key: cord-0034796-6etgnuta authors: Ferrazza, Alessandro Maria; Baldassarri, Paolo title: Presentation and Diagnosis of Interstitial Lung Diseases date: 2020-02-01 journal: Thoracic Radiology DOI: 10.1007/978-3-030-35765-8_9 sha: 70407f3b60ded2ec2b95c27c324553a941b59543 doc_id: 34796 cord_uid: 6etgnuta Diffuse interstitial lung disease is a heterogeneous group of lung pathologies with similar clinical presentations. Radiologists and pathologists attempted to identify precise diagnostic criteria. Often, the pattern and distribution of the disease allow to narrow down the possible diagnoses, but the correlation with the clinical presentation is essential. Alessandro Maria Ferrazza and Paolo Baldassarri Diffuse interstitial lung disease is a heterogeneous group of lung pathologies with similar clinical presentations. Radiologists and pathologists attempted to identify precise diagnostic criteria. Often, the pattern and distribution of the disease allow to narrow down the possible diagnoses, but the correlation with the clinical presentation is essential. The main radiological patterns are: • Nodular • Septal • Cystic • Alveolar (ground-glass) • Reticular • Honeycombing To recognize the radiological pattern of the disease, it is necessary to search and study on HRCT images the secondary pulmonary lobule (SPL) that is the smallest structural unit in the lung. It is a roughly polyhedral structure, 1-2 cm in size, lined by connective tissue septa; the lobules in the peripheral regions of the lung are larger and more regular in shape, becoming smaller and more irregular in the central portions. Each SPL is constituted by 3-15 acini and 30-50 alveoli and is fed by a small lobular bronchiole and a pulmonary artery branch. These structures run in parallel in the central portion of the lobule and are therefore described as centrilobular. In the peripheral region, the venous and lymphatic vessels are contained in the interlobular interstitium. The SPL is composed by three main elements: -The interlobular septa: normally about 0.1 mm thick and therefore not visible on HRCT except in the peripheral region where they are slightly thicker and can barely be identified. The venous branches running within them have a caliber of about 0.5 mm and can, therefore, be visualized. Diseases affecting the venous or lymphatic systems of the lung will affect this region, e.g., "perilobular" patterns. -The centrilobular structures: consist of the intralobular arterial and bronchial branches. In normal conditions, it is possible to identify the lobular artery (1 mm), the terminal artery (0.7 mm), and the acinar artery (0.5 mm). The bronchial branches contain air and cannot be visualized as their wall thickness is inferior to the lower limit of resolution on HRCT (0.15 mm). When the bronchiolar lumens become plugged with dense materials such as fluids, blood, or pus, the tracings of the intralobular branches become visible on HRCT as branched structures terminating in small nodules (tree-in-bud appearance). -The lobular parenchyma and acini: not visible on HRCT under normal conditions. They include the functional units of the lung, i.e., the alveoli and the capillary bed with their supportive structures of connective tissue (intralobular interstitium). In some pathologies, e.g., inflammatory diseases, the involvement of the acinus appears as a small intralobular nodular opacity, about 0.6-1 mm in size. The nodular pattern is characterized by nodules less than 1 cm in size with variable characteristics and distribution, based on which it can subdivided into: • Nodules in a random pattern ( Fig. 9 .1) • Nodules in a miliary pattern (Figs. 9.1 and 9.2) • Nodules in a centrilobular (or bronchovascular) pattern ( Fig. 9 .3) • Nodules in a lymphatic or perilymphatic pattern ( Fig. 9 .4) They are usually secondary to pathologies with hematogenous dissemination (Table 9 .1). Thus, they are: • Diffuse (and never focal, as can occur in the bronchovascular pattern) • More numerous in the periphery (within 2-3 cm from the pleura) and at the bases (where there is more blood flow) • Possibly associated to a feeding vessel, that is, an arterial vessel entering the nodule ( Fig. 9 .1, in the center) If they are few