Diagnostic Approach to Advanced Fibrotic Interstitial Lung Disease: Bringing Together Clinical, Radiologic, and Histologic Clues.
In the lung, repeated injury to the delicate alveolar parenchyma may lead to progressive interstitial fibrosis, and lung fibrosis is a cardinal feature of a variety of diseases. Regardless of the underlying etiology, in humans fibrosis generally is an irreversible change of state. Significant pulmonary fibrosis compromises respiratory function and, if the injury continues with progressive accrual of fibrosis, death eventuates from respiratory failure and its complications. A patient presenting with clinical and radiographic evidence of advanced pulmonary fibrosis will often undergo surgical lung biopsy in the hopes of identifying a treatable or preventable cause of fibrosis, especially when the imaging findings are of a mixed pattern or are otherwise nondiagnostic. (1,2) It therefore behooves the pathologist to know the various causes thereof and to be familiar with the features that can enable their distinction, because accurate and timely diagnosis can have a profound impact on prognosis, treatment, and outcome for at least some of these patients and their family members. Nevertheless, surgical lung biopsies pose special challenges for the general surgical pathologist, and these challenges are compounded by the infrequency of these specimens in general practice and high clinical expectations for actionable diagnostic information derived from there.
In this review, we present an algorithmic approach to evaluating the surgical lung biopsy specimen for advanced fibrotic interstitial lung disease (ILD), emphasizing the clinical, radiologic, and histopathologic clues (summarized in Tables 1 and 2) that can aid the pathologist in distinguishing various entities from each other and establishing an accurate diagnosis. Idiopathic pulmonary fibrosis (IPF), connective tissue disease (CTD)-associated ILD, and chronic hypersensitivity pneumonitis are the most common entities encountered, and each is discussed in detail. Numerous less common and rare entities are also discussed, including idiopathic nonspecific interstitial pneumonia (NSIP), advanced pulmonary Langerhans cell histiocytosis (PLCH) and smokingrelated interstitial fibrosis, end-stage pulmonary sarcoidosis, Erdheim-Chester disease (ECD), and Hermansky-Pudlak syndrome. Lastly, asbestosis, fibrosing drug reactions, and immunoglobulin G4 (IgG4)-related disease are briefly presented. Each of these entities may be encountered by clinicians as idiopathic lung fibrosis, and the pathologist may be the first person to suggest the correct diagnosis.
IDIOPATHIC PULMONARY FIBROSIS
Idiopathic pulmonary fibrosis is an ILD of unknown etiology that usually presents in adults older than 60 years and results in relentless progressive lung destruction with fibrosis. (2,3) Microscopically, IPF displays a regionally and temporally variegated pattern of peripherally accentuated fibrosis that has been termed usual interstitial pneumonia (UIP), typically with numerous subepithelial foci of ongoing fibroblastic proliferation (so-called fibroblast foci; Figure 1). This UIP pattern in IPF is recapitulated on the macroscopic level and is visible radiographically as peripherally accentuated interstitial fibrosis with lower lobe predominance, traction bronchiectasis, and honeycombing. Idiopathic pulmonary fibrosis is an important diagnosis to make because the prognosis is significantly worse for patients with IPF than other fibrotic ILDs, with a median survival of less than 3 years, (4) rivaling the poor survival of many malignancies. Accurate diagnosis of IPF has become even more critical in the last few years, with the recognition of the adverse effects of prednisone, azathioprine, and N-acetylcysteine triple therapy in IPF, (5) and US Food and Drug Administration approval in 2014 of the targeted antifibrotic agents pirfenidone and nintedanib that slow disease progression in IPF. (6,7) It should be remembered, however, that IPF is not the only disease that can result in advanced lung fibrosis, even in elderly patients. Worldwide, CTD-associated ILD and chronic hypersensitivity pneumonitis are probably individually more common than IPF, and even in the United States these conditions are reasonably common and often underrecognized.
The familial form of IPF has been excluded from this discussion because several reviews about it have been published recently. (8,9)
Pulmonary fibrosis is a well-recognized complication of systemic CTDs that may result in significant morbidity and mortality. The most common CTDs associated with ILD include rheumatoid arthritis (RA), progressive systemic sclerosis, systemic lupus erythematosus, polymyositis-dermatomyositis, and Sjogren syndrome. (10) These CTDs are characterized by an exaggerated immune response to autoantigens, a response that can progressively destroy the pulmonary parenchyma. Although all may cause fibrosis, some cause a UIP pattern of fibrosis more commonly than others. Of the 5 most common CTDs listed above, RA is the prototypic CTD that causes a UIP pattern. The others more commonly present with an NSlP pattern of fibrosis, (11) characterized by diffuse and uniform alveolar septal fibrosis. However, it should be kept in mind that the pleuropulmonary manifestations of these disorders overlap, and either pattern of fibrosis can be seen with any of them. (11,12) Ultimately, the pattern of clinical disease and the serologic abnormalities that are present are crucial in establishing the correct rheumatologic diagnosis.
When an NSIP pattern is encountered radiologically and/or pathologically but no etiology can be established, a clinicopathologic diagnosis of "idiopathic NSIP" is used and is an officially recognized type of idiopathic interstitial pneumonia, (13) although from a practical standpoint, an underlying undifferentiated or evolving form of CTD is often suspected, even when an etiology cannot be identified. Many patients with an idiopathic interstitial pneumonia have clinical, radiologic, and/ or pathologic features that suggest an underlying CTD but do not meet established criteria for a specific CTD diagnosis. These patients remain a diverse and poorly understood group. Recently, the term interstitial pneumonia with autoimmune features (IPAF) was proposed by international consensus as a designation for such patients, to facilitate future research investigations on this challenging group. (14)
Presenting symptoms vary depending on the form of CTD that is present. It should be remembered that the lung can be the site of initial involvement or sole involvement in an evolving CTD; for example, although joint disease usually precedes the onset of pulmonary symptoms in patients with RA, occasionally patients present initially with lung disease, before developing joint symptoms. (15) The reported frequency of significant ILD in patients with RA is 14%, but evidence of subclinical lung disease can be identified in almost half of patients with RA. (16) Although RA more commonly is seen in women, men with RA are 3 times more likely to develop ILD. (17) In CTD-associated ILD, symptoms are generally nonspecific, including shortness of breath and cough. Prognosis depends on the extent of pulmonary disease, but development of a UIP pattern of fibrosis has a significant negative impact on prognosis, (18) with at least some studies showing poor survival rates approaching that of the UIP pattern occurring in the setting of IPF. (19) Treatment mainstays include steroids and immunosuppression. When medical therapies fail and progression to end-stage lung disease occurs, lung transplantation may be the only viable treatment option.
