Review Article | Thoracic Imaging eISSN 2005-8330 https://doi.org/10.3348/kjr.2020.1082 Korean J Radiol 2021;22(8):1416-1435 Non-Infectious Granulomatous Lung Disease: Imaging Findings with Pathologic Correlation Tomás Franquet1, Teri J. Franks2, Jeffrey R. Galvin3, Edson Marchiori4, Ana Giménez1, Sandra Mazzini1, Takeshi Johkoh5, Kyung Soo Lee6 1 Department of Diagnostic Radiology, Hospital de Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain; 2Department of Defense, Pulmonary & Mediastinal Pathology, The Joint Pathology Center, Silver Spring, MD, USA; 3Department of Diagnostic Radiology, Chest Imaging, & Pulmonary Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; 4Department of Radiology, Hospital Universitário Clementino Fraga Filho-Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil; 5Department of Radiology, Kansai Rosai Hospital, Hyogo, Japan; 6Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine (SKKU-SOM), Seoul, Korea Non-infectious granulomatous lung disease represents a diverse group of disorders characterized by pulmonary opacities associated with granulomatous inflammation, a relatively nonspecific finding commonly encountered by pathologists. Some lesions may present a diagnostic challenge because of nonspecific imaging features; however, recognition of the various imaging manifestations of these disorders in conjunction with patients’ clinical history, such as age, symptom onset and duration, immune status, and presence of asthma or cutaneous lesions, is imperative for narrowing the differential diagnosis and determining appropriate management of this rare group of disorders. In this pictorial review, we describe the pathologic findings of various non-infectious granulomatous lung diseases as well as the radiologic features and high-resolution computed tomography imaging features. Keywords: Non-infectious granulomatosis; Granulomatous lung disease; Lung parenchyma; Radiography; High-resolution computed tomography INTRODUCTION monocyte macrophages [4,5]. The early inflammatory process is followed by the organization of the granuloma, Non-infectious granulomatous lung disease represents a compact and highly dynamic structure composed of a a diverse group of disorders characterized by pulmonary central cluster of mononuclear phagocytes and epithelioid opacities associated with granulomatous inflammation, multinucleated cells, generally surrounded by a rim of a relatively nonspecific finding commonly encountered lymphocytes [6-9]. by pathologists [1-3]. Granuloma formation is a chronic Patients with non-infectious pulmonary granulomatosis inflammatory reaction involving the macrophage system may initially be identified based on pulmonary symptoms and other inflammatory cells. In affected organs, the or chest radiographic abnormalities [10-12]. A large first manifestation of granuloma is an accumulation variety of non-infectious pulmonary disorders may be of mononuclear inflammatory cells, mostly T cells and associated with occasional granulomatous lesions: 1) inflammatory: sarcoidosis and necrotizing sarcoid Received: August 31, 2020 Revised: October 26, 2020 Accepted: November 1, 2020 granulomatosis (NSG); 2) pulmonary lymphoid lesions: Corresponding author: Tomás Franquet, MD, Department of lymphomatoid granulomatosis (LYG); granulomatous- Diagnostic Radiology, Hospital de Sant Pau, Universitat Autónoma lymphocytic interstitial lung disease (GLILD); 3) aspiration/ de Barcelona, Sant Quintí 89, Bloc F, Planta-1, Barcelona 08041, exposure: aspiration pneumonia, talcosis, berylliosis, Spain. • E-mail: tfranquet@santpau.cat and hypersensitivity pneumonitis (HP); 4) vasculitis: This is an Open Access article distributed under the terms of granulomatosis with polyangiitis (GPA) (formerly Wegener's the Creative Commons Attribution Non-Commercial License granulomatosis) and eosinophilic granulomatosis with (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in polyangiitis (EGPA) (formerly Churg-Strauss syndrome); and any medium, provided the original work is properly cited. 5) collagen vascular disorders: rheumatoid lung nodules. 1416 Copyright © 2021 The Korean Society of Radiology Non-Infectious Granulomatous Lung Disease Diverse and nonspecific findings may be seen on inflammation [20,21]. Immune checkpoint blockade has conventional chest radiography. High-resolution computed been associated with multiple distinctive side effects tomography (HRCT) demonstrates more characteristic termed as immune-related adverse events. The most patterns and distribution of parenchymal opacities than common pulmonary toxicities of these agents include chest radiography. Although CT findings are often helpful, pneumonitis and sarcoid-like granulomatosis that may be there is still a considerable overlap of imaging findings detected during follow-up imaging studies, such as CT or among the various forms of non-infectious pulmonary PET/CT [22]. granulomatosis [13,14]. The diagnosis of sarcoidosis is confirmed when typical Herein, we describe and illustrate the imaging features of clinical and radiological findings are supported by common and uncommon non-infectious granulomatous lung histological evidence of non-necrotizing granulomas and disease and correlate these features with the pathologic exclusion of possible alternative diagnoses [23-26]. findings in order to suggest a specific diagnosis or to The classic histologic findings in sarcoidosis are well- substantially narrow the differential diagnosis using the formed, compact, non-necrotizing granulomas often imaging appearance and anatomic location of the lesion. surrounded by concentric layers of hyaline collagen, confined to the interstitial compartment, and distributed Pulmonary Inflammatory Lesions in a characteristic lymphangitic pattern [23,27-29]. Sarcoid granulomas are always well-circumscribed interstitial groups Sarcoidosis of epithelioid histiocytes, multinucleated giant cells, Sarcoidosis