- Email: [email protected]
Cross sectional imaging of pulmonary fibrosis translating pathology into radiology
Clinical Imaging 51 (2018) 332–336
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Cross sectional imaging of pulmonary fibrosis translating pathology into radiology
T
⁎
Mary Salvatorea, , Maxwell L. Smithb a b
Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, United States of America
A R T I C LE I N FO
A B S T R A C T
Keywords: Pulmonary fibrosis Idiopathic pulmonary fibrosis Nonspecific interstitial pneumonitis Airway centered fibrosis Honeycombing
There are three major pathologic patterns of pulmonary fibrosis; usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and airway-centered fibrosis (ACF). These pathologic patterns correspond with radiographic patterns of UIP, NSIP, and chronic hypersensitivity pneumonitis (CHP). Previous studies have demonstrated that the radiologic diagnosis is correct approximately 50% of the time for these fibrotic lung diseases. Understanding the microscopic pathologic patterns that are recapitulated at a macroscopic level in the high resolution CT scan is key to radiologists' ability to correctly diagnose pulmonary fibrosis and thus improve patient outcomes with early diagnosis and avoidance of biopsy. We investigate the similarities between the pathology and radiology features of UIP, NSIP, and ACF.
1. Introduction There are dozens of radiologic patterns of pulmonary fibrosis but the three most common fibrotic pulmonary diseases, usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (CrHP) have been confirmed with many registries including the Mount Sinai ILD registry [1, 2]. In 2008, Silva showed the characteristic CT features of CrHP, UIP, and NSIP which allowed confident distinction between these entities in approximately 50% of patients [3]. UIP is the radiologic and pathologic pattern seen in the clinical disease of idiopathic pulmonary fibrosis (IPF), a relentlessly progressive idiopathic fibrotic lung disease with a poor prognosis. The American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association (ATS/ERS/JRS/ALAT) published consensus diagnostic criteria for IPF in 2011 and clearly defined the criteria for the confident radiographic diagnosis of UIP pattern. These criteria include sub-pleural, basilar predominant fibrosis with reticulations and honeycombing and absence of features suggesting an alternative diagnosis such as air trapping and nodules [4]. In 2013 the American Thoracic Society/European Respiratory Society published an update of the Multidisciplinary Classification of Idiopathic Interstitial Pneumonias (IIPs) and created four categories which include chronic fibrosing IIPs (UIP and NSIP); acute or subacute IIPs; smoking related IIPs; and rare IIPs [5]. The chronic fibrosing IIPs are most common and with their overlapping imaging features can
⁎
cause radiologic diagnostic dilemma. CrHP is not considered an IIP but it is frequently misdiagnosed as IPF. Morell reported that, 20 of the 46 patients with initially diagnosis of IPF had a subsequent diagnosis of chronic hypersensitivity pneumonitis [6]. Since early and correct diagnosis improves outcomes for patients with pulmonary fibrosis it follows that differentiating the three most common fibrotic entities is of utmost importance. Smith reviewed the three major pathologic patterns of pulmonary fibrosis including UIP, fibrotic NSIP, and airway-centered fibrosis and provided accompanying illustrations [7]. These patterns correspond to the clinical syndromes of IPF, NSIP, and CrHP most often in clinical practice. The illustrations are a simple and powerful way to highlight the key microscopic features of the patterns of pulmonary fibrosis. Because microscopic anatomy and pathology is recapitulated at the macroscopic level, the illustrations also allow comparisons between the pathologic and radiologic patterns. These comparisons are useful in understanding the concepts of pulmonary fibrosis and may provide radiologists a better understanding of what is occurring at the microscopic level. Familiarity with the pathologic patterns of pulmonary fibrosis has the potential to increase diagnostic accuracy when interpreting high-resolution CT (HRCT) studies with pulmonary fibrosis. 2. Normal lung The normal lung parenchyma is composed of secondary pulmonary lobules measuring approximately 1.7 cm, that are outlined by interlobular septa which act like the scaffolding of the lung and transport the
Corresponding author at: Department of Radiology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, United States of America. E-mail address: [email protected] (M. Salvatore).
https://doi.org/10.1016/j.clinimag.2018.06.013 Received 9 March 2018; Received in revised form 4 June 2018; Accepted 15 June 2018 0899-7071/ © 2018 Elsevier Inc. All rights reserved.
Clinical Imaging 51 (2018) 332–336
M. Salvatore, M.L. Smith
Fig. 1. A and B. Normal anatomy of the secondary pulmonary lobule. Each lobule contains a central bronchovascular bundle. At the periphery of the lobules are subtle interlobular septae. C. Normal CT image of the lung parenchyma with subtle interlobular septae. Reprinted from [Smith M, Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. Arch Pathol Lab Med. 2016; 140 (3):221–229] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2016 College of American Pathologists.