Connective tissue disease-associated ILD may present with several radiologic patterns of fibrotic lung disease on high-resolution computed tomographic (HRCT) imaging, the most common of which are UIP and NSIP. (18) A definitive diagnosis of the UIP pattern on HRCT may be made when 4 criteria are met: (1) subpleural, basilar predominance of findings; (2) presence of reticular abnormalities; (3) presence of honeycombing; and (4) absence of features inconsistent with a UIP pattern, including extensive ground-glass abnormalities, profuse micronodules, discrete cysts, diffuse mosaic perfusion/air trapping, and segmental/lobar consolidation. Radiologically, the UIP pattern in CTD-associated ILD (Figure 2, A) is indistinguishable from IPF and requires correlation with clinical and pathologic findings.
Connective tissue disease-associated ILD may also present with a pattern of NSIP on HRCT (Figure 2, B). Similar to the UIP radiologic pattern, the NSIP pattern is also typically subpleural/basilar predominant and shows findings of fibrosis, including irregular reticulation, traction bronchiectasis, and honeycombing, although several differences also occur. Subpleural sparing is seen almost exclusively with the NSIP radiologic pattern, (20) wherein the abnormalities may be extensive and even peripherally distributed but the lung immediately deep to the pleura is not as severely affected. Honeycombing may be seen with the NSIP pattern but is usually limited in extent, as opposed to the UIP pattern, in which honeycombing is often more extensive. Ground-glass opacity in the absence of reticulation favors the NSIP pattern. (21) When HRCT findings are compatible with the NSIP pattern, particularly in the appropriate clinical setting, a diagnosis of CTD-associated ILD or interstitial pneumonia with autoimmune features may be favored over IPF, but it should be remembered that HRCT is still relatively unreliable for consistently separating the UIP and NSIP patterns, (22,23) and correlation with pathologic findings is often still required to confidently distinguish them.
Patients with CTD who develop pulmonary fibrosis will often show a UIP pattern on a surgical lung biopsy, mimicking the UIP pattern of IPF, especially patients with RA. Despite their similarities, the UIP pattern of CTD and the UIP pattern of IPF show several histologic differences (Figure 2, C through H) that can enable their distinction. (10-12,24) At low magnification, RA-associated ILD often shows a mixed pattern of fibrosis that is difficult to classify as either UIP or NSIP, with both patterns represented in the biopsy. Even when the fibrosis is patchy and heterogeneous, in our experience, the boundary between fibrotic areas and preserved parenchyma in RA-associated ILD tends to be indistinct and ill defined, unlike the UIP pattern of IPF, where the boundary between fibrosis and normal parenchyma is often sharp and well defined. Prominent lymphoid hyperplasia should always prompt consideration of CTD-associated ILD, particularly when germinal center formation is seen. Lymphoid aggregates will often be prominent around airways but can also be present in areas of fibrosis and also in the pleura, the latter being a particularly useful clue. Pleural adhesions suggest a previous bout of pleuritis, even if pleural inflammation is absent in the biopsy, and it should be remembered that pleuritis is a characteristic pleuropulmonary manifestation of CTD. (10) Rheumatoid nodules are very helpful when present, but they are uncommon.
Other patients with CTD who develop advanced pulmonary fibrosis will show an NSIP pattern on a surgical lung biopsy, especially patients with progressive systemic sclerosis, systemic lupus erythematosus, polymyositis-dermatomyositis, and Sjogren syndrome. (11) The NSIP histologic pattern is characterized by relatively uniform alveolar thickening by a chronic inflammatory cell infiltrate, and mild to moderate fibrosis. Although the extent of changes can vary along a spectrum ranging from more cellular to more fibrotic ("cellular NSIP" and "fibrotic NSIP"), the pulmonary architecture is relatively preserved. One of the more common diagnostic challenges in pulmonary pathology is the distinction between the UIP pattern and the NSIP pattern, particularly when fibrosis is more advanced and cellular infiltrates are less prominent. In such instances, the most helpful distinguishing feature is the presence of diffusely abnormal alveolar septa in the NSIP pattern; in the UIP pattern, areas of completely normal, preserved parenchyma should still be present. It should be remembered that honeycombing and fibroblast foci can occasionally be seen with an NSIP pattern.
Although distinction between CTD-associated ILD and other causes of advanced fibrosis may not be possible in all cases by histology alone, a UIP or "UIP-like" pattern with one or more of the above clues, or an NSIP pattern should prompt consideration of CTD-associated ILD and performance of comprehensive serologic testing, if not done previously. Ultimately, diagnosis of CTD-associated ILD requires correlation of clinical and laboratory findings. In patients with suggestive findings but insufficient diagnostic features for a specific type of CTD, a clinicopathologic designation of interstitial pneumonia with autoimmune features may be appropriate, although the significance of and treatment for this newly proposed term remain unknown.
CHRONIC HYPERSENSITIVITY PNEUMONITIS
Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is an inflammatory lung disorder caused by an exaggerated immune response to the inhalation of a variety of organic antigenic particles found in the environment. (25) The antigens may be fungal, bacterial, protozoal, or animal (typically avian) proteins, or low-molecular weight chemical compounds. Hypersensitivity pneumonitis may potentially arise in any work or home environment where bacteria and fungi grow or birds are kept. Regardless of the antigenic stimulus, the ensuing inflammatory response can destroy the delicate pulmonary parenchyma and, over time, may culminate in dense fibrosis that mimics the UIP pattern of IPF.