is a multisystem granulomatous disorder of and variable numbers of chronic inflammatory cells. This unknown origin with worldwide distribution and protean feature is helpful and is in contrast to the poorly formed clinical manifestations. It is a global disease with a granulomas seen in HP [30]. Gross findings comprise worldwide incidence of 1–40 cases per 100000 people per variably sized nodules showing a distinctive predilection for year and a prevalence of 0.2–64 cases per 100000 people bronchovascular bundles, interlobular septa, and visceral [15-18]. The disease mainly affects people in the third and pleura. Distribution of granulomas in a lymphangitic pattern fourth decades of life but may also occur in children and is a distinctive feature of sarcoidosis that can be extremely elderly subjects. It is characterized by a T-helper response helpful for diagnosis. Infectious granulomas tend to be in which CD4 lymphocytes and activated macrophages randomly scattered in the parenchyma, and the granulomas accumulate in affected organs, resulting in granuloma of HP are often centrilobular. Usually, a biopsy is required formation. to demonstrate non-necrotizing granulomas. However, an Pulmonary involvement is the most common feature, accurate distinction between different causes of granulomas occurring in more than 95% of patients with bilateral is, in many cases, not possible. hilar lymphadenopathy; multiple organ systems may also Parenchymal disease results from interstitial involvement be involved [18]. Approximately 30% to 50% of patients by the granulomatous process leading to irreversible are asymptomatic, with bilateral hilar lymphadenopathy parenchymal changes related to fibrosis. At presentation, detected incidentally on chest radiography. The most the chest radiograph is abnormal in approximately 90% of common pulmonary complaints are cough, shortness patients. The most characteristic radiologic findings are of breath, dyspnea, and bronchial hyperreactivity; symmetric bilateral hilar and right paratracheal lymph node constitutional symptoms are common and include fever, enlargement or diffuse micronodular pulmonary infiltration. fatigue, weakness, malaise, and weight loss [15,16,19]. Eggshell calcification is thought to develop only in affected Although in the majority of patients, pulmonary sarcoidosis nodes and is related to disease duration. follows a benign course and tends to resolve spontaneously, Several HRCT findings have been associated with in a significant minority, granulomas evolve to progressive sarcoidosis, reflecting the histologic findings; small nodules fibrosis. Löfgren’s syndrome is a clinically distinct along the bronchovascular bundles, interlobular septa, phenotype of sarcoidosis; patients typically experience an major fissures, and pleural/subpleural regions represent acute disease onset usually with fever, and characteristic the typical perilymphatic distribution (Fig. 1) [24,31,32]. symptoms of bilateral hilar lymphadenopathy, erythema Other HRCT signs of sarcoidosis are the reversed halo sign, nodosum, and/or bilateral ankle arthritis or periarticular a focal, rounded area of ground-glass surrounded by an kjronline.org https://doi.org/10.3348/kjr.2020.1082 1417 Franquet et al. approximately complete ring of consolidation (Fig. 2) and trapping because of small airway obstruction may also be the galaxy sign, a lung nodule formed by the confluence observed [35]. Superimposed infection of fibrocystic spaces, of multiple small-sized nodules which separate from one particularly with Aspergillus, is a frequent complication another (Fig. 3). Confluence of granulomas may also of sarcoidosis and accounts for significant morbidity and result in nodules or masses measuring 1–4 cm in diameter. mortality [36-38]. Fibrotic conglomerate masses, reminiscent of those seen in silicosis, may also develop in advanced disease. These Necrotizing Sarcoid Granulomatosis findings typically predominate in the middle and upper lung NSG is a form of granulomatous lung disease first zones [33]. If less characteristic clinical or radiological described in 1973 by Liebow [39] and is characterized by manifestations predominate, fluorodeoxyglucose (FDG)- extensive vascular granulomas that infiltrate and occlude FDG-PET, which is highly sensitive in detecting active pulmonary arteries and veins, accompanied by widespread granulomatous lesions, can be used [34]. necrosis of lung tissue. Initially, NSG was considered as Progressive fibrosis and architectural distortion lead a provisional diagnostic term; however, the problem was to honeycombing, fibrocystic changes, bullae, traction whether the disease represented necrotizing angiitis bronchiectasis, and retraction of the pulmonary hila. Air with sarcoid reaction or sarcoidosis with necrosis of the A B Fig. 1. Sarcoidosis in 51-year-old male (perilymphatic pattern). A. Close-up view of an axial CT scan shows sparse micronodules with a typical perilymphatic distribution, especially along the fissures (arrowheads) and bronchovascular bundles (arrows). B. Low-power scanning magnification demonstrates the lymphangitic distribution of granulomas involving bronchovascular bundles, pleura, and interlobular septa typical of sarcoid (arrows). These findings correlate with the CT appearance (hematoxylin and eosin stain, X 40). A B Fig. 2. Sarcoidosis in 28-year-old female (reversed halo sign). A. Close-up view of a coronal CT scan shows two central ground-glass opacities surrounded by a more or less complete ring of consolidation (reversed halo sign) (arrow). B. Medium power magnification demonstrates the compact, well-circumscribed non-necrotizing granulomas containing multinucleated giant cells typical of sarcoid (arrow) (hematoxylin and eosin stain, X 200). 