(GGO) unless the patient is undergoing an acute exacerbation or has a superimposed acute lung injury. The rare FF seen microscopically is typically below the level of detectability on HRCT. Distinguishing early UIP from NSIP can be a radiologic challenge. GGO in the periphery of the lungs may be seen in both entities [8]. However, the distribution of GGO in early disease may help in the distinction. Early UIP is more heterogeneously distributed and may be accentuated in the basilar, subpleural, and paraseptal regions. In contrast, NSIP is more homogenous and may spare the subpleural region. The distinction of UIP from CrHP and other ACF diseases also often rests in differences in distribution. While UIP is basilar, ACF is typically upper lung zone predominant (like many inhalation diseases). Associated findings can assist in the radiologic UIP diagnosis. Older age and male sex support the correct diagnosis. A hiatal hernia may be an associated finding as GERD may be related to the development of the disease [9]. UIP is more common in smokers and as such emphysema is often associated with UIP [10]. Mediastinal lymphadenopathy has been reported in UIP, NSIP and sarcoid [11]. In patients with UIP and liver cirrhosis, short telomeres should be considered [12].
pulmonary veins and lymphatics (Fig. 1). In the normal lung, the interlobular septa are nearly imperceptible. The pleura is typically thin in the normal setting. Fibrosis, pulmonary edema or lymphangitic spread of malignancy can cause thickening of these interlobular septa radiographically. If there is associated traction bronchiectasis or bronchiolectasis the process is fibrosis. The bronchus and its accompanying artery are centrally located in the bronchovascular bundle, and the alveoli, with their thin walls to allow gas transfer, surround the central artery and bronchus. 3. UIP pattern UIP was first described by Liebow and Carrington in 1969. The pathologic hallmark for UIP is geographic and temporal heterogeneity. The geographic heterogeneity manifests as areas of dense fibrosis immediately adjacent to normal lung parenchyma with thin delicate alveolar walls. The temporal heterogeneity refers to the presence of advanced old scarring (dense mature collagenized scar, often with fatty and smooth muscle metaplasia) and young new scarring in the form of fibroblast foci. Fibroblast foci are small polyps of immature fibrosis often seen at the intersection between the advanced fibrosis and normal appearing lung. As the fibrosis progresses and destroys the pulmonary lobule, microscopic honeycomb remodeling occurs. This microscopic honeycombing is the earliest precursor to the macroscopic honeycomb cysts characteristic of the radiographic UIP-pattern. In 2011, the ATS/ERS/JRS/ALAT provided criteria for the radiographic diagnosis of UIP-pattern that include sub-pleural, basilar predominant fibrosis with reticulations and honeycombing and absence of features which suggest an alternative diagnosis. The sub-pleural distribution of fibrosis is one of the most important because it is most consistent with UIP of IPF. Fig. 2 compares the pathology pattern of pulmonary fibrosis to the HRCT. Notice in the pathology illustration that the peripheral fibrosis in white has scalloped edges as it abuts the normal lung parenchyma and how this is analogous on the adjacent CT image. On both the radiology and pathology images of UIP there is spatial heterogeneity with areas of normal tissue (dark) immediately adjacent to fibrosis (light). The fibrosis also is accentuated in the subpleural region in both figures. The lines of reticulation in the HRCT can be seen as dense paraseptal fibrosis in the pathology illustration. Microscopic honeycombing seen in the pathology figure will eventually become the macroscopic honeycomb cysts identified radiologically. Traction bronchiolectasis (in the pathology illustration) and bronchiectasis (in the radiology figure) are consistent airway alterations seen in the setting of UIP pattern fibrosis. Radiologic UIP pattern fibrosis does not show ground glass opacities
4. Fibrotic NSIP Fibrotic nonspecific interstitial pneumonia (NSIP) was initially described as a cohort of patients with a temporally uniform fibrosing disease process that could not be easily classified as one of the three main categories of IIPs [13]. It was considered an “other” fibrosis. Now, following detailed exclusion of other causes, idiopathic fibrotic NSIP is one of the main patterns of fibrosis in the classification of IIPs. The fibrosis is uniform with simplification of the alveolar walls and thickening of the septum. Normal lung is typically absent in the areas of fibrosis. There may or may not be an associated inflammatory cell infiltrate. The fibrotic form of NSIP pattern is far more common than the cellular form. The geographic and temporal heterogeneity, honeycombing, and fibroblast foci of UIP are usually absent. On HRCT, NSIP and UIP are both lower lobe predominant. In contrast to UIP, NSIP may show sub-pleural sparing [15]. The most common HRCT abnormality in NSIP is bilateral homogeneous lower lobe predominant ground-glass opacities with traction bronchiectasis [14]. The presence of ground glass opacities (GGO) may be related to the thickened alveolar walls if the fibrosis is advanced. The GGO on HRCT suggests more active inflammation and increased likelihood of response to steroids. There is often significant lower lobe volume loss. Honeycombing maybe present in advanced disease. Fig. 3 shows the characteristic features of fibrotic NSIP. Note the similarities between the pathology illustration and the HRCT in NSIP. 333
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Fig. 2. A. Histologic features of UIP at scanning magnification. Peripheral, subpleural, and paraseptal fibrosis creating “rings” or donuts of fibrosis with central “windows” of spared lung. B. Pathology illustration of UIP with subpleural fibrosis (white) and temporal (gray FF) and geographic (areas of sparing) heterogeneity. C. CT image of UIP demonstrates subpleural basilar predominant fibrosis. Spatial heterogeneity is reflected in areas of normal lung immediately adjacent to fibrotic lung. Temporal heterogeneity is manifest with areas of honeycombing adjacent to areas with bronchiolectasis. Fig. B modified from [Smith M, Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. Arch Pathol Lab Med. 2016; 140 (3):221–229] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2016 College of American Pathologists.