Classically, HP has been classified into acute, subacute, and chronic forms, although this classification scheme is problematic because the definition of and criteria for subacute HP are not agreed upon, and distinction between subacute and chronic disease on clinical or radiologic grounds is not always possible. (26,27) One alternative classification scheme (and the one we prefer) is as follows (26,28): (1) acute (or episodic) HP; (2) chronic HP with superimposed acute episodes; and (3) chronic HP without apparent acute episodes. The chronic forms of HP are thought to result from continuous, low-level exposure to organic antigens, with superimposed acute episodes resulting from brief higher-level antigen exposures. In contrast with acute HP, chronic forms of HP are insidious, showing a more gradual onset and often a progressive course, resulting in pulmonary fibrosis. When findings indicative of fibrosis are found on HRCT imaging, the survival is poor. (29,30)
The clinical presentation varies in HP and is determined by the frequency and intensity of antigen exposure. With chronic disease, there is a gradual onset of exertional dyspnea, fatigue, cough, sputum production, anorexia, and weight loss, which may be substantial. Interestingly, smokers have a lower likelihood of developing HP compared with nonsmokers, but when disease occurs in smokers it appears to be more severe and chronic. (25) In chronic HP, bibasilar crackles are typically audible by lung auscultation, and finger clubbing may be present. A rather unique clinical finding in chronic HP, in contrast to other fibrotic lung diseases, is the presence of inspiratory squeaks, which are caused by coexisting bronchiolitis. Pulmonary function tests characteristically demonstrate restriction, often with decreased diffusing capacity and hypoxemia during exercise. An elevated FEV1:FVC ratio indicates a poorer survival. (29,30)
Bronchioloalveolar lavage fluid analysis can provide supportive evidence for a diagnosis of chronic HP in certain circumstances. An elevated percentage of lymphocytes in bronchioloalveolar lavage fluid (usually more than 50%) is characteristic of HP, especially during acute episodes, but this finding is nonspecific and is often absent in chronic HP or in smokers, and therefore routine evaluation of the CD4:CD8 lymphocyte ratio in bronchioloalveolar lavage fluid is not recommended. (31)
Diagnosis of chronic HP requires careful correlation of clinical, radiologic, and pathologic findings, and is supported by (1) evidence of exposure to and/or specific antibodies against a specific offending antigen; (2) clinical behavior of chronic ILD; (3) restrictive pulmonary physiology plus hypoxemia and reduced carbon monoxide diffusing capacity; (4) bronchioloalveolar lavage fluid lymphocytosis (when present); (5) radiologic findings compatible with HP, as outlined below; and (6) a lung biopsy, if there is insufficient evidence for diagnosis.
On HRCT, chronic HP shows signs of fibrosis, including irregular reticulation, traction bronchiectasis, and honeycombing. Chronic HP has several imaging features that can help to distinguish it from IPF and other causes of fibrotic lung disease. The most important of these is the coexistence of airway obstruction. Airway obstruction on inspiratory HRCT is manifested by mosaic perfusion, with geographic lobular regions of lung that are decreased in attenuation (ie, too dark). Mosaic perfusion will correspond to regions of air trapping on expiratory images. When a combination of fibrosis and significant mosaic perfusion or air trapping is present (Figure 3, A), chronic HP is a very likely diagnosis. (20) In addition, chronic HP will typically show a different distribution pattern in the lung compared with IPF, usually sparing the lung bases (best appreciated when HRCT is viewed in the craniocaudal plane), unlike IPF, which shows a strong subpleural and basilar predominance, although exceptions do occur. In the axial plane, chronic HP will generally not be subpleural predominant, but instead will show significant involvement of the central lung.
Hypersensitivity pneumonitis is an airway-centered process that is characterized microscopically by a triad of airway-centered pathologic features, including peribronchiolar interstitial pneumonia, peribronchiolar giant cells and poorly formed granulomas, and chronic bronchiolitis. (32,33) Over time, chronic inflammatory injury results in considerable fibrosis that may resemble the UIP pattern of IPF (34) and is sometimes indistinguishable from the latter. (35) In other cases, an NSIP pattern may be seen. In many cases, however, subtle histologic clues (Figure 3, B through D) can suggest the correct diagnosis. This distinction is important because subsequent discovery of an inhaled antigen (and removal thereof) could potentially halt progression of the disease in some patients. In our experience, the pathologist is often the first to suggest a diagnosis of chronic HP, or is the impetus for reconsider ation of the diagnosis, prompting a more exhaustive (and sometimes successful) search for offending antigens.
Several histologic clues should prompt consideration of chronic HP in the differential diagnosis of fibrotic ILD. (34,36,37) Centrilobular or airway-centered accentuation of fibrosis is an important diagnostic clue suggesting chronic HP, even when this finding is focal or when an airway cannot be readily identified. When accompanied by peribronchiolar metaplasia, centrilobular fibrosis strongly suggests prior small airway injury, perhaps due to chronic HP, and a careful search for residual granulomas or giant cells should be undertaken. Although chronic HP is not the only condition that shows airway-centered fibrosis, (38) recognition of bronchiolocentricity in a case of advanced fibrosis should always prompt consideration of chronic HP. As with other ILDs, diagnosis usually requires correlation with clinical and radiologic findings, and multidisciplinary discussion can be extremely helpful.