1418 https://doi.org/10.3348/kjr.2020.1082 kjronline.org Non-Infectious Granulomatous Lung Disease granulomas and the vessels [40-43]. Granulomatous or systemic vasculitis; extrapulmonary involvement has pulmonary angiitis is a nonspecific lesion observed in a been observed in 20% to 30% of cases [46,47]. variety of conditions, including Wegener’s granulomatosis, The histopathologic features of pulmonary NSG show NSG, chronic beryllium disease (CBD), foreign body sarcoid-like granulomas with central necrosis and embolization in drug abusers, and schistosomiasis [44]. granulomatous vasculitis [44,46,48]. NSG no longer qualifies as a separate entity [42]. The term The predominant radiologic findings were multiple round “sarcoidosis with NSG pattern” should be used in place of or oval pulmonary nodules without a specific relationship NSG to reflect the clinical entity of nodular sarcoidosis [45]. to lobular structures and interlobular septa. A uniform or Although the clinical presentation is variable, the random distribution throughout the lungs and a relationship majority of patients present with respiratory and systemic with pleural surfaces and fissures are common. The nodule symptoms and nodular lung lesions simulating metastatic or margin is most often well defined. Cavitation may be seen primary lung neoplasms. Cough is the most common clinical on follow-up CT images [49]. manifestation, followed by chest pain, dyspnea, fever, and Multiple large nodular lesions, seen in 1.5% to 4% constitutional symptoms of weight loss and fatigue. Patients of patients, are a rare manifestation of pulmonary with NSG have no upper airway disease, glomerulonephritis, sarcoidosis (Fig. 4) [50]. A B Fig. 3. Sarcoidosis in 40-year-old male (galaxy sign). A, B. Axial (A) and coronal (B) CT images show multiple upper lobe–predominant solid pulmonary nodules surrounded by tiny satellite micronodules 1–2 mm (arrows). A B C Fig. 4. Necrotizing sarcoid granulomatosis. A. Coronal (MIP reformatted image) chest CT shows bilateral nodular opacities with irregular borders (arrows). B. Coronal (minIP reformatted image) chest CT shows hypodense nodules (arrow). Mediastinal and hilar adenopathies are also seen (arrowheads). C. Medium-power magnification demonstrates a conglomeration of necrotizing (pale eosinophilic hypocellular zones) granulomas with scattered multinucleated giant cells (arrows) compatible with “sarcoidosis with necrotizing sarcoid granulomatosis pattern” that correlates with nodules and masses seen on chest CT (hematoxylin and eosin stain, X 40). kjronline.org https://doi.org/10.3348/kjr.2020.1082 1419 Franquet et al. Pulmonary Lymphoid Lesions overt EBV-positive lymphoma. The most common radiologic and CT features observed in Lymphomatoid Granulomatosis (LYG) approximately 80% of all cases are unilateral or bilateral LYG is a very rare Epstein-Barr virus (EBV)-driven multiple lung nodules 0.5–8 cm in diameter with a lymphoproliferative disease involving extra-nodal sites and peribronchovascular distribution and basal predominance is composed of EBV-positive B cells admixed with reactive (Fig. 5) [58]. The lesions can progress rapidly, coalesce, T cells, which usually predominate [51-55]. In the current and cavitate (Fig. 6). Nodules can disappear or migrate WHO classification, LYG is grouped along with NHL as a spontaneously, and a “reversed halo sign” is frequently neoplasm of mature B cells [56]. Histologically, LYG shows observed [59,60]. Mediastinal lymph node enlargement an angiocentric and angiodestructive accumulation of is rare. Pleural effusion is sometimes present. FDG PET-CT heterogeneous polymorphous group of T cells with varying shows avid FDG uptake in these lesions [61]. numbers of atypical clonal EBV-positive B cells around the muscular arteries and veins, with the invasion of these Common Variable Immunodeficiency (CVID)/ vessels and areas of necrosis presenting later in the disease Granulomatous-Lymphocytic Interstitial Lung Disease process [51,57]. (GLILD) Pulmonary involvement occurs in > 90% of patients and Common variable immunodeficiency is a primary is usually present at initial diagnosis. The clinical behavior immunodeficiency of unknown etiology that leads to a of LYG varies widely; the disease ranges from an indolent clinical syndrome with low levels of serum immunoglobulins process, which may result in spontaneous remission, and an inability to make specific antibodies [62,63]. CVID is to an aggressive large B-cell lymphoma. Predisposing characterized by recurrent bacterial infections, particularly conditions include patients with an underlying acquired or in the respiratory tract, and due to defects in cellular inherited immunodeficiency syndrome (e.g., Wiskott Aldrich immunity, CVID may also predispose to opportunistic syndrome, X-linked lymphoproliferative syndrome, HIV/ infections [64,65]. Secondary causes of decreased serum AIDS, allogeneic organ transplantation) or autoimmune immunoglobulin levels must be ruled out in any patient diseases (e.g., Sjögren syndrome, rheumatoid arthritis, that meets the diagnostic criteria for CVID [66]. A CT sarcoidosis, ulcerative colitis, and common variable scan at the time of diagnosis can identify bronchiectasis, immunodeficiency). LYG can lead to progressive pulmonary interstitial lung disease, and granulomatous lung disease, failure, central nervous system disease, or progression to even in asymptomatic patients. Follow-up chest CT should A B C Fig. 5. Lymphomatoid granulomatosis a 56-year-old female. A. Axial pre-contrast CT image demonstrates multiple pulmonary nodules and masses (arrows). Nodules and masses are distributed along bronchovascular bundle and in subpleural region. Large mass in the right lower lobe is cavitary (arrowhead). B. Autopsy gross specimen shows multiple ill-defined yellowish nodules (black arrows) that coalesce leading to large masses (white arrows). C. High-power magnification demonstrates vessel wall destruction by marked infiltrates of small Tlymphocytes that obscure malignant large B-lymphocytes seen in lymphomatoid granulomatosis (arrows) (hematoxylin and eosin stain, X 400). 