Practical Pulmonary Pathology 3rd ed. Kevin O. Leslie, MD

Chapter 8. Chronic Diffuse Lung Diseases

Mikiko Hashisako, MD, PhD, Junya Fukuoka, MD, PhD, and Maxwell L. Smith, MD

Diffuse or interstitial lung diseases (ILDs) include a spectrum of primarily nonneoplastic inflammatory conditions that share the common property of diffuse involvement of the lung parenchyma. The term ILD has become so thoroughly entrenched across multiple medical disciplines that it seems practical to continue its usage, although we would emphasize that many of the diseases discussed in this chapter also involve the alveolar spaces and terminal bronchioles to a variable extent and would There fore not be considered entirely interstitial by the anatomic purist.¹

This chapter focuses on the subacute and chronic forms of ILD (acute ILDs are discussed in Chapter 6), which includes diseases that typically evolve over weeks, months, or years. Patients with ILD share a number of clinical and radiologic manifestations, including (1) shortness of breath (dyspnea), (2) diffuse abnormalities in lung mechanics and gas transfer (pulmonary function), and (3) diffuse abnormalities on chest radiographs and computed tomography (CT) scans of the chest.²

An overview of ILD from the pathologist’s perspective is presented in Box 8.1. In this chapter we restrict our focus to a limited number of predominantly inflammatory diseases that come to biopsy relatively frequently (Box 8.2). Our emphasis is on the histopathologic patterns of these diseases as observed through the microscope. These patterns help narrow the differential diagnosis and, when coupled with clinical and radiologic data, often allow for a definitive diagnosis.

ILDs have in common as their main histopathologic finding the accumulation of inflammatory and immune effector cells in the lung interstitium. The interstitium of the lung is the compartment that exists between the basement membrane of lung epithelial cells (The lining cells of the airways and alveoli in direct contact with inspired air) and that of adjacent blood vessels. There is a general misconception that the lung interstitium is confined to the “space” that exists within the alveolar walls. In fact, this compartment extends as a continuum from the alveolar septa to the pleura.

Unlike neoplasms, which may have distinctive or even unique morphologic features, ILDs are distinguished from one another by (1) location involved (anatomic compartment or structure), (2) distribution (focal or diffuse), and (3) cellular composition (e.g., acute, chronic, or histiocytic) of the inflammatory reaction. Additional identification criteria include the mechanism by which repair is taking place (organizing or not) and the stage of the reparative process (acute: fibroblastic proliferation; subacute: fibroblasts accompanied by matrix and epithelial regeneration; chronic: dense fibrosis and structural remodeling).²

Transbronchial and surgical wedge biopsy interpretation in the ILD patient is complicated by several factors.³ First, these diseases involve the interstitium, but they are frequently attended by reactive changes in the surrounding alveolar spaces and associated terminal airways. Such reactive changes can be quite impressive and commonly distract the observer from recognizing the interstitial nature of the process. Second, the inherent variability and natural history of inflammatory diseases pose problems, wherein early phases of a disease may differ in appearance from later phases, and the intensity of a reaction may vary from individual to individual. Third, more than one inflammatory disease can involve the lung simultaneously, adding further complexity to the morphologic picture. Finally, and perhaps of greatest importance, these predominantly medical diseases cannot be diagnosed accurately without some clinical and radiologic correlation.⁴

Despite extensive clinical and experimental research efforts over the past several decades, the etiology and pathogenesis of most ILDs remain unknown. In certain ILDs, a specific exposure can be identified (e.g., in hypersensitivity pneumonitis or with toxic reaction to a drug), whereas in others, a systemic autoimmune disease may be present (e.g., rheumatoid arthritis [RA] manifesting in the lung). When no clear associated exposure or underlying condition is identified after rigorous evaluation, an ILD is considered to be idiopathic.

Like most human organs, the lung has a limited repertoire of responses to injury of any type, and most of these responses are nonspecific. Without guidelines for interpretation and appropriate nomenclature, the surgical pathologist may experience difficulty coming to a clinically meaningful diagnosis for the patient with ILD. Additionally, because the lung biopsy for ILD is always a limited sampling, the pathologist and clinician must work cooperatively in establishing a differential diagnosis based on the clinical presentation, laboratory data, and radiologic findings. A purely descriptive pathologic diagnosis (e.g., chronic lung fibrosis) without clinical or radiologic correlation or a focused differential diagnosis is of marginal use in the contemporary practice of pulmonary medicine. In this chapter we present the essential clinical, radiologic, and histopathologic elements of chronic ILDs and provide the reader with specific terminology, wherever possible, for use in diagnosing these diseases.

One of the most important chronic lung diseases in pulmonary medicine today is known clinically as idiopathic pulmonary fibrosis (IPF). This most devastating of chronic ILDs is often the diagnosis of exclusion from a clinical perspective and one against which all other chronic lung diseases are judged. The reason for this is that IPF is a disease that progresses despite therapy and rivals many cancers in mortality rate, with death often occurring within 3 years of diagnosis.⁵ As emphasized in the 2002 joint consensus statement of the American Thoracic Society (ATS) and the European Respiratory Society (ERS), the pathologic manifestation of IPF in the lung is usual interstitial pneumonia (UIP).⁶ UIP was a term introduced by Liebow in reference to one of five forms of idiopathic interstitial pneumonia (IIP).⁷ In Liebow’s words, UIP represents “chronic lung fibrosis of the common or usual type”—a seemingly broad category of chronic lung disease.

As we explore chronic ILDs, it seems most appropriate to begin with UIP, recognizing that our current concept of this disease is more restrictive than perhaps was initially intended. The pathologist who is able to recognize the subtle but distinctive features of UIP and confidently distinguish it from other ILDs is well on the way to mastering the art of pulmonary pathology.

Idiopathic Interstitial Pneumonias

Liebow’s initial classification of IIPs is presented for historical purposes in Box 8.3. In the years following the introduction of this classification scheme, new information led to the modification or elimination of certain of these IIPs and the addition of others not previously included (Box 8.4).^8,9 Since Liebow’s time, it has been established that desquamative interstitial pneumonia (DIP), initially thought to be an early manifestation of UIP,¹⁰ is in fact a smoking-related disease in a majority of cases, most often affecting adults.¹¹’¹² Subsequent investigation also showed that most cases of giant cell interstitial pneumonia (GIP) were actually manifestations of cobalt exposure, as a pneumoconiosis in “hard metal disease” (see Chapter 10).¹³ Finally, it became apparent that many early cases of lymphoid interstitial pneumonia (LIP) evolved into lymphoproliferative disease and probably did not constitute “inflammatory” disease in the true sense of the word.¹⁴

Table 8.1 International Consensus Classification of Idiopathic Interstitial Pneumonias (2013)

Histopathologic Pattern	Clinical-Radiologic-Pathologic Diagnosis
Major Idiopathic Interstitial Pneumonias
Usual interstitial pneumonia	Idiopathic pulmonary fibrosis
Nonspecific interstitial pneumonia	Idiopathic nonspecific interstitial pneumonia
Respiratory bronchiolitis	Respiratory bronchiolitis-interstitial lung disease
Desquamative interstitial pneumonia	Desquamative interstitial pneumonia
Organizing pneumonia	Cryptogenic organizing pneumonia
Diffuse alveolar damage	Acute interstitial pneumonia
Rare Idiopathic Interstitial Pneumonias
Lymphoid interstitial pneumonia	Idiopathic lymphoid interstitial pneumonia
Pleuroparenchymal fibroelastosis	Idiopathic pleuroparenchymal fibroelastosis
Unclassifiable Idiopathic Interstitial Pneumonias

Modified from Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/ European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733—748. [Tables 8.1 and 8.2.]

Based on this evolution in our understanding, a modification to Liebow’s original classification of the IIPs was proposed by Katzenstein.^8,9 This new schema included the major categories of UIP and DIP but coupled DIP with respiratory bronchiolitis-associated interstitial lung disease (RBILD) and acknowledged the strong relationship of these diseases to cigare The smoking. Katzenstein also proposed a new category of acute interstitial pneumonia (AIP)¹⁵ as an entity separate from UIP, a distinction that Liebow did not make in his initial classification. Finally, Katzenstein created a new category to encompass a group of inflammatory diseases that differed in appearance from UIP, DIP, or AIP. The term nonspecific interstitial pneumonia (NSIP) was proposed for this “new” pattern.¹⁶ In our experience, a majority of IIPs can be classified using this scheme. We would add idiopathic (cryptogenic) organizing pneumonia, previously known as idiopathic bronchiolitis obliterans organizing pneumonia,¹⁷ to this classification, as had been recommended by the 2002 International Workshop on the classification of IIPs.⁶ In 2013 the consensus classification of IIPs from 2002 was updated (Table 8.1).¹⁸ This update divided the IIPs into major and rare histologic patterns. NSIP was recognized as a distinct clinicopathologic entity and was included as a major IIP. LIP was recategorized to the rare IIPs. Pleuro- parenchymal fibroelastosis (PPFE), a newly recognized form of IIP, was included in the rare IIPs.^18,19 As before, the terminology for the clinical and radiographic diagnoses is not always the same as the histopathologic diagnosis. In our experience, a majority of IIPs can be classified using this scheme.

IIPs are classically defined as diffuse pulmonary diseases that involve two or more lobes of the lung; in most patients, such diseases are bilateral in distribution.²⁰ Some localized lesions (such as infection, atelectasis, or tumor) may mimic IIP in a biopsy specimen. It is safe to say that if a disease process is confined to the biopsy area sampled, it is unlikely to be an IIP. AIP is an acute form of IIP (discussed in detail in Chapter 6). A comparison of the histopathologic findings in each of the IIPs is presented in Table 8.2. The importance of accurately diagnosing these IIPs lies mainly with differences in prognosis. UIP is a uniformly fatal disease for which the median survival period historically is less than 3 years in its classic presentation (CT with honeycombing), competing with many cancers in this respect.

Usual Interstitial Pneumonia

Pulmonary pathologists have debated for years what is and what is not UIP. To some, UIP is a relatively nonspecific pattern of chronic lung injury with fibrosis and “honeycomb” remodeling (see further on). Today it is recognized that not all lung diseases with fibrosis behave similarly and, in particular, do not run the aggressive course expected for clinical IPF. The most honest answer may be that clinical and radiologic IPF has UIP-type pathologic changes but that a UIP pattern of parenchymal fibrosis with remodeling may be seen in biopsy specimens and may not necessarily correlate with clinical and radiologic IPF. Fortunately, not all lung diseases that produce scarring fit the pattern now defined as UIP. Asbestosis,^21-23 chronic hypersensitivity pneumonitis,^24-26 systemic collagen vascular diseases (CVDs),^27-30 and even some chronic toxic drug reactions³¹ can all produce lung fibrosis. Unfortunately, in the 30 years following Liebow’s introduction of UIP as an “idiopathic” interstitial disease, pathologists often used the designation of UIP in a variety of nonidiopathic settings (e.g., “UIP from asbestosis” or “UIP from RA”). If UIP is defined as simply any form of lung fibrosis, then applying UIP as a synonym for fibrosis is perfectly reasonable. On the other hand, if UIP is a distinctive pathologic entity that corresponds to an idiopathic clinical disease (IPF), then UIP should have identifiable features that afford it status as a unique disease process. That There is a continued misconception of UIP among pathologists is underscored by feedback from our clinical colleagues, who note that many diagnoses of UIP provided by the pathology laboratory do not correspond to clinical IPF in their patients’ presentation, response to therapy, or observed outcome. The American Thoracic Society and European Respiratory Society (ATS/ ERS) attempted to address this issue by recommending the use of a four-tiered UIP-pattern classification system to biopsies with pulmonary fibrosis.³² There are significant challenges associated with the clinical use of these criteria (see the following discussion).

An examination of the subset of ILDs that correspond to clinical and radiologic IPF reveals a disease that is not overtly inflammatory but nevertheless has a clear tendency to produce fibrosis. Moreover, the fibrosis seen in the lungs of patients with IPF has a relatively reproducible pattern and distribution (subpleural and paraseptal). Such a focused analysis can reveal the subtle differences between the UIP of Data from 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; and American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2002;165(2):277-304, table 8.2.

IPF and the fibrosis that may occur in other lung diseases, most of which have an identifiable cause, etiologic agent, or associated systemic disease process.

Table 8.2 Histopathologic Features of the Idiopathic Interstitial Pneumonias

Feature	NSIP	UIP	DIP	AIP	LIP	COP
Temporal appearance	Uniform	Variegated	Uniform	Uniform	Uniform	Uniform
Interstitial inflammation	Prominent	Scant	Scant	Scant	Prominent	Scant
Interstitial fibrosis collagen	Variable, diffuse	Patchy	Variable, diffuse	No	Some cases	No
Interstitial fibrosis fibroblasts	Occasional, diffuse	No	No	Yes, diffuse	No	No
OP pattern	Occasional, focal	Occasional, focal	No	Occasional, focal	No	Prominent
Fibroblast foci	Occasional, focal	Typical	No	No	No	No
Honeycomb areas	Rare	Typical	No	No	Sometimes	No
Intraalveolar macrophages	Occasional, patchy	Occasional, focal	Yes, diffuse	No	Occasional, patchy	No
Hyaline membranes	No	No	No	Yes, focal	No	No
Granulomas	No	No	No	No	Focal, poorly formed	No

AIP, Acute interstitial pneumonia; COP, cryptogenic organizing pneumonia; DIP, desquamative interstitial pneumonia; LIP, lymphocytic interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; UIP, usual interstitial pneumonia.

Clinical Presentation

The incidence of UIP varies by gender, with males predominating. The disease may have a prevalence in the United States as high as 43 per 100,000, using broad criteria³³; roughly two thirds of patients are older than 60 years of age at diagnosis.^5,34 For this reason, caution should be exercised in considering a diagnosis of UIP in patients who are younger than 50 years of age, and preferably expert consultation should be sought in this setting. Symptoms typically progress insidiously for months to years before diagnosis. The onset of a nonproductive cough and slowly progressive dyspnea are characteristic. Dry inspiratory crackles (so-called Velcro crackles) are detected at the lung bases on chest auscultation in more than 80% of patients at presentation.⁵ Clubbing of the digits is seen in 25% to 50% of patients at presentation. Fever is rare, and its presence should suggest an alternate diagnosis, as should a significantly elevated erythrocyte sedimentation rate (ESR) (>100 mm/h). Serologic studies such as antinuclear antibody (ANA) or rheumatoid factor (RF) assays may reveal mildly elevated titers, but when significant elevation is present, a systemic connective tissue disease (CTD) should be strongly considered. Also, in patients presenting with clinical features of UIP or IPF in whom a defined CVD develops later, reclassification of their disease may be necessary.

Radiologic Findings

On chest radiographs, peripheral reticular opacities involving the lung bases are a characteristic finding.³⁵ When present, these are usually bilateral and often asymmetrical. Lung volumes are typically decreased at presentation except in cases with severe upper lobe (centriacinar) emphysema.³⁶ Unfortunately a normal chest radiograph does not exclude the diagnosis.³⁷ Confluent alveolar opacities are rare and, if present, suggest an alternate diagnosis or a comorbid process. CT scans, preferably of the high-resolution type (i.e., with scan sections <1 mm), commonly show patchy, predominantly peripheral (subpleural) reticular abnormalities involving the lung bases bilaterally.³⁸ Some asymmetry is expected between right and left lungs, and characteristic “skip” areas are present, with coarse pleural-based reticulation alternating with adjacent better preserved lung (so-called radiologic heterogeneity). The earliest findings may be quite subtle, consisting of delicate, peripherally accentuated pleural-based reticular opacities in the lower lung zones (Fig. 8.1). Ground-glass opacities are not typical and, if present, should be limited in extent.^39-41 Subpleural cysts—ranging from a few millimeters to a centimeter or more in diameter (“radiologic honeycombing”)—increase in prominence as the disease advances (Fig. 8.2). In areas of more severe involvement, traction bronchiectasis is often evident. Diagnostic accuracy for IPF on high-resolution CT scan by trained observers is in the range of 90% when typical findings are present (high specificity); however, approximately one third of cases of UIP will be missed in relying on high-resolution CT diagnosis alone (low sensitivity).^26,42 the 2011 ATS/ERS consensus document allows a diagnosis of IPF in the absence of surgical lung biopsy if the high-resolution CT shows reticular abnormality in a subpleural and basal predominance, honeycombing with or without traction bronchiectasis, and an absence of features inconsistent with UIP (upper, mid- or peribronchovascular distribution; extensive ground-glass opacities; micronodules cysts; airtrapping; and segmental consolidation).³²

Histopathologic Findings

UIP cannot be diagnosed with traditional bronchoscopic or transbronchial biopsy specimens. Cryobiopsy is a recently developed technique that uses a cryoprobe to obtain larger tissue biopsy fragments using a transbronchial approach. Cryobiopsy has been shown to be sufficient to make a diagnosis of UIP because of the larger sample size and lack of crush artifact associated with traditional biopsy forceps.^43-45 Surgically derived wedge lung biopsies (3-5 cm in length by 2-3 cm in breadth) obtained from video-assisted thoracoscopic surgery or open thoracotomy are the appropriate samples for diagnosis (see Chapter 3 for additional details on the lung biopsy). Occasionally UIP will be evident in lobectomy and pneumonectomy specimens obtained for other diseases. UIP is a process that involves the periphery of the lung lobule; these areas are not sampled adequately in even the most ambitious transbronchial biopsy scenario (where many large fragments of alveolar parenchyma may be present, but are mainly derived from the central portion of the lung lobules). More than one biopsy site should be sampled, and preferably a biopsy sample should be obtained from all lobes in the hemithorax chosen for surgical intervention. If only two areas can be sampled, midlung and lower lung are preferable to upper and midlung, and samples from the lower lobe should be taken above the most advanced areas of fibrosis.

