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Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally.

Surgical lung biopsies are often performed for the evaluation of suspected pulmonary fibrosis identified radiologically. There are 3 distinctive pathologic patterns of pulmonary fibrosis, including usual interstitial pneumonia (UIP), fibrotic nonspecific interstitial pneumonia (fNSIP), and airway-centered fibrosis (ACF). Their distinctive histology is primarily based on the distribution of the fibrosis (diffuse versus patchy) as well as the anatomic location of the fibrosis (subpleural/paraseptal versus interstitial versus 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.

This review is designed to provide an overview of the pathologic definitions, clinical and radiographic presentations, etiologies and differential diagnoses, treatments, and prognoses of these 3 pathologic forms of fibrosis. Pathologic challenges and controversies related to fibrosing interstitial lung diseases are reviewed in the discussion.

THE PATHOLOGIC UIP PATTERN

Pathologic Definition

The UIP pattern was first described in 1969 as a common form of pulmonary fibrosis occurring in older adults. (1) In the initial description, Liebow and Carrington (1) estimated approximately 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.

In 2011, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association issued a joint statement (3) revising the definition of the pathologic UIP pattern. They proposed that the UIP pattern should show marked fibrosis and architectural distortion (with or without honeycombing) in a predominantly subpleural and paraseptal distribution, patchy involvement of lung parenchyma by fibrosis, fibroblast foci, and the absence of features against a diagnosis of UIP suggesting an alternate diagnosis (hyaline membranes, organizing pneumonia, granulomas, marked interstitial inflammatory cell infiltrate away from honeycombing, predominant airway-centered changes, and other features of an alternate diagnosis) (Table 1; Figure 2, A and B). In addition, the consensus statement defined other pathology patterns along the spectrum of UIP that relay the "likelihood" of an IPF diagnosis, including a probable UIP pattern, a possible 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 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, Take-mura et al (7) identified granulomas, giant cells, organizing pneumonia, bridging fibrosis, lymphocytic alveolitis, lymphoid follicles, centrilobular fibrosis, and bronchiolitis as 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 UIP-pattern 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 middle-aged 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 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 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, Sjogren 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 less-involved 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, ErdheimChester 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, 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.

Please Note: Illustration(s) are not available due to copyright restrictions.

References

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(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.

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(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.

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Accepted for publication March 29, 2015.

From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona.

The author has no relevant financial interest in the products or companies described in this article.

Presented in part at the biennial meeting of the Pulmonary Pathology Society; June 3, 2015; San Francisco, California.

Reprints: Maxwell L. Smith, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259 (email: smith.maxwell@mayo.edu).

Caption: 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).

Caption: 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 X20 [A] and X100 [B]).

Caption: 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 X12.5 [A, C, and D], X200 [insets], and X100 [B]).

Caption: 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 X20 [A] and X100 [B]).

Caption: 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 X20 [A] and X100 [B]).
Table 1. Diagnostic Features and Differential
Diagnosis for the Different Patterns of Pulmonary
Fibrosis

Fibrosis Pattern       Diagnostic Features    Potential Etiologies

Usual interstitial     * Evidence of marked   * Idiopathic
pneumonia pattern      fibrosis/              pulmonary fibrosis
(3)                    architectural
                       distortion, with or    * Connective tissue
                       without honeycombing   disease associated
                       in a predominantly
                       subpleural/            * Chronic
                       paraseptal             hypersensitivity
                       distribution           pneumonitis

                       * Presence of patchy   * Pneumoconioses
                       involvement of lung
                       parenchyma by
                       fibrosis

                       * Presence of
                       fibroblast foci

                       * Absence of
                       features against a
                       diagnosis of usual
                       interstitial
                       pneumonia suggesting
                       an alternate
                       diagnosis

Fibrotic nonspecific   * Uniform              * Connective tissue
interstitial           interstitial           disease associated
pneumonia pattern      fibrosis, extending
(2,18)                 from the airway to     * Chronic
                       the pleura/septum,     hypersensitivity
                       with an even           pneumonitis
                       distribution

                       * With or without an   * Adverse drug
                       associated             reaction
                       inflammatory cell
                       infiltrate             * Infection

                       * Absence of           * Immunodeficiency
                       temporal and           diseases
                       geographic
                       heterogeneity          * Healed acute lung
                                              injury

                       * Absence of           * Smoking-related
                       microscopic            interstitial
                       honeycomb remodeling   fibrosis
                       and fibroblast foci
                       (more often then
                       not)                   * Idiopathic
                                              fibrotic nonspecific
                                              interstitial
                                              pneumonia

Airway-centered        * Presence of          * Chronic
fibrosis (27)          interstitial           hypersensitivity
                       fibrosis centered      pneumonitis
                       and extending around
                       the bronchioles        * Chronic aspiration

                       * Presence of          * Adverse drug
                       bronchiolar            reaction
                       inflammation
                                              * Connective tissue
                                              disease associated

                       * Presence of          * Smoking/other
                       bronchiolar            inhalational
                       metaplasia of the
                       epithelium             * Chronic/recurrent
                                              infection

                                              * Chronic allograft
                                              rejection

                                              * Potential
                                              idiopathic disease

Other rare,            * Other fibrosis       * Sarcoidosis/
fibrosing lung         patterns not fitting   berylliosis
diseases               well into the above
                                              * Immunoglobulin G4-
                                              related disease

                                              * Erdheim-Chester
                                              disease

                                              * Hermansky-Pudlak
                                              syndrome

                                              * Idiopathic
                                              pleuroparenchymal
                                              fibroelastosis

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                     +++           +           +
Fibrotic NSIP pattern            -           +++          +
ACF                              -            +          +++
Fibroblast foci                 +++           +           +
Microscopic honeycomb           +++           +           +
  remodeling
Normal areas                     +        [+ or -]     [+ or -]
Hyaline membranes             [+ or -]        +           -
Organizing pneumonia          [+ or -]        +           +
Granulomas                       -        [+ or -]        +
Peribronchiolar metaplasia    [+ or -]    [+ or -]        +
Marked interstitial
  inflammatory cell
infiltrate away from             -            +           +
  honeycombing
Predominant airway centered
inflammation                     -        [+ or -]       +++
Chronic pleuritis                -           +++          -
Lymphoid aggregates              -            +           +
Bridging fibrosis                -        [+ or -]        +
Plasma cells                     -            +           +
Chronic bronchiolitis            -            +           +
Cellular or fibrotic             -           +++          +
  NSIP-like areas
Multiple patterns on             -            +        [+ or -]
 the same biopsy

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) +++, hallmark feature; +, present; [+ or -],
variable; -, absent.
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Author:Smith, Maxwell L.
Publication:Archives of Pathology & Laboratory Medicine
Date:Mar 1, 2016
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