result in the ACF pattern including CrHP and chronic aspiration. In CrHP, the hallmark disease resulting in ACF, centrilobular organizing pneumonia, poorly formed interstitial granulomas, and giant cells help solidify the diagnosis [16]. Radiographically, similar fibrotic changes are seen following the bronchovascular bundles (Fig. 4). This is a key distinguishing feature from the more common pattern of UIP which is sub-pleural. Subpleural sparing is often present, especially early in the disease. The ACF along with cellular bronchiolitis contribute to the presence of air-trapping, a common HRCT finding in ACF and CrHP. Ground glass opacities can be seen particularly in early disease. While UIP and NSIP are lower lobe predominant diseases, CrHP is often but not always upper lobe predominant and this is likely due to antigen inhalation in upper lobes with high airflow volumes. Emphysema and tuberculosis, also inhalational diseases, are upper lobe predominant as well. It is interesting that emphysema is infrequently associated with CrHP and if they are seen together the prognosis is worse for the patient. Instead of being sub-pleural like UIP, CrHP follows the broncho-vascular bundles. Instead of being homogeneous like NSIP, CHP is heterogeneous. Air-trapping on expiratory images is a helpful finding but can be seen with other types of lung fibrosis as well.
Both show a more uniform process in comparison to UIP. No normal appearing lung is presenting the areas of fibrosis. In practice, the fibrotic NSIP-pattern is seen most often in the setting of connective tissue disease (CTD) associated ILD. Patchy areas of superimposed consolidation are suggestive of a component of organizing pneumonia. Esophageal dilatation can be seen in conjunction with an NSIP pattern and supports the diagnosis of scleroderma. Considering the homogeneous lower lobe distribution of NSIP that may spare the periphery it is reasonable to hypothesize that the fibrotic NSIP pattern is a response to a systemic intravascular inflammatory process associated with blood flow related to lower lobe predominance, as opposed to inhalational exposure or small vessel insult. 5. Chronic hypersensitivity pneumonitis Pathologically, the airway centered fibrosis (ACF) pattern demonstrates centrilobular fibrosis surrounding the bronchovascular bundle. Most cases also have associated airway inflammation and peribronchiolar metaplasia supporting the idea of chronic airway injury as a mechanism of disease and fibrosis. In ACF the periphery of the lobules are spared. ACF may have fibroblast foci but they are typically in a centrilobular distribution. Microscopic honeycombing may be present in more advanced disease. Several chronic inhalational diseases may
Fig. 3. A. Histologic features of fibrotic NSIP from scanning magnification. Diffuse fibrosis with uniform involvement of the interstitium. B. Pathology illustration of fibrotic NSIP with homogeneous thickening of alveolar walls, pleura, and interlobular septa. Alveolar walls are simplified. C. Radiologic NSIP pattern with homogeneous lower lobe fibrosis and bronchiectasis. Figure B modified from [Smith M, Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. Arch Pathol Lab Med. 2016; 140 (3):221–229] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2016 College of American Pathologists. 334
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Fig. 4. A. Histologic features of CrHP at scanning magnification. Centrilobular stellate scars of fibrosis. B. Pathology illustration of CrHP with peri-bronchial fibrotic changes and bronchioloectasia. Note the sparing of the pleural regions due to the limiting of the scarring to the center of the lobule. C·CrHP pattern radiographically. Note there is fibrosis surrounding the broncho-vascular bundles with air trapping. Figure B modified from [Smith M, Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. Arch Pathol Lab Med. 2016; 140 (3):221–229] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2016 College of American Pathologists.