Figure 8.1 Usual interstitial pneumonia (UIP). (A) This computed tomography scan shows the early subtle findings in UIP, with delicate pleura-based reticular opacities in the lower lung zones and a few small honeycomb cysts. (B) Higher magnification of the boxed area from part A.

Figure 8.2 Usual interstitial pneumonia (UIP). (A) Computed tomography scan showing characteristic changes of UIP, with subpleural cysts (black arrow) and traction bronchiectasis (white arrow). (B) Gross lung specimen shows subpleural (P) cysts, ranging from a few millimeters to a centimeter or more in diameter (i.e., radiologic honeycombing), which increase in prominence as the disease advances.

The characteristic histopathologic findings of UIP have been referred to as being “temporally heterogeneous” or having a “patchwork quilt” appearance,35,46-49 concepts and terms that are often misunderstood by surgical pathologists and pulmonologists. An expanded description of temporal heterogeneity is that of transitions in the biopsy from dense scar (The “past”) to normal lung ( The “future”—lung tissue yet to be involved). At the juncture of these, transitions occur through patches of active lung injury referred to as “fibroblast” or “fibroblastic” foci (Fig. 8.3). These transitions are often abrupt in UIP of IPF, occurring in less than a single high-power field under the microscope. The remodeled lung is present mainly beneath the pleura and at the periphery of the secondary lobule, adjacent to interlobular septa (Fig. 8.4). When UIP is recognizable as a distinct pathologic entity, the pleural fibrosis contains smooth muscle proliferation in disorganized fascicles (Fig. 8.5), and foci of microscopic honeycombing are evident, even when the overall process appears to be mild or early in its evolution (Fig. 8.6).

Microscopic honeycombing probably represents one of the early manifestations of the gross honeycomb cysts seen in the end stage of UIP. As used by radiologists, the term honeycombing refers to an array of much larger cysts (in the range of 0.5 to 3 cm or larger) as a localized manifestation of advanced lung remodeling (Fig. 8.7). Microscopic honeycomb cysts are considerably smaller (in the range of 1 to 3 mm) and are typically present subpleurally (Fig. 8.8). The cysts are lined by columnar ciliated epithelium and typically filled with mucus, with variable amounts of acute inflammation or proteinaceous material that may mimic pulmonary alveolar proteinosis (PAP) (Fig. 8.9). Microscopic honeycomb remodeling is not specific to UIP of IPF but rather represents the histologic manifestation of advanced fibrosis. As such, honeycomb remodeling can be seen as advanced fibrosis secondary to collagen vascular disease and chronic hypersensitivity, among others. When dense chronic inflammation is present in UIP, it is seen around these localized inflammatory lesions.

Exactly how honeycomb cysts (gross or microscopic) form is unclear, but we believe they represent centrilobular airways, trapped in the fibrous remodeling, that are then pulled to the periphery of the lobule. In support of this concept, lobules with foci of microscopic honeycombing often lack a visible central airway and tractional emphysema is nearly always present. This hypothesis would also explain the presence of smooth muscle fascicles in subpleural fibrosis and may thus be more tenable than the hypothesis that such muscle forms by fibroblast metaplasia.

Between the two temporal extremes of “old” peripheral fibrosis and uninvolved lung present centrally in the lobule is the presumed active zone of injury in UIP, evidenced by a crescent-shaped bulge of immature fibroblasts (technically, myofibroblasts) and ground substance (Fig. 8.3). This lesion is known as the fibroblastic focus and typically is not extensive in the biopsy. Fibroblast foci have been shown to be continuous linear structures in three-dimensional reconstruction.⁵⁰ Some investigators have postulated that the increased number of these foci in a given UIP patient’s biopsy is associated with a worse prognosis, and that a relative lack of fibroblastic foci may be an explanation for the better prognosis observed for patients with UIP-like lung fibrosis related to systemic CVDs.⁵¹

Figure 8.3 Usual interstitial pneumonia (UIP). The histopathologic temporal heterogeneity of UIP is characterized by abrupt transitions in the biopsy tissue, from dense remodeled lung parenchyma ("old” injury, evident at right in this image) to normal alveolar walls ("new” or not-yet-involved lung, center and left in this image) at the center of the lobule. This transition occurs through patchy areas of lung injury evidenced by the "fibroblast” or "fibroblastic” focus (ff).

UIP is not an overtly inflammatory condition in the absence of so-called acute exacerbation (see further on). This is not to imply that fibrosis occurs “mysteriously” in the disease. Some form of injury is occurring in UIP, but it seems to be subtle and is probably directed at the alveolar epithelium and its underlying basement membrane (epithelial-mesenchymal transitions). The fibroblastic foci of UIP appear immediately beneath reactive-appearing alveolar lining epithelium, where they obscure the epithelial basement membrane and bulge into the adjacent airspace (Fig. 8.10), as though they were aborted Masson polyps of the type seen in organizing pneumonia (OP) (see later under Cryptogenic Organizing Pneumonia). Further evidence of an injury repair phenotype for UIP/IPF is the consistent presence of reactive type II cell proliferation overlying fibroblastic foci. Conceptually, the subtle inflammatory disease of UIP burns like a smoldering fire through the lung, leaving fibrosis, smooth muscle proliferation, microscopic honeycombing, and fibrosis in its path.

Figure 8.5 Usual interstitial pneumonia (UIP). When UIP is recognizable as a distinct pathologic entity, the subpleural fibrous tissue contains areas of smooth muscle proliferation, seen here as large disorganized fascicles.

Figure 8.4 Usual interstitial pneumonia (UIP). (A) the remodeled lung is present mainly beneath the pleura and at the periphery of the secondary lobule, adjacent to interlobular septa. A slightly shrunken lobule is circled at upper center. CL, Center of lobule. (B) An interlobular septum (ILS) widened by fibrosis is seen at center, with less involved lung lobules above and below.

Figure 8.6 Usual interstitial pneumonia. Even in patients with early disease as determined radiologically, foci of microscopic honeycombing typically are present. To distinguish bronchiolar metaplasia from microscopic honeycombing, noting the location of the lesion is often helpful because microscopic honeycombing is present more peripherally in lobules and associated with dense scar, whereas bronchiolar metaplasia develops at the center of lobules, in association with respiratory bronchioles.

The ATS/ERS recommends classifying histologic lung biopsies with fibrosis into four categories based on the likelihood of a UIP designation: UIP pattern, probable UIP pattern, possible UIP pattern, and non-UIP pattern.³² the UIP pattern must show all of the following: (1) marked fibrosis with architectural distortion with or without honeycombing in a subpleural/paraseptal distribution, (2) patchy involvement with normal areas of lung, (3) fibroblast foci, and (4) the absence of features arguing against a diagnosis of UIP (eSlide 8.1). Probable UIP pattern also shows marked fibrosis with or without honeycombing, absence of either patchy involvement of fibroblast foci but not both, and the absence of features arguing against a diagnosis of UIP. Biopsies with honeycomb change alone are categorized as probable UIP pattern. Possible UIP pattern shows patchy or diffuse involvement of the lung by fibrosis with or without interstitial inflammation and the absence of features arguing against a diagnosis of UIP. Biopsies in the non-UIP pattern show hyaline membranes, OP, granulomas, marked interstitial inflammation away from honeycombing, and predominant airway-centered changes. Some of the challenges associated with the implementation of these criteria in clinical practice are the lack of well-defined criteria as to the quantity of granulomas, giant cells, interstitial inflammation, or airway-centered changes that may be sufficient to trigger a non-UIP-pattern designation. In addition, patients with IPF in acute exacerbation (see further on) often show hyaline membranes and OP. Nevertheless, pathologists should be aware of the existence of these criteria and should use caution in using the term UIP pattern in their reports unless they are confident that the biopsy is consistent with IPF.

Figure 8.8 Usual interstitial pneumonia. Microscopic honeycomb cysts are considerably smaller (in the range of 1 to 3 mm in diameter) than those identified radiologically.

Figure 8.7 Usual interstitial pneumonia (UIP). As used by radiologists, the term honeycombing refers to an array of much larger cysts (in the range of 0.5 to 3 cm or more in diameter) as a localized manifestation of advanced lung remodeling. (A) A patient with advanced UIP has many peripheral honeycomb cysts and traction bronchiectasis. (B) the gross lung shows dramatic confluent cyst formation.

Figure 8.9 Usual interstitial pneumonia (UIP). Microscopic honeycomb cysts are lined by columnar ciliated epithelium and are typically filled with mucus, with variable amounts of acute inflammation and inflammatory debris. When dense chronic inflammation is present in UIP, it is most often seen around microscopic honeycombing.

Figure 8.10 Usual interstitial pneumonia (UIP). The fibroblastic foci of UIP are patchy and present immediately beneath reactive-appearing cuboidal alveolar lining epithelium (type II cell hyperplasia). The fibroblastic proliferation bulges toward the airspace but does not appear to make a polypoid structure.

Acute Exacerbation

In his writings, Liebow conceived of UIP as a chronic lung disease resulting from repeated subclinical episodes of “diffuse alveolar damage” (DAD).⁷ In support of this hypothesis, episodic deterioration is typical in patients with IPF.⁵ In some patients with IPF, however, clinical deterioration is abrupt and overwhelming. Many of these acute deteriorations are of unidentifiable cause and have been referred to as acute exacerbations of IPF. Acute exacerbations have been the subject of considerable laboratory investigation, but the mechanism of their occurrence remains unknown. We do know that when such episodes are biopsied, the most consistent pathologic finding is that of DAD.⁵² Acute exacerbations of IPF can manifest as other patterns of acute lung injury, such as OP, but they may rarely show increased numbers of fibroblastic foci as a lone pathology. Despite the implication of the term, the “acute” exacerbation tends to evolve over several weeks rather than a few days.⁵³ the mixed histopathologic changes can be confusing to the surgical pathologist (and to the radiologist) examining the lung biopsy because the background older fibrosis with microscopic honeycombing of UIP is often overshadowed by diffuse acute lung injury (Fig. 8.11).

The three patients described by Kondoh and coworkers all showed some degree of improvement in the short term after high-dose corticosteroid therapy, but no consistently effective therapy has emerged.⁵² Several investigators have proposed that acute exacerbations may be the common terminal episode in many patients with IPF even though respiratory failure has always been presumed to be of slower evolution.⁵⁴ Based on all available data, including data from the placebo arms of several large randomized, double-blind, placebo-controlled trials in patients with IPF, an estimated 10% to 15% of patients with UIP experience overwhelming acute exacerbation during the course of their disease, and this is often the fatal event for those affected.^53,55

Differential Diagnosis

A number of diseases can cause heterogeneous pulmonary fibrosis reminiscent of the UIP pattern. When the biopsy shows heterogeneous fibrosis and There is radiographic evidence of a diffuse bilateral process, the main entities in the differential diagnosis are listed in Box 8.5. If the biopsy meets the strict criteria of a UIP pattern as described by the ATS/ERS³² (see earlier), the differential diagnosis is significantly shortened to IPF, collagen vascular disease, chronic hypersensitivity pneumonitis, and pneumoconioses. A practical approach to the differential diagnosis of biopsies showing advanced fibrosis is given at the end of this chapter. Final diagnosis often requires clinical exclusion of the other possibilities and multidisciplinary discussion.³² There are cases showing coexistence of histopathologic patterns of NSIP and UIP in the same patient in multiple lobe biopsies.⁵⁶ Such cases can be considered discordant UIP.⁵⁷ However, the clinical course of discordant UIP is still more like that of nondiscordant UIP, with possibly longer survival.⁵⁸ the 2013 classification of IIPs suggests the use of “unclassifiable IIPs” for the cases showing multiple histologic patterns.¹⁸

Clinical Course

The most common causes of death among patients with IPF are listed in Box 8.6. As defined clinically, IPF patients have a median survival time of less than 3 years.⁵⁹ At present, no effective therapy has been established for IPF, but newer therapies are on the horizon, using human recombinant cytokines as agents antagonistic to the effects of potentially “responsible” molecules.

A number of therapeutic approaches have been attempted in clinical trials. These include the use of human recombinant interferon y-1β, the antifibrotic compound pirfenidone, the antioxidant N-acetylcysteine, and several endothelin receptor antagonists (e.g., bosentan, ambrisentan).

Figure 8.11 Usual interstitial pneumonia (UIP). Acute exacerbation of idiopathic pulmonary fibrosis is associated with mixed histopathologic changes, typically with diffuse alveolar damage (A) superimposed on a background of older fibrosis and microscopic honeycombing of UIP. The background disease may be highlighted with the trichrome stain (B), which shows peripherally accentuated perilobular fibrosis. These two images are of the same biopsy section.

The use of collagen vascular disease immunosuppression treatment regimens in patients with IPF has been shown to speed the time to death or hospitalization.⁶⁰ To date, no trial has revealed a successful cure for the disease. Antifibrotic agents, such as pirfenidone, have been shown to slow functional loss in IPF patients and have become the mainstay of treatment.^61-63 However, these agents are potentially quite costly and do have significant side effects.

Essential Requirements for Accurate Diagnosis

For pulmonary physicians, a pathologic diagnosis of UIP implies clinical IPF; accordingly, pathologists should use great caution in making a diagnosis of UIP in the absence of clinical and radiologic correlation. The gravity of the prognosis and the divergent treatments strongly support this notion.⁵ If the pathologic findings are compelling for a UIP pattern, it is reasonable to use a descriptive diagnosis such as that presented in Box 8.7. This approach provides an opportunity for further correlation by clinical colleagues and radiologists in solidifying the diagnosis.

Familial Idiopathic Pulmonary Fibrosis

There is a small subset of patients with IPF who have a history of unexplained lung disease in first-degree relatives. This form of pulmonary fibrosis has been referred to as familial IPF or familial interstitial pneumonia (although in most studies of familial interstitial pneumonia, fibrosis seems to be the dominant pattern of disease). A compelling body of evidence suggests that IPF is a genetic disorder,⁶⁴’⁶⁵ and its familial occurrence is not surprising. Steele and colleagues examined the population of persons with familial interstitial pneumonia from 111 candidate families and found that more than 80% of these individuals had clinical IPF, followed by NSIP.⁶⁶ Genetic analysis was performed in search of the mechanism underlying familial IPF, and telomerase germline mutations were identified in 8%.⁶⁷ the role of telomerase mutations was hypothesized to be a function of excess telomere shortening over time, resulting in cellular dysfunction and premature cell death.

Nonspecific Interstitial Pneumonia

For many years after Liebow’s classification of IIPs was widely adopted, a number of diffuse inflammatory lung diseases were identified that did not fit well within this classification scheme. Various terms were applied to such diffuse lung diseases, including “chronic cellular” and “unclassifiable” interstitial pneumonia.⁶⁸ In 1994 the term NSIP was proposed by Katzenstein and Fiorelli, based on data from 64 patients who presented with diffuse lung disease and a chief complaint of dyspnea, usually present for several months before evaluation.¹⁶ Radiologic studies showed bilateral interstitial infiltrates with variable consolidation. Importantly, the 64 patients in this study had a significantly better prognosis than that observed for patients with UIP.

Katzenstein and Fiorelli recognized that the constellation of histopathologic patterns seen in NSIP did not represent one disease and, in follow-up investigations, found that these patients often had hypersensitivity, resolving infection, or systemic CVD, among other occurrences. Nagai and coworkers studied a group of patients with cellular interstitial pneumonia and rigorously excluded possible etiologies. The reported survival rate in this “idiopathic NSIP” was 90% at 5 years.⁶⁹ Thus when used in the true idiopathic context, the designation NSIP may actually be useful if it consistently implies an interstitial chronic inflammatory disease of unknown etiology with an expected good response to therapy and excellent survival rate. If, on the other hand, the term is applied indiscriminately as a substitute for any histopathologically unrecognized ILD, clinical behavior will be impossible to predict, there by significantly reducing the benefit of lung biopsy.

