Update on Pulmonary Fibrosis

Update on Pulmonary Fibrosis Not All Fibrosis Is Created Equally Maxwell L. Smith, MD Context. Three distinct patterns of pulmonary fibrosis, including usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis, can be identified on surgical lung biopsies. Objectives. To compare the pathologic definitions, clinical and radiographic presentations, etiologies and differential diagnoses, treatments, and prognoses of usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis patterns, and to address the challenges and controversies related to pulmonary fibrosis. Data Sources. Data were derived from published literature and clinical experience. Conclusions. Although there may be overlap, identification of the dominant form of fibrosis in a particular case can provide a general category of disease and assist in identifying an etiology. (Arch Pathol Lab Med. 2016;140:221 229; doi: 10.5858/ arpa.2015-0288-sa) Surgical lung biopsies are often performed for the challenges and controversies related to fibrosing interstitial evaluation of suspected pulmonary fibrosis identified lung diseases are reviewed in the discussion. radiologically. There are 3 distinctive pathologic patterns of pulmonary fibrosis, including usual interstitial pneumonia THE PATHOLOGIC UIP PATTERN (UIP), fibrotic nonspecific interstitial pneumonia (fnsip), Pathologic Definition and airway-centered fibrosis (ACF). Their distinctive histology is primarily based on the distribution of the fibrosis The UIP pattern was first described in 1969 as a common (diffuse versus patchy) as well as the anatomic location of form of pulmonary fibrosis occurring in older adults. 1 In the the fibrosis (subpleural/paraseptal versus interstitial versus initial description, Liebow and Carrington 1 estimated approximately airway centered, respectively). Figure 1, A through D, illustrates the distinct pathologic differences. For fnsip and ACF, the distribution of fibrosis is suggestive of the etiology and pathogenesis (autoimmune versus inhalational injury as broad categories). For UIP, the pattern generates a differential diagnosis that includes connective tissue disease (CTD), chronic hypersensitivity pneumonitis (CrHP), and idiopathic pulmonary fibrosis (IPF). Recognizing the basic pattern of fibrosis is helpful as an initial step in the pathologic evaluation, allowing rapid narrowing of the differential diagnosis as to an etiology. The etiology of the fibrosis has important prognostic and treatment implications. one-half of the patients had idiopathic disease, whereas the other one-half showed pulmonary fibrosis secondary to a known exposure. For many years, the UIP pattern was defined histologically as surgical lung biopsies with fibrosis showing both geographic and temporal heterogeneity. Geographic heterogeneity referred to the areas involved by fibrosis alternating with areas of uninvolved parenchyma. Temporal heterogeneity referred to areas of old, mature fibrosis consisting of dense collagen and areas of new fibrosis in the form of fibroblastic foci. These criteria remained as components of the initial, multidisciplinary, consensus histologic classification of UIP until 2002. 2 In 2011, the American Thoracic Society, European This review is designed to provide an overview of the Respiratory Society, Japanese Respiratory Society, and pathologic definitions, clinical and radiographic presentations, etiologies and differential diagnoses, treatments, and statement 3 revising the definition of the pathologic UIP Latin American Thoracic Association issued a joint prognoses of these 3 pathologic forms of fibrosis. Pathologic pattern. They proposed that the UIP pattern should show marked fibrosis and architectural distortion (with or without honeycombing) in a predominantly subpleural Accepted for publication March 29, 2015. From the Department of Laboratory Medicine and Pathology, and paraseptal distribution, patchy involvement of lung Mayo Clinic, Scottsdale, Arizona. parenchyma by fibrosis, fibroblast foci, and the absence of The author has no relevant financial interest in the products or features against a diagnosis of UIP suggesting an alternate companies described in this article. diagnosis (hyaline membranes, organizing pneumonia, Presented in part at the biennial meeting of the Pulmonary granulomas, marked interstitial inflammatory cell infiltrate Pathology Society; June 3, 2015; San Francisco, California. Reprints: Maxwell L. Smith, MD, Department of Laboratory away from honeycombing, predominant airway-centered Medicine and Pathology, Mayo Clinic, 13400 E Shea Blvd, changes, and other features of an alternate diagnosis) Scottsdale, AZ 85259 (email: smith.maxwell@mayo.edu). (Table 1; Figure 2, A and B). In addition, the consensus Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith 221