Radiology allows the non-invasive evaluation of the effect of fibrosis on the secondary pulmonary lobule as well as overall distribution and associated findings to suggest the best diagnosis. Radiology has the advantage of imaging the entire lung and not suffering from significant sample bias as the pathologic specimens do. The pattern and distribution of fibrosis is most interesting because it is likely a result of the etiology of the fibrosing process. The key imaging features for the three most commonly encountered pulmonary fibrosis are highlighted in Table 2. UIP is sub-pleural, basilar predominant fibrosis with honeycombing and spatial and temporal heterogeneity but the most important feature is the sub-pleural distribution as there is no overlap with other diagnoses. The features for the correct diagnosis of NSIP radiographically are lower lobe predominant fibrosis with traction bronchiectasis and ground glass opacities. There is often sub-pleural sparing and there may be esophageal dilatation. The most important finding though is the homogeneity because the other fibrotic lung diseases are heterogeneous. Radiographically CHP is upper lobe predominant with fibrosis that follows the broncho-vascular bundles and has air trapping. The most helpful finding however is the broncho-vascular distribution and the air trapping. CT is an excellent tool for the accurate non-interventional differentiation of chronic fibrosing interstitial lung diseases. The pathologic features studies microscopically are recapitulated macroscopically on the HRCT. Therefore radiologists' recognition and understanding the pathology of pulmonary fibrosis allows for more accurate non-invasive radiology diagnosis.
Table 1 Overlapping histology findings [7].
Fibroblast Foci (FF) Honeycombing (HC)
UIP
fNSIP
ACF
FF is hallmark of the disease HC is hallmark of the disease
24% have FF
50% have FF
12% have HC
30% have HC
Table 2 Key pathology and radiology features of pulmonary fibrosis Histopathology UIP/IPF
NSIP
ACF/CHP
• Heterogeneous foci • Fibroblast • Honeycombing • Homogeneous Organizing • +/− pneumonia metaplasia • Peribronchiolar granulomas • Interstitial infiltrates • Interstitial • Organizing pneumonia
Radiology lobe predominant • Lower • Peripheral Honeycombing • +/− lobe predominant • Lower • Homogeneous • Bronchovascular Esophageal dilatation • +/− Subpleural Sparing • +/− lobe predominant • Upper distribution • Peribronchiolar attenuation or air • Mosaic trapping
6. Discussion Cross sectional imaging has the potential to act as a pathology translator. This would not have been possible in 1971 when the first CT scans were introduced, however it is becoming reality with the new, ultrafast micro CT scanners with resolutions of 1 to 10 μm [17]. The ability to understand the microanatomy of pulmonary fibrosis will facilitate the early and correct diagnosis of disease with cross-sectional imaging [18]. Pulmonary fibrosis is the result of an injury to the lung in a susceptible person. Multiple inciting agents have been identified which cause epithelial and endothelial damage. There is a subsequent abnormal repair process with abundant myofibroblasts and collagen deposition. Three distinctive pathologic patterns of pulmonary fibrosis have been described, UIP, NSIP, and ACF. The histology of these entities is based on the distribution of the fibrosis as it relates to the secondary pulmonary lobule. Fibroblast foci and microscopic honeycombing can be present in each diagnosis and are therefore not diagnostic in and of themselves. This overlap has caused many cases of NSIP and CrHP to be misdiagnosed as UIP with its worse prognosis (Table 1).
References [1] Singh S, Collins BF, Sharma BB, et al. Interstitial Lung Disease (ILD) in India: results of a prospective registry. Am J Respir Crit Care Med Mar 15 2017;195(6):801–13. [2] Bando M, Sugiyama Y, Azuma A, et al. A prospective survey of idiopathic interstitial pneumonias in a web registry in Japan. RespirInvestig Mar 2015;53(2):51–9. [3] Silva CI, Müller NL, Lynch DA, Curran-Everett D, Brown KK, Lee KS, Chung MP, Churg A. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology Jan 2008;246(1):288–97. [4] Raghu G, Collard HR, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011 Mar 15;183(6):788–824. [5] Travis WD, Costabel U, Hansell DM, King Jr. TE, Lynch DA, Nicholson AG, Ryerson CJ, Ryu JH, Selman M, Wells AU, Behr J, Bouros D, Brown KK, Colby TV, Collard HR, Cordeiro CR, Cottin V, Crestani B, Drent M, Dudden RF, Egan J, Flaherty K, Hogaboam C, Inoue Y, Johkoh T, Kim DS, Kitaichi M, Loyd J, Martinez FJ, Myers J, Protzko S, Raghu G, Richeldi L, Sverzellati N, Swigris J, Valeyre D, ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med Sep 15 2013;188(6):733–48. [6] Morell F, Villar A, Montero MÁ, Muñoz X, Colby TV, Pipvath S, Cruz MJ, Raghu G.