1420 https://doi.org/10.3348/kjr.2020.1082 kjronline.org Non-Infectious Granulomatous Lung Disease be used judiciously because of the malignancy risk [66,67]. The presence of bronchiectasis has been correlated with Approximately 10–30% of patients with CVI develop abnormal CD4+ T cell levels [73]. clinical evidence of a non-infectious multisystemic The term GLILD has been used to describe lymphoid lymphoproliferative disease, which includes diffuse parenchymal proliferation that usually consists of adenopathy, splenomegaly, and granulomatous noncaseating granulomas, lymphocytic interstitial inflammation in a variety of organs. While airway diseases pneumonia, peribronchiolar lymphoid proliferation (follicular include infection, obstructive disease, and bronchiectasis, bronchiolitis), and lymphoid hyperplasia [74]. Organizing interstitial lung diseases include granuloma, organizing pneumonia has also been sometimes considered a part of pneumonia, and lymphoid infiltrative disease [66]. GLILD [62,75]. Typical CT imaging findings include solid Pathologically, it is characterized by both granulomatous nodules (< 3 cm), semisolid nodules, pure ground-glass and lymphoproliferative histologic patterns [68]. Imaging opacities, enlarged thoracic (hilar and/or mediastinal) findings consist of bronchiectasis (cylindrical, varicoid, or lymph nodes, and splenomegaly (Fig. 7) [76]. cystic), mucoid impaction, and airway thickening [69-72]. A B Fig. 6. Lymphomatoid granulomatosis a 62-year-old male. A. Posteroanterior chest imaging shows a large cavitary mass in the left upper lobe (arrows). Ill-defined randomly distributed rounded opacities are iobserved in the rest of the lung parenchyma (arrowheads). B. Corresponding axial chest CT scan shows multiple rounded peripheral solid (black arrows) or cavitary nodules (white arrows). A B C Fig. 7. Granulomatous-lymphocytic interstitial lung disease. A. Axial chest CT scan shows multiple peripheral and peribronchovascular ground-glass and consolidation (arrows). B. Low-power scanning magnification of lung demonstrates airway centered marked infiltrates of chronic inflammatory cells (black arrows) that results in cystic remodeling of distal small airways (white arrows) (hematoxylin and eosin stain, X 40). C. High-power magnification demonstrates poorly formed collection of histiocytes and a multinucleated giant cell (arrows). The airway centered lung injury correlates with the peribronchovascular ground glass and consolidation seen on the chest CT (hematoxylin and eosin stain, X 200). kjronline.org https://doi.org/10.3348/kjr.2020.1082 1421 Franquet et al. Aspiration/Exposure distribution of the aspirated material [83]. On HRCT, lentil aspiration pneumonia manifests as centrilobular nodules, The term aspiration describes a variety of situations some with a tree-in-bud appearance [81]. Material from involving the intake of solid or liquid materials into the repeated aspirations may appear as disseminated miliary airways and lungs [77,78]. Aspiration may occur from nodules representing inflammation with foreign body exogenous or endogenous gastric sources. The development reaction in bronchioles, ducts, and alveolar sacs [77,83]. of aspiration-related pulmonary syndrome depends on the Histologically, aspiration pneumonia is classically quantity and nature of the aspirated material, chronicity, characterized by acute inflammation and necrosis centered and host responses [79]. Alcoholism is probably the most on bronchioles with remnants of aspirated vegetable important predisposing factor for pulmonary aspiration in material surrounded by multinucleated giant cells [83,84]. adults, although other factors (e.g., general anesthesia, loss of consciousness, structural abnormalities of the pharynx Talcosis and esophagus, neuromuscular disorders, and deglutition Talc (hydrous magnesium silicate) is a mineral widely abnormalities) may also contribute to aspiration [78,80-82]. used in the ceramic, paper, plastics, rubber, paint, and cosmetic industries. The term “talc” is used not only for Aspiration Pneumonia pure magnesium silicate but also for a mixture of minerals Pulmonary aspiration of gastric contents is a significant with various other products [85,86]. cause of morbidity and mortality and is the most common Pulmonary talcosis should be suspected in patients with cause of pneumonia [77,81]. Predisposing factors, such a known history of occupational exposure or drug addiction. as neurologic disorders, structural abnormalities of the The causes of pulmonary talcosis may include inhalation pharynx and esophagus, emergency surgical procedures, of pure talc, inhalation of talc in association with silica and dementia are frequently associated with this condition (talcosilicosis), or inhalation of talc in association with [77]. The most common radiographic pattern is that of asbestos fibers (talcoasbestosis). Intravenous injection bronchopneumonia with scattered air-space opacities. CT of talc (intravascular talcosis) occurs most often during has been regarded as the imaging modality of choice for the recreational drug use when the drug is crushed, melted, evaluation of suspected esophagopleural fistula, because dissolved in water, and IV-injected. the site of communication between the pleural space History of occupational exposure or drug addiction is and the esophagus can often be seen (Fig. 8). Aspiration the major clue to diagnosis [87-91]. Clinically, patients of leguminous vegetables can cause a granulomatous with pulmonary talcosis can range from asymptomatic pneumonitis know as lentil aspiration pneumonia. Typically to severe disease [92]. A wide variety of pulmonary manifesting as diffuse, ill-defined, small 1–3 mm nodular complications, including asthma exacerbation, barotrauma, areas of increased opacity representing the bronchiolar hilar lymphadenopathies, and bullous emphysema, may be A B C Fig. 8. Aspiration pneumonia in 72-year-old male smoker. A. Coronal reformatted contrast-enhanced CT shows right upper lobe heterogeneous consolidation and a large empyema (arrows). B. Medium- power magnification of lung shows airway centered fibrosis containing two clusters of multinucleated giant cells (arrows) (hematoxylin and eosin stain, X 40). C. On high-power magnificent in the right histologic image, the multinucleated giant cells and organizing pneumonia surround fragments of plant material (arrows) (hematoxylin and eosin stain, X 400). 