Figure 1. Schematic representation of the 3 basic patterns of pulmonary fibrosis and their comparison to healthy lung. A, Healthy lung with thin alveolar walls and pleura, bronchovascular bundles located at the center of the lobules, and barely perceptible interlobular septae. B, Fibrotic nonspecific interstitial pneumonia pattern of fibrosis showing diffuse involvement of the alveolar walls with thickening, fusion, and simplification. The pleura is similarly affected. In areas, there is more-significant fusion and thickening lending a suggestion of heterogeneity, despite it being a diffuse process. C, Airway-centered pattern of fibrosis with centrilobular stellate appearing fibrosis, occasional bridges from one airway to another, and scattered fibroblast foci. Note the marked heterogeneity from field to field. D, Usual interstitial pneumonia pattern of fibrosis with marked irregular fibrosis in a peripheral and subpleural distribution. The fibrosis transitions to completely normal alveolar walls abruptly, with numerous fibroblast foci at the interface zone. In some lobules, microscopic honeycombing change has occurred (upper lobule). statement defined other pathology patterns along the spectrum of UIP that relay the likelihood of an IPF diagnosis, including a probable UIP pattern, apossible UIP pattern, and not UIP pattern. Notably, a not UIP pattern designation excluded IPF based on the pathology alone, regardless of the clinical and radiologic presentation. Clinical Presentation Most patients with pathologic UIP present with shortness of breath, cough, and exertional dyspnea. 4 Restrictive physiology is seen on pulmonary function testing. Other clinical features depend on the underlying etiology but can be used to help narrow the differential diagnosis. The UIP of 222 Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith

Table 1. Diagnostic Features and Differential Diagnosis for the Different Patterns of Pulmonary Fibrosis Fibrosis Pattern Diagnostic Features Potential Etiologies Usual interstitial pneumonia pattern 3 Evidence of marked fibrosis/ architectural distortion, with or without honeycombing in a predominantly subpleural/paraseptal distribution Presence of patchy involvement of lung parenchyma by fibrosis Presence of fibroblast foci Absence of features against a diagnosis of usual interstitial pneumonia suggesting an alternate diagnosis Idiopathic pulmonary fibrosis Connective tissue disease associated Chronic hypersensitivity pneumonitis Pneumoconioses Fibrotic nonspecific interstitial pneumonia pattern 2,18 Airway-centered fibrosis 27 Other rare, fibrosing lung diseases Uniform interstitial fibrosis, extending from the airway to the pleura/septum, with an even distribution With or without an associated inflammatory cell infiltrate Absence of temporal and geographic heterogeneity Absence of microscopic honeycomb remodeling and fibroblast foci (more often then not) Presence of interstitial fibrosis centered and extending around the bronchioles Presence of bronchiolar inflammation Presence of bronchiolar metaplasia of the epithelium Other fibrosis patterns not fitting well into the above Connective tissue disease associated Chronic hypersensitivity pneumonitis Adverse drug reaction Infection Immunodeficiency diseases Healed acute lung injury Smoking-related interstitial fibrosis Idiopathic fibrotic nonspecific interstitial pneumonia Chronic hypersensitivity pneumonitis Chronic aspiration Adverse drug reaction Connective tissue disease associated Smoking/other inhalational Chronic/recurrent infection Chronic allograft rejection Potential idiopathic disease Sarcoidosis/berylliosis Immunoglobulin G4-related disease Erdheim-Chester disease Hermansky-Pudlak syndrome Idiopathic pleuroparenchymal fibroelastosis Figure 2. Usual interstitial pneumonia pattern of fibrosis in a case of idiopathic pulmonary fibrosis. A, At low-power magnification, the peripheral and subplueral distribution of the fibrosis is evident, creating rings of fibrosis surrounding normal alveolar walls. The fibrosis is marked with resulting architectural distortion. B, At high-power magnification, the smooth muscle metaplasia, characteristic of any type of advanced fibrosis, is evident (asterisk). Fibroblast foci (arrow) are present at the abrupt transition from advanced fibrosis to completely normal alveolar walls (hematoxylin-eosin, original magnifications 320 [A] and 3100 [B]). Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith 223