Pulmonary Langerhans cell histiocytosis is an isolated form of Langerhans cell histiocytosis that occurs primarily in cigarette smokers. The disease has no known incidence or prevalence in the smoking population, despite a very large number of isolated case reports and several large case series (39-42) describing the expected clinical, radiologic, and histopathologic attributes of the disease. Pulmonary Langerhans cell histiocytosis is characterized by a spectrum of airway-centered lesions containing variable numbers of Langerhans cells, a form of histiocytic antigen-presenting cell. (43) The initial lesion is dominated by the collection of abundant Langerhans cells and has a nodular configuration on imaging and histopathologic examination. With time, the lesions become stellate in profile and less cellular. At this chronic stage, discrete fibrotic lesions dominate the histopathology, frequently attended by tractional dilation of nearby airspaces. It is this late "phase" of the disease that may be mistaken for other forms of advanced pulmonary fibrosis, including the UIP pattern of IPF. Thankfully, only a minority of individuals with this ILD progress to end-stage fibrosis, and it is this uncommon manifestation of PLCH that will be explored in this review. For a detailed overview of the entire disease, the reader is referred to several excellent reviews on the topic. (44-46)
Most of the available data on PLCH are derived from patients with the nodular and cystic forms of the disease (presumed to be "earlier" disease manifestations), and data on PLCH with significant fibrosis are limited to case reports and a few small studies. (41,47) From these limited reports, severe dyspnea appears to be a nearly universal symptom of advanced PLCH, often with a marked reduction in carbon monoxide diffusing capacity, and either purely obstructive or mixed obstructive and restrictive physiology. Pulmonary hypertension is associated with increased morbidity and mortality and is almost universally present in advanced disease. (42) The prognosis for patients with earlier-stage PLCH is generally good, with smoking cessation being the main treatment strategy despite no (or low-quality) evidence that this has any measurable effect on the disease. (48) Once advanced fibrosis ensues, no medical intervention has proven beneficial, and lung transplantation remains the only viable treatment option. (47)
The HRCT findings of PLCH, in most cases, are easily distinguished from IPF. The most common radiologic findings in PLCH are cysts and nodules. (49) Cysts in PLCH can potentially be confused with honeycombing in IPF. Both are air density abnormalities that are circular in shape; however, there are distinguishing features. The cysts of PLCH are central in location, may be thin walled or thick walled, and are often irregular or bizarrely shaped (Figure 4, A). The cysts of honeycombing in IPF are subpleural in location, clustered or stacked, and demonstrate smooth oval walls. Nodules in PLCH are either ill defined or well defined and may have lucent centers. Profuse nodules should not be seen in IPF. In advanced PLCH, imaging studies may demonstrate an "inverted UIP" radiologic appearance with significant centrilobular fibrosis, a helpful clue that distinguishes PLCH from the peripherally accentuated fibrosis of IPF.
In its earlier stages, PLCH is characterized by multiple nodular aggregates of Langerhans-type histiocytes within the pulmonary interstitium, often with abundant eosinophils and usually associated with small airways. (50) These Langerhans cells are characterized by their abundant eosinophilic cytoplasm, reniform nuclei, and distinctive immunophenotype (positive for CD68, CD1a, langerin, and sometimes S100 protein). (51,52) In older "burned-out" PLCH lesions, the histiocytic and inflammatory infiltrates regress almost entirely and are replaced by dense fibrosis that often shows a characteristic stellate or starfishlike shape.
In occasional advanced cases of PLCH, the fibrotic lesions can become quite extensive and confluent, producing an appearance that may be confused with other fibrotic interstitial diseases, including the UIP pattern of IPF. Despite the paucity of lesional cells, advanced PLCH can usually be distinguished from the UIP pattern of IPF on morphologic grounds. (50,53) Identification of stellate-shaped fibrotic areas (Figure 4, B through D) can be an important clue. Unlike the UIP pattern of IPF, the pleura and subpleural parenchyma may be relatively spared in advanced PLCH, with fibrosis tending to be more prominent in the center of the lobule.
Given the strong association of PLCH with cigarette smoking, the presence of other chronic smoking-related changes in advanced PLCH is not surprising, and these additional findings can both aid and hinder recognition of PLCH. Respiratory bronchiolitis and desquamative interstitial pneumonia-like changes are almost universally present in PLCH, (54) characterized by accumulation of abundant lightly pigmented macrophages in alveolar spaces and a variable degree of interstitial fibrosis. So-called smoking-related interstitial fibrosis may also be present in cases of PLCH, and in our experience it can even overshadow the fibrotic, stellate lesions of "burned-out" PLCH in some cases.
Smoking-related interstitial fibrosis is a recently coined term to describe a common, histologically distinctive pattern of interstitial fibrosis in smokers that is characterized by marked and relatively uniform thickening of alveolar septa by dense, hyalinized, and relatively hypocellular fibrosis, usually most prominent in the subpleural zone, with associated emphysema and respiratory bronchiolitis. (55,56) In some cases, distinction from the fibrotic NSIP pattern may be challenging, but the fibrosis of NSIP is composed of looser collagen, rather than the dense hyalinized collagen of smoking-related interstitial fibrosis, and usually has at least a few chronic inflammatory cells present. Fibrotic NSIP is also more diffusely distributed and is not associated with the stellate fibrotic lesions of PLCH.
ADVANCED PULMONARY SARCOIDOSIS
Sarcoidosis is a systemic granulomatous inflammatory disorder of unknown etiology that preferentially affects the lungs. This disorder most frequently presents in adolescence or early adulthood, with 70% to 90% of cases occurring between 10 and 40 years of age. The lungs are involved in more than 90% of cases, but sarcoidosis may also involve almost any extrapulmonary site, including the heart, skin, eyes, upper respiratory tract, musculoskeletal system, exocrine glands, kidneys, central nervous system, and others, depending on the patient's sex, race, and age. (57) Although most cases resolve spontaneously or with treatment, it has been estimated that about 5% of patients with pulmonary sarcoidosis will develop significant progressive fibrosis, (58-60) a situation that may mimic IPF.
Clinical symptoms of end-stage pulmonary sarcoidosis are nonspecific but generally include shortness of breath, dyspnea on exertion, and/or cough. Nearly half of patients will also show evidence of extrapulmonary disease, (61) a potentially helpful feature to distinguish sarcoidosis from IPF if involvement of another site is recognized clinically. Pulmonary function tests are nonspecific, often showing either a pure restrictive pattern or a mixed restrictive and obstructive pattern, usually with reduced diffusing capacity. The prognosis of end-stage sarcoidosis is poor, with a median survival of less than 2 years, and is particularly grim for patients with concomitant pulmonary hypertension. (61) Treatment strategies for advanced pulmonary sarcoidosis include steroids as well as immunosuppressive agents in refractory cases and possibly agents to combat pulmonary hypertension, although these approaches remain controversial, with no specific guidelines. (62) In the end, lung transplantation may be the only viable option in some patients. (60,62)
As with the other disorders discussed above, the HRCT findings of end-stage sarcoidosis can show overlap with IPF, including irregular reticulation, traction bronchiectasis, and honeycombing. (63) The distribution of findings in sarcoidosis is an important distinguishing feature (Figure 5, A and B) from IPF. Sarcoidosis usually shows a strong upper lobe and peribronchovascular distribution of findings on HRCT. (64) Consolidative masses of fibrosis, resembling progressive massive fibrosis, are not uncommon with sarcoidosis but are rare in IPF. Perilymphatic nodules may be seen in association with findings of fibrosis in sarcoidosis when both active granulomatous disease and scarring are present.