in number, it may be difficult to distinguish this pattern from a centrilobular or perilymphatic one. They are secondary to pathologies with hematogenous dissemination (Tables 9.2 and 9 .3) and have the following characteristics: • Small nodules (<5 mm), too many to be counted ( Fig. 9 .1, lower part; Fig. 9 .2); • Random distribution within the SPL. CXR may be negative due to their small size. Dense or calcific nodules in a miliary pattern can be secondary to healed histoplasmosis, healed chickenpox, thyroid metastases after radioactive Iodine-131 treatment, talcosis, and pulmonary alveolar microlithiasis. Nodules are due to hemosiderin-laden macrophages that accumulate after localized hemorrhages. On CT, they are seen as ground-glass opacities, in general with a centrilobular distribution These nodules are located in the bronchovascular core of the SPL and are a typical manifestation of bronchiolocentric or bronchiolar interstitial lung diseases (Table 9 .4). They are: • Located at least 5-10 mm from the pleural surface or the interlobar fissures or the SPL margins • Generally of ground-glass density • Associated to other signs of bronchiolar obstruction: -Tree-in-bud opacities: the bronchioles are dilated and plugged by dense contents (mucus, pus, or fluid) and peribronchial inflammation is present -Mosaic pattern: due to hyperinflation of some SPLs • Common in bronchiectasis of any cause Ground-glass nodules, usually centrilobular, but in case of hematogenous dissemination they can be miliary and random These are nodules located around the lymphatic vessels and the perilymphatic channels (Figs. 9.4 and 9.5; Table 9 .5). Their characteristics are as follows: • Well-defined nodules (2-5 mm) • Axial distribution: in the peribronchovascular interstitium, from the hilum to the periphery Correlated to smoking (at least 2 years of smoking history) and characterized by pigmented macrophages within the respiratory bronchioles. There are centrilobular nodules with prevalent involvement of the superior lobes and progression to emphysema Subacute hypersensitivity pneumonitis Formation of granulomas in response to various types of antigens (farmer's lung or bird fancier's lung). There are centrilobular nodules that progress to thin-walled cysts and a prevalent involvement of the upper lobes with sparing of the inferior zones and costophrenic angles (typical aspect). A mosaic pattern can co-occur Langerhans cell histiocytosis Correlated to smoking, it is most likely due to an allergic response to some smoke components. Centrilobular nodules evolve into thinwalled cysts that can aggregate in bizarre shapes. There is prevalent involvement of the upper lobes and sparing of the inferior zones and costophrenic angles Follicular bronchiolitis Associated to hyperplasia of the Bronchus-Associated Lymphoid Tissue (BALT) in pathologies such as rheumatoid arthritis, Sjögren's, AIDS, infections, and hypersensitivity reactions. There are centrilobular nodules, subpleural nodules, thin-walled cysts, and ground-glass areas. It can be associated to interlobular septal thickening Less common Aspiration Usually secondary to chronic leguminous material aspiration. Characterized by centrilobular nodules in a gravity-dependent pattern Bronchioloalveolar carcinoma Early on, it can appear as centrilobular nodules Centrilobular nodules with ground-glass opacity due to the presence of hemosiderin-laden macrophages after localized hemorrhages Pulmonary hypertension Centrilobular nodules can be present in all forms of pulmonary hypertension. They are due to plexogenic arteriopathy in primary pulmonary arterial hypertension, to capillary dilatations in pulmonary veno-occlusive disease, and to capillary proliferation in pulmonary capillary hemangiomatosis Kidney failure Calcific nodules (calcified-cauliflower sign) can be seen in the most advanced stages of kidney failure Laryngeal papillomatosis Nodules can be seen in 1% of cases and are due to endobronchial seeding in the lung. The centrilobular nodules tend to cavitate forming cysts Fig. 9 .5 Nodules in a perilymphatic pattern in a patient with sarcoidosis Table 9 .5 Differential diagnosis of nodules in a perilymphatic pattern Perilymphatic nodules in an