SS complicated with cystic lesions, the number of cysts ranged from 0 to 92, with an average count of 25 [3]. In another study on 21 patients with SS complicated with cystic lesions, 67% of them had < 5 cysts, 19% had 5 to 10 cysts, and 14% had > 10 cysts [4]. Cystic lesions associated with SS are predominantly located in the lower lobes of the lungs and often contain an artery or vein—a feature that is not frequently observed in pulmonary lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH). (as shown in Fig. 1) In addition, pulmonary cysts in SS rarely rupture to cause pneumothorax.

Fig. 1.

Cystic lesions associated with SS are predominantly located in the lower lobes of the lungs

Differential diagnosis of the pulmonary cyst in sjögren’s syndrome

Identification of true and false cysts

In the context of SS, it is critical to distinguish between true pulmonary cysts and other similar conditions such as cavitation, cystic bronchiectasis, and emphysema that are similar to cystic lung disease. These “pseudocysts” should be excluded first in the differential diagnosis of pulmonary cysts. (as shown in Fig. 2)

Fig. 2.

Flowchart of differential diagnosis of cystic lung disease in Sjögren’s syndrome. LIP: Lymphocytic interstitial pneumonia. PLCH: Pulmonary Langerhans cell histiocytosis. DIP: Desquamative interstitial pneumonia. BHD: Birt-Hogg-Dubé. LAM: Pulmonary lymphangioleiomyomatosis

Cavitation

Cavitation is also located within the lung parenchyma, but unlike a pulmonary cyst, its wall thickness is usually more than 4 mm [5]. Conditions commonly associated with cavitation include bronchial tumors, lung metastases, vasculitis, and infectious diseases such as lung abscesses, tuberculosis, and fungal infections.

Centrilobular emphysema

Centrilobular emphysema is characterized by cystic dilation of distal second-degree respiratory bronchioles. This disease is mainly associated with smoking and is often observed in the upper lobes of the lungs. The sacs formed by emphysema are usually polygonal, in contrast to the typically round shape of pulmonary cysts [6]. Emphysema can be distinguished from pulmonary cysts based on the morphology of the sacs.

Cystic bronchiectasis

Bronchiectasis is characterized by persistent local or diffuse dilation of the bronchial tubes, resulting in cystic changes in the dilated bronchi. Due to inadequate ventilation and atrophy of the affected lung parenchyma, the dilated airways tend to converge, presenting a “double-track sign” on the longitudinal section and an “annular shadow” on the transverse section. Consequently, cystic bronchiectasis can be distinguished from pulmonary cysts through image reconstruction in the coronal and sagittal views, respectively.

Honeycomb lungs

Honeycomb lungs are distinguished by the aggregation of multiple small sacs of varying thickness, which is a hallmark of the advanced stage of pulmonary fibrosis. Pulmonary cysts are typically embedded within the lung parenchyma, whereas honeycomb lungs are often located subpleurally. (as shown in Fig. 3)

Fig. 3.

Pulmonary cysts are typically embedded within the lung parenchyma, whereas honeycomb lungs are often located subpleurally

Bullae

Bullae are air-filled cavities formed by the rupture and subsequent fusion of alveolar walls due to increased pressure within the alveolar cavity. In contrast, pulmonary cysts are mainly caused by bronchial or bronchiole valve formation due to various reasons, leading to the dilation and fusion of distal small bronchi. Bullae are predominantly located at the apex of the lungs, while pulmonary cysts are usually located in the lower lobes of the lungs and are frequently associated with blood vessels.

Other complications associated with pulmonary cysts

Complications with nodules

Lymphocytic interstitial pneumonia (LIP)

Lymphocytic interstitial pneumonia (LIP) is a rare lymphoproliferative disorder that is histologically characterized by the infiltration of lymphocytes and plasma cells into the alveoli and interlobular septum [7]. The main clinical manifestations are progressive dyspnea and coughing. The incidence and prevalence of LIP are unknown. It more commonly affects women than men (male to female ratio of 1:2.75) [7]. LIP is often secondary to immune diseases such as SS, rheumatoid arthritis, systemic lupus erythematosus, or immunodeficient diseases such as human immunodeficiency virus (HIV) infection. Notably, approximately 25% of LIP cases are associated with SS [8].

Typical imaging findings of LIP include ground-glass opacities, thickening of the interlobular septum, subpleural nodules of varying sizes, and cystic lesions. (as shown in Fig. 4). The cysts are predominantly located in ground-glass opacities surrounding the blood vessels or in the lower lobes of the lungs and are usually less than 30 mm in diameter [9–11]. The formation of these cysts may be caused by obstructive bronchiectasis due to vascular occlusion or secondary bronchiole dilation due to the compression of bronchioles by lymphoid tissue [12].

Fig. 4.