Clinical Presentation

Some general statements can be made regarding the clinical presentation in NSIP, recognizing that most of the available data have been derived from studies in which a heterogeneous group of disorders were represented. Patients with NSIP histopathology in lung biopsies (i.e., an NSIP pattern) tend to be younger than patients with UIP^69-71; the NSIP pattern might also appear in children.¹⁶ As with many of the chronic diffuse lung diseases, symptoms develop gradually. Shortness of breath, cough, fatigue, and weight loss are the most common complaints. Fever and digital clubbing have been reported but are uncommon.^16,70

Radiologic Findings

As in UIP, most of the chest x-ray abnormalities in NSIP are confined to the lower lung zones and tend to be bilateral and symmetrical.⁷² Less than 40% of the lung volume is typically involved. Patchy parenchymal (alveolar) opacification is a commonly reported abnormality,⁷² but reticular (interstitial) changes have also been identified.¹⁶ High-resolution CT findings are variable and nonspecific.⁷³ the most common findings are a reticular pattern and traction bronchiectasis, followed by lobar volume loss and ground-glass attenuation. As uncommon features, subpleural sparing, irregular linear opacities, patchy honeycombing, and nodular opacities can be seen.^69,70 As might be anticipated, some of the findings described for NSIP overlap with those in other ILDs, such as hypersensitivity pneumonitis and cryptogenic organizing pneumonia (COP). At the stage before honeycomb cysts are visible, even UIP can be indistinguishable from NSIP.

Histopathologic Findings

Katzenstein and Fiorelli emphasized that the histopathologic pattern in NSIP was temporally uniform (Fig. 8.12), in contrast with the UIP pattern, in which variable zones of established (dense) fibrosis, more active fibroplasia, and normal lung all coexist in the same biopsy specimen (i.e., temporal heterogeneity). As initially defined, the inflammatory process in NSIP is diffuse and uniform, mainly involving the alveolar walls (Fig. 8.13) and variably affecting the bronchovascular sheaths (Fig. 8.14) and pleura (Fig. 8.15).¹⁶ In some patients infiltrates are predominantly peribronchial, whereas in others germinal centers may be seen along with chronic pleuritis. When airspace organization (The OP pattern) is present, it is not uniformly distributed (Fig. 8.16), as might occur in organizing infectious pneumonia.¹⁶ When fibrosis occurs in NSIP, it is usually mild and preserves lung structure (Fig. 8.17). Peribronchiolar metaplasia of variable extent may be seen, but microscopic honeycombing is characteristically absent.^16,19

Historically, there has been debate as to whether NSIP is a new interstitial lung disease or simply a wastebasket category of diseases with some overlapping features. The most recent classification of IIPs includes idiopathic NSIP as a major IIP. However, caution is advised in using this term for any lung disease with interstitial inflammation, just as it is imprudent to diagnose all fibrosing lung diseases as UIP.

Differential Diagnosis

The main entities in the differential diagnosis of the NSIP pattern include hypersensitivity pneumonitis, systemic CVDs manifesting in the lung, resolving infection, and low-grade lymphoproliferative disease masquerading as LIP (see later). A practical approach to the cellular interstitial infiltrates is provided at the end of this chapter. Cellular NSIP and LIP may be difficult to distinguish from one another on histopathologic grounds; There fore once lymphoproliferative disease has been rigorously excluded, they might be considered synonymous from the pathologist’s perspective. Kinder and associates hypothesized that a majority of NSIP cases fall into the category of undifferentiated CTD manifesting in the lung. Because of significant overlap between NSIP and ILD in CVD, careful follow-up with serologic testing is recommended.^74,75 NSIP is one of the major histologic patterns included in the criteria for the newly introduced term interstitial pneumonia with autoimmune features (IPAF).⁷⁶ Details of IPAF are described later in this chapter. In clinical practice, in view of the limited arsenal of available therapies for ILD, managing NSIP as a systemic autoimmune disorder with immunosuppressive strategies (even though it may not be initially diagnosable by a rheumatologist) often proves to be the best course of action for the patient.

Figure 8.12 Nonspecific interstitial pneumonia (NSIP). The histopathology of NSIP is temporally uniform, in contrast with the temporal heterogeneity of the usual interstitial pneumonia pattern. Two examples are shown here: (A) Small lymphoid aggregates can be appreciated at scanning magnification; (B) the process is uniform and may be associated with interstitial widening and some interstitial fibrosis.

Figure 8.13 Nonspecific interstitial pneumonia (NSIP). (A) the chronic inflammatory infiltration in NSIP is diffuse and relatively uniform, mainly involving the alveolar walls. (B) Lymphocytes and plasma cells are the dominant cells.

Clinical Course

The overall survival rate for patients with NSIP is estimated to be in the range of 82.3% at 5 years and 73.2% at 10 years.¹⁹ the purely “cellular” form of NSIP seems to be a disease with a good prognosis compared with UIP and AIP.

When significant fibrous remodeling with microscopic honeycombing is permitted in the diagnosis of NSIP, 5- and 10-year survival rates change significantly for the worse.^69,77 This observation suggests that fibrotic forms of NSIP may be within the spectrum of other fibrosing lung diseases, such as UIP of IPF, and certain systemic CTDs that manifest in the lung with fibrosis.

Cryptogenic Organizing Pneumonia

Airspace organization is an extremely common manifestation of lung injury and can be seen after a wide variety of insults, from organizing lung infarction to bacterial pneumonia (Box 8.8). For this reason, the OP pattern in the lung biopsy is the least specific and perhaps the most misunderstood.

It is well known that lung repair following a wide spectrum of injuries frequently evolves through a phase of airspace organization. When organization is diffuse, involving the entire surgical biopsy, OP (or “diffuse airspace organization”) is an appropriate designation. When no etiology can be identified for an OP pattern, the clinical diagnosis of COP has been proposed (referred to previously as “idiopathic bronchiolitis obliterans organizing pneumonia”).^6,17,78

The term bronchiolitis obliterans organizing pneumonia (BOOP), designating an idiopathic disease, was first proposed by Davison and coworkers⁷⁸ and later used by Epler and associates¹⁷ to define a specific clinical disease course in a group of patients in whom lung biopsies showed variable amounts of airspace organization (OP pattern) of unexplained etiology. The importance of recognizing the pattern of OP in the clinical context that has been defined relates to therapy and prognosis. Patients with clinical COP respond well to systemic corticosteroid administration, and pulmonologists expect a good prognosis when this diagnosis is implied histopathologically. When BOOP is used in a pathology report as a descriptive term for the occurrence of OP in a biopsy, the clinician may misinterpret this to mean that idiopathic BOOP is the correct diagnosis. For example, the BOOP pattern may be seen in a disease with abundant background lung fibrosis. In this setting, the prognosis is best considered to be guarded.⁷⁹

Clinical Presentation

As described by Epler and coworkers for the original idiopathic BOOP, the patient typically presents several weeks after an episode of clinical symptoms suggesting upper respiratory tract infection.¹⁷ the mean age at onset is 55 years, and a majority of patients are nonsmokers.^80,81 Slowly worsening symptoms of cough (sometimes productive) and dyspnea are typically present, often leading to surgical lung biopsy within 3 months of disease onset. Weight loss, night sweats, chills, intermittent fever, and myalgias are common. Upon study, mild to moderate restrictive pulmonary function is identified in a majority of patients.^81-83 Hemoptysis and wheezing are typically absent. Often There is a marked increase in the ESR. Digital clubbing is not a feature of the disease.

Figure 8.14 Nonspecific interstitial pneumonia. Variable widening of alveolar walls by chronic inflammation can be seen, with little if any spared alveolar parenchyma in the biopsy. Bronchovascular sheaths are also typically involved by the inflammatory process to a variable degree.

Figure 8.16 Nonspecific interstitial pneumonia. When airspace organization (organizing pneumonia pattern) is seen (center), it is not diffusely or uniformly distributed, as might occur in organizing infectious pneumonia.

Figure 8.15 Nonspecific interstitial pneumonia (NSIP). (A and B) Pleuritis is very common in NSIP, emphasizing the strong association between the NSIP pattern in biopsy tissue and the presence of known or evolving systemic collagen vascular disease.

Figure 8.17 Nonspecific interstitial pneumonia (NSIP). When fibrosis occurs in NSIP (so-called fibrotic NSIP), it is usually mild to moderate in degree, with preservation of lung structure and generally without microscopic honeycombing or heterogeneity (i.e., normal lung adjacent to advanced fibrosis). (A) Changes of NSIP seen at low magnification. (B) Different specimen showing more prominent fibrosis.

Radiologic Findings

Chest radiography and CT show a number of abnormalities, none of which are specific for one disease. Patchy airspace consolidation (loss of visible structure underlying opacification) is the most consistent finding and is present in 90% of cases.^84,85 Air bronchograms can be seen in areas of consolidation. Ground-glass attenuation accompanies consolidation in more than half of the patients. The disease involves the lower more often than the upper lung zones.⁸⁶ Small nodular opacities can be seen in 10% to 50% of patients.⁸⁷

In a small percentage of patients, large nodules may be seen⁸⁷; rarely, reticulonodular infiltrates occur.⁸³ It is speculated that the latter finding identifies a subset of COP that may not respond to therapy. Opacities may be recurrent and/or migratory.^88,89 Lung volumes are normal in most patients, and pleural effusions rarely occur.^84,85,90

Histopathologic Findings

The OP pattern is characterized by variably dense airspace aggregates of fibroblasts in ground substance (immature collagen matrix) (Fig. 8.18). This alveolar filling process can be seen to extend into or from terminal bronchioles (Fig. 8.19). Typically the lung architecture is preserved in COP, and lymphocytes, plasma cells, and histiocytes are present in variable numbers within the interstitium (Fig. 8.20).^17,91,92 Fibrin may be seen focally in association with airspace organization (Fig. 8.21). The presence of prominent intraalveolar fibrin may be associated with increased risk of relapse of COP.⁹³ Alveolar macrophage accumulation may be present, attesting to some degree of airway obstruction.^17,91,92 When airspace organization is confluent and diffuse in the biopsy, COP is less likely to be the accurate diagnosis. Interstitial fibrosis and honeycomb lung remodeling are not components of the cryptogenic (idiopathic) form of OP.^17,91,92

Treatment and Prognosis

The expected response to systemic corticosteroid therapy is excellent.^17,88,94 Because relapses may occur if therapy is stopped abruptly, patients with COP generally require extended corticosteroid tapering, sometimes over a year or more.^17,88,94 There appears to be a small subset of patients with OP who develop progressive fibrosis with remodeling. This has been called fibrosing OP or variant of organizing pneumonia with supervening fibrosis and does not have the same excellent prognosis as steroidresponsive OP.^95,96

Differential Diagnosis

A practical approach to biopsies showing the histopathologic pattern of OP is presented at the end of this chapter. The term organizing pneumonia alone is too broad in scope to be of clinical use. In general, it is fair to say that the presence of the organizing pneumonia pattern is much more commonly associated with slowly organizing infection, systemic CTDs, hypersensitivity pneumonitis, and idiosyncratic reaction to drug or medication rather than a “cryptogenic” disease. Rarely, airspace organization may ossify and produced “racemose” or “dendriform” ossification (Fig. 8.22).

Figure 8.18 Organizing pneumonia pattern. This histopathologic pattern is characterized by variably dense airspace aggregates of loose fibroblasts within ground substance (immature collagen associated with an acellular pale or basophilic matrix). (A) At scanning magnification, slight nodularity of the process is evident. (B) At higher magnification, growth of loose granulation tissue can be seen within terminal airways and adjacent alveolar spaces.

Figure 8.19 Organizing pneumonia pattern. A branching tongue of fibroblastic proliferation can be seen to extend into or from an alveolar duct. Note the mild inflammatory interstitial infiltrate in surrounding alveolar walls.

Respiratory Bronchiolitis-Associated Interstitial Lung Disease

Respiratory bronchiolitis (RB) is a histopathologic lesion of the small airways that is common in cigare The smokers.⁹⁷ In some smokers, an exuberant form of RB occurs as a clinical and radiologic manifestation of diffuse ILD. This ILD manifestation of RB has been referred to as RBILD.⁹⁸ RB, RBILD, and DIP have been proposed as existing along a continuum in smokers,⁹⁹ with RB on the asymptomatic end of a spectrum that culminates in DIP on the other. The 2013 update on the classification of IIPs recognized the increasing use of the term smoking-related interstitial lung disease to describe the spectrum of pathologic findings seen in the setting of smoking. This term encompasses the spectrum of respiratory bronchiolitis and DIP but also includes histologic findings seen in the setting of fibrosis that are not true interstitial pneumonias: smoking-related interstitial fibrosis (SRIF), and airspace enlargement with fibrosis (AEF). Both SRIF and AEF were described in the setting of lobectomy specimens for carcinoma and may be seen in the spectrum of RBILD and DIP.^100,101 Pulmonary Langerhans cell histiocytosis is also generally considered to be a smoking-related ILD. Whether RB, RBILD, and DIP are truly manifestations of a single disease process remains to be proved. Certainly all three have some histopathologic elements in common, but the two main clinical manifestations in the spectrum (RBILD and DIP) also differ in a number of ways clinically and radiologically.

Clinical Presentation

Patients with RBILD are typically a decade younger than those with DIP and present in early midlife, with a mean age of 36 years in two studies.^98,102 A relationship between smoking pack-years and onset of disease suggests a dose-related effect, with a threshold in the vicinity of 30 pack-years. There tends to be a gender predilection toward men,^98,99 but men and women were equally affected in one study.¹⁰² Mild breathlessness and cough are the most common initial complaints.^98,102 Clubbing of the digits is unusual in RBILD.^102-104 Pulmonary function abnormalities parallel the mild clinical symptoms and may show evidence of both obstruction and restriction, with mild reduction in the diffusing capacity.⁹⁸

Radiologic Findings

The chest x-ray appearance of RBILD reflects the presence of disease centered on the airways, mainly with thickening of airway walls.⁹⁹ Ground-glass opacity is seen in more than 50% of chest radiographs in RBILD. On CT scans, ground-glass opacities and centrilobular nodules are typical findings, often best seen at the periphery of the upper lung zones.⁹⁹

Figure 8.20 Organizing pneumonia pattern. In cryptogenic organizing pneumonia (COP), the lung architecture is typically preserved. Lymphocytes, plasma cells, and histiocytes are present to variable degree within the interstitium. (A) Note the very patchy organization. (B) the prototypical appearance of COP, with patchy organization and mild interstitial pneumonia.

Figure 8.21 Organizing pneumonia pattern. Fibrin (center right) may be seen focally in association with airspace organization (center left) in cryptogenic organizing pneumonia.

Histopathologic Findings

RB is a common reactive process in the lungs of cigare The smokers; its presence alone does not imply the manifestation of diffuse lung disease.¹⁰⁴ Moreover, even when the histopathologic changes are diffuse and distinctive in the biopsy specimen, clinical correlation is required for accurate diagnosis. For example, a patient with a lung mass, which is resected and found to be a bronchogenic carcinoma, may have extensive RB in surrounding lung parenchyma. In the absence of a clinically and radiologically defined ILD, a diagnosis of RBILD would be inappropriate.

The essential morphologic constituents of RB are (1) scant inflammation around the terminal airways (Fig. 8.23), (2) metaplastic bron- chiolar epithelium extending out from terminal airways to involve alveolar ducts (Fig. 8.24), and (3) variable numbers of lightly pigmented, dusty brown airspace macrophages within bronchiolar lumens and in immediate surrounding alveoli (Fig. 8.25). Scant peribronchiolar fibrosis may be present and may extend to involve contiguous alveolar walls (Fig. 8.26). When bronchiolocentric scarring is prominent, an alternative diagnosis, such as chronic hypersensitivity pneumonitis, should be considered. So-called SRIF can be seen in RBILD¹⁰⁵; it is characterized by dense collagenous thickening of the alveolar septa without inflammation. The fibrosis is not consolidated, like that seen in UIP, but it can be patchy in the surgical biopsy, alternating with spared alveolar parenchyma. Such fibrosis does not appear to progress to honeycomb fibrosis.¹⁰⁶ the presence of fibroblastic foci or destruction of the lung architecture should always raise the possibility of an alternative diagnosis, especially undersampled UIP.

Figure 8.22 Racemose (dendriform) alveolar calcification. (A and B) Rarely, airspace organization may ossify, producing "racemose” or "dendriform” ossification.

Figure 8.23 Respiratory bronchiolitis. This pathologic process is characterized by the presence of scant inflammation around the terminal airways.

Figure 8.24 Respiratory bronchiolitis. Metaplastic bronchiolar epithelium extends out from terminal airways to involve alveolar ducts.

Differential Diagnosis

RB may be confused with bronchiolitis of some other etiology. When bronchiolar metaplasia is a prominent component, distinction from other small airway disease, such as idiopathic constrictive bronchiolitis, may be difficult. Patients with idiopathic constrictive bronchiolitis in surgical biopsies tend to have more severe pulmonary function abnormalities than patients with RB or RBILD (see Chapter 9 for a discussion of small airway disease). The distinction between RB and RBILD is largely based on the presence of clinical and radiographic abnormalities and cannot be made on histologic features alone.

Figure 8.25 Respiratory bronchiolitis. Variable numbers of lightly pigmented (dusty brown) airspace macrophages are seen within bronchiolar lumens and in immediately surrounding alveoli.

Figure 8.26 Respiratory bronchiolitis. Scant peribronchiolar fibrosis may be present; this may extend to involve contiguous alveolar walls, with or without prominent smooth muscle bundles.