1422 https://doi.org/10.3348/kjr.2020.1082 kjronline.org Non-Infectious Granulomatous Lung Disease associated with the inhalation of talc, silica, and lactose [93]. capillaries resulting in thrombosis, vascular and perivascular The majority of patients usually present with nonspecific fibrosis, and chronic inflammation; intravascular and complaints, including progressive exertional dyspnea and perivascular granulomas can be seen. cough [93,94]. Late complications include interstitial In early-stage disease, radiologic diagnosis of pulmonary pneumonitis, fibrosis, emphysema, pulmonary arterial talcosis is difficult because the findings are often minimal hypertension, cor pulmonale, and lung cancer [95-98]. or nonspecific, consisting of extremely tiny, round opacities Whether inhaled or injected, talc causes non-necrotizing diffusely distributed throughout both lungs [100]. Earlier granulomatous inflammation. In the early stages of the thin-section CT findings show a diffuse micronodular pattern disease, talcosis consists of multiple, small, foreign body with well-defined centrilobular nodules or diffuse ground- granulomas composed of multinucleated cells containing glass opacities (Fig. 9); apices and costophrenic sulci are birefringent crystals, which are identified in the alveolar generally spared. In more advanced disease, thin-section septa and air spaces [11,99]. As the disease progresses, CT shows progressive massive fibrosis associated with lower the granulomas can become confluent, resulting in lobe emphysema and diffuse reticulonodular changes [101]. heterogeneous conglomerate masses. Microscopic Although CT findings in advanced talcosis are similar to examination under polarized light shows birefringent those reported in silicosis, conglomerate masses with areas needle-shaped talc crystals in multinucleated giant cells of high attenuation usually involve the upper lung zones in and macrophages. These features differ from those seen silicosis, while in talcosis, they are distributed throughout after intravenous talc injection where the talc particles are all lung zones [11,100]. larger and become trapped within pulmonary arterioles and A B C D Fig. 9. Talcosis. A, B. Axial and coronal reformatted CT images show numerous small bilateral centrilobular nodules, associated with a tree-in-bud pattern (arrows). C. Lung tissue biopsy demonstrates an interstitial granulomatous reaction to the talc particles (arrowhead) with a giant-cell reaction (arrow) (hematoxylin and eosin stain, X 400). D. Under polarized light, birefringent crystals are visible (arrows) (hematoxylin and eosin stain, X 400). kjronline.org https://doi.org/10.3348/kjr.2020.1082 1423 Franquet et al. Berylliosis between pneumoconioses and sarcoidosis [113]. Beryllium is a naturally light-weight metal extracted In the early stage of the disease, minimal or no visible from ores and processed into metal, oxides, alloys, and abnormalities may be observed on chest radiographs, composite materials [102]. The major applications are in although thin-section CT scans demonstrate thickened automotive electronics, telecommunications, computers, intralobular and interlobular lines [114,115]. aerospace, ceramics, fluorescent lamps and neon lights, and Chest radiography is often normal in early-stage dentistry and dental supplies [103-105]. disease but disease progression depicts small nodules Berylliosis, a granulomatous disorder caused by exposure and reticulation, typically with predominant distribution and inhalation of dust, fumes, or aerosols of beryllium metal in the middle and upper lung (early) [115]. Reticulation, or its salts, is characterized by the accumulation of CD4+ T architectural distortion, honeycombing, and mass-like cells and macrophages in the lower respiratory tract [86]. lesions are observed because of the coalescence of small The clinical course varies with the intensity and nodules and lymphadenopathy [115,116]. chronicity of exposure, and patients can range from Characteristic CT findings include the presence of small asymptomatic to those with severe disease [106,107]. nodules (< 3 mm) in a perilymphatic distribution and nodular Symptoms usually include dyspnea, cough, fever, anorexia, thickening along the lymphatics in the bronchovascular and weight loss [108]. Pulmonary function testing shows sheath and, to a lesser extent, in the interlobular septa and restriction with diminished diffusing capacity. There are two subpleural lung regions (Fig. 10) [86,115]. distinct types of lung injury related to beryllium exposure: 1) acute beryllium pneumonitis caused by direct acute Hypersensitivity Pneumonitis lung injury resulting from the inhalation of high levels HP, one of the most common diffuse parenchymal lung of beryllium particles and 2) CBD caused by delayed-type diseases, is an immunologically mediated diffuse lung hypersensitivity developed months or years after exposure. disease characterized by a complex immunological reaction CBD may be nearly radiographically indistinguishable from of the lung parenchyma in response to repetitive inhalation sarcoidosis; current workplace protection has virtually of a sensitized allergen [117,118]. The severity of the eliminated acute disease [109,110]. CBD continues to occur disease and clinical presentation varies depending on the in the nonoccupational setting and among