CT Findings of Thoracic Manifestations of Primary Sjögren Syndrome: Radiologic-Pathologic Correlation
Primary Sjögren syndrome is an immune-mediated exocrinopathy characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands. Various systemic extraglandular disorders are associated with primary Sjögren syndrome, and the thorax is commonly affected. The pulmonary manifestations of primary Sjögren syndrome may be categorized as airway abnormalities, interstitial pneumonias, and lymphoproliferative disorders; in each category, bronchiectasis or centrilobular nodules, nonspecific interstitial pneumonia, and lymphoid interstitial pneumonia are common. These manifestations do not usually occur in isolation; they are concomitantly seen with other types of lesions. Mucosa-associated lymphoid tissue (MALT) lymphoma and amyloidosis are key components of lymphoproliferative disorders, and MALT lymphoma should always be considered because its morphologic characteristics are similar to those of benign lymphoproliferative disorders. Amyloidosis is rare but important because it carries a risk for underlying MALT lymphoma or plasmacytoma, and it may lead to hemoptysis during biopsy. In addition, thin-walled air cysts are characteristic of primary Sjögren syndrome, irrespective of the main pulmonary manifestations. Lymphadenopathy and multilocular thymic cysts may be seen in the mediastinum. During the follow-up period, there is a risk for acute exacerbation of interstitial pneumonia and development of malignant lymphoma. Often, primary Sjögren syndrome is subclinical, but there are various underlying risks. Thus, imaging findings are important. In addition to the various types of interstitial pneumonia and airway abnormalities, air cysts and mediastinal manifestations may help diagnose primary Sjögren syndrome.
© RSNA, 2013
After completing this journal-based SA-CME activity, participants will be able to:
■ List three common pulmonary manifestations of primary Sjögren syndrome.
■ Describe the CT features of primary Sjögren syndrome.
■ Discuss interpretation of CT findings in patients with primary Sjögren syndrome during the follow-up period.
Sjögren syndrome is characterized by lymphocytic infiltration of the exocrine glands, which results in dry mouth and eyes. It may occur either in isolation (primary Sjögren syndrome) or as a complication of other autoimmune diseases (secondary Sjögren syndrome) (1–3). Various systemic extraglanduler disorders may occur in patients with primary Sjögren syndrome; the thorax is a commonly affected site. Sometimes, pulmonary manifestations are detected before Sjögren syndrome; these manifestation may be a clue to its diagnosis.
In this article, we discuss the various pulmonary and thoracic manifestations of primary Sjögren syndrome and their appearance on high-resolution computed tomographic (CT) and histopathologic images. To better understand these complex pulmonary lesions, we categorized the pulmonary manifestations of primary Sjögren syndrome into three groups: airway abnormalities, interstitial pneumonia, and lymphoproliferative disorders.
Sjögren syndrome is an immune-mediated exocrinopathy characterized by lymphocytic infiltration of the salivary and lacrimal gland tissues that results in dry mouth and eyes. The pulmonary manifestations of Sjögren syndrome are more common in women than in men. The causes and pathogenesis of Sjögren syndrome are not clearly understood; however, epithelial cells and B-cell hyperactivation are considered to play an important role. T lymphocytes, mainly CD4+ cells, are considered to initiate the autoimmune process (4). Glandular epithelial cells express high levels of the DR subregion of human leukocyte antigen; it is possible that they present antigen to invading T cells. Then, cytokines, especially interferon (IFN) gamma and interleukin-2, are produced in the salivary glands, which leads to CD4+ T-cell activation and glandular inflammation (4). Recently, evidence of the role of B cells in primary Sjögren syndrome has grown. Now, B cells are considered to play a central role in the development of the disease by becoming over-stimulated and producing immunoglobulins and various autoantibodies (5). Anticipated findings of Sjögren syndrome include positive rheumatoid factor and antinuclear antibodies, as well as a positive reaction to extractable nuclear antigens (anti-SSA and anti-SSB) (2). Recent studies have focused on the central role of type 1 IFNs and the more recently described B-cell stimulating factor (BAFF), which may represent an interaction between the innate and adaptive immune systems (6). Furthermore, higher levels of BAFF were related to lymphoproliferative complications in patients with Sjögren syndrome (4).