Clinical Course

RBILD generally carries an excellent prognosis. However, symptomatic or physiologic improvement occurs in a limited number of patients. Smoking cessation, with or without immunosuppressive therapy, has been recommended, but a recent report demonstrated benefit in only a small subset of patients.¹⁰⁷

Desquamative Interstitial Pneumonia

Liebow⁷ proposed the term desquamative interstitial pneumonia for a diffuse lung disease that occurred in patients who were typically 10 or more years younger than patients who developed UIP. The disease often presented in mid-adulthood, and most patients were cigare The smokers.¹⁰⁸ Liebow also believed that the desquamated cells that filled the airspaces in DIP were epithelial cells. It has now been established that the airspace cells of Liebow’s DIP are actually macrophages, and that DIP is not a credible precursor lesion for UIP, as had been proposed by a number of authorities.

Figure 8.27 Desquamative interstitial pneumonia (DIP). (A) DIP is often a scanning magnification diagnosis. (B) the surgical lung biopsy has an eosinophilic appearance owing to the presence of eosinophilic macrophages uniformly filling airspaces.

Our current concept of DIP overlaps with that of RBILD, with both being considered components of the smoking-related diffuse lung diseases (see the discussion of pulmonary Langerhans cell histiocytosis further on). Whether DIP occurs as a separate disease in nonsmoking adolescents remains debatable, but it is unlikely. Another debate is centered on whether a form of UIP coexists with DIP as a “hybrid” entity. Those who still believe that DIP is a precursor lesion to UIP embrace this as proof of concept for instances in which this association is suggested in surgical lung biopsies. The counterargument is that smokers accumulate alveolar macrophages in areas of lung fibrosis, and because a majority of patients with UIP are current or former smokers, some of these patients will have prominent smoker-type macrophages coexisting with UIP.

Clinical Presentation

As currently defined, DIP is a very rare smoking-related lung disease. Patients with DIP are typically older than those with RBILD⁹⁹ and roughly a decade younger than those with UIP.^104,108 Most patients with DIP are cigare The smokers; men are more frequently affected than women. Like UIP, the clinical presentation is dominated by an insidious onset of dyspnea and dry cough over several weeks or months.^104,109 Digital clubbing is present in 50% of patients with DIP, a finding in sharp contrast with RBILD. ’Лю symptoms of DIP are usually more pronounced and more severe than those of RBILD,⁹⁹ supported by pulmonary function testing showing mild restriction and moderate reduction in diffusing capacity.¹⁰⁹

Radiologic Findings

The chest radiograph may be normal in 3% to 22% of patients. When abnormalities are present, patchy areas of ground-glass opacification predominate. The lung bases and periphery are most commonly affected.^99,110,111 On CT scans, ground-glass opacification is universally present, mostly in a bibasilar distribution.¹¹⁰ Linear and reticular opacities may accompany ground-glass opacities at the bases but tend to be quite limited in extent. Focal areas of peripheral honeycombing may be identified in as many as one third of patients,¹¹⁰ but when these are prominent and associated with more pronounced reticular abnormalities, an alternate diagnosis should be considered (probably UIP).

Figure 8.28 Desquamative interstitial pneumonia (DIP). Variable thickening of alveolar walls by fibrous tissue is the rule in DIP and is typically uniform in appearance. The expected presence of some alveolar wall fibrosis often makes the distinction of DIP from fibrotic forms of nonspecific interstitial pneumonia in heavy smokers the main issue, especially because the prognosis may be quite different for the two diseases.

Histopathologic Findings

On scanning magnification, the surgical lung biopsy in DIP has an eosinophilic appearance due to the presence of eosinophilic macrophages uniformly filling airspaces (Fig. 8.27).^11,102 Mild interstitial thickening by fibrous tissue is the rule and is uniform in appearance (Fig. 8.28). When chronic inflammation is evident at scanning magnification, it is centrilobular and associated with respiratory bronchioles (Fig. 8.29).

Figure 8.29 Desquamative interstitial pneumonia (DIP). When chronic inflammation is evident in DIP at scanning magnification, it is centrilobular and associated with respiratory bronchioles.

Figure 8.30 Desquamative interstitial pneumonia. Scant numbers of plasma cells and rare eosinophils may be seen within slightly thickened alveolar walls at high magnification.

Scant numbers of plasma cells and rare eosinophils may be seen within slightly thickened alveolar walls at high magnification (Fig. 8.30).

Differential Diagnosis

An attempt to distinguish DIP from RBILD is probably a useless exercise for pathologists; the inclusion of these two smoking-related diseases together as a diagnostic entity seems reasonable in the absence of clinical and radiologic data. Eosinophilic lung disease can simulate the low- magnification appearance of DIP, as can chronic passive congestion, pulmonary hemorrhage syndromes, GIP in hard metal disease, and pulmonary Langerhans cell histiocytosis (pulmonary histiocytosis X) when a prominent “DIP reaction” is identified. Progression to end-stage fibrotic lung disease is atypical and should raise consideration of alternative diagnoses including comorbid disease.

Clinical Course

As with RBILD, the prognosis for patients with DIP tends to be good, with an estimated 10-year survival rate of 70%.¹⁰⁹ Smoking cessation and corticosteroid therapy have proved effective in older studies.¹⁰⁸

Lymphoid Interstitial Pneumonia

LIP was originally thought of as a chronic cellular interstitial pneumonia with distinctive histopathologic features, quite different in cellular composition and form from Liebow’s other IIPs (e.g., UIP, bronchiolitis obliterans interstitial pneumonia, DIP, GIP).⁷ LIP became controversial because many of the cases originally classified as LIP by Liebow (and his contemporaries) evolved into (or were actually indolent forms of) low-grade lymphoproliferative disease involving the lung.^112-114 It is now generally acknowledged that the accrual of dense lymphoid tissue in the lung carries strong implications for lymphoproliferative disease, especially small B-cell lymphomas of the extranodal marginal zone type (so-called lymphomas of The mucosa-associated lymphoid tissue [MALT]) and polymorphous lymphoproliferative disorders associated with viral infection, including EBV or human T-lymphotropic virus type 1 (HTLV-1).^112-117 LIP, as currently defined, is included as an entity in this chapter because a recent international consensus panel chose to keep LIP as a form of IIP, partly for historical reasons. The panel participants acknowledged that many pulmonary pathologists might classify the described histopathologic findings of “idiopathic LIP” as a cellular form of NSIP.

More recently, Cha and colleagues¹¹⁸ described a series of nonlymphoma LIP cases in which 9 of 15 patients were found to have a CVD, mainly Sjogren syndrome. In that series, three patients with idiopathic LIP were identified. All three survived longer than 10 years, and their disease did not progress to lymphoma or leukemia despite the fact that one had a monoclonal gammopathy.¹¹⁸

Clinical Presentation

The clinical manifestations of the idiopathic form of the LIP pattern are not well studied but seem to be similar to those associated with definable systemic conditions, such as CVD. Women are more commonly affected than men; patients are typically between 40 and 50 years of age.¹¹⁹ Interestingly, all of the “idiopathic LIP” patients described by Cha and colleagues were men, whereas most of the secondary LIP patients were women.¹¹⁸ Slowly progressive breathlessness is a common feature, with or without nonproductive cough; the disease may evolve over months or years.

In the classic description of LIP, systemic signs and symptoms such as weight loss, pleuritic pain, arthralgias, adenopathy, and fever were reported, depending on whether an associated systemic condition was present.^119-121 Findings may include bibasilar crackles, cyanosis, and clubbing. Immunoglobulin abnormalities in serum are present in some patients.¹²² More commonly, the LIP pattern is associated with a systemic condition that dominates the clinical presentation and clinical course (e.g., Sjogren syndrome, pernicious anemia, hypogammaglobulinemia).

Radiologic Findings

The published radiologic features of idiopathic LIP seem to describe more than one pattern of disease.¹²³ Bibasilar reticular opacities along with ground-glass attenuation and thickening of interlobular septa are frequently observed abnormalities.^118,123-125 ttere may be mixed alveolar and interstitial infiltrates and thin-walled cysts, honeycombing, and changes suggesting pulmonary hypertension late in the disease.^119,126 Nodular patterns can also occur.¹²⁷ Pleural effusion is rare and, if present, should increase concern for low-grade malignant lymphoma.

A distinctive cystic disease has also been referred to by radiologists as lymphocytic interstitial pneumonia (or simply, LIP); on biopsy, however, the process has no significant interstitial inflammatory infiltrates or fibrosis, exhibiting only thin-walled, dilated airways with scant associated bronchiolitis.¹²⁸ An association with Sjogren syndrome has been documented.¹²⁹

Figure 8.31 Lymphoid interstitial pneumonia. (A) This histopathologic pattern is characterized by the presence of a dense, diffuse alveolar septal infiltrate made up of lymphocytes, plasma cells, plasmacytoid cells, and histiocytes. (B) Multinucleated giant cells and small nonnecrotizing granulomas are commonly present.

Figure 8.32 Lymphoid interstitial pneumonia (LIP). Microscopic honeycomb cystic remodeling (A) with some interstitial fibrosis (B); these can also be components of idiopathic LIP.

Histopathologic Findings

The histopathologic pattern in LIP is characterized by the presence of a dense and diffuse alveolar septal infiltrate made up of lymphocytes, plasma cells, and histiocytes (Fig. 8.31). This definition helps exclude diseases with less intense cellular interstitial infiltrates, such as certain hypersensitivity reactions and systemic CTDs. Multinucleated giant cells or small, ill-defined granulomas in the interstitium have been described in the idiopathic form of LIP, but microscopic honeycomb remodeling with some interstitial fibrosis (Fig. 8.32) can also be a part of idiopathic LIP. To a variable extent, germinal centers may be present along airways and lymphatic routes (Fig. 8.33). When these are prominent and interstitial lymphocytic infiltration is less remarkable, diffuse lymphoid hyperplasia has been used as a preferable term. In this situation, lymphoproliferative disorders—such as multicentric Castleman disease, idiopathic plasmacytic lymphadenopathy with hyperimmunoglobu- linemia, or even MALT lymphoma—are the main considerations.¹³⁰ When the idiopathic form of the LIP pattern is identified, immuno- phenotyping and gene rearrangement studies typically show an absence of clonality.¹²³ When nodular lymphoid hyperplasia is prominent around bronchioles, typically accompanied by an interstitial infiltrate, Sjogren syndrome should be rigorously investigated as a potential etiology.

Differential Diagnosis

The LIP pattern is most consistently seen when systemic CVDs manifest in the lung.^119,131 the LIP pattern may also be seen in the setting of bone marrow transplantation¹³² and has frequently been observed in both children and adults who have congenital or acquired immunodeficiency syndromes¹³³; it is also seen in the setting of adult HIV infection, including vertical transmission from mother to child.^134-136

Much of what has been written about the histopathology of LIP is similar to writings about the histopathologic patterns of NSIP. If LIP and cellular NSIP can be distinguished from each other microscopically, it is usually on the basis of the sheer density of the lymphoid infiltrate in LIP, accompanied by fibrosis and some degree of remodeling (The latter would be unexpected for the cellular form of NSIP). Naturally, in this setting gene rearrangement studies are important in distinguishing idiopathic LIP from low-grade lymphoproliferative disease (see Chapter 16 for further discussion). Once the pattern is established, it is useful to suggest the potential systemic conditions that may be associated with this pattern (Box 8.9) in a “comment” section of the surgical pathology report. In practice, a diagnosis of LIP is quite rare compared with cellular NSIP, emphasizing the idea that the infiltrate seen in LIP should be robust enough to strongly suggest the possibility of lymphoma. A practical approach to biopsies with dense cellular infiltrates is provided at the end of this chapter.

Clinical Course

The clinical outcome and response to therapy for patients with the LIP pattern is largely dependent on whether systemic disease is present. In the idiopathic form, an accurate prognosis has not been forthcoming, although three patients survived more than 10 years in the series reported by Cha and coworkers.¹¹⁸ In symptomatic patients, corticosteroid administration may result in significant benefit,¹¹⁹ lending further support to LIP’s being an immunologic disease rather than a neoplastic one in most instances. When honeycomb cysts, clubbing, or cor pulmonale is present, the prognosis is less favorable, with as many as one third of patients succumbing to the disease.^119,127 Infection is a common complication, especially when LIP is associated with dysproteinemia.^119,120,137

Figure 8.33 Lymphoid interstitial pneumonia. Germinal centers may be present to a variable extent along airways and lymphatic routes. When these are prominent, diffuse lymphoid hyperplasia has been used as a preferable alternative term for this clinical entity.

Idiopathic Pleuroparenchymal Fibroelastosis

In 1992, Amitani and coworkers reported a distinctive pattern of upper pulmonarylobe fibrosis in Japanese patients.¹³⁸ Subsequently, Frankel and coworkers referred to a similar form of pleuroparenchymal ILD as idiopathic pleuroparenchymal fibroelastosis (IPPFE).¹³⁹ This upper lobe-predominant fibrotic disease slowly progresses to involve the lower lung. On histopathologic examination, elastotic fibrosis, similar to that seen in an apical cap, is the dominant feature. The major differences between apical cap and IPPFE are that the patients with IPPFE are symptomatic and the disease is progressive; it can result in death within several years. The 2013 updated classification of IIPs placed IPPFE in the category of rare IIPs.¹⁸

Clinical Presentation

The median age of a patient diagnosed with IPPFE is 57 years, and There is no sex predilection.¹⁴⁰ Patients present with dyspnea on exertion and cough. Pneumothorax and recurrent infections have been reported in some patients. Reports have raised the possibility of familial and neoplastic associations with IPPFE.

Radiologic Findings

Plain films show volume loss in both upper lungs with marked apical pleural thickening. CT images show marked visceral pleural thickening extending into the lung parenchyma, with subpleural reticular abnormalities. Traction bronchiectasis is a common finding in areas of fibrosis. Lower lung zones may be hyperinflated (Fig. 8.34A).

Histopathologic Findings

The histopathology of IPPFE overlaps with that of apical cap. Fibrotic areas show dense elastotic scarring without inflammation. Scattered lymphoid aggregations are common, but There is no associated cellular interstitial pneumonia. Margins between normal lung and affected fibrotic areas are sharply defined. Uninvolved lung shows minimal abnormalities, mainly involving the airways (bronchiolar fibrosis or ectasia). Broad pleural adhesions, probably due to the common history of pneumothorax, may be present (Fig. 8.34B and eSlide 8.2).

Differential Diagnosis

The histologic distinction between apical cap and IPPFE can be quite challenging. Apical cap should be relegated to the immediate subpleura zone, while IPPFE shows finger-like projections deeper into the lung parenchyma. The background elastotic fibrosis is identical between the two. The progressive and “infiltrative” fibrosis of IPPFE can affect survival through eventual loss of lung compliance. The presence of dense collagenous fibrosis (that lacks elastic fibers) should raise an alternative diagnosis, such as UIP/NSIP. Honeycomb fibrosis in the lower lung is not an expected finding in patients with IPPFE.

Clinical Course

The expected clinical course varies considerably from case to case; however, up to 40% of patients may die of the disease.^140,141

Figure 8.34 Idiopathic pleuroparenchymal fibroelastosis (IPPFE). (A) Biapical pleural fibrotic changes, more prominent on the right (computed tomography image). A subcutaneous Port-A-Cath reservoir is present on the left anterior chest wall. (B) An upper lobe biopsy seen at scanning magnification from a patient with IPF. Note the elastotic fibrosis in a subpleural location, extending into the parenchyma. ([A] Reprinted with permission from Becker CD, Gil J, Padilla ML. Idiopathic pleuroparenchymal fibroelastosis: an unrecognized or misdiagnosed entity? Mod Pathol. 2008;21:784-787, case 2, figure 4.)

Chronic Manifestations of Systemic Collagen Vascular Disease

Systemic CVDs play an extremely important role in the etiology of ILDs. Knowledge of rheumatic ILD is derived mainly from retrospective studies, typically including small numbers of patients. Because of differences in patient populations reported and in the severity (and duration) of rheumatic disease at the time of study, many important questions remain concerning the frequency, pathogenesis, natural history, clinical relevance, and prognosis of ILD occurring in the rheumatic diseases. It is estimated that ILD in CVD is responsible for 1600 deaths annually in the United States, accounting for roughly 25% of all ILD deaths and 2% of all deaths from respiratory causes.¹⁴² Not surprisingly, most interstitial pneumonia patterns raise CVD as a consideration in the differential diagnosis. On the other hand, certain CVDs are associated with reasonably reproducible findings in the lung.² Table 8.3 summarizes the different patterns of inflammatory lung disease that have been described as lung manifestations of the known CTDs. The five rheumatic diseases that are more commonly associated with ILD are (1) RA, (2) progressive systemic sclerosis (PSS), (3) systemic lupus erythematosus (SLE), (4) polymyositis-dermatomyositis (PM-DM), and (5) Sjogren syndrome. The estimated frequency of lung involvement and the patterns produced are presented in Table 8.4. This section is restricted to the more chronic manifestations of these diseases. Acute lung manifestations of the rheumatic diseases are described in Chapter 6.