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disease. Minerva Med 2016 Feb;107(1 Suppl 1):9–14. [13] Katzenstein A, Fiorelli R. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol 1994;18:136–47. [14] Johkoh T. Nonspecific interstitial pneumonia and usual interstitial pneumonia: is differentiation possible by high-resolution computed tomography? Semin Ultrasound CT MR 2014 Feb;35(1):24–8. [15] Silva CI, Müller NL, Hansell DM, Lee KS, Nicholson AG, Wells AU. Nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis: changes in pattern and distribution of disease over time. Radiology 2008;247:251–9. [16] Churg A, Bilawich A, Wright JL. Pathology of chronic hypersensitivity pneumonitis what is it? What are the diagnostic criteria? Why do we care? Arch Pathol Lab Med 2018 Jan;142(1):109–19. [17] Metscher BD. MicroCT for developmental biology: a versatile tool for high-contrast 3D imaging at histological resolutions. Dev Dyn 2009;238(3):632–40. [18] Mai C, Verleden SE, McDonough JE, Willems S, et al. Thin-section CT features of idiopathic pulmonary fibrosis correlated with micro-CT and histologic analysis. Am J Roentgenol 2005;184:613–22.
Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir Med Nov 2013;1(9):685–94. Maxwell L. Smith (2016) update on pulmonary fibrosis: not all fibrosis is created equally. Arch Pathol Lab Med March 2016;140(3):221–9. Miller WT, Shah RM. Isolated diffuse ground-glass opacity in thoracic CT: causes and clinical presentations. Chest Imaging February 2005;184(2). Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastrooesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006;27:136–42. Papaioannou AI, Kostikas K, Manali ED, Papadaki G, Roussou A, Kolilekas L, Borie R, Bouros D. PapirisSA.Combined pulmonary fibrosis and emphysema: the many aspects of a cohabitation contract. Respir Med Aug 2016;117:14–26. Niimi H, Kang EY, Kwong JS, Carignan S, Müller NL. CT of chronic infiltrative lung disease: prevalence of mediastinal lymphadenopathy. J Comput Assist Tomogr 1996 Mar–Apr;20(2):305–8. Stella GM, Balestro E, Lacedonia D, Baraldo S. Telomeropathies: an emerging spectrum of disorders with important implications for patients with interstitial lung
336
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Cross sectional imaging of pulmonary fibrosis translating pathology into radiology
T
⁎
Mary Salvatorea, , Maxwell L. Smithb a b
Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, United States of America
A R T I C LE I N FO
A B S T R A C T
Keywords: Pulmonary fibrosis Idiopathic pulmonary fibrosis Nonspecific interstitial pneumonitis Airway centered fibrosis Honeycombing
There are three major pathologic patterns of pulmonary fibrosis; usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and airway-centered fibrosis (ACF). These pathologic patterns correspond with radiographic patterns of UIP, NSIP, and chronic hypersensitivity pneumonitis (CHP). Previous studies have demonstrated that the radiologic diagnosis is correct approximately 50% of the time for these fibrotic lung diseases. Understanding the microscopic pathologic patterns that are recapitulated at a macroscopic level in the high resolution CT scan is key to radiologists' ability to correctly diagnose pulmonary fibrosis and thus improve patient outcomes with early diagnosis and avoidance of biopsy. We investigate the similarities between the pathology and radiology features of UIP, NSIP, and ACF.
1. Introduction There are dozens of radiologic patterns of pulmonary fibrosis but the three most common fibrotic pulmonary diseases, usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (CrHP) have been confirmed with many registries including the Mount Sinai ILD registry [1, 2]. In 2008, Silva showed the characteristic CT features of CrHP, UIP, and NSIP which allowed confident distinction between these entities in approximately 50% of patients [3]. UIP is the radiologic and pathologic pattern seen in the clinical disease of idiopathic pulmonary fibrosis (IPF), a relentlessly progressive idiopathic fibrotic lung disease with a poor prognosis. The American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association (ATS/ERS/JRS/ALAT) published consensus diagnostic criteria for IPF in 2011 and clearly defined the criteria for the confident radiographic diagnosis of UIP pattern. These criteria include sub-pleural, basilar predominant fibrosis with reticulations and honeycombing and absence of features suggesting an alternative diagnosis such as air trapping and nodules [4]. In 2013 the American Thoracic Society/European Respiratory Society published an update of the Multidisciplinary Classification of Idiopathic Interstitial Pneumonias (IIPs) and created four categories which include chronic fibrosing IIPs (UIP and NSIP); acute or subacute IIPs; smoking related IIPs; and rare IIPs [5]. The chronic fibrosing IIPs are most common and with their overlapping imaging features can
⁎
cause radiologic diagnostic dilemma. CrHP is not considered an IIP but it is frequently misdiagnosed as IPF. Morell reported that, 20 of the 46 patients with initially diagnosis of IPF had a subsequent diagnosis of chronic hypersensitivity pneumonitis [6]. Since early and correct diagnosis improves outcomes for patients with pulmonary fibrosis it follows that differentiating the three most common fibrotic entities is of utmost importance. Smith reviewed the three major pathologic patterns of pulmonary fibrosis including UIP, fibrotic NSIP, and airway-centered fibrosis and provided accompanying illustrations [7]. These patterns correspond to the clinical syndromes of IPF, NSIP, and CrHP most often in clinical practice. The illustrations are a simple and powerful way to highlight the key microscopic features of the patterns of pulmonary fibrosis. Because microscopic anatomy and pathology is recapitulated at the macroscopic level, the illustrations also allow comparisons between the pathologic and radiologic patterns. These comparisons are useful in understanding the concepts of pulmonary fibrosis and may provide radiologists a better understanding of what is occurring at the microscopic level. Familiarity with the pathologic patterns of pulmonary fibrosis has the potential to increase diagnostic accuracy when interpreting high-resolution CT (HRCT) studies with pulmonary fibrosis. 2. Normal lung The normal lung parenchyma is composed of secondary pulmonary lobules measuring approximately 1.7 cm, that are outlined by interlobular septa which act like the scaffolding of the lung and transport the
Corresponding author at: Department of Radiology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, United States of America. E-mail address: [email protected] (M. Salvatore).