In primary Sjögren syndrome, various systemic disorders may be associated with lymphoplasmacytic infiltration and hypergammaglobulinemia or the presence of autoantibodies (3). Activating lymphocytes form ectopic germinal centers, the formation of which may make communication between lymphocytes more effective and facilitate lymphocyte function (7,8). Production of antoantibodies may increase with the formation of more immune complexes, contributing to the occurrence of extraglandular manifestations (8). Lung involvement is common, and its frequency in patients with primary Sjögren syndrome varies depending on the imaging modality used, with a range of 9% to 75% (1,9–11). A high frequency of airway abnormalities is a characteristic finding of pulmonary involvement (1,9–11).
The pulmonary manifestations of primary Sjögren syndrome encompass airway abnormalities, interstitial pneumonia, and lymphoproliferative disorders (1,2,9,11–13). Follicular bronchiolitis and lymphocytic interstitial pneumonia may be considered lymphoproliferative disorders, as well as airway abnormalities and interstitial pneumonia. Although amyloidosis is difficult to categorize, both its distribution of findings at CT and its causes suggest that it is a type of lymphoproliferative disorder. These manifestations often coexist in patients with primary Sjögren syndrome, complicating the analysis of CT and histopathologic findings (Fig 1) (2,14,15). Hyperplastic changes in lymphoid tissue and lymphoplasmacytic inflammation are also commonly seen in the mediastinum (16). Although pulmonary involvement is common in primary Sjögren syndrome, it is usually not visualized at chest radiography. Thus, high-resolution CT is often required to depict pulmonary manifestations, which may be seen in patients with and without respiratory symptoms (11,17). In this section, we describe the characteristic clinical, histopathologic, and imaging features of the pulmonary manifestations of primary Sjögren syndrome in terms of airway abnormalities, interstitial pneumonia, and lymphoproliferative disorders.
Airway abnormalities are a characteristic pulmonary manifestation of primary Sjögren syndrome. They may occur in isolation or in combination with other pulmonary manifestations. Follicular bronchitis, which is associated with both airway abnormalities and lymphoproliferative disorders, is described herein (18,19).
Clinical Features.—Airway abnormalities are a common manifestation of primary Sjögren syndrome, with a frequency of 48%–68% according to recent CT studies (9,10). In general, respiratory symptoms are not severe, and most patients present with chronic dry cough or dyspnea (20). However, Borie et al (21) reported that severe respiratory symptoms were present in cases of small airway disease. Use of a pulmonary function test facilitates evaluation of obstructive abnormalities according to disease progression.
Histopathologic Features.—Chronic active inflammation with lymphoplasmacytic infiltration affects both central and peripheral bronchi and bronchioles. At histopathologic analysis, cellular bronchiolitis, follicular bronchitis, peribronchial and peribronchiolar fibrosis, and bronchiectasis are commonly observed (Fig 2) (2). Follicular bronchitis is characterized by peribronchiolar lymphoid follicular hyperplasia and peribronchiolar lymphocytic infiltration (18,22).
Imaging Features.—At high-resolution CT, chronic active inflammation with lymphoplasmacytic infiltration and associated fibrotic changes of central and peripheral bronchi and bronchioles is seen as bronchi- or bronchiolectasis, bronchial wall thickening, and areas of centrilobular or branching attenuation. Occasionally, mosaic attenuation, which indicates obstructive bronchiolitis, may be observed and demonstrates enhancement on expiratory high-resolution CT images (Fig 2d–2g) (17,23). High-resolution CT findings of follicular bronchitis include areas of nodular centrilobular or ground-glass attenuation; mild thickening of interlobular septa and bronchovascular bundles; and, occasionally, air cysts (Fig 3) (24).
Imaging Differential Diagnosis.—Bronchitis or bronchiolitis resulting from bacterial or nontuberculous mycobacterial infection should always be considered and ruled out first. However, infectious lesions may coexist with preexisting bronchial disorders.