Rheumatoid Arthritis

RA is a chronic systemic disease that produces symmetrical arthritis and occurs more commonly in women than in men. ILD was not recognized as a manifestation of RA until 1948,¹⁵⁴ possibly because lung manifestations of the disease are difficult to recognize on purely clinical grounds. Today, with the use of pulmonary function testing, bronchoalveolar lavage, and CT imaging, significant lung disease is identified in 14% of patients who meet the American College of Rheumatology (formerly the American Rheumatism Association) criteria for RA; subclinical disease is seen in as many as 44%.¹⁵⁵ Interestingly, men are 3 times more likely to develop ILD with RA than are women.²⁷ Clinically significant ILD in RA is associated with increased morbidity and mortality.²⁷

Table 8.3 Lung Manifestations of the Collagen Vascular Diseases

Manifestation	RA	SLE	PSS	PM-DM	MCTD	SS AS
Pleural inflammation, fibrosis, effusions	X	X	X	X	X	XX
Airway disease
Inflammation (bronchiolitis)	X	X		X	X	X
Constrictive bronchiolitis	X				X
Bronchiectasis	X				X
Follicular bronchiolitis	X	X			X	X
Interstitial disease
Acute (DAD), with or without hemorrhage	X	X	X	X	X
Subacute/organizing (OP pattern)	X	X	X	X	X	X
Subacute cellular	X	X	X	X	X
Chronic cellular and fibrotic	X	X	X	X	X	X
Eosinophilic infiltrates	X				X
Granulomatous interstitial pneumonia	X	X			X
Vascular diseases; hypertension/ vasculitis	X	X	X	X	X	X
Parenchymal nodules	X
Apical fibrobullous disease	X		X		X
Lymphoid proliferation (reactive, neoplastic)	X		X		X

AS, Ankylosing spondylitis; DAD, diffuse alveolar damage; MCTD, mixed connective tissue disease; OP, organizing pneumonia; PM-DM, polymyositis-dermatomyositis; PSS, progressive systemic sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjogren syndrome. Modified from Colby TV, Lombard C, Yousem SA, et al. Atlas of pulmonary surgical pathology. In: Bordin G, ed. Atlases in Diagnostic Surgical Pathology. Philadelphia: WB Saunders; 1991:380; and Travis WD, Colby T, Koss M, et al. Non-neoplastic disorders of the lower respiratory tract. In: King DW, ed. Atlases of Nontumor Pathology Washington, DC: Armed Forces Institute of Pathology; 2002.

Table 8.4 Pulmonary Manifestations of the Rheumatic Diseases

Disease	Estimated Frequency	Type of ILD	Anatomic Involvement/Dominant Finding
Rheumatoid arthritis (RA)143	20%	UIP/NSIP » OP	Pleuritis > bronchiolitis > ILD > RA nodule
Progressive systemic sclerosis144,145	40%	NSIP » OP > UIP > DAD	ILD > aspiration > PHT
Systemic lupus erythematosus146,147	<10%	DAD > DAH > OP > UIP/NSIP	Pleuritis > infection > ILD > PHT
Polymyositis-dermatomyositis148	10%-35%*	NSIP > DAD > OP > UIP	Aspiration > ILD
Sjogren syndrome149-151	25%	NSIP > OP > UIP > LIP	Bronchiolitis > ILD
Mixed connective tissue disease152	40%	UIP/NSIP > OP > DAD > DAH	ILD > pleuritis > PHT > aspiration

*75%-100% when patient is seropositive for Jo-1, CADM-140, or other aminoacyl-tRNA synthetase (ARS).^65,153

DAD, Diffuse alveolar damage; DAH, diffuse alveolar hemorrhage; DIP, desquamative interstitial pneumonia; ILD, interstitial lung disease; LIP, lymphocytic interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; PHT, pulmonary hypertension; UIP, usual interstitial pneumonia.

Clinical Presentation

Diffuse lung disease in RA is typically noted in patients with diagnosed RA; rarely, however, ILD may precede articular manifestations.^{156,157 the} clinical presentation is dominated by shortness of breath and cough. Adults are more commonly affected than children,¹⁵⁸ and despite a higher incidence of RA in women, men with long-standing rheumatoid disease and subcutaneous nodules seem to develop lung manifestations more often.¹⁵⁶ Physical examination may reveal bibasilar inspiratory crackles, digital clubbing, and evidence of cor pulmonale, the last due to pulmonary hypertension arising as a result of hypoxic vasoconstriction.^27,156 When fibrosis and honeycomb remodeling accompany diffuse lung disease in RA, UIP enters into the differential diagnosis. Affected patients are often younger than those with idiopathic UIP. Cigare The smoking has been reported to be an independent predictor of lung disease in persons with RA.¹⁵⁹

Radiologic Findings

Several radiologic manifestations are described in RA, including reticular opacities with or without honeycombing, airway-associated abnormalities (bronchiectasis, nodules, centrilobular branching lines), and parenchymal opacities.¹⁶⁰ When ground-glass infiltrates and reticular opacities are present, there is a predilection for involving the bases and lung periphery. High-resolution CT findings include ground-glass attenuation with mixed alveolar and interstitial infiltrates. As lung disease advances, dense reticular and nodular opacities appear, and honeycomb lung may be seen in late stages of the disease.^160,161

Figure 8.35 Rheumatoid arthritis (RA) lung disease. (A) Chronic inflammation typically manifests in RA lung as lymphoid aggregates and follicular lymphoid germinal centers. (B) A variably cellular chronic interstitial infiltrate rich in plasma cells and lymphocytes is typical.

Histopathologic Findings

Despite the seemingly nonspecific nature of the histopathologic manifestations of RA, a few key elements emerge on review of many well- documented cases of RA-associated ILD. Chronic inflammation, in the form of lymphocyte aggregates and germinal centers, is typical though not unique (Fig. 8.35). Most of the lymphoid aggregations are present around the terminal airways (“follicular bronchiolitis” when lymphoid germinal centers are prominent) (Fig. 8.36), but lymphoid follicles may also present in the pleura. In fact, the presence of chronic pleuritis should always raise RA as a consideration in the differential diagnosis. Areas of subacute lung injury attended by reactive type II cells and airspace organization (Fig. 8.37) can be seen with cellular interstitial pneumonia (Fig. 8.38) and variable interstitial fibrosis (Fig. 8.39). This combination of subacute and chronic inflammatory reactions haphazardly involving the same lung biopsy, including the pleura, should raise the possibility of RA lung disease. When fibrosis is prominent, it is often difficult to classify as UIP or NSIP. That may be one of the reasons for the variable reported incidence of these two patterns of fibrosis in the disease. Fibroblastic foci are usually less prominent and normal lung may be absent. Vasculitis (including capillaritis) and even pulmonary hemorrhage have been described as manifestations of RA lung. When silicosis occurs with RA, the resulting disease is referred to as Caplan syndrome. Rheumatoid nodules can occur in the lung and pleura and must be distinguished from granulomatous infection and granulomatosis with polyangiitis (GPA; previously known as Wegener granulomatosis) (Fig. 8.39). Rheumatoid nodules show central eosinophilic necrosis/ necrobiosis with surrounding lymphoplasmacytic inflammation, giving the lesion a basophilic rim. Granulomatous infection shows a similar pattern. In contrast, nodules of GPA have central basophilic necrosis (often with abundant neutrophils) and surrounding collections of histiocytes appearing as an eosinophilic rim. Infection stains and correlation with final culture studies is imperative in all cases of granulomatous inflammation. Intrapulmonary lymph nodes may become prominent in RA and typically show reactive lymphoid hyperplasia when subjected to biopsy.

Figure 8.36 Rheumatoid arthritis (RA) lung disease. Most of the lymphoid aggregations in RA (A) are present around the terminal airways (“follicular bronchiolitis” when lymphoid germinal centers are prominent), but lymphoid follicles may also be present in the pleura. In fact, the presence of chronic pleuritis (B) should always raise the possibility of RA in the differential diagnosis.

Differential Diagnosis

RA lung manifestations are frequently confused with the IIPs (COP, NSIP, or even UIP), especially when the lung disease precedes the systemic disease. In a minority of patients pulmonary disease may be the first manifestation of RA, even preceding serologic evidence of disease. In patients with RA who develop pulmonary symptoms, biopsies are usually performed only when superimposed lung infections or drug reactions are suspected clinically. Surgical lung biopsy in this context can be extremely difficult to interpret, given significant overlap in the morphologic patterns of drug reactions, low-grade infection, and the systemic CVD itself.

Figure 8.37 Rheumatoid arthritis lung disease. Areas of subacute lung injury, attended by reactive-type II cells and airspace organization, can be seen. Fresh hemorrhage, probably related to the biopsy procedure, is also evident.

Figure 8.38 Rheumatoid arthritis (RA) lung disease. The cellular interstitial pneumonia of RA may be attended by diffuse reactive type II cell hyperplasia, but this finding is not particularly diagnostic absent other features more characteristic of RA (lymphoid germinal centers, follicular bronchiolitis, pleuritis, rheumatoid nodules).

Clinical Course

As with other CTDs, therapeutic strategies in RA have focused on immunosuppression.¹⁶² Although the reported survival significance of RA-ILD varies, a majority of published papers indicate better survival rates for patients with RA-ILD than for those with UIP/IPF.¹⁶³ Needless to say, the development of pulmonary fibrosis with a UIP pattern has a significant negative impact on survival.¹⁵⁷’¹⁵⁹’¹⁶⁴’¹⁶⁵

Progressive Systemic Sclerosis

PSS is a relatively rare systemic autoimmune disease, with cutaneous manifestations (dermal sclerosis) frequently accompanied by Raynaud phenomenon. Pulmonary involvement (mainly ILD) occurs more commonly in patients with PSS than in those with any other CTD,^144,166 with lung disease ranking fourth in frequency (after skin, peripheral vascular, and esophageal manifestations) in the disease, but involvement of the lungs is the primary cause of death in PSS.¹⁶⁷ As in RA, lung involvement in PSS is associated with increased morbidity and mortality.¹⁶⁷

Figure 8.39 Rheumatoid arthritis (RA) lung disease. (A) Variable interstitial fibrosis is typical and often resembles the fibrotic form of nonspecific interstitial pneumonia. (B) Typical rheumatoid nodules may occur in RA lung and must be distinguished from lesions seen with infection and in granulomatosis with polyangiitis.

Clinical Presentation

Chronic exertional dyspnea is the most common presentation, followed in frequency by chronic cough. Bibasilar inspiratory crackles are present in two-thirds of patients.^144,168 Digital clubbing may be present but is uncommon. Pulmonary fibrosis and cor pulmonale may eventually develop.¹⁶⁹ As in other CVDs, lung involvement can precede the development of diagnostic systemic manifestations.^144,170

Radiologic Findings

Bibasilar interstitial infiltrates with relative sparing of the upper lung zones are typical radiologic features.^171,172 Loss of lung volume, honeycomb cysts, and findings consistent with pulmonary hypertension may also be seen. Mixed reticular and nodular infiltrates are common.^171,172 Pleural effusion and pleural thickening may occur as minor findings.

Histopathologic Findings

The pulmonary manifestations of PSS can be quite characteristic. The interstitial fibrosis of PSS is paucicellular and diffuse with preservation of underlying lung architecture (Fig. 8.40). This distinctive “collageniza- tion” of the lung interstitium has been confused with the pattern of lung fibrosis seen in idiopathic UIP.¹⁶⁹ the lack of so-called temporal heterogeneity (see earlier section titled Usual Interstitial Pneumonia) is a useful finding and helps exclude UIP (of IPF) from the differential diagnosis. Pulmonary hypertensive changes (Fig. 8.41) may be present and merit careful attention because this is a major cause of death in patients with scleroderma and lung disease.¹⁷³ Because patients with PSS can also develop esophageal motility problems, subclinical chronic aspiration should be carefully excluded as a comorbid disease process.¹⁷⁴,¹⁷⁵

Clinical Course

The mean survival time for patients with scleroderma is 12 years from the time of diagnosis; pulmonary disease has emerged as the major cause of death.¹⁷⁶ Pulmonary function status at presentation is a reasonable predictor of survival; high-dose immunosuppressive therapy, typically in combination with a cytotoxic agent, seems to benefit those patients with severe manifestations.¹⁷⁷

Systemic Lupus Erythematosus

SLE is a chronic systemic autoimmune disorder characterized by arthropathy, mucocutaneous manifestations, renal disease, and serositis.^{178 the} lung may be the major site of involvement in SLE, ranging from acute lupus pneumonitis (ALP) at one end of the spectrum to fibrotic forms of NSIP at the other.^146,179,180 Acute lung injury and pulmonary hemorrhage are more commonly associated with SLE than with other systemic CTDs,^146,181 but hemoptysis occurs in only little more than half of the affected patients.^182,183

Clinical Presentation

SLE rivals PSS as the leader in pleuropulmonary manifestations in CVD.^{147,179,184,185} the spectrum of lung disease in SLE is quite broad^{146,180,181,186} and includes pleuritis (Fig. 8.42), ALP (Fig. 8.43), NSIP with fibrosis (Fig. 8.44), and diffuse alveolar hemorrhage (Fig. 8.45). Constrictive small-airway disease, pulmonary arterial hypertension, and pulmonary embolism can also occur as rare manifestations. Patients with lung disease often have high serum ANA or RF titers.

Radiologic Findings

The radiologic findings are similar to those in other CTDs: variable ground-glass attenuation, pleural thickening, pleural and pericardial effusions, and linear parenchymal opacities.^146,187-190 Acute pneumonitis can produce more extensive changes, but, rarely, chest radiography and high-resolution CT may show normal findings.¹⁹¹

Histopathologic Findings

Two general categories of pulmonary disease are described in SLE. The first is ALP. ALP is characterized by alveolitis with variable interstitial inflammation and edema (Fig. 8.46). Siderophages and capillaritis occur to a variable degree (Fig. 8.47). Pleuritis is commonly present. The second category of disease includes cellular interstitial pneumonia (lymphocytes and plasma cells) with variable interstitial fibrosis (Fig. 8.48). The latter NSIP pattern is associated with a better prognosis than that for ALP. When pulmonary hemorrhage occurs, the prognosis may be adversely affected. One dramatic but fortunately rare complication of SLE is the occurrence of lung infarction related to the lupus anticoagulant.^192-194 Whenever lung infarction is encountered in a young, otherwise healthy patient, this possibility should be considered (even if the patient does not have evident SLE).

Figure 8.40 Progressive systemic sclerosis (PSS). (A) the interstitial fibrosis of PSS is typically paucicellular and diffuse, with preservation of underlying lung architecture. (B) When fibrosis is more advanced, distinction from usual interstitial pneumonia (of idiopathic pulmonary fibrosis) may be difficult on morphologic grounds.

Figure 8.41 Progressive systemic sclerosis. Pulmonary hypertensive changes may be present and deserve careful attention, since this is a major cause of mortality in scleroderma patients with lung disease.

Clinical Course

Systemic corticosteroid therapy may be effective in SLE-associated lung disease, although sometimes the addition of a cytotoxic agent (e.g., cyclophosphamide, azathioprine) may be required.¹⁹⁵ In some series ALP is reported to have a high mortality rate.¹⁸⁴ More chronic forms of diffuse lung disease in SLE have a relatively good prognosis and response to therapy.¹⁹⁶

Polymyositis-Dermatomyositis

PM-DM comprises inflammatory disorders of the skeletal muscle and dermis. Five groups of primary or secondary disease are recognized, including childhood forms and overlap syndromes.^197,198 Pulmonary complications in PM-DM occur less commonly than in other systemic CTDs, but in a percentage of patients the pulmonary manifestations can be quite dramatic.¹⁹⁹

Clinical Presentation

Although most patients with PM-DM develop lung manifestations after the clinical diagnosis has been established, lung disease can occasionally precede the clinical and serologic diagnosis by months or even years.²⁰⁰ A variety of autoantibodies have been associated with PM-DM and are used in the diagnostic criteria; these include anti-Jo-1, anti-PL-12, and anti-MDA5.^201-209 Onset of pulmonary symptoms may occur at any age, with a mean occurrence in the sixth decade.^166,200,210 Women are more commonly affected than men. Digital clubbing is rare. In contrast with most other systemic CTDs, with the exception of SLE, patients with PM-DM can present with acute lung disease typically manifesting as rapidly progressive DAD.^199,210 This is seen most often in the setting of an anti-MDA5 antibody. Importantly, both acute aspiration pneumonitis secondary to underlying respiratory muscle weakness and bronchopneumonia occurring in the setting of immunosuppressive therapy are more common in PM-DM than is chronic diffuse lung disease.^211,212

Radiologic Findings

As with other CVDs manifesting in the lung, radiologic abnormalities in PM-DM predominantly affect the lung bases.²¹⁰ Ikezoe and colleagues reviewed the high-resolution CT findings in 23 of 25 patients with PM-DM who had high-resolution CT abnormalities.²¹³ These researchers identified ground-glass opacities in 92%, linear opacities in 92%, irregular interfaces in 88%, airspace consolidation in 52%, parenchymal micronodules in 28%, and honeycombing in 16% of the cases. The most dramatic radiologic finding associated with PM-DM is the rapid onset of airspace consolidation associated with the development of DAD.²⁰⁰,²¹⁰

Figure 8.42 Systemic lupus erythematosus (SLE). The spectrum of lung disease in SLE is quite broad and includes pleuritis (A), sometimes accompanied by "lupus erythematosus bodies” or simply, "LE bodies” ([B] center).