Figure 3. Pulmonary fibrosis due to etiologies other than idiopathic pulmonary fibrosis, connective tissue disease, or chronic hypersensitivity pneumonitis. A, Coal workers pneumoconiosis. Biopsies show advanced pulmonary fibrosis with marked geographic heterogeneity, reminiscent of the usual interstitial pneumonia pattern. However, fibroblast foci are rare and on higher-power magnification (inset) numerous dust macrophages are present within the fibrosis. Polarization microscopy (not shown) revealed numerous birefringent particles consistent with silicates. The patient was a coal miner for more than 20 years. B, Smoking-related interstitial fibrosis. The biopsy shows a fibrosis pattern consistent with fibrotic, nonspecific interstitial pneumonia. However, the interstitial fibrosis consists of dense collagen, and there are numerous lightly pigmented macrophages in the airspace (arrow), both of which are clues to the etiology. The patient had a 40 pack-year smoking history. C, Aspiration-induced airway-centered fibrosis. This biopsy from the upper lobe shows advanced fibrosis with an airway-centered distribution. A few scattered, multinucleated giant cells are present in the airspaces, some with cholesterol clefts. No foreign material was identified. The patient had a long history of gastroesophageal reflux disease, documented recurrent aspiration pneumonia, and an abnormal swallow study. D, Erdheim-Chester disease. Surgical biopsies show fibrosis in a subpleural and lymphangitic distribution not characteristic of any of the other basic patterns of fibrosis. At higher-power magnification, the inflammatory and histiocytic nature of the fibrosis is recognized (inset) (hematoxylin-eosin, original magnifications 312.5 [A, C, and D], 3200 [insets], and 3100 [B]). IPF is typically seen in men 60 years and older. Patients with IPF often have a history of smoking. Radiology Radiologic UIP requires the presence of lower-lobe, peripheral-predominant honeycombing that is not segmentally distributed. 5 In more-advanced disease, the upper lobes may become involved, but they are typically less involved than the lower lobes. Reticulation and traction bronchiectasis are commonly seen. Ground-glass opacities are usually absent, unless there is superimposed, acute lung injury (which may be seen in acute exacerbation of IPF but is more often seen in other etiologies such as CTD). 6 Etiology and Differential Diagnosis When strictly defined as above, the pathologic UIP pattern has few associated clinical conditions (Table 1). The prototype disease is the clinical syndrome IPF. The UIP pattern is compared to pulmonary fibrosis due to etiologies other than IPF in Figure 3, A through D. Because CTD, CrHP, and pneumoconioses (Figure 3, A) remain etiologic possibilities when faced with a UIP pattern, close scrutiny of these patients for exposure and clinical/serologic evidence of CTD is warranted. 3 From a pathologic perspective, Takemura et al 7 identified granulomas, giant cells, organizing pneumonia, bridging fibrosis, lymphocytic alveolitis, lymphoid follicles, centrilobular fibrosis, and bronchiolitis as 224 Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith

histologic features statistically more common in UIP of CrHP when compared with IPF. We have performed preliminary studies suggesting chronic bronchiolitis, chronic pleuritis, organizing pneumonia, and lymphoid aggregate density may be more common in the UIP of CTD compared with IPF (data not shown). The 2011 joint consensus document 3 strongly emphasized the importance of a multidisciplinary approach to patients with fibrosing lung disease. 3 Despite these criteria and literature stressing the fact that the UIP pattern is not synonymous with IPF, 8 confusion still remains in communicating to clinicians, with many health care providers still equating a UIP pattern on biopsy to a diagnosis of IPF. A possible UIP pattern, according to the 2011 joint consensus, includes biopsies with diffuse fibrosis and interstitial inflammation, features most pathologists associate with the fnsip pattern. Pathogenesis A variety of pathogenic mechanisms have been proposed for the development of the UIP pattern of fibrosis, including infection, autoimmune disease, inhalational injury (including smoking and aspiration), inflammation, oxidant stress, and abnormal cytokine/chemokine cascade. 9 The pattern is peculiar because it is strikingly geographic in its distribution (subpleural/paraseptal), with fibrosis directly adjacent to areas of completely normal alveolar walls, and advancing fronts of fibrosis in the form of fibroblast foci at the interface of the dense fibrosis and normal lung. Any plausible hypothesis must be able to account for those observations. Leslie 10 posed an intriguing hypothesis that UIP of IPF was caused by recurrent tractional injury to the peripheral alveoli in aging lung tissue. Treatment The treatment depends on the underlying etiology. In the case of IPF, until recently, there were no well-characterized treatment strategies. In fact, treating patients with IPF with the standard CTD therapy of prednisone, azathioprine, and N-acetyl cysteine actually increased their risk of death or hospitalization. 11 In the past few years, antifibrotic agents were approved for use in IPF, but not in cases of UIPpattern fibrosis from other etiologies. 12,13 It remains to be seen whether these antifibrotic agents might be effective in other causes of the UIP pattern. Prognosis The pathologic UIP pattern seems to have the worst prognosis among all the fibrosing interstitial lung diseases. 