In its earlier stages, pulmonary sarcoidosis is characterized microscopically by the presence of well-formed, usually nonnecrotizing granulomas that display a lymphangitic distribution along the pleura, interlobular septa, and bronchovascular bundles. (65-67) With progression of the disease, granulomas become confluent and coalescent with associated fibrosis, and in time the granulomatous infiltrates regress and are replaced by broad areas of dense, paucicellular hyalinized or elastotic fibrosis that can mimic the UIP pattern of IPF. Thankfully, several histopathologic features (Figure 5, C and D) can aid in the distinction between end-stage sarcoidosis and IPF. (68) Although peripheral fibrosis may be seen in end-stage sarcoidosis as well as the UIP pattern of IPF, prominent centrilobular, lymphangitic, or masslike areas of fibrosis are more characteristic of sarcoidosis. The presence of residual granulomas or giant cells embedded within the dense fibrotic areas, even if only focal, should raise suspicion for sarcoidosis. Honeycombing and bronchiolectasis may be present in the fibrotic areas, but these findings are generally central in distribution, unlike the subpleural distribution of honeycombing that is characteristic of the UIP pattern. Although rare fibroblast foci can occasionally be seen in sarcoidosis, (68) they are not a prominent feature.
Erdheim-Chester disease is a rare non-Langerhans histiocytosis, characterized by accumulation or proliferation of foamy histiocytes within long bones in nearly all cases. Concomitant involvement of extraskeletal sites is often present, including the lungs, where ECD produces a distinctive pattern of advanced fibrosis along lymphatic routes. Although ECD may occur at any age, it most commonly arises in middle-aged adults, with a slight male predominance, and does not appear to be a heritable genetic disorder. Its etiology remains unknown, but recent identification of V600E mutations in the BRAF gene in at least half of cases suggests that ECD may be a clonal neoplastic disorder. (69,70)
Symptoms and clinical course vary in ECD, depending on the sites of involvement, but they usually include juxta-articular pain in the legs due to multiple diaphyseal osteosclerotic lesions in the long bones that are almost always bilateral and symmetric. Almost all patients will also show involvement of at least 1 extraskeletal site, with the most common sites including the retroperitoneum (59%), heart (57%), lungs (46%), and central nervous system (41%). (71) Pulmonary consequences of ECD include cardiogenic pulmonary edema, secondary to cardiac involvement, or histiocytic infiltration of the lung parenchyma with interstitial fibrosis. Symptoms of pulmonary involvement by ECD are nonspecific, most commonly including progressive dyspnea and dry cough. (72)
Prognosis in ECD is variable, depending on the extent of disease, but is generally poor with cardiac, pulmonary, or central nervous system involvement. Treatment is usually reserved for those with visceral organ involvement and has traditionally included interferon [alpha], systemic chemotherapy, and/or glucocorticoids, with limited effectiveness. Recent identification of BRAF V600E mutations in ECD, and dramatic early results with the B-Raf inhibitor vemurafenib in a few patients, both suggest that a new treatment era for this enigmatic disease may be unfolding. (73)
Thickening of the interlobular septa (Figure 6, A) is the most common HRCT finding of ECD. (74) This thickening is smooth and identical to that seen with interstitial pulmonary edema or lymphangitic spread of tumor. Smooth interlobular septal thickening is easily distinguished from the irregular reticulation seen in IPF by its typical morphology. The usual signs of fibrosis, such as traction bronchiectasis, architectural distortion, and honeycombing, are usually absent in ECD. Ill-defined nodules, usually in a centrilobular distribution, may also be seen with ECD but should be absent in IPF.
Pulmonary involvement in ECD is characterized microscopically by interstitial accumulations of non-Langerhanstype histiocytes in a lymphangitic distribution pattern (Figure 6, B through D), typically with an abrupt, smooth interface with the adjacent uninvolved alveolar parenchyma. (75,76) These histiocytes are the cardinal feature of this disorder and are characteristically bland, with abundant lightly eosinophilic glassy cytoplasm, and they show a characteristic immunophenotype (positive for CD68 and factor XIIIa; variably positive for S100 protein; negative for CD1a). Scattered lymphocytes and Touton-type giant cells accompany the histiocytic infiltrate in many cases. Over time, significant fibrosis ensues along the involved areas of the pleura, interlobular septa, and bronchovascular bundles. Although this fibrosis is patchy, its distribution is strikingly lymphangitic, temporal heterogeneity is absent, and fibroblast foci are usually not seen. Recognition of its distinctive appearance at low magnification and its striking lymphangitic distribution pattern is the key to distinguishing ECD from the UIP pattern of IPF.
Originally described by Hermansky and Pudlak in 1959, (77) Hermansky-Pudlak Syndrome (HPS) is caused by a related group of autosomal recessive disorders that are characterized by the triad of oculocutaneous albinism, bleeding diathesis due to a platelet storage pool deficiency, and lysosomal accumulation of ceroid lipofuscin. (78) Currently, 9 distinct molecular subtypes of HPS are recognized (79); the most common form of HPS (type 1) is caused by a 16-bp duplication within the HPS1 gene on chromosome 10. (80) Pulmonary fibrosis is a significant and often lethal sequela of HPS that eventually develops in 100% of patients with HPS type 1 and also frequently occurs with HPS types 2 and 4.79 Most reported cases of HPS occur in northwest Puerto Rico, where its frequency is estimated at 1:1800, (81) although isolated cases of HPS in patients of non-Puerto Rican descent have been reported across the globe. (79)
Symptoms of pulmonary fibrosis in HPS are nonspecific, most commonly including nonproductive cough and exertional dyspnea. Patients usually show evidence of pulmonary fibrosis by the third or fourth decade of life, but anecdotal reports of significant pulmonary fibrosis by late adolescence have been made. (79) In the absence of lung transplantation, patients with pulmonary fibrosis usually die of their disease within a few years of diagnosis. Besides lung transplantation, no reliable treatments are available for pulmonary fibrosis in the setting of HPS, and results of recent trials with antifibrotic agents have been disappointing. (82,83)
The HRCT findings of HPS are not well described. Findings in one study included irregular septal thickening and reticulation, traction bronchiectasis (Figure 7, A), and subpleural cysts. (84) Ground-glass opacity is also often present. All of these findings may be seen in IPF. Approximately 40% of HPS patients with severe findings on HRCT show peribronchovascular thickening, a finding that is atypical for IPF, but additional studies are needed to determine which radiographic features, if any, can be used to reliably distinguish HPS from IPF.