bystanders in inhaled antigen and quantity. It has been conventionally industry, masquerading as sarcoidosis [111]. classified into acute, subacute, and chronic forms based on Histologically, well-formed non-necrotizing granulomas the time course and presentation. Chronic HP is a fibrotic are seen in a lymphatic distribution involving lung disease resulting from long-term exposure to an bronchovascular bundles, pleura, and interlobular septa offending antigen [119]. indistinguishable from other granulomatous disorders, such More recently, the results of a cluster analysis were as sarcoidosis [112]. Confluence of numerous interstitial compared with the classical classification of HP [120]. granulomas can result in large, irregular, mass-like opacities. Results suggest that patients with HP should be classified Environmental exposure history may help distinguish into only one of the two categories (Cluster 1 and Cluster 2) A B C Fig. 10. Berylliosis in a 49-year-old male who worked for 7 years in metal polishing. A, B. Axial thin-section CT scans (1.0-mm-thick-sections) obtained at the levels of the bronchus intermedius (A). At the basal segmental bronchus shows multiple small nodules along the bronchovascular bundles (straight arrows) and in subfissural regions (arrowheads) and enlarged hilar lymph nodes (curved arrows) (B). C. High-power magnification of a pathologic specimen obtained with mediastinoscopic lymph node biopsy shows multiple noncaseating granulomas (arrows) (Courtesy of Chong S) (hematoxylin and eosin stain, X 400). 1424 https://doi.org/10.3348/kjr.2020.1082 kjronline.org Non-Infectious Granulomatous Lung Disease based on clinical evaluation, pulmonary function tests, and changes on HRCT [120]. HRCT findings. In Cluster 1, patients would present with Histologic studies in acute HP are scanty, as lung biopsy recurrent systemic symptoms (chills and body aches) and is generally not necessary for diagnosis. The histologic tightness of the chest occurring a few hours after antigen changes of subacute HP occur at the level of the terminal exposure, inspiratory crackles would be frequent, and chest bronchioles and consist of a classic histologic triad of a X-rays would be normal in almost 30% of the cases. In lymphocytic interstitial infiltrate, organizing pneumonia, Cluster 2, patients would present with features of advanced and poorly formed non-necrotizing granulomas [121]. interstitial lung disease, clubbing, inspiratory crackles, a Typical granulomas are present in approximately 80% restrictive pattern on pulmonary function tests, and resting of surgical biopsies and consist of loose collections of hypoxemia. One-third of the patients showed fibrotic histiocytes or scattered giant cells. Necrosis is not a component of the granulomatous reaction in cases of HP [122]. A mild perivascular lymphoid accumulation is typically present in HP, but prominent germinal centers or dense lymphoplasmacellular infiltration along vascular sheaths are not typical and should raise concern for lymphoproliferative disease [121]. Chronic HP can appear like usual interstitial pneumonia (UIP) on histology, but it is distributed in the upper lobes rather than the lower lobes as in UIP/IPF. The characteristic HRCT findings of acute and subacute HP are characterized by ground-glass attenuation with poorly defined centrilobular nodular opacities (Fig. 11), thin-walled cysts, and mosaic perfusion (focal areas of air trapping) (Fig. 12) [123]. Coexisting thin-walled cysts have been reported in 13% of the patients with subacute Fig. 11. Subacute or cluster 1 hypersensitivity pneumonitis. HP and are believed to be caused by partial bronchiolar Axial thin-section CT scan at the level of lung bases shows diffuse ground-glass opacity interposed with areas of normal lung and lobular obstruction by peribronchiolar lymphocytic infiltration areas of decreased attenuation (arrows). [124]. Chronic HP has a bronchovascular distribution A B Fig. 12. Subacute or cluster 1 hypersensitivity pneumonitis. A. Close-up view of thin-section CT scan at the level of the right-lower lobe shows diffuse ground-glass opacities and poorly defined centrilobular nodules (arrows). Note lobular areas of decreased attenuation and vascularity reflecting air trapping (arrows). B. Medium-power magnification of lung demonstrates airway centered chronic inflammation containing poorly formed granulomata (arrows). The chronic inflammatory infiltrates surrounding small airways correlate with the centrilobular nodules and mosaic attenuation seen on the CT axial image A (hematoxylin and eosin stain, X 200). kjronline.org https://doi.org/10.3348/kjr.2020.1082 1425 Franquet et al. of fibrosis, reticular pattern, air trapping, and traction GPA has many histopathological features. The bronchiectasis (Fig. 13) [125,126]. Importantly, subacute microscopic hallmark is a triad of parenchymal necrosis, and chronic HP may mimic several interstitial lung diseases, vasculitis, and granulomatous inflammation. The major including nonspecific interstitial pneumonia and UIP, histopathologic features of GPA are those generally making diagnosis extremely difficult because of the overlap regarded as the diagnostic criteria: parenchymal necrosis, of the clinical history, and the functional and imaging vasculitis, and granulomatous inflammation accompanied findings [127-129]. The best diagnostic approach is to by a mixed infiltrate of neutrophils, lymphocytes, plasma integrate clinical, radiological, and pathological information cells, macrophages, giant cells, and eosinophils [134]. at a multidisciplinary team meeting. Less frequent features not representing diagnostic criteria are alveolar hemorrhage, organizing intraluminal Vasculitis fibrosis, lymphoid aggregates, tissue eosinophils, xanthogranulomatous lesions, alveolar macrophage Granulomatosis with Polyangiitis (GPA) accumulation, and organizing pneumonia-like fibrosis GPA, formerly