axial distribution from the hilum, with hilar and mediastinal adenopathy. They can aggregate forming masses (alveolar sarcoids) which can contain calcifications, i.e., the typical galaxy sign, characterized by a central mass surrounded by small nodules. It progresses to fibrosis with a reticular pattern Berylliosis Same presentation as sarcoidosis but with a history of occupational exposure to beryllium Round-shaped particles inhalation Perilymphatic nodules in an axial distribution from the hilum, with hilar lymphadenopathy. They can aggregate forming masses in the dorsal regions. It progresses to fibrosis. It is more prevalent in the superior lobes, being more ventilated. The most typical forms are silicosis, coal worker's pneumoconiosis (typical hilar eggshell calcifications in 5% of cases), talcosis, and siderosis Lymphangitic carcinomatosis Perilymphatic nodules in a predominantly axial distribution (75%). Usually associated to adenocarcinoma. It differs from pneumoconiosis in that whole lobes or a whole lung are usually spared, the lung architecture is preserved (while it is distorted in sarcoidosis and silicosis), and pleural effusions can be present (never present in pneumoconiosis) Less common Lymphocytic Interstitial Pneumonia (LIP) Idiopathic or secondary to HIV infection, EBV infection, dysproteinemia, or Sjögren's syndrome. It appears as nodules in a perilymphatic pattern, thin-walled cysts (80% of cases), and ground-glass opacities (100% of cases) Lymphoma Non-Hodgkin (25% of cases) or Hodgkin (40% of cases) with lung involvement. Pulmonary nodules >1 cm in size, often with bronchogram Miliary infections CMV, tuberculous, or fungal infections. It appears as pulmonary micronodules, usually in a random or miliary pattern, but they can mimic a perilymphatic pattern Follicular bronchiolitis Nodules are more often in a centrilobular pattern, associated to subpleural nodules, thin-walled cysts, ground-glass areas, and interlobular septal thickening. • Peripheral distribution: in the subpleural interstitium, in the interstitium of fissures and SPL contour • Associated to involvement of mediastinal lymph nodes Some diseases can start as a bronchovascular pattern (through inhalation) and then progress to a lymphatic pattern (through dissemination). The distinction of the nodular patterns depends mostly on the location, pattern, and appearance of the nodules (Table 9 .6). The presence of accessory signs of airways obstruction, such as a mosaic pattern or tree-in-bud opacities, can help to distinguish the centrilobular pattern from the others, in which they rarely occur. • Tree-in-bud opacities (TIB): They appear as quite defined centrilobular nodules (2-4 mm) from which linear opacities spread out in three or four V-shaped or Y-shaped branches ( Fig. 9 .6). They correlate to bronchiolar pathologies and are 9 .6 Tree-in-bud opacities in a patient with tuberculosis: (a) axial view, (b) coronal view caused by the dilation of the bronchiolar lumen, filled with mucus, pus, or fluid, and to the thickening of their walls. Rarely, they can be secondary to pathologies with hematogenous dissemination such as metastatic tumors or intravenous drug abuse, which can cause arteriolar dilation (Table 9 .7). • Mosaic pattern: There are areas of attenuation corresponding to the SPL ( Fig. 9.7 ; Tables 9.8 and 9.9). It can be caused by: -Obstruction of the small airways: emphysematous areas due to air-trapping -Vascular occlusive diseases: less vascularized areas. Usually, bronchoconstriction with air-trapping is also present in these regions as the lung attempts to maintain the ventilation-perfusion ratio within normal values -Patchy lung diseases: ground-glass opacification of only some SPL -Mixed: interstitial and small-airways disease It can be observed in 60% of normal subjects during expiration (maximum 1 lobule per CT section, mainly in the superior and ventral lobes). It can be difficult to recognize if almost all lobules are hyperextended. It represents the interlobular septal thickening of the SPL and is seen as short lines in the periphery of the lung that arrive to the pleura. They can have different morphology: smooth, nodular, irregular. The most common diagnoses are (Tables 9.10 and 9.11): • Pulmonary edema: smooth (Figs. 9.8a and 9.9) • Pulmonary fibrosis: irregular • Lymphangitic carcinomatosis: smooth or nodular ( Fig. 9.8b ). It can be associated with the following: -Prevalently septal pattern with nodular and irregular thickening -Often entire lobes or the contralateral lung are spared -Hilar lymphadenopathy Cause of acute respiratory failure requiring mechanical ventilation (DAD is the histological presentation of AIP and ARDS). The radiological presentation is characterized prevalently by ground-glass opacities, but also crazy paving can be observed (30-66%) Less common Diffuse alveolar hemorrhage Characterized by different phases: • Hemorrhage in alveolar spaces resulting in consolidations or ground-glass • Removal of blood by macrophages, which migrate in the interstitium and in the septa (2-3 days), with crazy paving pattern (10-20%) • Removal of macrophages by the lymphatic system (7-14 days) Acute eosinophilic pneumonia Characterized by migrating ground-glass areas, less frequently by crazy paving (10-20%) Table 9 .11 Differential diagnosis of septal pattern (subacute and chronic forms) Pulmonary Alveolar Proteinosis (PAP) Diffuse crazy paving pattern. The clinical symptoms (cough and dyspnea) are typically less severe than the radiological presentation Less common Non-Specific Interstitial Pneumonia (NSIP) Idiopathic or secondary to scleroderma, rheumatoid arthritis, druginduced lung disease It is characterized prevalently by ground-glass, reticular pattern, and traction bronchiectasis. There can also be a septal thickening more evident at the bases and at the periphery of the lung. Subpleural sparing of the lung in the dorsal regions is characteristic Cryptogenic Organizing Pneumonia (COP) Pathology characterized by granulomatous polypoid structures growing inside the bronchi. Different patterns can be observed: • Subpleural and peribronchial consolidations or ground-glass opacities (90%) with air bronchogram of variable shape and dimension (ranging from few centimeters to entire lobes), in a migrating pattern • Perilobular pattern: opacities or ground-glass at the periphery of the SPL that can mimic a septal pattern • Multiple or single opacities with the reversed halo sign, i.e., central ground-glass surrounded by consolidation, at least 2 mm • Ground-glass in peripheral zones, more common than crazy paving (10-20%) Chronic eosinophilic pneumonia The most frequent presentation is ground-glass opacity, but it can present as crazy paving in peripheral zones (10-20%) Lymphangitic carcinomatosis In general, it involves one or more lobes asymmetrically The septal pattern can be associated with ground-glass opacities, leading to the so-called crazy paving pattern (Fig. 9.8c ). This was initially described in pulmonary alveolar proteinosis, where the ground-glass appearance is due to the partial alveolar filling with proteinaceous material, and the septal pattern is It is characterized by air-filled or fluid-filled spaces with more or less defined walls. Superior lobes are more involved because the apical regions of the lung are subjected to greater gravity-induced stretching. All diseases causing a cystic pattern increase the risk of pneumothorax (Table 9 .12). Initially, pulmonary function tests show a restrictive pattern with reduction of lung diffusion for CO; later, they present an obstructive pattern. Table 9 .12 Differential diagnosis of cystic pattern Permanent enlargement of the distal air spaces up to the terminal bronchioles secondary to smoke, α1AT deficiency, intravenous drug abuse. It can be centrilobular, paraseptal, or panlobular Langerhans cell histiocytosis Centrilobular nodules that evolve into thin-walled cysts, which can aggregate in bizarre shapes. They spare the inferior zones and costophrenic angles. It correlates with smoke exposure and most likely is an allergic response to some smoke components ( Fig. 9.10 Observed only in women. On CT, there are uniform cysts throughout the lung which slowly replace the parenchyma ( Fig. 9 .10, on the right). Possible complications are pneumothorax and chylothorax Subacute hypersensitivity pneumonitis Characterized by centrilobular nodules evolving into thin-walled