14 However, even when etiologic diseases are restricted specifically to the UIP pattern, IPF may have a worse prognosis compared with UIP of CTD or CrHP. 15 17 These data suggest that identifying the etiology of the UIP pattern has clinical implications. THE PATHOLOGIC fnsip PATTERN Pathologic Definition Katzenstein and Fiorelli 18 first described nonspecific interstitial pneumonia (NSIP) as a group of idiopathic interstitial pneumonias that could not be pigeonholed into 1 of the 3 main groups (of Liebow and Carrington 1 ). Although NSIP was initially used as a waste-basket diagnosis for biopsies not fitting other defined categories, the term NSIP is now used almost exclusively to describe a type of idiopathic interstitial pneumonia. 2 However, in surgical pathology practice, the pathologic NSIP pattern is commonly seen in a wide variety of different etiologic conditions and is often used as a descriptive diagnostic entity. The fnsip pattern is far more common than the cellular forms. The classic fnsip pattern shows uniform fibrosis with an even distribution, with or without an inflammatory cell infiltrate 2 ; absence of temporal and geographic heterogeneity; and absence of honeycomb remodeling and fibroblast foci (more often then not) 19 (Table 1; Figure 4, A and B). Clinical Presentation The clinical presentation of fnsip depends entirely on the underlying etiology. However, when an etiology cannot be identified (idiopathic NSIP), the patients are typically middleaged women in their fifth to sixth decades who present with more than 6 months of dyspnea and cough. Patients typically show restrictive physiology on pulmonary function testing and may have other systemic signs or symptoms. 20 Radiology The imaging findings in fnsip are nonspecific. 21 The most common radiologic manifestation is symmetric, bilateral, ground-glass opacities. In the background, there may be fine reticulation with traction bronchiectasis. 22 Honeycombing may occur but should not be a dominant feature. Etiology and Differential Diagnosis There are several clinical conditions associated with the fibrotic NSIP pattern seen on surgical lung biopsies (Table 1). The most common condition encountered in practice is CTD. Other etiologies include hypersensitivity pneumonitis, drug-induced pneumonitis, infection, and immunodeficiency. 2 Healed, acute lung injury may also produce an fnsip pattern of injury. When no specific etiology is identified following multidisciplinary discussion, idiopathic NSIP may be diagnosed. When faced with this pattern of injury on biopsy, it is important to consider other possible disease processes, especially if the biopsy material is limited. Smoking-related interstitial fibrosis, at first glance, might appear similar to fibrotic NSIP (Figure 3, B). Identification of stellate lesions of pulmonary Langerhans cell histiocytosis, respiratory bronchiolitis, or even desquamative interstitial pneumonia (primarily based on the degree of intra-alveolar macrophages) can help suggest smoking as an etiology as well. Furthermore, smoking-related interstitial fibrosis tends to be airway centric (see below), and the fibrosis is hypocellular and composed mostly of dense bands of collagen with characteristic cracking. 23 Pathogenesis Considering the distribution of disease, identified both by radiology and pathology studies, it seems plausible the fnsip pattern is a response to a systemic disease process associated with blood flow, as opposed to inhalational exposure or anatomic forces. This pathologic disease process targets every square centimeter of the lung parenchyma. The fact that CTD is the most common etiology identified with this pathologic pattern lends support to this hypothesis. Many authors think idiopathic NSIP actually represents a yet to be fully elucidated form of autoimmune disease. 20 This has led to the suggestion of the term interstitial pneumonia with autoimmune features (IPAF), which was proposed as a placeholder for further research on patients with interstitial Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith 225

Figure 4. Fibrotic, nonspecific pneumonia pattern of fibrosis in a case of rheumatoid arthritis. A, At low-power magnification, the relatively uniform distribution of the fibrosis is evident; however, there are areas of more significant fibrosis and architectural distortion from field to field (asterisk). Note the lymphoid aggregates (arrow), some of which contain germinal centers, features supporting connective tissue disease as an etiology. B, At higherpower magnification, there is uniform interstitial fibrosis, a mild component of chronic interstitial inflammation (arrowhead), and a lack of fibroblast foci (hematoxylin-eosin, original magnifications 320 [A] and 3100 [B]). Figure 5. Airway-centered fibrosis in a case of chronic hypersensitivity pneumonitis. A, Low-power examination reveals the substantial airwaycentered fibrosis that is disrupting the architecture (asterisk). The fibrosis gradually dissipates at the periphery creating a poor demarcation between involved and uninvolved lung. B, At higher-power magnification, a mild component of chronic inflammation and peribronchiolar metaplasia are appreciated (arrow). In other fields, rare, poorly formed granulomas were present (hematoxylin-eosin, original magnifications 320 [A] and 3100 [B]). pneumonia and other autoimmune features who do not currently meet recognized criteria for a specific CTD (discussed further below). 