termed Wegener’s granulomatosis, is [133,135]. The diagnosis ultimately relies on a constellation an antineutrophil cytoplasmic autoantibodies (ANCA)- of radiographic and pathologic findings, laboratory values, associated systemic vasculitis typically involving the upper and accurate clinical history [136]. respiratory tract, lower respiratory tract (bronchi and GPA in the thorax presents with a wide variety of lungs), and kidneys, with varying degrees of disseminated radiologic findings [137-140]. Chest radiographs are vasculitis [39,130]. abnormal in 70% of the patients during the course of the The spectrum and severity of GPA are heterogeneous, disease. Lesions can be single or multiple (usually < 10 ranging from an indolent disease involving only one site lesions) and range in size from a few millimeters to over to fulminant, multi-organ vasculitis leading to death 10 cm. Common pulmonary radiologic findings include [131]. The disease classically presents with upper and bilateral waxing and waning nodules and masses, cavitation lower respiratory tract symptoms and renal involvement. in nodules larger than 2 cm with a thick wall and irregular Pulmonary involvement occurs in 55–90% of patients. inner lining, ground-glass opacities, and consolidations Clinical pulmonary manifestations include cough, dyspnea, (Fig. 14) [140]. Pleural effusion can result from primary impaired pulmonary function, bronchostenosis, and diffuse involvement or secondary to renal failure. alveolar hemorrhage [131-133]. The characteristic CT manifestations consist of bilateral subpleural or peribronchovascular nodules or masses (1–4 cm in diameter), sometimes spiculated; in approximately 50% of the cases, the masses may cavitate [140,141]. Nodules with feeding vessels and wedge-shaped lesions abutting the pleura are less frequent findings. In unusual cases, the disease may manifest itself as a solitary lung lesion that can measure up to 10 cm in diameter [142]. In up to 50% of patients, bilateral nonsegmental or peribronchovascular areas of airspace consolidation, peribronchial thickening, small centrilobular nodules, and branching linear structures (so-called tree-in-bud pattern) are frequently seen [138,143]. Ground-glass opacities and airspace consolidation correlate with focal or diffuse pulmonary hemorrhage that occurs in approximately 10% of Fig. 13. Chronic or cluster 2 hypersensitivity pneumonitis. patients [138,140,142,144-146]. Histologically, pulmonary Typical CT findings of biopsy-proven chronic hypersensitivity pneumonitis in a bird breeder. High-resolution CT scans show mild hemorrhage may result in areas of organizing pneumonia- reticulation with superimposed patchy ground-glass opacities and like reactions (Fig. 15) [147]. Calcification within areas traction bronchiectasis and bronchiolectasis (white arrowheads). Lobular areas of decreased attenuation and vascularity (black arrows) of consolidation, although rare, has also been described are also present. [148]. Moreover, GPA associated with abnormal pulmonary 1426 https://doi.org/10.3348/kjr.2020.1082 kjronline.org Non-Infectious Granulomatous Lung Disease A B Fig. 14. Granulomatosis with polyangiitis in a 68-year-old male. A, B. Axial thin-section CT scan at the level of lung bases (lung window) (A) and (B), mediastinal window show two rounded opacities of different sizes in the lateral segment of the middle lobe and in the superior segment of the right lower lobe (black arrows in A; white arrows in B); largest nodule shows central cavitation with thick walls and irregular inner margins (blackarrowhead in A). A B C Fig. 15. Granulomatosis with polyangiitis (reversed halo sign). A, B. Axial (A) and coronal (B) thin-section CT shows bilateral rounded opacities of different sizes with a central hypodense zone surrounded by a ring of consolidation (reversed halo sign) (arrows). C. Medium power magnification of lung demonstrates necrotizing vasculitis evidenced by an arterial wall (arrows) infiltrated and destroyed by neutrophils (hematoxylin and eosin stain, X 400). perfusion at the subsegmental level results in ischemia blood eosinophilia greater than 10% of white blood cell or frank infarctions leading to ground-glass opacities differential count, 3) neuropathy, 4) migratory or transient representing necrotic cellular infiltrates in the alveoli or pulmonary opacities, 5) paranasal sinus abnormalities, mosaic perfusion [140]. Enlarged mediastinal lymph nodes, and 6) tissue eosinophilia [150]. The diagnosis of EGPA always seen in association with parenchymal abnormalities, can be established if four or more of the previous criteria occur in up to 15% of cases [140]. are present. Asthma is present in almost all patients and usually precedes vasculitis for several years, and is often Eosinophilic Granulomatosis with Polyangiitis (EGPA) associated with rhinitis, nasal polyposis, or sinusitis The Chapel Hill consensus conference in 1994 defined [151]. ANCA are present in approximately 40% of patients. EGPA (formerly Churg-Strauss syndrome) as eosinophil-rich Symptomatic cardiac involvement occurs in as many as and granulomatous inflammation involving the respiratory 27–47% of cases and is a major contributor to disease- tract and necrotizing vasculitis affecting small to medium- related death in EGPA [152]. sized vessels, occurring in patients with late-onset asthma Clinically, EGPA occurs mainly in middle-aged adults and sustained peripheral blood eosinophilia [149]. with various degrees of eosinophilic inflammation and The American College of Rheumatology criteria for necrotizing vasculitis [153,154]. EGPA typically develops the diagnosis of EGPA include: 1) asthma, 2) peripheral into three sequential phases: 1) prodromal or allergic phase, kjronline.org https://doi.org/10.3348/kjr.2020.1082 1427 Franquet et al. usually in the fourth decade, may persist for many years, a predominantly peripheral distribution, ground-glass