Interstitial pneumonia is also common in patients with primary Sjögren syndrome and airway abnormalities (2,9,10). According to recent research, nonspecific interstitial pneumonia is the most common pattern of interstitial pneumonia in patients with primary Sjögren syndrome, both at histologic analysis and imaging, followed by organizing pneumonia and usual interstitial pneumonia (1,2,10,22). Lymphoid interstitial pneumonia is categorized as both an interstitial pneumonia and a lymphoproliferative disorder and, in this article, is described in the section that discusses lymphoproliferative disorders (19,25).
Clinical Features.—Although the frequency of respiratory symptoms differs among study populations, most patients present with dyspnea or dry cough on exertion, as well as features of Sjögren syndrome (1,2,11). In addition, bilateral inspiratory “crackles” may be heard at the lung base. At pulmonary function testing, constrictive changes according to the stage of disease progression are seen.
Patchy areas of dense collagenous fibrosis with adjacent fibroblastic foci are characteristic of usual interstitial pneumonia, with abrupt changes seen at histopathologic analysis (Fig 6c) (25). Honeycombing, which is characterized by clustered, well-defined cystic airspaces with thick fibrous walls, is also seen (Fig 6d). In areas affected by usual interstitial pneumonia, lymphoid infiltration is more severe than that in idiopathic usual interstitial pneumonia, and, occasionally, lymphoid follicles may be seen (26). In organizing pneumonia, immature intraluminal polypoid fibroblastic lesions with lymphocytic infiltration and mild airspace fibrin are seen around the alveolar ducts (Figs 7c, 8) (25).
Imaging Features.—Because of the complexity of primary Sjögren syndrome, it may not be diagnosed on the basis of imaging features alone. Even when the main disease pattern is a type of interstitial pneumonia, areas of other patterns of interstitial pneumonia or airway abnormalities often coexist. Nonspecific interstitial pneumonia demonstrates bilateral areas of ground-glass attenuation and reticulation accompanied by traction bronchiectasis and loss of volume, with both basal and peribronchovascular predominance and temporal homogeneity (Figs 4a, 5a, 5b) (25). Honeycombing is rarely seen. Findings in patients with primary Sjögren syndrome are similar to those in patients with idiopathic nonspecific interstitial pneumonia.
Usual interstitial pneumonia appears as bilateral areas of intralobular reticular attenuation accompanied by traction bronchiectasis and small cystic change, with both basal and peripheral predominance and temporal heterogeneity (25). Honeycombing is characteristic of usual interstitial pneumonia (Fig 6a, 6b). At high-resolution CT, organizing pneumonia is seen as multiple patchy areas of consolidation with a subpleural or peribronchovascular distribution (15,27). Lesions may be accompanied by areas of ground-glass attenuation or fine centrilobular nodules. The so-called reversed-halo sign is also seen in patients with primary Sjögren syndrome and those with cryptogenic organizing pneumonia or another secondary organizing pneumonia (Fig 7a, 7b) (28,29). Because interstitial pneumonia is associated with various conditions, its other causes should always be considered, especially drugs (eg, in cases of nonspecific interstitial pneumonia or organizing pneumonia) and infectious lesions (eg, in cases of organizing pneumonia).
Lymphoproliferative disorder is a vague and indistinct concept that includes both neoplastic and nonneoplastic lesions. Common pathologic findings of these diseases include aggregation and infiltration of many lymphoid cells. In this article, we use the term lymphoproliferative disorder to refer to the condition from which we must differentiate malignant lymphoma.
Lymphoproliferative disorders may manifest with various types of lesions.
Clinical Features.—The clinical features of lymphoproliferative disorders in patients with primary Sjögren syndrome receive little attention; however, dyspnea and cough have been reported in patients with lymphocytic interstitial pneumonia (10). The clinical symptoms of lymphoproliferative disorders may resemble those of chronic interstitial pneumonia. MALT lymphoma is the most common neoplasm in patients with primary Sjögren syndrome (14,32). Because its clinical symptoms are generally mild or absent, its prognosis is favorable; only a small percentage of lesions progress to diffuse large B-cell non-Hodgkin lymphoma (20,32,33).