Figure 8.43 Systemic lupus erythematosus (SLE). Acute lupus pneumonitis is the most dramatic manifestation of SLE lung disease and is a form of acute lung injury.

Figure 8.44 Systemic lupus erythematosus (SLE). The second most common manifestation of SLE lung disease is a nonspecific interstitial pneumonia pattern of injury with cellular infiltrates and variable fibrosis.

Figure 8.45 Systemic lupus erythematosus (SLE). Diffuse alveolar hemorrhage may occur in SLE, often without hemoptysis. In this specimen, prominent airspace fibrin and blood are accompanied by siderophages and marked reactive type II cell hyperplasia. An interstitial pneumonia is also evident in the widened alveolar walls.

Figure 8.46 Systemic lupus erythematosus. At high magnification the acute lung injury of acute lupus pneumonitis is characterized by alveolitis with variable interstitial inflammation and edema.

Figure 8.47 Systemic lupus erythematosus (SLE). Siderophages and capillaritis may be present in the diffuse alveolar hemorrhage of SLE.

Histopathologic Findings

The most frequent lung manifestation of PM-DM is a cellular interstitial pneumonia (Fig. 8.49) with some fibrosis,^200,210 indistinguishable from NSIP (see the later section Idiopathic Interstitial Pneumonias). The next most common pattern is DAD (Fig. 8.50). The fibrosis associated with PM-DM is distinguishable from that of idiopathic UIP based on a relative lack of peripheral accentuation (Fig. 8.51) and absence of the typical transitions from older lung fibrosis to normal lung through fibroblastic foci. Pleuritis, inflammatory small airway disease, and pulmonary hypertension are unusual findings; their occurrence should suggest a manifestation of a different CTD.

Sjogren Syndrome

Sjogren syndrome is an immune-mediated exocrinopathy characterized by lymphocytic infiltration of the salivary glands, with resulting dry mouth and dry eyes.²¹⁴ Lung involvement is common and is similar to that in other CVDs manifesting in the lung.^121,215,216 Sjogren syndrome can occur as a primary CTD or as a complication associated with other CTDs (occurrence rates for the two forms are approximately equal).²¹⁴ In both primary and secondary forms, the consistent pathologic manifestation is that of lymphoid accumulation in a bronchiolocentric distribution and the NSIP/LIP pattern of cellular interstitial pneumonia.

Clinical Presentation

Women are more commonly affected with lung disease in Sjogren syndrome than men; the most frequent presenting complaint is cough and dyspnea.^121,215 Positive results on RF and ANA assays are expected findings, as well as positive reactions to extractable nuclear antigens (anti-SSA, anti-SSB).²¹⁷ These latter serologic tests are specific for the primary form of the disease.²¹⁸

Radiologic Findings

Mixed alveolar and interstitial infiltrates are characteristic in Sjogren syndrome; they usually have a finely reticular or nodular pattern.^216,219 the occurrence of pleural effusion or hilar/mediastinal adenopathy in patients with Sjogren syndrome should raise concern for lymphoma.²²⁰

Figure 8.48 Systemic lupus erythematosus (SLE). The cellular interstitial pneumonia of SLE lung is often accompanied by subacute lung injury with reactive type II cells and variable amounts of airspace fibrin (A). Some diffuse fibrosis typically is present in the nonspecific interstitial pneumonia manifestation of lupus, but advanced pulmonary fibrosis may occur in SLE, with chronic pleuritis (B).

Histopathologic Findings

The histopathologic spectrum of pulmonary Sjogren syndrome includes bronchiolitis (Fig. 8.52) with or without airspace organization, follicular lymphoid hyperplasia along airways (Fig. 8.53), diffuse NSIP or LIP pattern interstitial inflammation (Fig. 8.54), and, rarely, interstitial fibrosis (Fig. 8.55). The last of these raises concern for an inflammatory version of UIP. Small nonnecrotizing granulomas, resembling those of hypersensitivity pneumonitis, are frequently identified in the interstitium (Fig. 8.56).²²¹ In some cases, more prominent granulomatous inflammation can be seen, especially in association with the LIP pattern of cellular infiltration. Patients with Sjogren syndrome are at risk for developing lymphoid hyperplasia and lymphoproliferative diseases; this predilection should be kept in mind in evaluating the lung biopsy in this setting. Some patients will develop cystic disease identified by imaging studies and cysts with mild inflammation of the cyst wall possibly being the dominant histologic finding (Fig. 8.57).

Figure 8.49 Polymyositis-dermatomyositis (PM-DM). (A and B) the most frequent lung manifestation of PM-DM is a cellular interstitial pneumonia with some fibrosis, indistinguishable from cellular or fibrotic forms of nonspecific interstitial pneumonia.

Figure 8.50 Polymyositis-dermatomyositis (PM-DM). PM-DM-associated diffuse alveolar damage may precede the systemic and serologic manifestations of the disease by a year or more. Note the prominent hyaline membranes. Without an explanation for this acute lung disease, idiopathic acute interstitial pneumonia may be the clinical diagnosis until the systemic disease manifests itself.

Figure 8.51 Polymyositis-dermatomyositis (PM-DM). The fibrosis associated with PM-DM may be indistinguishable from that of idiopathic usual interstitial pneumonia in limited samples. In general, there is a relative lack of peripheral accentuation and absence of the typical transitions from older lung fibrosis to normal lung through fibroblastic foci.

Figure 8.52 Sjogren syndrome (SS). (A) the histopathologic spectrum of pulmonary SS includes bronchiolitis as the dominant and consistent feature. (B) Cysts may occur in SS and may be seen both radiologically and in surgical biopsy specimens.

Figure 8.53 Sjogren syndrome (SS). Terminal airway and alveolar space organization commonly accompany the bronchiolitis and cellular interstitial pneumonia of SS.

Figure 8.54 Sjogren syndrome (SS). Nonspecific interstitial pneumonia or lymphoid interstitial pneumonia pattern of interstitial inflammation in SS lung must be distinguished from low-grade lymphoproliferative disease when lymphocytes are dense and dominant. Note the numerous multinucleated giant cells and poorly formed granulomas in this specimen. Prominent arteriopathic changes with marked adventitial fibrosis can be seen in the pulmonary artery (center right).

Interstitial Pneumonia With Autoimmune Features

Patients may present with clinical, radiologic, or pathologic features of autoimmune disease but not meet current criteria for a defined CTD. These patients have been a management challenge historically, as rheumatologists and pulmonologists cannot agree on a diagnosis or treatment approach in the absence of a defined systemic disease. In 2015, a multidisciplinary consensus group under the auspices of the ERS/ATS proposed the term IPAF for such patients.⁷⁶ the goal of this term and the criteria is not to create a new diagnostic entity but to create a subset of IP patients who have autoimmune features requiring further diagnosis, treatment, and prognostic studies. To be identified as having IPAF, patients must meet criteria in at least two of the three domains—clinical, serologic, and morphologic features of CTD—and have other etiologies to explain their CTD excluded clinically. The morphologic domain has both radiographic and pathologic criteria. The pathologic criteria include the following histologic features: NSIP, OP, or LIP as histologic patterns and lymphoplasmacytic infiltration, pleural/pericardial thickening, or vasculopathy.

Figure 8.55 Sjogren syndrome (SS). Advanced interstitial fibrosis rarely occurs in SS lung disease and may raise concern for an inflammatory version of usual interstitial pneumonia. Note the absence of transitions to normal lung and absence of peripheral accentuation here.

From a practical perspective, pathologists should not make an outright diagnosis of IPAF, especially in the absence of clinical, radiologic, and serologic data. However, if the pathologic patterns described earlier are encountered, it is reasonable to raise IPAF as possibility in the differential diagnosis and suggest a complete set of serologic studies as well as a review of the published qualifying criteria to further evaluate the possibility. Finally, note that UIP is not included in the criteria for IPAF. This is not because CTD cannot result in the histologic features of UIP pattern but rather an intentional decision by the committee in an effort to keep the IPAF cohort pure for future study.

Diffuse Eosinophilic Lung Disease (Pulmonary Eosinophilia)

Several conditions have been described in which the lungs become infiltrated by eosinophils.^222,223 An etiologic and clinical classification of the “eosinophil-rich lung diseases” is presented in Box 8.10. Asthma and hypersensitivity play important roles in a number of these. Eosinophilic lung diseases are discussed together here, but in practice, only an acute onset of diffuse lung injury accompanied by extravascular eosinophils is relatively predictable in terms of clinical behavior and responsiveness to therapy (i.e., corticosteroids). When pulmonary eosinophilia presents as a chronic condition, the behavior seems to be less predictable. The term chronic eosinophilic pneumonia has been applied in such cases, even though the histopathologic findings in biopsy specimens may not reflect this longer evolution with observable fibrosis or structural remodeling.

Clinical Features

Patients with the chronic form of eosinophilic pneumonia often exhibit a typical clinical syndrome and radiographic appearance.²²⁴ the condition frequently affects middle-aged women, and asthma is present in approximately one fourth of the cases. Nasal symptoms occur in roughly one third of affected individuals. The disease typically presents with severe systemic symptoms, including fever, sweats, weight loss, cough, and dyspnea. Peripheral blood eosinophilia can often be identified, but this may be transient or entirely absent.

Figure 8.56 Sjogren syndrome (SS). (A) Small nonnecrotizing granulomas, resembling those of hypersensitivity pneumonitis, are frequently identified in the interstitium in the lymphoid interstitial pneumonia pattern of SS. (B) Sometimes the granulomas are more diffusely distributed; in such instances, infection and aspiration pneumonia will be important considerations in the differential diagnosis.

Figure 8.57 Cysts in Sjogren syndrome (SS). Intraparenchymal cysts with chronic inflammation of the cyst wall may be seen in SS.

Radiologic Findings

Chronic eosinophilic pneumonia presents the most consistent radiologic pattern, with bilateral, poorly defined, subpleural airspace consolidation on chest radiographs, most commonly distributed at the lung apices and in the axillary region. One unifying concept for the diffuse forms of eosinophilic lung disease is the migratory infiltrate. These infiltrates may disappear spontaneously and recur in the same position or elsewhere. In the most extreme cases, the infiltrates are densest in the periphery of the lung and spare the central region. This phenomenon has been referred to as the photographic negative of pulmonary edema.²²⁴ CT scans detect the peripheral location of infiltrates even when this distribution is not apparent on the chest radiograph.²²⁵ Once the characteristic presentation is recognized, corticosteroid administration can lead to dramatic improvement in patients with some forms of the disease and may even be used as a diagnostic test. Atypical presentations occur, so surgical wedge biopsy may be required to establish the diagnosis.

Figure 8.58 Eosinophilic pneumonia. (A) In acute eosinophilic pneumonia, the alveolar spaces are diffusely filled with eosinophils and plump eosinophilic macrophages, sometimes with an associated mild interstitial pneumonia. (B) Eosinophilic microabscesses may be present.

Histopathologic Findings

The histopathologic features of chronic pulmonary eosinophilia are similar to those of the acute form; it has been said that the distinction must rely on the clinical course rather than on the constellation of morphologic findings.¹ Alveolar spaces are filled with eosinophils and plump eosinophilic macrophages (Fig. 8.58), and There is an associated mild interstitial pneumonia. Type II hyperplasia is characteristic (Fig. 8.59), and fibrin is often present in the airspaces (Fig. 8.60). Angiitis of small vessels may be seen, and patchy airspace and alveolar duct organization may be present. A vaguely granulomatous accumulation of dense macrophages may be seen within the alveolar spaces (Fig. 8.61), sometimes accompanied by multinucle- ated giant cells whose nuclei and cytoplasm closely resemble those of adjacent macrophages (Fig. 8.62). Chronicity may be suggested by the presence of variable interstitial fibrosis on histopathologic examination, but, as mentioned earlier, this is not a prerequisite for the diagnosis.

Figure 8.59 Eosinophilic pneumonia. Highly atypical type II hyperplasia is characteristic in acute eosinophilic pneumonia, often raising concern for viral cytopathic changes.

Differential Diagnosis

When airspace organization is prominent, disorders with the OP pattern must be considered in the differential diagnosis (Box 8.8). Some investigators have proposed an overlap syndrome between COP and eosinophilic pneumonia with subacute clinical course; it is interesting that both conditions are expected to have favorable responses to systemic corticosteroid administration. When corticosteroids have been administered before biopsy (which is quite common), eosinophils may be absent or inconspicuous in lung sections. In such cases, the differential diagnosis may include granulomatous disease if the dense histiocytic response and multinucleated giant cells dominate the picture. When fibrin is prominent in the setting of pretreatment with corticosteroids, generic acute lung injury (including DAD and acute fibrinous and OP, because both patterns can be seen in acute eosinophilic pneumonia; see Chapter 6) may enter the histopathologic differential diagnosis. Some patients with long-standing symptoms may have fibrosis on biopsy; in such cases, a fibrosing lung disease, such as UIP or NSIP, may enter the differential diagnosis, with eosinophilic pneumonia possibly manifesting as a comorbid process (e.g., drug reaction superimposed on NSIP).

Clinical Course

The clinical course is somewhat dependent on the underlying cause of the eosinophilic pneumonia, but in general most affected individuals will benefit from high-dose corticosteroid therapy (although the speed of recovery may not be as rapid as that seen in eosinophilic pneumonia of acute onset). As in all cases of eosinophilic pneumonia, it is always worthwhile to suggest the possibility of eosinophilic GPA (Churg-Strauss syndrome) (see Chapter 11) because the pulmonary manifestations of that systemic vasculitic disease in the lung are most commonly those of eosinophilic pneumonia.

Drug-Associated Diffuse Lung Disease

An increasing number of medications have been implicated in chronic diffuse lung disease.^226,227 ttree distinct forms are recognized: (1) drug- mediated chronic diffuse lung disease, (2) acute lung injury associated with drug administration, and (3) vascular diseases produced by medications.^228,229 the last two conditions are dealt with in Chapters 6 and 11, respectively.

Figure 8.60 Eosinophilic pneumonia. (A) Fibrinous airspace exudates are commonly present, typically with admixed eosinophils, as seen in this specimen. (B) Organizing pneumonia pattern repair may also occur.

Figure 8.62 Eosinophilic pneumonia. The multinucleated giant cells of eosinophilic pneumonia have nuclei and cytoplasm that closely resemble those of adjacent alveolar macrophages, but occasionally they may be more brightly eosinophilic.

Figure 8.61 Eosinophilic pneumonia. A vaguely granulomatous accumulation of dense macrophages may be seen within the alveolar spaces, sometimes accompanied by plump multinucleated macrophages.

The recognition of drug-induced diffuse lung disease is a major challenge in lung pathology because most of the histopathologic changes identified are nonspecific (Table 8.5) and simulate those seen with other causes of diffuse lung disease.²⁸⁷ Moreover, many affected patients have underlying diseases for which a drug has been administered, and some of these diseases also have pulmonary manifestations. The diagnosis of a drug-mediated diffuse lung disease requires careful exclusion of other causes.²⁸⁷ Unfortunately a clear onset of pulmonary symptoms with drug administration and abatement of symptoms on cessation of the drug may not be easily discernible. Clinical information regarding specific drug type, dose, and timing of administration relative to onset of symptoms is essential to an accurate diagnosis.

General Histopathologic Findings

Most of the inflammatory changes in the lung related to drug toxicity are nonspecific. More often than not, a mixture of both acute and chronic disease is apparent and can be a clue to the diagnosis of drug-mediated injury.²⁶³ In chronic drug toxicity, lung fibrosis may occur, sometimes with honeycomb remodeling. In such cases, UIP may be simulated. Type II cell hyperplasia with or without atypia, cytoplasmic vacuolation in type II cells and macrophages, and tissue eosinophilia can occur in drug reactions. Also, some drugs are associated with the production in the lung of small, poorly formed granulomas, simulating infection, hypersensitivity, or even Sjogren syndrome.²²⁶

General Treatment and Prognosis

Most patients with drug-mediated diffuse lung disease have a favorable prognosis when the implicated drug is withdrawn. Certain newer targeted molecular therapies have been associated with a higher mortality rate when diffhse acute injury occurs.²⁴⁹’²⁸⁸ Once fibrosis has occurred, changes are likely to be stable, with little improvement. Systemic corticosteroid therapy may be added when symptoms are severe.