Typical imaging findings of LIP include ground-glass opacities, thickening of the interlobular septum, subpleural nodules of varying sizes, and cystic lesions

Pulmonary langerhans cell histiocytosis

PLCH is a rare clonal proliferative disorder characterized by the infiltration of a large number of Langerhans cells within the lung parenchyma, leading to the activation of inflammatory factors. Approximately 90% of patients with PLCH have a history of smoking or exposure to secondhand smoke. Although the precise pathogenesis of PLCH remains unclear, smoking has been shown to cause the aggregation and activation of Langerhans cells in the lung tissues [13]. About 60% of patients have atypical symptoms such as shortness of breath and cough, which are often detected incidentally on imaging examinations. Radiologic findings also vary depending on the stage of the disease. Early stages of the disease are typically marked by the development of nodules, while pulmonary cysts form predominantly in the later stages. These nodules are formed due to the accumulation of Langerhans cells and other immune cells around the small airways, resulting in airway remodeling and cystic lung disease [14]. The cystic lesions in PLCH are extremely irregular in morphology, which is markedly different from the round cysts associated with pulmonary LAM and Birt-Hogg-Dubé syndrome (BHD) [15]. In addition, the cysts are often distributed around the base of the lungs and around the costophrenic angles. According to a comparative study, PLCH were similar in the adult and the pediatric populations, with the exception that costophrenic recess subpleural parenchyma was spared in the adult group but demonstrated pathology in the pediatric group [16].

Complications with ground-glass opacities

Desquamative interstitial pneumonia (DIP)

Desquamative interstitial pneumonia (DIP) is a distinct form of interstitial pneumonia characterized by the infiltration and deposition of macrophages in the alveoli. As evidenced by the reported cases, DIP generally presents in the fifth decade of life and there is a slight male predominance [17]. The primary clinical manifestations include a chronic cough and progressive dyspnea. Cystic changes have been reported in 32–75% of patients, which are usually less than 20 mm in diameter and scattered throughout various lobes of the lungs [14].

Imaging findings in DIP typically include ground-glass opacities at the base of the lungs and in the subpleural regions [15]. Unlike other types of cystic lesions, cysts associated with DIP are characterized by the absence of a thin wall, which distinguishes them from other cystic pathologies.

Lymphocytic interstitial pneumonia (LIP)

LIP is also complicated with ground-glass opacities. However, in LIP, the cysts are surrounded by thin walls and often contain internal structures, which distinguishes them from the cysts seen in DIP.

Pneumocystis jiroveci pneumonia (PJP)

Pneumocystis jiroveci pneumonia (PJP) is another condition that may present with ground-glass opacities. However, in PJP, the cysts are usually located in the upper lobes of the lungs, contrary to the distribution pattern observed in LIP. In addition, PJP does not present with small nodules—another feature that helps differentiate it from LIP.

Diffuse distribution of pulmonary cysts in both lungs

Pulmonary lymphangioleiomyomatosis (LAM)

Pulmonary LAM is a poorly differentiated malignancy that predominantly affects women of childbearing age, with an average age of onset of around 35 years [14]. It has varied clinical manifestations, with dyspnea being the most common symptom. Patients may present with recurrent episodes of pneumothorax, chest pain, cough, hemoptysis, or chylothorax.

Typical imaging findings of LAM include diffuse, round pulmonary cysts in both lungs, approximately 2–5 mm in diameter which often occur in large numbers, typically exceeding 10 cavities per lung [15]. The pathogenesis of cysts in LAM may be associated with the occlusion of the terminal bronchioles by LAM cells, resulting in distal bronchiectasis, or due to the imbalance between proteases and protease inhibitors, resulting in degradation and degeneration of the lung parenchyma.

Birt-hogg-dubé syndrome (BHD)

BHD syndrome is a rare autosomal dominant disorder characterized by the presence of trichofolliculomas, kidney tumors, and pulmonary cysts. The disease mainly affects those aged 40–50 years old, without a difference in males versus females [13]. The cysts in BHD syndrome are multiple, thin-walled, which vary in diameter from 2 mm to 78 mm and are often scattered at the base of the lungs. In mouse models of BHD, alveolar epithelial cell apoptosis and alveolar enlargement were observed, likely due to the loss of ovarian follicular hormone function. This suggests that ovarian follicular hormone may be involved in the formation of pulmonary cysts in patients with BHD [15].

Sporadic or scattered cysts

The results of a study comparing the difference in lung CT scans between an elderly group (> 75 years) and a younger group (< 55 years) revealed significant age-related differences in cystic lung disease. All patients were asymptomatic. Of the 40 patients in the elderly group, 10 (25%) developed cystic lung disease, whereas none of the individuals in the younger group did. These findings suggest that the development of cystic lung disease in asymptomatic elderly individuals may be a result of aging, associated with a decline in body mass index and pulmonary diffusion capacity in older adults [18]. In addition, patients with tumors may also have scattered pulmonary cysts.