Amyloid deposition in primary Sjögren syndrome is less well known, but it has been reported to occur in multiple organs other than the lungs (32). Two main types of amyloid deposits are observed in patients with primary Sjögren syndrome: Amyloid A (AA) deposits occur in patients with chronic inflammation, and amyloid light-chain (AL) deposits occur in those with amyloid-producing plasmacyte-type MALT lymphoma or plasmacytoma (34). Some patients present with cough or dyspnea (32). Sometimes, hemosputum occurs in patients with amyloidosis because of the vascular friability that results from amyloid deposition. In patients with suspected amyloidosis, the radiologist should inform the attending physician of the potential for hemoptysis during biopsy.
Histopathologic Features.—Both lymphocytic interstitial pneumonia and diffuse lymphoid hyperplasia are characterized by severe lymphocytic infiltration and lymphoid hyperplasia in the lungs. The difference between these entities lies in the distribution of lymphocytes: Diffuse infiltration of lymphocytes to the alveolar septa is categorized as lymphocytic interstitial pneumonia, whereas diffuse infiltration along the lymphatics (interstitia such as interlobular septa, bronchovascular bundles, and pleura) is characterized as diffuse lymphoid hyperplasia (25). Both the localized and nodular forms of lymphoproliferative disorder are categorized as nodular lymphoid hyperplasia.
Pulmonary MALT lymphoma is a tumor characterized by a predominance of small B cells, and it is considered to derive from bronchus-associated lymphoid tissue. It mainly grows in the marginal zone but may extend into the interfollicular region, and it often tracks along bronchovascular bundles and interlobular septa at the periphery of the mass (35). At histopathologic analysis, infiltration of lymphoid cells and follicles and fibrosis of the adjacent interstitium are seen (Fig 9b). Invasion of epithelia by atypical cells (a finding referred to as a lymphoepithelial lesion) is characteristic of MALT lymphoma (33,35).
Microscopically, the stromal material in amylodiosis is homogeneously eosinophilic and nonfibrillary, and it may contain a mixture of lymphocytes, plasma cells, and transitional lymphoplasmacytoid forms; polarization microscopy after Congo red staining demonstrates “apple-green” birefringence (Fig 10c) (35). In the lungs, amyloid deposition usually occurs on vascular walls (Fig 10c). Because amyloidosis often derives from lymphoma or plasmacytoma, histopathologic and genetic analysis are necessary to establish a differential diagnosis.
Imaging Features.—Lymphocytic interstitial pneumonia may be considered both a lymphoproliferative disorder and an interstitial pneumonia. In previous reports, the term lymphocytic interstitial pneumonia corresponded to what is currently described as diffuse lymphoid hyperplasia (25,36). Previously reported high-resolution CT findings of lymphocytic interstitial pneumonia included ground-glass attenuation, air cysts, interlobular septal thickening, thickening of the peribronchovascular interstitium, and poorly defined centrilobular or subpleural nodules (Fig 11) (36). Patients with predominantly alveolar lesions should receive a diagnosis of lymphocytic interstitial pneumonia. If the lesions are predominantly perilymphatic, including interlobular septal thickening or thickening of the peribronchovascular interstitium, a diagnosis of diffuse lymphoid hyperplasia should be given (25). Clinically, there is no distinction between lymphocytic interstitial pneumonia and diffuse lymphoid hyperplasia.
At CT, MALT lymphoma is seen as a solitary or multiple nodules or masses, with areas of airspace consolidation or ground-glass attenuation (Figs 9a, 12) (37–39). Typically, MALT lymphomas are located along a bronchovascular bundle, and they may be accompanied by traction bronchiectasis. Interlobular septal thickening may also be present within or around the lesion. Findings at air bronchography and CT angiography indicate prominent vasculature at contrast material–enhanced CT and are often seen within lesions (40). Very slow growth is characteristic of MALT lymphoma and is considered a hallmark of the condition. High-resolution CT findings of MALT lymphoma may resemble those of benign lymphoproliferative disorder; thus, any area of increased attenuation at high-resolution CT should be considered a likely sign of MALT lymphoma (23,24,36,38,39).
At CT, amyloidosis associated with primary Sjögren syndrome may appear as multiple nodules and cystic lesions or as an area of septal thickening with small randomly distributed nodules, which may calcify (Fig 10a, 10b) (14).
Imaging Differential Diagnosis.—Because lymphoproliferative disorders may spread along pulmonary lymphatics, the differential diagnosis includes disorders that involve the lymphatics, such as sarcoidosis, lymphangitic carcinomatosis, and malignant lymphoma from other organs. Organizing pneumonia or adenocarcinoma with a lepidic pattern may be a consideration in patients with localized disease.