24 Treatment The treatment of the pathologic NSIP pattern depends on the underlying etiology. Patients with CTD are often treated for their underlying disease with immune suppression and immune modulation. Prognosis The fnsip pattern, regardless of etiology, has an improved prognosis when compared with UIP. 25,26 These studies underscore the importance of recognizing this pattern of fibrosis. There are no studies, to our knowledge, directly comparing the prognosis of ACF to the fnsip pattern; however, the prognosis seems similar. PATHOLOGIC ACF PATTERN Pathologic Definition The ACF pattern was recently defined as surgical lung biopsy showing interstitial fibrosis centered on, and extending around, the bronchioles, with or without bronchiolar inflammation, and the presence of peribronchiolar metaplasia 27 (Table 1; Figure 5, A and B). Although this is a common finding in practice, the literature is relatively sparse, with initial reports beginning more than a decade ago referring to a lesion termed bronchiolocentric interstitial fibrosis and centrilobular fibrosis. 28,29 Most cases also have 226 Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith

associated airway inflammation and peribronchiolar metaplasia, further histologic evidence of airway injury. In the most comprehensive study to date, 27 features normally associated with the UIP pattern, including fibroblast foci, honeycombing, and geographic heterogeneity, were identified in 50%, 30%, and 27% of cases, respectively. Furthermore, organizing pneumonia was found in 37% of cases. Clinical Presentation Patients with ACF are more likely to be women and nonsmokers. The most common presenting symptoms are cough and dyspnea. More than one-half of patients have a bird or mold exposure history or gastroesophageal reflux disease. 27 Radiology Most cases of ACF show central and peribronchovascular reticulation consistent with the pathologic lesion. 27 The changes are usually symmetric with an upper-lobe accentuation. Etiology and Differential Diagnosis The prototypic clinical condition resulting in the ACF pattern is chronic hypersensitivity pneumonitis. The other major conditions to consider include chronic aspiration (Figure 3, C) and CTD. 27 Smoking and other inhalational exposures are also contributors to chronic airway-centered pathology. Completing the differential diagnosis are airway-centered adverse drug reactions and chronic infections (Table 1). Pathogenesis Not surprisingly, inhalation exposure and airway injury has a major role in the pathogenesis of ACF. In CrHP and smoking-related disease, the injury tends to be upper-lobe predominant in the more-active phases, corresponding to the higher airflow volumes. Despite its presumed role in pulmonary disease, studies investigating aspiration are rare. Some CTDs, particularly rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus, have a predisposition for involvement of the airways. 30 Treatment The treatment of ACF depends on the underlying etiology. In CrHP, the treatment is aimed at identifying and eliminating the exposure to the causative antigen. Steroids do not seem to be effective in the chronic phase of disease. In chronic aspiration, treatments are aimed at preventing gastroesophageal reflux disease with diet and lifestyle modification, proton pump inhibitors, histamine 2 receptor antagonists, and antireflux surgery. 31 Immune suppression and immune modulation are the mainstays of treatment for CTD-associated ACF. Prognosis The prognosis of ACF seems to be better than UIP with an overall 5-year survival of 67.5%. Features associated with a worse prognosis, by Cox univariate analysis, included oxygen saturation at rest, organizing pneumonia in the airway, fibroblast foci, and the presence of microscopic honeycombing. 27 COMMENT The basic patterns of pulmonary fibrosis provide an entry point for developing a differential diagnosis about the etiology responsible for the fibrosis. The fibrosis itself is simply a sign that past tissue injury has occurred, and the innate fibrosing repair mechanism has been engaged. What is of interest to the pathologist, pulmonologist, and patient is the etiology of the fibrosis because the etiology helps define the treatment and prognosis of various fibrosing interstitial lung diseases that can be disparate. However, even recognizing the basic pattern of fibrosis on a lung biopsy can be challenging because there is significant overlap in the histologic features. All the patterns show mature fibrosis with a degree of parenchymal heterogeneity. Fibroblast foci and microscopic honeycombing changes may be seen in all the patterns. The initial series of NSIP cases described by Katzenstein and Fiorelli 18 showed fibroblast foci and microscopic honeycombing changes in 24% and 12% of cases, respectively, 18 whereas cases of ACF showed fibroblast foci and microscopic honeycombing changes in 50% and 30% of cases, respectively. 