Pulmonary involvement in HPS is characterized by accumulation of ceroid lipofuscin within the lung, manifested by the presence of clear, vacuolated, ceroid-laden type 2 pneumocytes and alveolar macrophages (Figure 7, B through D) that are typically found in a background of prominent interstitial fibrosis. (85) Unlike the characteristic peripheral and temporally heterogeneous pattern of fibrosis in the UIP pattern of IPF, the distribution of fibrosis in HPS is patchy, with no clear distribution pattern, and is therefore difficult to classify. Identification of abnormal ceroid-laden type 2 pneumocytes and alveolar macrophages is an important distinguishing histologic feature, and the presence of abundant clear or vacuolated cells in a case of fibrotic ILD should prompt consideration of HPS. Electron microscopy may be used to identify the characteristic intracytoplasmic giant lamellar bodies within type 2 pneumocytes and macrophages. (85) Alternatively, electron microscopy of whole mounted platelets is a reliable method to confirm a diagnosis of HPS, whereby the ultrastructural absence of platelet-dense bodies can be demonstrated. (86) Recently, confirmatory genetic testing of peripheral blood for several molecular subtypes of HPS has become commercially available.
OTHER DIAGNOSTIC CONSIDERATIONS
Several other uncommon disorders can cause advanced pulmonary fibrosis and should be included in the differential diagnosis in an appropriate clinical scenario, including asbestosis, fibrosing drug reactions, and IgG4-related disease.
Asbestosis is a pneumoconiosis caused by inhalational exposure to asbestosis fibers with development of pulmonary fibrosis. Clinically, patients present with nonspecific symptoms that overlap with those of other fibrotic ILDs. Imaging studies frequently show calcified pleural plaques, in addition to features of fibrotic ILD, a helpful clue that should prompt consideration of asbestosis. Histologically, the lung shows marked peribronchiolar fibrosis that in some cases may be extensive, simulating the UIP pattern. A careful search should reveal the culprit iron-encrusted asbestos fibers ("asbestos bodies") that are the hallmark of the disease, embedded within the fibrotic peribronchiolar interstitium and sometimes within alveolar spaces. (87,88) Iron stains can facilitate recognition of asbestos bodies in difficult cases. Pleural plaques may also be present, showing characteristic "basket-weave" hyalinized collagen, a finding that is not seen in the UIP pattern of IPF.
Adverse drug reactions can sometimes result in significant pulmonary fibrosis. Common medications associated with lung fibrosis include bleomycin, (89) methotrexate, (90) and even amiodarone, (91) although numerous others can also cause pulmonary fibrosis, and the list of pneumotoxic agents is long. (92) When fibrosis occurs, it may assume a UIP or NSIP pattern, closely mimicking other causes of fibrotic lung disease. Most histologic findings are nonspecific, although prominent interstitial eosinophils should prompt consideration of a drug reaction, and poorly formed nonnecrotizing granulomas and giant cells are helpful clues that suggest the possibility of methotrexate toxicity in the appropriate clinical setting. (93) Accurate diagnosis requires a high index of suspicion in combination with careful clinical correlation, including details of the specific drugs and dosages administered and the timing of administration as it relates to the onset of symptoms. Even so, diagnosis can be exceedingly challenging, particularly in the chronic fibrotic setting, when temporal correlations are no longer obvious.
IgG4-related disease is a multisystem fibroinflammatory disorder characterized by chronic tumefactive or infiltrative storiform fibrosis and heavy lymphoplasmacytic inflammation rich in IgG4-positive plasma cells, involving a single or several anatomic sites, often associated with an elevated serum IgG4 level. Recently, specific consensus criteria were established for diagnosis of this disorder in different anatomic sites. (94) This disorder may involve the lung, where its manifestations are diverse, (95) including fibroinflammatory reactions with a UIP or NSIP pattern. (96-99) Distinction from more common forms of CTD-associated ILD maybe difficult, and serologic overlap can occur. (96) Recognition of a dense lymphoplasmacytic inflammatory infiltrate should prompt consideration of the diagnosis and performance of IgG and IgG4 immunohistochemistry. The presence of characteristic extrapulmonary manifestations can be a helpful clue to establish the diagnosis, as can IgG4 serologic testing.
Advanced pulmonary fibrosis can be encountered not only in IPF, but also in several other diseases, including CTD-associated ILD, chronic HP, PLCH, end-stage pulmonary sarcoidosis, ECD, and HPS. Like IPF, these causes of pulmonary fibrosis may be encountered as clinically idiopathic disease, and it is important for pathologists to be familiar with them because the surgical lung biopsy may be the first suggestion of a diagnosis other than IPF. For many of these disorders, the importance of multidisciplinary discussion in the diagnostic process cannot be overemphasized. Accurate subclassification of advanced pulmonary fibrosis is not only important for prognosis but also for treatment, given the rapidly evolving treatment guidelines for IPF, including targeted antifibrotic agents and recommendations against immunosuppression. In addition, correct identification of other treatable or preventable causes of fibrosis facilitates therapeutic intervention to hopefully delay progression of fibrosis and improve outcomes for at least some patients. Diagnosis may also carry implications for patients' family members with a similar genetic background or similar environmental exposures. Lastly, subclassification into clinically meaningful and more biologically homogeneous cohorts will ensure appropriate enrollment into clinical trials and hopefully enable development of future therapies for this disparate group of devastating diseases.
Please Note: Illustration(s) are not available due to copyright restrictions.
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Brandon T. Larsen, MD, PhD; Maxwell L. Smith, MD; Brett M. Elicker, MD; Jessica M. Fernandez, MD; Guillermo A. Arbo-Oze de Morvil, MD; Carlos A. C. Pereira, MD; Kevin O. Leslie, MD
Accepted for publication August 2, 2016.
Published as an Early Online Release September 15, 2016.