Two mechanisms have been hypothesized to form air cysts: a “check-valve” mechanism, which causes cystic changes in the dilated alveolar area and results from chronic inflammation and lymphoplasmacytic infiltration in the peripheral bronchiolar regions; and destruction of the alveolar wall, in which direct lymphoplasmacytic infiltration of alveoli destroys alveolar structures and creates cystic areas (Fig 13c) (10,14,36). However, the most likely scenario is that both mechanisms are involved (Fig 14).
Treatment and Prognosis
The optimal treatment for pulmonary lesions remains to be defined, but it may depend on the patient’s underlying condition. Low-dose steroid therapy may be used, and immunosuppressive therapy may be necessary later in the course of the disease. Most patients with primary Sjögren syndrome and pulmonary complications have a good prognosis, and no medication is required. In addition to progression of MALT lymphoma to high-grade lymphoma, infection and acute exacerbation of interstitial pneumonia are the main complications.
Infection.—Structural changes in the respiratory tract and the presence of stagnating pathogens, which result from destruction of alveolar structures, can cause severe infection in patients with advanced airway or interstitial lung disease (44). The possibility of an infection should be considered when superimposition of an area of ground-glass attenuation is seen over an existing lung lesion or consolidation of existing lung lesions is seen at high-resolution CT. Because airspace consolidation may be seen in both infection and organizing pneumonia, the degree of consistency between clinical and high-resolution CT findings should be considered.
Acute Exacerbation of Interstitial Pneumonia.—Acute exacerbation has been reported in patients with interstitial pneumonia associated with primary Sjögren syndrome, as it has in patients with idiopathic pulmonary fibrosis (1,45–47). Patients with disease that is resistant to therapy or with progressive respiratory failure may die from interstitial lung disease (1). New and extensive areas of airspace consolidation or ground-glass attenuation at CT should be considered a likely sign of acute exacerbation of interstitial pneumonia (46,47).
Multilocular thymic cysts have been reported in association with various autoimmune disorders, including primary Sjögren syndrome. They may also occur after thoracic surgery or chemotherapy, and it has been suggested that they are related to chronic noninfectious inflammation (50–52). At histologic analysis, multilocular thymic cysts are seen as a multilocular cystic lesion lined with a squamous or glandular epithelium, with severe acute or chronic inflammation, fibrovascular proliferation, necrosis, hemorrhage, and cholesterol granuloma formation (50). Reactive lymphoid hyperplasia with prominent germinal centers is also seen (Fig 16b). At CT, multilocular thymic cysts are usually seen as a thin-walled multilocular cystic lesion involving the anterior mediastinum. Occasionally, intracystic attenuation may be heterogeneously increased, a finding that may correspond to hemorrhage or an elevated concentration of protein (Fig 16a). The presence of a solid component or irregular thickening of the cyst wall may indicate a coexistent malignancy, such as thymic carcinoma or MALT lymphoma (16). Thymoma with severe cystic change, mature cystic teratoma, and Hodgkin disease are the important differential diagnoses for multilocular thymic cyst.
Often, primary Sjögren syndrome may not be diagnosed on the basis of clinical findings alone, and imaging plays an important role in its diagnosis. In addition to the various types of interstitial pneumonia and the findings of airway abnormalities and lymphoid hyperplasia, mediastinal involvement, including lymph node enlargement and thymic lesions, may help diagnose the condition. Air cysts are characteristic of primary Sjögren syndrome, irrespective of the main pulmonary lesion; thus, close interpretation of the entire imaging area may help establish the diagnosis. In patients with a pulmonary disorder, it is important to monitor for potential infections and acute exacerbation of interstitial pneumonia during the follow-up period, and the possibility of concomitant malignant lymphoma should always be recognized.
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For this journal-based SA-CME activity, the authors, editor, and reviewers have no financial relationships to disclose.
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Article HistoryReceived: May 12 2012
Revision received: June 15 2012
Revision received: Mar 13 2013
Accepted: July 17 2013
Published online: Nov 2013
Published in print: Nov 2013