27 Because of these features, and perhaps because UIP is the most well-known fibrosing interstitial pneumonia, it is not surprising that cases with fnsip and ACF are often overcalled a UIP pattern. For years, the general approach to lung biopsies with fibrosis has been to start at a UIP pattern and then look for other features that argue against a UIP diagnosis. What if the paradigm were shifted to comparing cases to the 3 basic patterns of fibrosis seen in lung biopsies, identifying the best-fitting pattern, and then looking for specific histologic features to confirm the initial suspicion? The clues to the correct pattern classification and the eventual etiology are often found in the relative degree of histologic changes, as well as in the presence of additional findings. The UIP pattern of fibrosis should be subpleural and paraseptal in distribution, have numerous fibroblast foci, have areas of completely normal alveolar walls, and have sharp demarcations between fibrotic and normal areas. The fnsip pattern of fibrosis should involve most alveolar walls, without predilection for the airways or subpleural regions, but the extent of involvement is variable from one field to the next, with some alveolar walls approaching normal thickness. The transitions between involved and lessinvolved areas are poorly defined, with gradual tapering of the fibrosis. Cellular interstitial infiltrates, the presumed precursor to the fibrosis, are commonly seen. Some alveolar walls may coalesce with resulting fibrosis, causing some architectural distortion (reminiscent of UIP). The ACF pattern of fibrosis should be centered on the airways with occasional bridging of fibrosis from the airway to the septum/pleura or from the airway to an adjacent airway. Associated peribronchiolar metaplasia and other features of small airway remodeling (bronchiolectasis and mucostasis) are common. Similar to the NSIP pattern, the transitions are usually ill defined. As a practical matter at the surgical pathology desk, the most-common differential diagnosis for all forms of fibrosing lung disease includes IPF, CTD-associated interstitial lung disease, and CrHP. Of course, there are many other causes of pulmonary fibrosis to consider, including smoking-related disease, pneumoconiosis, sarcoidosis/berylliosis, immunoglobulin G4-related disease, Erdheim- Chester disease (Figure 3, D), Hermansky-Pudlak syndrome, and idiopathic pleuroparenchymal fibroelastosis (Table 1). Several histologic features have been shown to be more common in cases of CrHP-associated UIP when compared with IPF, including granulomas, giant cells, Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith 227

Table 2. Comparison of the Histologic Findings Seen in the Prototype Diseases of the 3 Patterns of Fibrosis, Usual Interstitial Pneumonia (UIP), Fibrotic Nonspecific Interstitial Pneumonia, and Airway-Centered Fibrosis (ACF) a Disease b Histologic Feature IPF CTD CrHP UIP pattern þþþ þ þ Fibrotic NSIP pattern þþþ þ ACF þ þþþ Fibroblast foci þþþ þ þ Microscopic honeycomb remodeling þþþ þ þ Normal areas þ 6 6 Hyaline membranes 6 þ Organizing pneumonia 6 þ þ Granulomas 6 þ Peribronchiolar metaplasia 6 6 þ Marked interstitial inflammatory cell infiltrate away from honeycombing þ þ Predominant airway centered inflammation 6 þþþ Chronic pleuritis þþþ Lymphoid aggregates þ þ Bridging fibrosis 6 þ Plasma cells þ þ Chronic bronchiolitis þ þ Cellular or fibrotic NSIP-like areas þþþ þ Multiple patterns on the same biopsy þ 6 Abbreviations: CrHP, chronic hypersensitivity pneumonitis; CTD, connective tissue disease; IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial pneumonia. a Some data derived from Wuyts et al, 8 2014. b þþþ, hallmark feature; þ, present; 6, variable;, absent. organizing pneumonia, bridging fibrosis, lymphocytic alveolitis, lymphoid follicles, centrilobular fibrosis, and bronchiolitis. 