From the Department of Laboratory Medicine & Pathology (Drs Larsen, Smith, and Leslie), Mayo Clinic, Scottsdale, Arizona; the Department of Radiology (Dr Elicker), University of California, San Francisco; Juan Max Boettner Hospital (Drs Fernandez and Arbo-Oze de Morvil), Asuncion, Paraguay; and the Department of Medicine (Dr Pereira), Federal University of Sao Paulo, Sao Paulo, Brazil.
The authors have no relevant financial interest in the products or companies described in this article.
Presented in part at the 3rd Princeton Integrated Pathology Symposium; May 14, 2016; Plainsboro, New Jersey.
Reprints: Brandon T. Larsen, MD, PhD, Department of Laboratory Medicine & Pathology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259 (email: firstname.lastname@example.org).
Caption: Figure 1. Idiopathic pulmonary fibrosis (IPF). A, High-resolution computed tomography of a patient with IPF shows a usual interstitial pneumonia (UIP) pattern as evidenced by subpleural, basilar-predominant honeycombing and reticulation. B, At scanning magnification, IPF shows a UIP pattern of advanced fibrosis that is accentuated in subpleural and paraseptal zones, with relatively sharp demarcation from adjacent uninvolved parenchyma. C, Smooth muscle metaplasia (arrow) is often prominent in areas of fibrosis, particularly in areas of microscopic honeycombing. D, Numerous active areas of subepithelial fibroblastic proliferation ("fibroblast foci"; arrows) are found at the interface between established fibrosis and uninvolved parenchyma (hematoxylin-eosin, original magnifications x20 [B], x100 [C], and x200 [D]).
Caption: Figure 2. Connective tissue disease-associated interstitial lung disease. A, Prone high-resolution computed tomography (HRCT) of a patient with rheumatoid arthritis shows a usual interstitial pneumonia (UIP) pattern that is indistinguishable from idiopathic pulmonary fibrosis (IPF; cf Figure 1, A). B, Other cases may show an HRCT pattern of nonspecific interstitial pneumonia (NSIP), with peripherally distributed irregular reticulation and traction bronchiectasis. Note the relative sparing of the immediate subpleural interstitium (arrows). A radiologic NSIP pattern favors connective tissue disease (CTD) rather than IPF but does not exclude the possibility that a UIP pattern will be seen in the biopsy. C, At scanning magnification, CTD may show a UIP pattern of fibrosis, although numerous lymphoid aggregates are also present, a helpful clue that argues against a diagnosis of IPF. D, In some cases, the pattern is difficult to classify, with some areas resembling UIP and other areas resembling NSIP. In our experience, demarcation from adjacent uninvolved parenchyma is often less distinct in CTD-associated interstitial lung disease than in the UIP pattern of IPF. E, Connective tissue disease can also present with a cellular NSIP pattern, with relatively uniform thickening of alveolar walls by fibrosis and chronic inflammatory cells. F, In other cases, a fibrotic NSIP pattern may be seen. When fibrosis becomes advanced, focal honeycombing may be seen, but the uniformly abnormal alveolar walls distinguish the fibrotic NSIP pattern from UIP, which would show areas of preserved, completely normal alveoli. G, Germinal center formation (arrows) should always prompt consideration of CTD. H, Fibrinous pleuritis (arrow) also suggests evolving CTD; the pleurae are generally uninvolved in IPF (hematoxylin-eosin, original magnifications x20 [C, D, and F] and x40 [E, G, and H]).
Caption: Figure 3. Chronic hypersensitivity pneumonitis. A, Fibrosis is present on high-resolution computed tomography as evidenced by traction bronchiectasis and irregular reticulation. The findings involve both the central and peripheral lung. Geographic areas of mosaic perfusion (ie, decreased lung density; arrows) are also present. These latter findings are strongly suggestive of chronic hypersensitivity pneumonitis (HP) rather than idiopathic pulmonary fibrosis (IPF). B, At scanning magnification, chronic HP may show a patchy usual interstitial pneumonia-like pattern of advanced fibrosis, although areas of centrilobular accentuation are also apparent, which would not be expected in IPF. C, Peribronchiolar metaplasia is often prominent, indicative of previous small airway injury D, Poorly formed, nonnecrotizing granulomas in the interstitium are characteristic (arrow) and often near small airways, favoring chronic HP and arguing against IPF (hematoxylin-eosin, original magnifications x20 [B], x100 [C], and x200 [D]).
Caption: Figure 4. Advanced pulmonary Langerhans cell histiocytosis. A, High-resolution computed tomography shows air-density cysts, predominating in the central lungs, some of which have irregular or bizarre shapes. Nodules (arrow) are also present. B, At scanning magnification, advanced pulmonary Langerhans cell histiocytosis shows patchy stellate-shaped areas of fibrosis, centered on bronchovascular bundles. C, Paucicellular, stellate-shaped fibrotic scars are accompanied by paracicatricial emphysema. Langerhans cells are markedly depleted or absent in mature lesions. D, In some cases, stellate scars of old pulmonary Langerhans cell histiocytosis (arrow) may be accompanied or even overshadowed by smoking-related interstitial fibrosis in the periphery of the lobule (hematoxylin-eosin, original magnifications x20 [B and D] and x40 [C]).
Caption: Figure 5. End-stage pulmonary sarcoidosis. High-resolution computed tomography through the (A) upper and (B) lower lungs shows an upper and central predominance of traction bronchiectasis and irregular reticulation. This distribution of findings would be distinctly unusual for idiopathic pulmonary fibrosis. C, At scanning magnification, end-stage pulmonary sarcoidosis shows advanced fibrosis that may mimic the usual interstitial pneumonia pattern of idiopathic pulmonary fibrosis. Recognition of the lymphangitic distribution pattern is an important clue. D, Residual giant cells or well-formed granulomas (arrow) are characteristic of end-stage sarcoidosis but may be scarce (hematoxylin-eosin, original magnifications x20 [C] and x100 [D]).