and is characterized by the occurrence of asthma, allergic opacities, areas of airspace consolidation, centrilobular rhinitis, and sinusitis; 2) eosinophilic phase, with marked nodules, and airway abnormalities attributable to asthma peripheral eosinophilia and eosinophilic organ infiltrations, [158]. These findings reflect the presence of eosinophilic especially in the lungs, heart, and gastrointestinal system; infiltration of the airspaces, interstitium, airways, and 3) vasculitic phase, with consequences of a necrotizing interstitial edema [159]. Interlobular septal thickening vasculitis generally associated with vascular or extravascular may be seen as a result of interstitial edema secondary granulomatosis and constitutional symptoms, such as fever, to cardiac involvement [159]. Histologically, airspace malaise, and weight loss [151,155]. consolidation is due to eosinophils, fibrin, foci of organizing There is a spectrum of histopathologic findings of EGPA pneumonia, and reactive type II pneumocytes. Up to 25% in the lung. The combination of eosinophilic pneumonia, of patients have few or no imaging abnormalities, and necrotizing vasculitis, and granulomatous inflammation is imaging is often of little help in arriving at this somewhat considered diagnostic but is infrequently present [156]. elusive diagnosis (Fig. 16) [160]. Alveolar spaces are often involved in eosinophils, fibrin, organizing fibrosis, and reactive type II pneumocytes. In Collagen Vascular Diseases the absence of vasculitis (clinical or histological), it may be difficult to distinguish between EGPA and other eosinophilic Rheumatoid Lung Nodules disorders. Rheumatoid pulmonary nodules are an uncommon but The most common radiographic findings consist of bilateral well-described extra-articular manifestation of rheumatoid multifocal consolidation, patchy nonsegmental consolidation, disease, occurring most often in cigarette smokers with and multiple nodules. Less common intrathoracic findings clinical and radiographic evidence of rheumatoid arthritis include mediastinal or hilar lymphadenopathy and pleural or [161,162]. The incidence in the lung is approximately pericardial effusion [138,157]. 30–40% of cases [163]. Usually, they are multiple and HRCT appearances largely reflect the eosinophilic pleural based, and may vary in size from a few millimeters infiltrate, including migrating patchy infiltrates with to 7 cm. They may resolve spontaneously, wax and wane in A B C Fig. 16. Eosinophilic granulomatosis with polyangiitis in a 23-year-old male with severe asthma. A. Axial thin-section CT scan (lung window) at the level of the carina shows an ill-defined nodule surrounded by a halo of ground-glass attenuation (arrow) in the right upper lobe. Note bilateral thickening of bronchial walls (arrowheads). B. Axial thin-section CT at the level of lung bases shows bilateral thickening of bronchioles (arrows), mucous plugging and basilar-predominant centrilobular nodules of varying sizes (arrowheads). C. Lung biopsy was done through video-assisted thoracic surgery. Low-power magnification shows airway destruction (arrows) with submucosal infiltration and luminal filling with lymphocytes and eosinophils (arrowheads) (hematoxylin and eosin stain, X 400). 1428 https://doi.org/10.3348/kjr.2020.1082 kjronline.org Non-Infectious Granulomatous Lung Disease concert with the disease activity, or may antedate arthritis Histologically, necrobiosis with and palisading epithelioid [164]. Nodules are typically asymptomatic and require no histiocytes is a typical feature. The area of central necrosis treatment unless they become quite large, infected, or contains necrotizing endothelial cells and histiocytes. The cavitated. Approximately 50% of rheumatoid pulmonary outer area tends to show granulation tissue with chronic nodules will cavitate and can sometimes be associated inflammatory cells and significant stromal fibrosis. Focal with pleural effusion, pneumothorax, or pyopneumothorax vasculitis and occasional giant cells can also be found [168]. [165,166]. The majority of spontaneous pneumothoraces Overall, this represents an immune-mediated granulomatous related to rheumatoid arthritis are associated with process and shows granulation tissue with chronic subpleural necrobiotic pulmonary nodules [167]. inflammatory cells and significant stromal fibrosis [169]. A B Fig. 17. Rheumatoid nodules. A, B. Axial (A) and sagittal thin-section CT (B) images show numerous subpleural pulmonary necrotic (arrows) and solid (arrowheads) necrobiotic pulmonary nodules. A B C Fig. 18. Rheumatoid nodule. A. Coronal reformatted contrast-enhanced CT shows a peripheral right upper lobe cavitary mass (arrow). B. Surgical gross specimen shows an ill- defined cavitary mass (black arrows) containing necrotic tissue (white arrows). C. Low-power scanning magnification of lung demonstrates a necrotizing granuloma with a central zone of necrosis (white arrow) surrounded by a rim of palisading histiocytes (black arrows). The dark blue periphery of the necrotic zone is nuclear debris (small arrows) (hematoxylin and eosin stain, X 40). kjronline.org https://doi.org/10.3348/kjr.2020.1082 1429 Franquet et al. CT features more commonly associated with rheumatoid Takeshi Johkoh lung nodules consist of multiplicity, smooth border, https://orcid.org/0000-0003-1237-2349 cavitation, satellite nodules, pleural contact, and a Kyung Soo Lee subpleural rind of soft tissue (Figs. 17, 18) [170]. https://orcid.org/0000-0002-3660-5728 CONCLUSION REFERENCES The diagnosis of non-infectious pulmonary granulomatosis 1. Myers JL, Tazelaar HD. Challenges in pulmonary fibrosis: 6 · is difficult because of the variable clinical manifestations Problematic granulomatous lung disease. Thorax 2008;63:78- and radiologic features. The anatomic distribution of the 84 2. Ohshimo S, Guzman J, Costabel U, Bonella F. 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