https://doi.org/10.1016/j.clinimag.2018.06.013 Received 9 March 2018; Received in revised form 4 June 2018; Accepted 15 June 2018 0899-7071/ © 2018 Elsevier Inc. All rights reserved.
Clinical Imaging 51 (2018) 332–336
M. Salvatore, M.L. Smith
Fig. 1. A and B. Normal anatomy of the secondary pulmonary lobule. Each lobule contains a central bronchovascular bundle. At the periphery of the lobules are subtle interlobular septae. C. Normal CT image of the lung parenchyma with subtle interlobular septae. Reprinted from [Smith M, Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. Arch Pathol Lab Med. 2016; 140 (3):221–229] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2016 College of American Pathologists.
(GGO) unless the patient is undergoing an acute exacerbation or has a superimposed acute lung injury. The rare FF seen microscopically is typically below the level of detectability on HRCT. Distinguishing early UIP from NSIP can be a radiologic challenge. GGO in the periphery of the lungs may be seen in both entities [8]. However, the distribution of GGO in early disease may help in the distinction. Early UIP is more heterogeneously distributed and may be accentuated in the basilar, subpleural, and paraseptal regions. In contrast, NSIP is more homogenous and may spare the subpleural region. The distinction of UIP from CrHP and other ACF diseases also often rests in differences in distribution. While UIP is basilar, ACF is typically upper lung zone predominant (like many inhalation diseases). Associated findings can assist in the radiologic UIP diagnosis. Older age and male sex support the correct diagnosis. A hiatal hernia may be an associated finding as GERD may be related to the development of the disease [9]. UIP is more common in smokers and as such emphysema is often associated with UIP [10]. Mediastinal lymphadenopathy has been reported in UIP, NSIP and sarcoid [11]. In patients with UIP and liver cirrhosis, short telomeres should be considered [12].
pulmonary veins and lymphatics (Fig. 1). In the normal lung, the interlobular septa are nearly imperceptible. The pleura is typically thin in the normal setting. Fibrosis, pulmonary edema or lymphangitic spread of malignancy can cause thickening of these interlobular septa radiographically. If there is associated traction bronchiectasis or bronchiolectasis the process is fibrosis. The bronchus and its accompanying artery are centrally located in the bronchovascular bundle, and the alveoli, with their thin walls to allow gas transfer, surround the central artery and bronchus. 3. UIP pattern UIP was first described by Liebow and Carrington in 1969. The pathologic hallmark for UIP is geographic and temporal heterogeneity. The geographic heterogeneity manifests as areas of dense fibrosis immediately adjacent to normal lung parenchyma with thin delicate alveolar walls. The temporal heterogeneity refers to the presence of advanced old scarring (dense mature collagenized scar, often with fatty and smooth muscle metaplasia) and young new scarring in the form of fibroblast foci. Fibroblast foci are small polyps of immature fibrosis often seen at the intersection between the advanced fibrosis and normal appearing lung. As the fibrosis progresses and destroys the pulmonary lobule, microscopic honeycomb remodeling occurs. This microscopic honeycombing is the earliest precursor to the macroscopic honeycomb cysts characteristic of the radiographic UIP-pattern. In 2011, the ATS/ERS/JRS/ALAT provided criteria for the radiographic diagnosis of UIP-pattern that include sub-pleural, basilar predominant fibrosis with reticulations and honeycombing and absence of features which suggest an alternative diagnosis. The sub-pleural distribution of fibrosis is one of the most important because it is most consistent with UIP of IPF. Fig. 2 compares the pathology pattern of pulmonary fibrosis to the HRCT. Notice in the pathology illustration that the peripheral fibrosis in white has scalloped edges as it abuts the normal lung parenchyma and how this is analogous on the adjacent CT image. On both the radiology and pathology images of UIP there is spatial heterogeneity with areas of normal tissue (dark) immediately adjacent to fibrosis (light). The fibrosis also is accentuated in the subpleural region in both figures. The lines of reticulation in the HRCT can be seen as dense paraseptal fibrosis in the pathology illustration. Microscopic honeycombing seen in the pathology figure will eventually become the macroscopic honeycomb cysts identified radiologically. Traction bronchiolectasis (in the pathology illustration) and bronchiectasis (in the radiology figure) are consistent airway alterations seen in the setting of UIP pattern fibrosis. Radiologic UIP pattern fibrosis does not show ground glass opacities