cysts; usually 1-14 cysts are observed in 10% of cases Lymphocytic Interstitial Pneumonia (LIP) Can be idiopathic or secondary to infections (HIV, EBV), dysproteinemia, and Sjögren's syndrome. On CT, there are thin-walled cysts in 80% of cases, usually less than 20 in number, ground-glass appearance (100%), and nodules in a perilymphatic pattern Desquamative Interstitial Pneumonia (DIP) The etiology is unknown; it has a higher prevalence in heavy smokers. It is characterized by thin-walled cysts (80%) of usually small dimension in the lower lobes and ground-glass opacities Idiopathic Pulmonary Fibrosis (IPF) Presents with basal or peripheral honeycombing (multiple rows of cysts, 0.3-1 cm in dimension). It can mimic a cystic pattern Laryngeal papillomatosis Characterized by centrilobular nodules affecting gravitydependent regions; they can evolve into cysts Coccidioidomycosis Fungal infection that is endemic in the southwestern regions of the USA (valley fever). In its late form, it presents as often single, thin-walled cysts in the superior lobes α1AT Alpha-1 antitrypsin, HIV human immunodeficiency virus, EBV Epstein-Barr virus Can be associated to ground-glass areas A mosaic pattern is present in 85% of cases but ground-glass can also be observed (continued) Idiopathic pathology with a characteristic histopathologic pattern of Usual Interstitial Pneumonia (UIP). The pattern has temporal and spatial heterogeneity. It can be primary (IPF) or secondary to drugs such as chemotherapy, nitrofurantoin, and paraquat The typical radiological presentation is a reticular pattern more evident at the bases and in subpleural regions and traction bronchiectasis with pleural and bronchovascular distortion. It progresses to subpleural honeycombing (multiple rows of cysts, 2-25 mm in size) Migrating ground-glass opacities with septal thickening and pleural effusion Drug reaction Can present in different ways: ARDS, hypersensitivity pneumonitis, pulmonary hemorrhage Chronic forms Non-Specific Interstitial Pneumonia (NSIP) Can be idiopathic or secondary to scleroderma, rheumatoid arthritis, or drug-induced lung disease It is prevalently characterized by ground-glass, a reticular pattern and traction bronchiectasis. Septal thickening can also be present, more evident at the bases and at the periphery of the lungs. There is subpleural sparing of the lung in the dorsal regions Chronic eosinophilic pneumonia Presents with consolidations (100%) and ground-glass appearance (90%) in the peripheral regions and in the upper lobes, with subpleural sparing of the lung Desquamative Interstitial Pneumonia (DIP) Of unknown etiology, is more prevalent in heavy smokers. It is characterized by thin-walled cysts (80%), usually in the lower lobes and small in dimension, and ground-glass opacities Lymphocytic Interstitial Pneumonia (LIP) Can be idiopathic or secondary to infections (HIV or EBV), dysproteinemia or Sjögren's syndrome. On CT, it appears as thin-walled cysts in 80% of cases, usually less than 20 in number, ground-glass appearance (100%), and nodules in a lymphatic pattern Primary alveolar proteinosis The typical presentation is crazy paving pattern, but ground-glass alone may also occur Less common Bronchioloalveolar carcinoma Focal ground-glass areas not well-defined from surrounding structures or ground-glass associated to solid tissue (part-solid nodule). Air bronchograms may be present Atypical Adenomatous Hyperplasia (AAH) Often a precancerous condition. It has a prevalence of 3-7% in the population (higher in elderly patients). It presents as spherical ground-glass opacities that are better delineated than those found in bronchioloalveolar carcinoma CMV cytomegalovirus, ARDS acute respiratory distress syndrome, HIV human immunodeficiency virus, EBV Epstein-Barr virus Idiopathic or secondary to scleroderma, rheumatoid arthritis, polymyositis, or dermatomyositis. The pattern has temporal and spatial homogeneity The typical radiological presentation is ground-glass opacities that progress to a reticular pattern with septal thickening, which is more evident at the bases and periphery of the lungs. There is sparing of the subpleural lung in dorsal regions. Traction bronchiectasis can also