Table 8.5 Pulmonary Reactions and Associated Drugs

Drug	FIP	CIP	OP	Edema	DAD	Eos	AH BO PVOD Gran
Amiodarone230-232	+	++	+	++	+	+	++ +
Beta blockers233	+	++	+			+
Bevacizumab234							+
Bleomycin235,236	++	++	+	++	+	+	+
Busulfan237,238	+				+		+ +
Carmustine (BCNU)239240	+	++		++	+		+
Cocaine24'242					+	+	+ +
Cyclophosphamide243-246	+		+	++	+		+
Docetaxel247		+		+	+
Ergolines248	+	++	+
Erlotinib249					+
£ о p		++			+
Everolimus3',33		+	++	+	+		+
Gefitinib25'		+	+		++	+
Gemcitabine252	+	+		+	+		+
GM-CSF		++		++	+	+
Gold253	+	++	+		++	+
Heroin254,255		++		++			+
Hexamethonium256,257	+		+		+
Hydrochlorothiazide258,259,260		++		++	+	+
Imatinib		+			+
Infliximab26'	+	+			+	+
Leflunomide		+			++	+	+
Lomustine (CCNU)262	+				+
Methotrexate263,264	++	++	+	+	+	+	+ +
Minocycline265,266			+	++		+
Mitomycin C267,268	+	++		++	+		++ +
Nitrofurantoin269-27'	+	++	+	++	+	+	++ +
Paclitaxel272		+				+
Penicillamine273-275		+	+		+	+	++ +
Phenytoin276,277		+	+			+	++
Procarbazine278-280		+			+	+	+
Prozac (fluoxetine)28'		+
Rituximab282	+	+			+		+
Sulfasalazine283	+	++		++	+	+
L-Tryptophan284285		+				+
Zinostatin286					+		+

AH, Alveolar hemorrhage; BO, bronchiolitis obliterans; CCNU, chloroethyl-cyclohexyl-nitrosourea; CIP, cellular interstitial pneumonia including cellular NSIP and LIP patterns; DAD, diffuse alveolar damage; Eos, tissue eosinophilia; FIP, fibrosing interstitial pneumonia including UIP and fibrosing NSIP pattern; GM-CSF, granulocyte-macrophage colony-stimulating factor; Gran, granulomatous inflammation; LIP, lymphocytic interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; PVOD, pulmonary venoocclusive disease; UIP, usual interstitial pneumonia.

Specific Drugs Associated With Interstitial Lung Disease

Methotrexate

Methotrexate (MTX) lung toxicity is uncommon; when it occurs, it is predominantly a manifestation in women taking the drug.^289,290 Because MTX is used in the treatment of a variety of disorders (e.g., RA, some leukemias, some visceral cancers), these tend to be the associated underlying diseases that must be considered in the differential diagnosis for the lung manifestations identified. Interstitial inflammation and fibrosis (Fig. 8.63) are common findings in the surgical lung biopsy.^264,291,292 Giant cells and small nonnecrotizing granulomas (Fig. 8.64) are the only relatively specific markers for MTX in comparison with other drugs.²⁶⁴ Type II pneumocyte hyperplasia and tissue eosinophilia may be seen (Fig. 8.65). Hyaline membranes are rarely identified.²⁶⁴

Figure 8.63 Methotrexate toxicity. Nonspecific interstitial inflammation (A) and fibrosis (B) are common findings' and scattered lymphoid aggregates may be seen. When the latter are prominent and accompanied by bronchiolitis' the possibility of exacerbation of an underlying connective tissue disease (e.g.' rheumatoid arthritis) comes into the differential diagnosis.

Figure 8.64 Methotrexate toxicity. Giant cells and scattered small nonnecrotizing granulomas (center) are the only relatively specific markers for lung injury due to methotrexate.

Figure 8.65 Methotrexate toxicity. Type II pneumocyte hyperplasia (A) and variable acute lung injury with airspace organization (B), with or without tissue eosinophilia can be seen.

Amiodarone

Amiodarone is the drug of choice for the treatment of certain refractory cardiac arrhythmias. Pulmonary toxicity has been reported in 5% to 10% of patients taking this medication. Older patients are more likely to develop lung disease. The clinical onset is characterized by slowly progressive dyspnea and dry cough occurring within months of initiating therapy. Approximately one-third of patients experience an acute febrile illness mimicking infectious pneumonia.^232,293-295 High-resolution CT scans show diffuse infiltrates combined with basal or peripheral high- attenuation opacities and nonspecific infiltrates.^296,297 the most common pathologic manifestation is a cellular interstitial pneumonia (Fig. 8.66) associated with prominent intraalveolar macrophages whose cytoplasm shows fine vacuolation.^232,298-300 This vacuolation can also be seen in reactive type II pneumocytes (Fig. 8.67); published reports have described

Figure 8.66 Amiodarone toxicity. The most common pathologic change seen in amiodarone toxicity is a cellular interstitial pneumonia associated with prominent intraalveolar macrophages whose cytoplasm shows fine vacuolation.

The presence of characteristic lamellar cytoplasmic inclusions ultra- structurally.²²⁵ Unfortunately these cytoplasmic changes are an expected manifestation of the drug, so the mere presence of such changes is not sufficient to warrant a diagnosis of amiodarone toxicity.²⁹⁸ Pleural inflammation and pleural effusion have also been reported.³⁰¹ Some patients with amiodarone toxicity may develop an OP pattern (Fig. 8.68), a nodular pattern,²³⁰ or even DAD.^298,302,303 A majority of patients with amiodarone-related pulmonary toxicity will recover once the drug is discontinued.^{232,293,298-300}

BCNU

BCNU (carmustine) is the treatment of choice for patients with certain brain tumors and is used in some combination chemotherapy regimens. Acute and organizing DAD is the most common manifestation of acute BCNU pulmonary toxicity.^304-307 Delayed lung toxicity has been described in survivors of childhood brain tumors who received BCNU, with lung changes appearing 8 to 20 years after cessation of treatment.^304,308,309 the histopathologic features of BCNU toxicity can be generally grouped within the NSIP pattern (Fig. 8.69). In children, fibrosis develops in the upper lung zones, with peripheral accentuation.³⁰⁹ In adults, this upper lobe distribution is uncommon.³¹⁰ Pleural disease can accompany pulmonary abnormalities in some patients.

Busulfan

Busulfan is an alkylating agent that has been used in the treatment of chronic myelogenous leukemia. Pulmonary toxicity has been reported to occur in 4% of patients,^238,311,312 most commonly as acute lung injury. Unfortunately the prognosis for patients with busulfan-induced acute lung disease is poor. Rarely, patients with busulfan toxicity develop chronic diffuse lung disease (Fig. 8.70).²³⁷

Bleomycin

Bleomycin is a chemotherapeutic agent used in the treatment of lymphomas, epidermoid carcinomas, and malignant testicular tumors. Lung toxicity appears to be dose-related, but irradiation or oxygen therapy may predispose the lung to injury.^235,313-315 the typical clinical presentation begins with dry cough and progresses to breathlessness. Chest imaging reveals areas of nodular consolidation or diffuse reticulation.³¹⁶ In experimental models, the initial site of injury seems to be the venous endothelial cell, followed by necrosis of type I cells with consequent fibroplasia.^317-320 In humans, toxicity results in acute lung injury with airspace organization in the early phase and fibrosis as a late consequence (Fig. 8.71).

Figure 8.67 Amiodarone toxicity. (A and B) Amiodarone effect (fine cytoplasmic vacuolation; arrows) can be seen in airspace macrophages (arrow in A) and in reactive type II pneumocytes (arrow in B). Published reports have described the presence of characteristic lamellar cytoplasmic inclusions ultrastructurally. Unfortunately these cytoplasmic and ultrastructural changes are expected with treatment with this drug' so that the mere presence of such changes is not sufficient to warrant a diagnosis of amiodarone toxicity.

Figure 8.68 Amiodarone toxicity. (A) In some patients with amiodarone toxicity an organizing pneumonia pattern develops; resulting in a mass effect on thoracic imaging studies. (B) Rarely, chronic toxicity may result in advanced lung fibrosis.

Targeted Molecular Therapies

Progress in the application of newer anticancer therapies using antibodies and small molecules directed at molecular signaling pathways has led to increasing reports of pulmonary toxicity. For example, the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib is said to produce ILD in 1% of patients treated with this agent (2% to 4% in Japanese patients and 0.3% in US patients).^321,322 the most common histopathologic pattern associated with gefitinib use is DAD. The other main EGFR-TKI, erlotinib, is also reported to produce a DAD reaction pattern.²⁴⁹ the common risk factors for toxicity with these agents are smoking history, age, and the presence of preexisting ILD.²⁸⁸ Similar trends are seen with conventional cytotoxic chemotherapies, such as paclitaxel, docetaxel, and gemcitabine.

Figure 8.69 BCNU (carmustine) toxicity. The histopathologic features of BCNU toxicity are those of a nonspecific cellular interstitial pneumonia with variable interstitial fibrosis.

Figure 8.70 Busulfan toxicity. (A and B) the prognosis for patients with busulfan-induced acute lung disease is poor. In the subacute form of injury' airspace organization is often accompanied by marked atypia of reactive type II cells.

Figure 8.71 Bleomycin toxicity. Pulmonary changes may include acute lung injury with airspace organization in the early phase (A) and fibrosis resembling that of usual interstitial pneumonia as a late consequence (B).

Newer additions to the anti-inflammatory drug arsenal, such as the anti-tumor necrosis factor-а inhibitor infliximab, are also associated with adverse reactions, including an apparent risk for certain pulmonary infections, such as tuberculosis and aspergillosis, followed by DAD and pulmonary fibrosis.³²³

Everolimus and temsirolimus are mechanistic target of rapamycin (mTOR) inhibitors used in the treatment of renal cell carcinoma.^324,325 Both agents are reported to cause ILD. The predominant histologic findings are acute lung injury and inflammatory changes including OP, alveolar hemorrhage, and lymphocytic infiltration. Less common histologic manifestations reported include granulomatous inflammation, DIP, PAP, pulmonary vasculitis, and necrosis. The mechanism of lung injury is unclear, but some data suggest a hypersensitivity-type reaction, including a high level of helper T cells and a favorable response to corticosteroids.

Illicit Drug Abuse

Many of the described pulmonary manifestations of illicit drug use (Box 8.11) are related to infections derived from the use of contaminated needles for intravenous injection or comorbidity related to the use of inhaled substances.³²⁶ For a minority of substance abusers, intravenously injected solubilized analgesic tablets are the drug of choice. In current practice, the presence of perivascular talc particles in giant cells usually indicates a residual injury from earlier in the patient’s life, because tablet manufacturers today most often use microcrystalline cellulose compounds as binding and filling agents instead of talc, which was the practice several decades ago. When intravenous drug use entails injection of crushed analgesic tablets nowadays, microcrystalline cellulose is the commonly identified injurious particle in the lung parenchyma. The physical characteristics and histochemical staining reactions of this material are different than those of talc; these may sometimes be useful distinguishing features.³²⁷

Injected particles generally average 10 to 15 μm in diameter,^327-329 in contrast with inhaled substances, for which particle sizes tend to be smaller, usually less than 5 μm (with red blood cells used for size comparison). Cornstarch is another filler agent; it appears as a spherical structure with a “Maltese cross” pattern under plane-polarized light. Talc appears as irregular, platelike crystals that are strongly birefringent (Fig. 8.72) and may be slightly yellow on routine hematoxylin and eosin staining when a single polarizing filter is in place. Microcrystalline cellulose particles appear as elongated crystalline structures (Fig. 8.73) that may stain positively with digested periodic acid-Schiff reagent (PAS), methenamine silver, and Congo red stains. The reaction in the lung is generally interstitial and perivascular (Fig. 8.74) rather than intraalveolar. Intravenous foreign material may rarely become encrusted with iron (ferruginated), and sometimes colored tablet coatings (such as blue crospovidone) may be present and quite striking in histopathologic appearance.

Figure 8.72 Intravenous drug: talc. (A) the patient had intravenous talcosis' manifested on histopathologic examination as small clusters of multinucleated histiocytes containing irregular platelike crystals that are strongly birefringent under full polarization. (B) Birefringent talc particles may be seen in routine hematoxylin and eosin staining using plane-polarized light.

Figure 8.73 Intravenous drug: microcrystalline cellulose. (A) Microcrystalline cellulose particles appear as elongated crystalline structures in the cytoplasm of foreign body giant cells in the perivascular interstitium. (B) These particles are strongly birefringent in polarized light.

Figure 8.74 Intravenous drug: microcrystalline cellulose. (A) the reaction in the lung is generally interstitial and perivascular rather than intraalveolar. (B) the extent of intravenous foreign material may be better appreciated using polarizing filters.

Figure 8.75 Intravenous drug. (A) Normal light. (B) Polarized light. A perivascular interstitial foreign body-type granulomatous reaction is associated with prominent vascular changes' as seen here.

Figure 8.76 Intravenous drug. One complication of intravenous drug abuse is lung fibrosis (A); sometimes this can be massive (B).

Table 8.6 Pathologic Lesions and Clinical Syndromes Related to Intravenous Drug Use

Pathologic Lesion	Clinical Syndrome
Vascular' perivascular' and interstitial foreign body granulomas with:
Pulmonary arterial hypertension (with or without thrombotic lesions)	Pulmonary hypertension (may cause sudden death)
Interstitial fibrosis	Interstitial lung disease
Massive fibrosis	Complicated "pneumoconiosis" (tends to be bilateral and to involve the mid- and upper lung zones)
Panacinar emphysema	Emphysema/chronic airflow obstruction

Histopathologic Findings

As the intravenous material becomes lodged in the pulmonary microvasculature, a perivascular interstitial foreign body-type granulomatous reaction is produced (Fig. 8.75); this may be associated with prominent vascular changes (including pulmonary hypertension and thrombotic lesions and others)³³⁰ as well as interstitial fibrosis (Fig. 8.76), which may be focal or diffuse and sometimes massive.³³¹ Among the pathologic manifestations presented in Table 8.6, pulmonary hypertension is the most common, whereas emphysema is quite uncommon. Emphysema associated with intravenous drug abuse is typically of the panacinar type (similar to that in (α1-antitrypsin deficiency) and has most frequently been associated with methylphenidate (Ritalin) abuse.³³² In contrast with smoking-associated emphysema, the radiologic changes seen in so-called Ritalin lung are more severe in the lower lobes. Bullae may be present. In one report it was suggested that the presence of basilar pulmonary emphysema should always alert the radiologist to the possibility of intravenous drug abuse.³³² the pathogenesis of panlobular emphysema associated with intravenous drug abuse is unknown. Some of the postulated mechanisms include synergism with cigare The smoke, direct toxic effects of the drug, and induced intravascular leukocyte sequestration causing proteolytic pulmonary injury.

Because the foreign material remains in the lung, progression of the clinical and pathologic lesions may occur after discontinuation of intravenous drug use. Recurrence of the changes of intravenous drug abuse have been described rarely in transplanted lung tissue, although such recurrence appears to be a consequence of resumed intravenous drug abuse.³³³

Diffuse Lung Diseases With Granulomas

Granulomas occur in the lung in a variety of infectious and noninfectious diseases (Box 8.12).³³⁴ Infectious diseases with granulomas are discussed in Chapter 7. Although noninfectious granulomas can occur diffusely in the lungs in certain drug reactions and in Sjogren syndrome, the relatively specific disease entities of sarcoidosis, berylliosis, and hypersensitivity pneumonitis are discussed separately here because of their distinctive clinical, radiologic, and histopathologic presentations. A practical approach to lung biopsies with granulomas is presented at the end of this chapter.

Sarcoidosis

Clinical Presentation

Sarcoidosis is a systemic disease of uncertain etiology and with frequent lung manifestations.³³⁵ the lung disease is usually mild, accompanied by variable degrees of shortness of breath, chest pain, and cough.³³⁵ As many as two thirds of patients are asymptomatic.^294,336 Sarcoidosis is predominantly a disease of young adults but has been described in patients of all ages.^337-339 It can have an acute, subacute, or chronic presentation in the lung. In symptomatic patients, restrictive defects and decreased diffusing capacity are commonly described. Serum angiotensin-converting enzyme (ACE) is elevated in 30% to 80% of patients. ACE has also been detected within granulomas, bronchial alveolar lavage fluid, tears, and even cerebrospinal fluid in these patients. Unfortunately ACE levels can be elevated in a variety of disorders, including infectious granulomatous diseases, lymphoma, hepatitis, and diabetes.²⁹⁴ the Kveim test²⁹⁴ is relatively specific for sarcoidosis, employing an injected antigenic extract derived from human sarcoid granulomas, but the test is not widely used today,³³⁵ given the widespread adoption of bronchoscopic biopsy for confirming the diagnosis in patients suspected of having the disease on clinical and radiologic grounds.

Radiologic Findings

The clinical staging of sarcoidosis is based on the findings of chest radiography. Five stages of pulmonary sarcoidosis are described, corresponding to the extent of disease. Stage I and stage II disease are most common, with only 15% of patients presenting with parenchymal infiltrates alone.^294,335 When sarcoidosis involves the lung parenchyma, the disease is upper lobe predominant.³³⁵ CT scans are not usually necessary for the diagnosis but will show reticulonodular opacities along lymphatic routes, with or without alveolar infiltrates.^294,340-342 Bullae with honeycombing may be seen in advanced disease, sometimes associated with progressive lung fibrosis.^343,344 A peculiar form of sarcoidosis with rapid onset of symptoms and a diffuse alveolar filling pattern on CT scans has been referred to as alveolar sarcoidosis.⁵⁴⁵ the pathologic manifestations of this form of the disease are distinctive only for the large number of small interstitial granulomas present throughout the lung parenchyma.