In addition to age-related factors, scattered pulmonary cysts may occur in isolation in patients with SS or in conjunction with other lung pathologies, including pulmonary amyloidosis. Amyloid-associated cystic lung disease is rare. It can be associated with collagen vascular disease. In a study twenty-one subjects (13 female, eight male; median age, 61 years) with cystic pulmonary amyloidosis were identified. The most common associated CVD was Sjögren syndrome (10 of 12). Cystic lesions in the lung are commonly numerous, often are peribronchovascular or subpleural, and are frequently associated with nodular lesions that are often calcified [19]. Therefore, SS can be differentiated from other cystic lung diseases based on the patient’s clinical presentation, laboratory results, and imaging findings.

Mechanisms underlying the formation of pulmonary cysts in sjögren’s syndrome

The precise mechanisms underlying the formation of pulmonary cysts have not been fully understood. The following conjectures have been proposed based on the pathophysiological processes observed in different diseases:

First, one of the most well-known mechanisms that cause pulmonary cysts is “check-valve obstruction.” This involves obstructive bronchiectasis due to vascular occlusion or secondary bronchiole dilation caused by bronchiole compression from lymphoid tissue. Another potential mechanism involved in causing pulmonary cysts is local ischemia, where obstruction of the small capillaries supplying the terminal bronchioles leads to airway necrosis and ischemic dilation [12].

Current molecular mechanisms for cystic lesions include the involvement of matrix metalloproteinases, matrix-degrading enzymes, and flat foot proteins like D2-40, which induce lung tissue remodeling [20]. In addition, genetic mutations, such as those involved in BHD, may contribute to cyst formation. However, these mechanisms do not fully explain the occurrence of thymic or parotid cysts associated with SS or HIV infection.

The formation of pulmonary cysts in SS may be associated with recurrent lung infections and weakening of bronchiole walls due to retroviruses, Epstein-Barr virus (EBV), or human herpesvirus [21]. In addition, there is evidence indicating a potential association between the presence of anti-Sjögren’s syndrome-related antigen B (anti-SSB) antibody or anti-Sjögren’s syndrome-related antigen A (anti-SSA) antibody in serum and the development of pulmonary cysts in patients with SS.

Current strategies for the treatment of pulmonary cysts in sjögren’s syndrome

It has been suggested that pulmonary cysts are a subclinical pulmonary complication in SS that typically does not affect the prognosis of the disease [4]. Therefore, the presence of pulmonary cysts alone should not be considered an indication for immunosuppressive therapy in patients with SS.

In another study of 13 patients with SS and pulmonary cysts, there was no significant change in the size and number of cysts in patients treated with and without immunosuppressants [3]. In addition, some studies have indicated similarities between pulmonary cysts and pulmonary fibrosis, suggesting that early diagnosis and treatment may potentially delay disease progression [13]. However, there is no clear consensus among experts regarding the optimal diagnostic and treatment approaches for pulmonary cysts due to the unclear mechanisms underlying the formation of pulmonary cysts in SS.

Summary

Pulmonary cysts represent a characteristic presentation of Sjögren’s syndrome, predominantly localized in the lower lobes of the lungs and showing minimal progression in serial imaging examinations. This cystic presentation is associated with older age, anti-SSA antibodies, and the diagnosis of secondary Sjögren’s syndrome [22]. Pulmonary cysts are an irreversible manifestation, and early diagnosis and treatment may prevent this process [23].

At present, while there has been extensive research on the imaging characteristics, pathogenesis, mechanisms of cyst formation, and related risk factors of pulmonary cysts in SS both in China and the rest of the world, studies on their pathology are limited. Future research should focus on the pathogenesis of the pulmonary cyst in Sjögren’s syndrome in terms of exploring pathophysiological processes, molecular biological mechanisms, and gene expression. A comprehensive approach integrating clinical, imaging, and pathological analyses of pulmonary cysts is warranted. In addition, the identification and validation of biomarkers associated with pulmonary cyst injury require further investigation.

Abbreviations

SS

Sjögren’s syndrome

LIP

Lymphocytic interstitial pneumonia

HIV

Human immunodeficiency virus

PLCH

Pulmonary langerhans cell histiocytosis

LAM

Pulmonary lymphangioleiomyomatosis

BHD

Birt-hogg-dubé

DIP

Desquamative interstitial pneumonia

PJP

Pneumocystis jiroveci pneumonia

EBV

Epstein-bars virus

Anti-SSBautoantibodies

Anti-Sjögren’s-syndrome-related antigen B

Anti-SSAautoantibodies

Anti-sjögren’s-syndrome-related antigen A

Author contributions

Conception and design of the research: Cai-Hong Pan, Xiao-Bei AnLiterature review: Xu-Fei Zhang, Chen ChenWriting of the manuscript: Cai-Hong Pan, Xu-Fei Zhang, Chen ChenCritical revision of the manuscript for intellectual content: Cai-Hong Pan, Xiao-Bei An All authors read and approved the final draft.

Funding

No external funding has been received for conducting the study.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.