be present, out of proportion to the reticular pattern ( Fig. 9 .12) Superior lung fields Chronic hypersensitivity pneumonitis Can mimic IPF and NSIP. It is characterized by a reticular pattern with small fibrous septa that extend from the centrilobular bronchiole to the periphery of the lobule. It has a prevalent involvement of middle portions of the lung in case of chronic exposure (bird fancier's lung); in case of intermittent exposure (farmer's lung), the involvement is more prevalent in the superior portions. Traction bronchiectasis can co-occur (20%) Sarcoidosis A reticular pattern may become evident in late stage disease (stage IV) at the level of perihilar regions and in the superior and middle portions of the lung, with distortions and bronchiectasis. The typical presentation is characterized by nodules in a perilymphatic pattern and perihilar and mediastinal adenopathy, which decreases as the fibrosis progresses Less common Asbestosis Prevalent involvement of the inferior lobes. Pleural plaques may be associated Ankylosing spondylitis Prevalent involvement of the superior lobes Usually presents with a septal pattern but can mimic a reticular one. It is characterized by an asymmetric involvement of one or more lobes Table 9 .14 (continued) Fig. 9 .12 Reticular pattern in a patient with NSIP On CT it progresses to honeycombing only rarely but on histologic examination the so-called microscopic honeycombing is observed frequently Asbestosis Presents, similarly to IPF, the histological pattern of UIP. Its distinguishing features are pleural plaques (80%), fibrosis centered at the respiratory bronchiole (where the fibers deposit) and ramifying towards the pleura, peripheral hump-or wedge-shaped homogeneous opacities due to the obstruction of the respiratory bronchioles, lobular air-trapping (infrequent in IPF). Infrequently, it progresses to honeycombing Superior lung fields Stage IV sarcoidosis Can cause honeycombing prevalently in the superior lobes. Fibrous bands are present from the hilum along the bronchovascular bundles Chronic hypersensitivity pneumonitis Honeycombing can develop in the superior and middle regions, with relative basal sparing. Centrilobular nodules (not common in IPF) and lobular air-trapping (not common in IPF) can co-occur Less common diagnoses Ionizing radiations Secondary to thoracic radiotherapy Diffuse alveolar damage (ARDS) Occurs secondary to the fibrotic repair response to an acute damage and after the barotrauma occurring in the setting of positive-pressure ventilation CT staging and monitoring of fibrotic interstitial lung diseases in clinical practice and treatment trials: a position paper from the Fleischner Society Atlas of Diffuse Ling Diseases: A Multidisciplinary Approach What every radiologist should know about idiopathic interstitial pneumonia A practical approach to high-resolution CT of diffuse lung disease The alveolar patterns are ground-glass opacity and parenchymal consolidation.The ground-glass opacities are characterized by an increased opacity of the lung parenchyma that does not obscure the underlying structures ( Fig. 9 .11). In the pulmonary consolidation, the bronchovascular structures are obscured.Ground-glass opacities represent an acute process or an acute flare of a chronic disease (Table 9 .13). The radiological presentation is due to:• Partial filling of air spaces (edema, hemorrhage, pus) • Interstitial thickening secondary to edema, inflammation, or fibrosis, usually associated to a reticular pattern or traction bronchiectasis • Tumor growth preserving the parenchymal structures The reticular pattern is characterized by small and numerous intralobular linear opacities (Table 9 .14). As the disease progresses, interlobular septal thickening and traction bronchiectasis are observed. It represents a fibrotic and severely damaged lung, characteristic of end-stage lung disease. It presents with multiple well-defined small cysts, from 3-10 mm in size up to 2.5 cm, uniform in size and clustered together. They are associated to traction bronchiectasis ( Fig. 9.13) .The diagnosis is challenging as it usually represents an advanced stage of a lung disease and the biopsy is often non-conclusive (Table 9 .15).