Caption: Figure 6. Erdheim-Chester disease. A, High-resolution computed tomography through the lung bases shows smooth symmetric interlobular septal thickening, a finding more commonly seen with edema and malignancy. Small cysts and nodules are also present. This picture is distinctly different than the usual interstitial pneumonia pattern of idiopathic pulmonary fibrosis. B, At scanning magnification, Erdheim-Chester disease shows advanced fibrosis, typically with an abrupt interface with the adjacent uninvolved parenchyma, but the lymphangitic distribution pattern is striking and distinctly different than the UIP pattern. C, Numerous pale eosinophilic or xanthomatous histiocytes infiltrate the interstitium of the involved fibrotic areas. D, Immunohistochemical staining for factor XIIIa is typically positive in the histiocytic infiltrate, as is that for CD68 (not shown), but stains for CD1a are negative (not shown) (hematoxylin-eosin, original magnifications x20 [B] and x400 [C]; original magnification x400 [D]).
Caption: Figure 7. Hermansky-Pudlak syndrome. A, High-resolution computed tomography shows patchy bilateral irregular reticulation, traction bronchiectasis, and cysts. The abnormalities differ from those of idiopathic pulmonary fibrosis in that they are not peripheral in distribution. B, At scanning magnification, Hermansky-Pudlak syndrome shows patchy interstitial fibrosis in a distribution pattern that is difficult to characterize. C, At high magnification, distinctive clear, vacuolated, ceroid-laden type 2 pneumocytes and alveolar macrophages are present in the fibrotic background. D, Immunohistochemical dual staining for TTF-1 (brown) and CD68 (red) confirm that the vacuolated cells are composed of both type 2 pneumocytes and alveolar macrophages (hematoxylin-eosin, original magnifications x20 [B] and x400 [C]; original magnification x400 [D]).
Table 1. Comparison of Clinical and Radiologic Features of Disorders Causing Advanced Pulmonary Fibrosis Feature IPF CTD-ILD Age > 60 y Middle-aged Sex M >> F F >> M Smoking history Frequent Variable Systemic manifestations Rare Frequent Autoimmunity Rare Frequent (positive serology) Steroid-responsive No Maybe HRCT distribution Peripheral and lower Peripheral and lower of fibrosis lobe predominant lobe predominant HRCT honeycombing Frequent Frequent HRCT cysts Rare Rare HRCT nodules Rare Rare HRCT mosaic perfusion Rare Rare Feature Chr. HP Adv. PLCH Age < 60 y Middle-aged Sex F > M F>M Smoking history Uncommon Nearly always Systemic manifestations Rare Rare Autoimmunity Rare Rare (positive serology) Steroid-responsive Maybe No HRCT distribution Spares costophrenic Mid-upper lung of fibrosis angles, diffuse in predominant, axial plane spares bases HRCT honeycombing Frequent None HRCT cysts Uncommon Frequent HRCT nodules Frequent Frequent HRCT mosaic perfusion Frequent Rare Feature Adv. Sarcoidosis ECD HPS Age Middle-aged Middle-aged 20-40 y Sex F > M M > F M = F Smoking history Variable Variable Variable Systemic manifestations Frequent Frequent Frequent Autoimmunity Rare None None (positive serology) Steroid-responsive Maybe No No HRCT distribution Central and Variable, Mixed; of fibrosis upper lobe often irregular predominant diffuse HRCT honeycombing Variable None Uncommon HRCT cysts Frequent Rare Frequent HRCT nodules Variable Variable Uncommon HRCT mosaic perfusion Variable Rare Variable Table 2. Comparison of Histologic Features of Various Causes of Advanced Pulmonary Fibrosis Feature IPF CTD-ILD Distribution of fibrosis Peripheral, Mixed peripheral paraseptal and centrilobular Fibrotic NSIP-like areas Variable Frequent Interface between fibrosis Distinct Indistinct and preserved parenchyma Fibroblast foci Numerous Variable Smooth muscle metaplasia in Frequent Uncommon fibrosis Pleuritis Rare Frequent, often with adhesions Lymphoid hyperplasia Rare Frequent, often with germinal centers Peribronchiolar metaplasia Variable, mild Frequent, may be and focal extensive Interstitial granulomas Absent Absent Histiocytic infiltrates Absent Absent Vacuolated or clear type 2 Absent Absent pneumocytes and macrophages Feature Chr. HP Adv. PLCH Distribution of fibrosis Mixed peripheral and Centrilobular, centrilobular stellate Fibrotic NSIP-like areas Variable Variable Interface between fibrosis Variable Distinct and preserved parenchyma Fibroblast foci Variable Rare Smooth muscle metaplasia in Variable Variable fibrosis Pleuritis Uncommon Rare Lymphoid hyperplasia Variable Rare Peribronchiolar metaplasia Frequent, usually Variable extensive Interstitial granulomas Present, Absent poorly formed Histiocytic infiltrates Absent Absent Vacuolated or clear type 2 Absent Absent pneumocytes and macrophages Feature Adv. Sarcoidosis Distribution of fibrosis Lymphangitic Fibrotic NSIP-like areas Uncommon Interface between fibrosis Distinct and preserved parenchyma Fibroblast foci Rare Smooth muscle metaplasia in Uncommon fibrosis Pleuritis Frequent Lymphoid hyperplasia Rare Peribronchiolar metaplasia Variable Interstitial granulomas Present, well formed, but often scarce Histiocytic infiltrates Absent Vacuolated or clear type 2 Absent pneumocytes and macrophages Feature ECD HPS Distribution of fibrosis Exquisitely Irregular lymphangitic Fibrotic NSIP-like areas Rare Variable Interface between fibrosis Sharp Variable and preserved parenchyma Fibroblast foci Rare Variable Smooth muscle metaplasia in Rare Variable fibrosis Pleuritis Frequent Uncommon Lymphoid hyperplasia Rare Variable Peribronchiolar metaplasia Rare Variable Interstitial granulomas Absent Absent Histiocytic infiltrates Present, positive Absent for factor XIIIa and CD68, negative for CD1a Vacuolated or clear type 2 Absent Present pneumocytes and macrophages Abbreviations: Adv., advanced; Chr. HP, chronic hypersensitivity pneumonitis; CTD-ILD, connective tissue disease-associated interstitial lung disease; ECD, Erdheim-Chester disease; HPS, Hermansky-Pudlak syndrome; IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial pneumonia; PLCH, pulmonary Langerhans cell histiocytosis.
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|Author:||Larsen, Brandon T.; Smith, Maxwell L.; Elicker, Brett M.; Fernandez, Jessica M.; de Morvil, Guillerm|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Jul 1, 2017|
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