4. Fibrotic NSIP Fibrotic nonspecific interstitial pneumonia (NSIP) was initially described as a cohort of patients with a temporally uniform fibrosing disease process that could not be easily classified as one of the three main categories of IIPs [13]. It was considered an “other” fibrosis. Now, following detailed exclusion of other causes, idiopathic fibrotic NSIP is one of the main patterns of fibrosis in the classification of IIPs. The fibrosis is uniform with simplification of the alveolar walls and thickening of the septum. Normal lung is typically absent in the areas of fibrosis. There may or may not be an associated inflammatory cell infiltrate. The fibrotic form of NSIP pattern is far more common than the cellular form. The geographic and temporal heterogeneity, honeycombing, and fibroblast foci of UIP are usually absent. On HRCT, NSIP and UIP are both lower lobe predominant. In contrast to UIP, NSIP may show sub-pleural sparing [15]. The most common HRCT abnormality in NSIP is bilateral homogeneous lower lobe predominant ground-glass opacities with traction bronchiectasis [14]. The presence of ground glass opacities (GGO) may be related to the thickened alveolar walls if the fibrosis is advanced. The GGO on HRCT suggests more active inflammation and increased likelihood of response to steroids. There is often significant lower lobe volume loss. Honeycombing maybe present in advanced disease. Fig. 3 shows the characteristic features of fibrotic NSIP. Note the similarities between the pathology illustration and the HRCT in NSIP. 333
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Fig. 2. A. Histologic features of UIP at scanning magnification. Peripheral, subpleural, and paraseptal fibrosis creating “rings” or donuts of fibrosis with central “windows” of spared lung. B. Pathology illustration of UIP with subpleural fibrosis (white) and temporal (gray FF) and geographic (areas of sparing) heterogeneity. C. CT image of UIP demonstrates subpleural basilar predominant fibrosis. Spatial heterogeneity is reflected in areas of normal lung immediately adjacent to fibrotic lung. Temporal heterogeneity is manifest with areas of honeycombing adjacent to areas with bronchiolectasis. Fig. B modified from [Smith M, Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. Arch Pathol Lab Med. 2016; 140 (3):221–229] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2016 College of American Pathologists.
result in the ACF pattern including CrHP and chronic aspiration. In CrHP, the hallmark disease resulting in ACF, centrilobular organizing pneumonia, poorly formed interstitial granulomas, and giant cells help solidify the diagnosis [16]. Radiographically, similar fibrotic changes are seen following the bronchovascular bundles (Fig. 4). This is a key distinguishing feature from the more common pattern of UIP which is sub-pleural. Subpleural sparing is often present, especially early in the disease. The ACF along with cellular bronchiolitis contribute to the presence of air-trapping, a common HRCT finding in ACF and CrHP. Ground glass opacities can be seen particularly in early disease. While UIP and NSIP are lower lobe predominant diseases, CrHP is often but not always upper lobe predominant and this is likely due to antigen inhalation in upper lobes with high airflow volumes. Emphysema and tuberculosis, also inhalational diseases, are upper lobe predominant as well. It is interesting that emphysema is infrequently associated with CrHP and if they are seen together the prognosis is worse for the patient. Instead of being sub-pleural like UIP, CrHP follows the broncho-vascular bundles. Instead of being homogeneous like NSIP, CHP is heterogeneous. Air-trapping on expiratory images is a helpful finding but can be seen with other types of lung fibrosis as well.