7 We have undertaken a similar study comparing the histologic features of CTD-associated UIP to IPF and have identified some potentially significant histologic discriminators. Table 2, modified from Wuyts et al, 8 compares IPF, CTD, and CrHP for a variety of histologic findings, including overall patterns of fibrosis as well as more subtle findings (see also Figures 2, 4, and 5). Note that IPF is strictly defined as the UIP pattern histologically, and most other histologic findings (aside from cases in clinical acute exacerbation) argue for an alternative diagnosis. One of the results of this approach is the identification of patients with pulmonary fibrosis and other histologic features suggestive of a CTD but not meeting the full criteria for a defined CTD. This situation can be challenging to navigate for the pathologist in their communication with pulmonologists and rheumatologists. Most studies estimate about 20% of patients with these findings will eventually go on to develop a defined CTD. 32 However, in the absence of a defined CTD, the pulmonologist and rheumatologists do not have a specific disease to target for treatment. To help address this issue and to provide a better cohort of patients to study prospectively, an American Thoracic Society/ European Respiratory Society task force recently proposed the term IPAF. 24 The IPAF designation is used to describe individuals with both ILD [interstitial lung disease] and combinations of other clinical, serologic, and/or pulmonary morphologic features that putatively stem from an underlying systemic autoimmune condition, but do not meet current rheumatologic criteria for a characterized CTD. 24 To meet criteria for IPAF, patients must have at least 1 feature from 2 of 3 domains: clinical, serologic, and morphologic. The morphologic domain includes both radiologic and pathologic features. The histopathologic features meeting criteria for the morphologic domain include NSIP, organizing pneumonia, lymphoid interstitial pneumonia, interstitial lymphoid aggregates with germinal centers, and diffuse lymphoplasmacytic infiltration. 24 The primary goal of this term is to provide the foundation for the investigation of a more-unified cohort of patients who have interstitial lung disease but do not meet criteria for a defined CTD. Histologic overlap between the major types of pulmonary fibrosis may occur. This may be due to a single disease process affecting multiple sites (CTD causing fnsip and ACF) or due to multiple etiologies involving the lung at once (fibrotic pulmonary Langerhans cell histiocytosis from smoking [ACF] in a patient with UIP of IPF). Some have proposed that NSIP is a precursor to UIP and that, given sufficient time, NSIP will progress to UIP. 33 It may be true that as NSIP progresses and as the fibrosis accumulates, the lung architecture continues to be remodeled and destroyed to the point where all that is left is end-stage lung with microscopic honeycombing. This suggests, however, an alternative etiology to the fibrosis than IPF because classic cases of IPF show completely normal alveolar walls away from the fibrosis. Others have identified that the prognosis of cases with one lobe showing UIP and another lobe showing NSIP (discordant UIP) had a prognosis that was worse than NSIP alone and concordant UIP. 34 Because of this, it has been suggested that cases showing overlap of NSIP and UIP should be classified as UIP. However, these studies were performed before the revision to the classification of UIP in 2011 and involved only a few patients. Many of the discordant biopsies may not be classified as the UIP pattern according to present guidelines. Many of these patients may be better categorized as having IPAF with more-advanced fnsip pattern of fibrosis. Further studies, both using standardized histologic criteria as well as an investigation of the individual histologic findings, are required to continue to elucidate the etiology, prognosis, and treatment strategies for these different patterns of pulmonary fibrosis. References 1. Liebow A, Carrington CB. The interstitial pneumonias. In: Simon M, Potchen EJ, Le May M, eds. Frontiers of Pulmonary Radiology: Pathophysiologic, Roentgenographic and Radioisotopic Considerations Proceedings of the Symposium Sponsored by Harvard Medical School, April 21 22, 1967. New York, NY: Grune & Stratton; 1969:102 141. 2. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias [published correction appears in Am J Respir Crit Care Med. 2002;166(3):426]. Am J Respir Crit Care Med. 2002;165(2):277 304. 3. Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788 824. 4. Smith M, Dalurzo M, Panse P, Parish J, Leslie K. Usual interstitial pneumonia-pattern fibrosis in surgical lung biopsies: clinical, radiological and histopathological clues to aetiology. J Clin Pathol. 2013;66(10):896 903. 5. Mueller-Mang C, Grosse C, Schmid K, Stiebellehner L, Bankier AA. What every radiologist should know about idiopathic interstitial pneumonias. Radiographics. 2007;27(3):595 615. 6. MacDonald SL, Rubens MB, Hansell DM, et al. Nonspecific interstitial pneumonia and usual interstitial pneumonia: comparative appearances at and diagnostic accuracy of thin-section CT. Radiology. 2001;221(3):600 605. 7. Takemura T, Akashi T, Kamiya H, et al. Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia. Histopathology. 2012;61(6):1026 1035. 228 Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith

8. Wuyts WA, Cavazza A, Rossi G, Bonella F, Sverzellati N, Spagnolo P. Differential diagnosis of usual interstitial pneumonia: when is it truly idiopathic? Eur Respir Rev. 2014;23(133):308 319. 9. Kottmann RM, Hogan CM, Phipps RP, Sime PJ. Determinants of initiation and progression of idiopathic pulmonary fibrosis. Respirology. 2009;14(7):917 933. 10. Leslie KO. Idiopathic pulmonary fibrosis may be a disease of recurrent, tractional injury to the periphery of the aging lung: a unifying hypothesis regarding etiology and pathogenesis. Arch Pathol Lab Med. 2012;136(6):591 600. 11. Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N- acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968 1977. 12. King TE Jr, Bradford WZ, Castro-Bernardini S, et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis [published correction appears in N Engl J Med. 2014;371(12):1172].N Engl J Med. 2014;370(22):2083 2092. 13. Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis [published correction appears in N Engl J Med. 2015;373(8):782]. N Engl J Med. 2014; 370(22):2071 2082. 14. Ryerson CJ, Vittinghoff E, Ley B, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest. 2014;145(4):723 728. 15. Churg A, Sin DD, Everett D, Brown K, Cool C. Pathologic patterns and survival in chronic hypersensitivity pneumonitis. Am J Surg Pathol. 2009;33(12): 1765 1770. 16. Moua T, Zamora Martinez AC, Baqir M, Vassallo R, Limper AH, Ryu JH. Predictors of diagnosis and survival in idiopathic pulmonary fibrosis and connective tissue disease-related usual interstitial pneumonia. Respir Res. 2014;15:154. 17. Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175(7):705 711. 18. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol. 1994;18(2):136 147. 19. Katzenstein AL, Myers JL. Nonspecific interstitial pneumonia and the other idiopathic interstitial pneumonias: classification and diagnostic criteria. Am J Surg Pathol. 2000;24(1):1 3. 20. Poletti V, Romagnoli M, Piciucchi S, Chilosi M. Current status of idiopathic nonspecific interstitial pneumonia. Semin Respir Crit Care Med. 2012;33(5):440 449. 21. 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(1):251 259. 22. Screaton NJ, Hiorns MP, Lee KS, et al. Serial high resolution CT in nonspecific interstitial pneumonia: prognostic value of the initial pattern. Clin Radiol. 2005;60(1):96 104. 23. Katzenstein AL. Smoking-related interstitial fibrosis (SRIF): pathologic findings and distinction from other chronic fibrosing lung diseases. J Clin Pathol. 2013;66(10):882 887. 24. Fischer A, Antoniou K, Brown K, et al; ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD. An Official European Respiratory Society/ American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015;46(4):976 987. 25. Romagnoli M, Nannini C, Piciucchi S, et al. Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders? Eur Respir J. 2011;38(2):384 391. 26. Travis WD, Hunninghake G, King TE Jr, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project [published correction appears in Am J Respir Crit Care Med. 2008;178(2): 211]. Am J Respir Crit Care Med. 2008;177(12):1338 1347. 27. Kuranishi LT, Leslie KO, Ferreira RG, et al. Airway-centered interstitial fibrosis: etiology, clinical findings and prognosis. Respir Res. 2015;16:55. 28. de Carvalho ME, Kairalla RA, Capelozzi VL, Deheinzelin D, do Nascimento Saldiva PH, de Carvalho CR. Centrilobular fibrosis: a novel histological pattern of idiopathic interstitial pneumonia. Pathol Res Pract. 2002; 198(9):577 583. 29. Yousem SA, Dacic S. Idiopathic bronchiolocentric interstitial pneumonia. Mod Pathol. 2002;15(11):1148 1153. 30. Fukuoka J, Leslie KO. Chronic diffuse lung diseases. In: Leslie KO, Wick MR, eds. Practical Pulmonary Pathology. 2nd ed. Philadelphia, PA: Elsevier; 2011:213 276. 31. DeVault KR, Castell DO; American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005;100(1):190 200. 32. Homma Y, Ohtsuka Y, Tanimura K, et al. Can interstitial pneumonia as the sole presentation of collagen vascular diseases be differentiated from idiopathic interstitial pneumonia? Respiration. 1995;62(5):248 251. 33. du Bois R, King TE Jr. Challenges in pulmonary fibrosis 3 5: the NSIP/UIP debate. Thorax. 2007;62(11):1008 1012. 34. Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001; 164(9):1722 1727. CAP16 Abstract Program Submission Dates Announced Abstract and case study submissions to the College of American Pathologists (CAP) 2016 Abstract Program will be accepted beginning on Friday, January 8 through 5 p.m. Central time Friday, March 11, 2016. Accepted submissions will appear on the Archives of Pathology & Laboratory Medicine Web site as a Web-only supplement to the September 2016 issue. The CAP16 meeting will be held from September 25 to 28 in Las Vegas, Nevada. Visit the CAP16 Web site (www.cap.org/cap16) for additional abstract program information as it becomes available. Arch Pathol Lab Med Vol 140, March 2016 Update on Pulmonary Fibrosis Smith 229