Both show a more uniform process in comparison to UIP. No normal appearing lung is presenting the areas of fibrosis. In practice, the fibrotic NSIP-pattern is seen most often in the setting of connective tissue disease (CTD) associated ILD. Patchy areas of superimposed consolidation are suggestive of a component of organizing pneumonia. Esophageal dilatation can be seen in conjunction with an NSIP pattern and supports the diagnosis of scleroderma. Considering the homogeneous lower lobe distribution of NSIP that may spare the periphery it is reasonable to hypothesize that the fibrotic NSIP pattern is a response to a systemic intravascular inflammatory process associated with blood flow related to lower lobe predominance, as opposed to inhalational exposure or small vessel insult. 5. Chronic hypersensitivity pneumonitis Pathologically, the airway centered fibrosis (ACF) pattern demonstrates centrilobular fibrosis surrounding the bronchovascular bundle. Most cases also have associated airway inflammation and peribronchiolar metaplasia supporting the idea of chronic airway injury as a mechanism of disease and fibrosis. In ACF the periphery of the lobules are spared. ACF may have fibroblast foci but they are typically in a centrilobular distribution. Microscopic honeycombing may be present in more advanced disease. Several chronic inhalational diseases may
Fig. 3. A. Histologic features of fibrotic NSIP from scanning magnification. Diffuse fibrosis with uniform involvement of the interstitium. B. Pathology illustration of fibrotic NSIP with homogeneous thickening of alveolar walls, pleura, and interlobular septa. Alveolar walls are simplified. C. Radiologic NSIP pattern with homogeneous lower lobe fibrosis and bronchiectasis. Figure B modified from [Smith M, Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. Arch Pathol Lab Med. 2016; 140 (3):221–229] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2016 College of American Pathologists. 334
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Fig. 4. A. Histologic features of CrHP at scanning magnification. Centrilobular stellate scars of fibrosis. B. Pathology illustration of CrHP with peri-bronchial fibrotic changes and bronchioloectasia. Note the sparing of the pleural regions due to the limiting of the scarring to the center of the lobule. C·CrHP pattern radiographically. Note there is fibrosis surrounding the broncho-vascular bundles with air trapping. Figure B modified from [Smith M, Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. Arch Pathol Lab Med. 2016; 140 (3):221–229] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2016 College of American Pathologists.
Radiology allows the non-invasive evaluation of the effect of fibrosis on the secondary pulmonary lobule as well as overall distribution and associated findings to suggest the best diagnosis. Radiology has the advantage of imaging the entire lung and not suffering from significant sample bias as the pathologic specimens do. The pattern and distribution of fibrosis is most interesting because it is likely a result of the etiology of the fibrosing process. The key imaging features for the three most commonly encountered pulmonary fibrosis are highlighted in Table 2. UIP is sub-pleural, basilar predominant fibrosis with honeycombing and spatial and temporal heterogeneity but the most important feature is the sub-pleural distribution as there is no overlap with other diagnoses. The features for the correct diagnosis of NSIP radiographically are lower lobe predominant fibrosis with traction bronchiectasis and ground glass opacities. There is often sub-pleural sparing and there may be esophageal dilatation. The most important finding though is the homogeneity because the other fibrotic lung diseases are heterogeneous. Radiographically CHP is upper lobe predominant with fibrosis that follows the broncho-vascular bundles and has air trapping. The most helpful finding however is the broncho-vascular distribution and the air trapping. CT is an excellent tool for the accurate non-interventional differentiation of chronic fibrosing interstitial lung diseases. The pathologic features studies microscopically are recapitulated macroscopically on the HRCT. Therefore radiologists' recognition and understanding the pathology of pulmonary fibrosis allows for more accurate non-invasive radiology diagnosis.
Table 1 Overlapping histology findings [7].
Fibroblast Foci (FF) Honeycombing (HC)
UIP
fNSIP
ACF
FF is hallmark of the disease HC is hallmark of the disease
24% have FF
50% have FF
12% have HC
30% have HC
Table 2 Key pathology and radiology features of pulmonary fibrosis Histopathology UIP/IPF
NSIP
ACF/CHP
• Heterogeneous foci • Fibroblast • Honeycombing • Homogeneous Organizing • +/− pneumonia metaplasia • Peribronchiolar granulomas • Interstitial infiltrates • Interstitial • Organizing pneumonia
Radiology lobe predominant • Lower • Peripheral Honeycombing • +/− lobe predominant • Lower • Homogeneous • Bronchovascular Esophageal dilatation • +/− Subpleural Sparing • +/− lobe predominant • Upper distribution • Peribronchiolar attenuation or air • Mosaic trapping
6. Discussion Cross sectional imaging has the potential to act as a pathology translator. This would not have been possible in 1971 when the first CT scans were introduced, however it is becoming reality with the new, ultrafast micro CT scanners with resolutions of 1 to 10 μm [17]. The ability to understand the microanatomy of pulmonary fibrosis will facilitate the early and correct diagnosis of disease with cross-sectional imaging [18]. Pulmonary fibrosis is the result of an injury to the lung in a susceptible person. Multiple inciting agents have been identified which cause epithelial and endothelial damage. There is a subsequent abnormal repair process with abundant myofibroblasts and collagen deposition. Three distinctive pathologic patterns of pulmonary fibrosis have been described, UIP, NSIP, and ACF. The histology of these entities is based on the distribution of the fibrosis as it relates to the secondary pulmonary lobule. Fibroblast foci and microscopic honeycombing can be present in each diagnosis and are therefore not diagnostic in and of themselves. This overlap has caused many cases of NSIP and CrHP to be misdiagnosed as UIP with its worse prognosis (Table 1).
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