Histopathologic Findings

The characteristic histopathologic lesion of pulmonary sarcoidosis is the nonnecrotizing (immune) granuloma, typically occurring within areas of sclerotic fibrosis (Fig. 8.77). In sarcoidosis, small granulomas have a tendency to coalesce to form larger nodular lesions, all embedded in refractile eosinophilic collagen (Fig. 8.78). A narrow rim of lymphocytic inflammation is typically seen at the periphery of these confluent nodules (Fig. 8.79). Granulomas are distributed along lymphatic routes in the pleura, within the intralobular septa, and along the bronchovascular bundles (Fig. 8.80). Multinucleated giant cells are characteristically present in the disease, often accompanied by a variety of distinctive cytoplasmic inclusions (e.g., Schaumann bodies, asteroid bodies) (Fig. 8.81). A mild inflammatory interstitial infiltrate is said to occur occasionally in pulmonary sarcoidosis, but in practice this is rarely seen. In bronchoscopic or transbronchial biopsies, granulomas are typically seen immediately beneath the airway mucosa (Fig. 8.82).

Figure 8.77 Sarcoidosis. The characteristic pathologic lesion of pulmonary sarcoidosis is the nonnecrotizing (immune) granuloma (A), typically occurring within sclerotic fibrosis (B).

Figure 8.78 Sarcoidosis. In sarcoidosis, small granulomas have a tendency to coalesce to form larger nodular lesions all embedded in refractile eosinophilic collagen.

Figure 8.79 Sarcoidosis. A variable (but rarely intense) rim of lymphocytic inflammation is typically seen at the periphery of confluent granulomas.

Gilman and coworkers showed that the chance of obtaining a positive result in patients with sarcoidosis increased to 90% when four biopsy specimens were obtained.³⁴⁶ When five to six samples were obtained, the probability rose to 100% for patients with stage II and III disease.

Special stains for organisms (acid-fast stains and silver stains) should be routinely used when granulomas are identified in lung biopsies to exclude infection, even in the absence of necrosis. In a retrospective study performed by Hsu and colleagues, positive microbiologic cultures were identified in 11% of biopsies in which granulomas were present despite negative special stains of tissue sections.³⁴⁷ In the culture-positive cases, clinical and radiographic findings were judged to be of low or intermediate suspicion for sarcoidosis. As might be expected, necrosis in granulomas was more frequently associated with culture-positive cases.

Figure 8.80 Sarcoidosis. (A) Granulomas are distributed along lymphatic routes in the pleura within the intralobular septa and along the bronchovascular bundles. This image is diagnostic of sarcoidosis' but berylliosis should always be included as a diagnostic possibility. (B) Perivascular granulomas embedded in sclerosis are commonly seen. Despite this potential for vasocentric growth, pulmonary hypertension is an uncommon complication of sarcoidosis.

Differential Diagnosis

Granulomatous infection leads the differential diagnosis for sarcoidosis and is the diagnosis of exclusion. The granulomas of hypersensitivity pneumonitis are vague and poorly formed. Aspiration pneumonia can be associated with granuloma formation, but these tend to resemble foreign body-type granulomas with characteristic multinucleated giant cells, often containing foreign material (primarily partially digested food).

Chronic Berylliosis

Beryllium, derived from the mineral beryl, is the etiologic agent for berylliosis.^348-350 the disease occurs after inhalation of this metal or its salts.³⁵¹ Today exposure to beryllium occurs mainly as an occupational lung disease, particularly in the computer manufacturing and aerospace engineering fields. However, recent reports indicate that individuals with low-level exposure, such as residents living near facilities that use beryllium, can also develop berylliosis (for additional discussion, see Chapter 9).^352-354

Figure 8.81 Sarcoidosis. Multinucleated giant cells characteristically are present, often accompanied by a variety of distinctive (but not specific) cytoplasmic inclusions: (A) asteroid body; (B) Schaumann body; (C) Schaumann (conchoidal) bodies; (D) Schaumann body in polarized light.

Figure 8.82 Sarcoidosis. In bronchoscopic or transbronchial biopsies, granulomas may be quite dramatic in appearance (A), but sometimes the histopathologic pattern is more subtle. (B) In bronchial mucosal biopsies, lesions are typically present in the immediate subepithelial region of the airway.

Acute berylliosis occurs after heavy exposure; fortunately it is rare today as a consequence of strict industrial exposure regulations and aggressive surveillance in such settings. When acute berylliosis occurs, the histopathologic findings are similar to those of DAD. The chronic form of berylliosis is indistinguishable from sarcoidosis on histopathologic grounds.^348-350 Like sarcoidosis, chronic berylliosis produces fibrosis of variable severity and comprises distinct granulomas with giant cells (Fig. 8.83). Chronic berylliosis may produce large, centrally hyalinized nodules (Fig. 8.84), which can mimic resolved lesions of histoplasmosis. When granulomas are less prominent, chronic berylliosis may also simulate hypersensitivity pneumonitis histopathologically (Fig. 8.85).

Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

Environmental antigens (typically, “organic” protein antigens) are known to produce characteristic inflammatory reactions in the lung in certain predisposed individuals.^355-358 the classic descriptions of farmer’s lung, resulting from exposure to thermophilic actinomycetes in hay, and bird fancier’s lung, resulting from the inhalation from avian antigens, are examples of hypersensitivity pneumonitis. Similar reactions to ingested antigens associated with some medications can also occur. In general usage, however, hypersensitivity pneumonitis refers to disease occurring as a result of inhalation exposure. The more common antigens implicated in hypersensitivity pneumonitis are presented in Table 8.7.

Clinical Presentation

Hypersensitivity pneumonitis can occur as acute or subacute and chronic forms. The acute form occurs within hours of inhalational exposure to the antigen. Affected individuals experience malaise, dyspnea, dry cough, and occasionally fever and chills. With this symptom complex, the differential diagnosis will include viral infection. Recurrence of symptoms and signs follows subsequent exposure episodes.³⁵⁹ Women are more commonly affected than men. Cigare The smoking seems to reduce the risk of developing hypersensitivity, although the mechanism for this protective effect is unknown.³⁶⁰

Figure 8.83 Berylliosis. Like sarcoidosis, chronic berylliosis produces variable fibrosis (A) and distinct granulomas with giant cells (B). There may be a suggestion of more lymphocytic inflammation, but this finding is not sufficiently reliable to be useful diagnostically.

Figure 8.84 Berylliosis. (A and B) Chronic berylliosis may produce large, centrally hyalinized nodules, which can mimic resolved lesions of histoplasmosis.

Figure 8.85 Berylliosis. When granulomas are less prominent, as in this specimen, hypersensitivity pneumonitis may enter the differential diagnosis.

Table 8.7 Agents of Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

Antigen	Source	Disease
Thermophilic Bacteria
Micropolyspora faeni	Moldy hay	Farmer’s lung
Thermoactinomyces vulgaris	Moldy compost	Mushroom worker’s disease
Thermoactinomyces sacchari	Moldy sugar cane	Bagassosis
Thermoactinomyces vulgaris	Air conditioners, humidifiers	Air conditioner lung/ humidifier lung
Thermoactinomyces candidus	Air conditioners, humidifiers	Air conditioner lung/ humidifier lung
Molds
Cryptostroma corticale	Moldy maple bark	Maple bark stripper’s disease
Aspergillus clavatus	Moldy barley	Malt worker’s lung
Graphium spp.	Moldy wood dust	Sequoiosis
Pullularia spp.	Moldy wood dust	Sequoiosis
Trichosporon cutaneum	Home environment	Summer-type hypersensitivity pneumonitis (Japan)
Other Bacteria
Bacillus subtilis	Water	Detergent worker’s lung
Bacillus cereus	Water	Humidifier lung
Bacterial products	Cotton	Byssinosis
Amebae	Water	Humidifier lung
Insect products	Grain	Wheat weevil disease
Chemicals
Trimellitic anhydride (TMA)	Plastics, rubber manufacturing	Chemical worker’s lung
Methylene diisocyanate (MDI)	Plastics, rubber manufacturing	Chemical worker’s lung
Toluene diisocyanate (TDI)	Plastics, rubber manufacturing	Chemical worker’s lung
Pyromellitic dianhydride (PMDA)	Epoxy resin	Chemical worker’s lung

Reprinted with permission from Katzenstein A, Askin F, eds. Surgical Pathology of Non-Neoplastic Lung Disease. 2nd ed. Philadelphia: WB Saunders; 1990:139.

The chronic form of hypersensitivity pneumonitis probably results from lower levels of antigen exposure over time, presumably accompanied by more subtle symptoms, so that the affected person may not associate the symptom with a specific exposure.^359,361 the frequency of disease occurrence in smokers and men is higher in the chronic form than in the acute and subacute forms of the disease. Unfortunately the chronic form of hypersensitivity pneumonitis may be progressive, eventuating in death from end-stage lung fibrosis.^359,361 As in the acute phase, patients experience chronic malaise and varying degrees of breathlessness on exertion, sometimes accompanied by weight loss. Several excellent reviews of hypersensitivity pneumonitis are available.^{357-359,361,362}

Radiologic Findings

In acute hypersensitivity pneumonitis, a diffuse ground-glass appearance is seen on CT scans of the chest, sometimes accompanied by fine nodules.³⁶³ In subacute disease, abnormalities tend to be confined to the upper half or two thirds of the lung and are characterized radiologi- cally as ill-defined centrilobular nodules. In more chronic forms, small nodules, variable ground-glass change, and irregular linear opacities may be seen, most often in the middle lung zones (with relative sparing of the apices and bases) or without a specific zonal predilection.²⁵ the presence of irregular linear opacities correlates with the presence of lung fibrosis.^359,362 At a very late stage of chronic hypersensitivity pneumonitis, honeycomb remodeling may be identified radiologically, mimicking UIP.^25,26 Interestingly, the CT appearance of subacute hypersensitivity pneumonitis may be indistinguishable from that if low-grade atypical mycobacterial infection occurring in the immunocompetent host as a result of bioaerosol exposure to nontuberculous mycobacteria (so-called hot tub lung; see Chapter 7).^364,365

Figure 8.86 Hypersensitivity pneumonitis. This pathologic process manifests as a chronic inflammatory interstitial pneumonia associated with bronchiolitis (A) and small, indistinct, nonnecrotizing interstitial granulomas (B).

Figure 8.87 Hypersensitivity pneumonitis. At low magnification, the surgical lung biopsy shows a moderately dense interstitial infiltrate, causing slight widening of the alveolar walls.

Figure 8.88 Hypersensitivity pneumonitis. A bronchiolocentric distribution may be evident, as indicated either by the presence of a terminal bronchiole or by some degree of nodularity to the infiltrates at low magnification.

Figure 8.89 Hypersensitivity pneumonitis. The characteristic interstitial granulomas are sufficiently vague in appearance as to escape notice in many cases. Prominent, well-formed granulomas are not a typical manifestation of the disease.

Figure 8.90 Hypersensitivity pneumonitis. Multinucleated giant cells may also be seen in the interstitium and constitute a helpful feature at low magnification in drawing the eye to features meriting closer examination.

Figure 8.91 Hypersensitivity pneumonitis. Patchy airspace organization can be seen in as many as 60% of affected patients.

Histopathologic Findings

The histopathologic features of hypersensitivity pneumonitis are typically those of a chronic inflammatory interstitial pneumonia associated with bronchiolitis and small, indistinct, nonnecrotizing interstitial granulomas (see Case 4 and Fig. 8.86).^355-367 In early reports of farmer’s lung, acute inflammation and vasculitis were also observed.³⁶⁸ the histopathology of hypersensitivity pneumonitis raises a differential diagnosis that includes other cellular interstitial pneumonias, such as NSIP. At low magnification, the surgical lung biopsy shows a moderately dense interstitial infiltrate, composed of plasma cells and small lymphocytes, causing slight widening of the alveolar walls (Fig. 8.87). A bronchiolocentric distribution may be evident, either by the presence of a terminal bronchiole or by some degree of nodularity in the infiltrates at low magnification (Fig. 8.88). The interstitial granulomas of hypersensitivity pneumonitis are inconspicuous (Fig. 8.89) and may often easily escape notice. Multinucleated giant cells (Fig. 8.90) may be seen in the interstitium at scanning magnification and constitute a helpful feature in prompting closer examination of the interstitium for epithelioid histiocytes in small aggregates. Necrosis is not a component of the granulomatous reaction in hypersensitivity pneumonitis. Airspace organization (Fig. 8.91) with immature fibroblasts and matrix (OP pattern) can be seen in as many as 60% of patients with hypersensitivity pneumonitis.³⁶⁶ In general this is not confluent organization as seen in OP of infectious etiology. Rather, small tufted patches of organization can be seen scattered throughout the lung biopsy. Some degree of bronchiolitis is expected in hypersensitivity pneumonitis; this is characterized by aggregates of lymphocytes and plasma cells surrounding terminal airways (Fig. 8.92). A mild perivascular lymphoid accumulation is typically present in hypersensitivity pneumonitis, but prominent germinal centers or dense lymphoplasmacellular infiltration along vascular sheaths (especially veins in the interlobular septa) is not typical and should raise concern for lymphoproliferative disease (which on occasion can simulate the cellular phase of chronic hypersensitivity pneumonitis). In the chronic form, dense fibrosis with microscopic honeycombing can be seen (Fig. 8.93). Peribronchiolar metaplasia along with peribronchiolar fibrosis is frequent. There may be bridging formations between peribronchiolar areas and subpleural scar, analogous to “bridging fibrosis” in liver disease.³⁶⁹ Refractile oxalate crystals in giant cells may be sufficiently prominent to suggest aspiration pneumonia or even pneumoconiosis (Fig. 8.94).

Clinical Course

The clinical course in hypersensitivity pneumonitis varies with the intensity and chronicity of exposure.^359,368,370 If an offending antigen cannot be identified in the patient’s environment, the prognosis is guarded, since patients may not respond to corticosteroid therapy in the continued presence of the initiating antigen.^371-375 Once lung fibrosis ensues, immunosuppressive therapy is of little benefit, especially if continued antigen exposure occurs.³⁷⁵

Differential Diagnosis

Cellular interstitial pneumonias with or without small nonnecrotizing granulomas can be a component of drug reactions and low-grade infections (especially those produced by atypical mycobacterial species). Whether true hypersensitivity pneumonitis can occur due to the ingestion of drugs is controversial. Early sarcoidosis is included in the differential diagnosis, but the presence of more characteristic, well-formed granulomas of sarcoidosis and the presence of sclerotic fibrous tissue matrix surrounding the granulomas is helpful in differentiating sarcoidosis from hypersensitivity pneumonitis. Also, interstitial inflammation can be seen in sarcoidosis, but it is exceedingly mild if present at all. As mentioned earlier, when lymphoplasmacellular infiltrates are dense or confluent, LIP or low-grade malignant lymphoma of MALT enters the differential diagnosis. In that situation, immunohistochemical stains (CD20, CD3, kappa and lambda immunoglobulin light chains) may be helpful in demonstrating a predominance of CD20-positive B lymphocytes or a lambda light chain predominance; such findings should raise serious consideration of malignant lymphoma.

Figure 8.92 Hypersensitivity pneumonitis. (A) Bronchiolitis' an expected feature in this disorder is manifested here as aggregates of lymphocytes and plasma cells surrounding a terminal airway. (B) Presumably as a consequence of bronchiolitis and some degree of obstruction' prominently vacuolated macrophages may be present in a bronchiolocentric distribution.

Miscellaneous Diffuse Lung Diseases

Pulmonary Langerhans Cell Histiocytosis

In addition to smoking-related ILD, another important consequence of smoking is pulmonary Langerhans cells histiocytosis (PLCH), a lung disease previously referred to as pulmonary eosinophilic granuloma or pulmonary histiocytosis X. PLCH is considered to be a reactive proliferative disease of Langerhans cells,^376,377 in contrast to extrapulmonary forms of Langerhans cell histiocytosis, which are thought to be neoplasms.³⁷⁸ A compelling association with cigare The smoking has led to the general acceptance of this lung disorder as a smoking-related disease.^379,380 the pathobiology of PLCH has been comprehensively reviewed by Vassalo and associates.³⁷⁷ Although PLCH is unrelated to the systemic diseases of Langerhans cells (eosinophilic granuloma,

Figure 8.93 Hypersensitivity pneumonitis. (A) In chronic hypersensitivity pneumonitis, prominent bronchiolization (“Lambertosis”) attests to chronic airway injury from inhaled antigen. (B) Dense fibrosis with microscopic honeycombing resembling that in usual interstitial pneumonia may also be seen.

Figure 8.94 Hypersensitivity pneumonitis. Refractile oxalate crystals in giant cells may be sufficiently prominent to suggest aspiration pneumonia or even pneumoconiosis.

Figure 8.95 Pulmonary Langerhans cell histiocytosis. At scanning magnification, the characteristic nodules have a stellate appearance and are centered on the small airways.

Letterer-Siwi disease, Hand-Schüller-Christian disease), systemic eosinophilic granuloma involving the lung, when it occurs, is said to be indistinguishable from the cellular phase of PLCH on histopathologic grounds.³⁸¹

Two distinctive histopathologic manifestations of PLCH occur—a cellular form and a fibrotic form. The natural history of PLCH suggests that the early lesions of PLCH are cellular, with many Langerhans cells and tissue eosinophils, whereas older lesions are predominantly fibrotic. Such a natural progression may occur continuously in the same patient, with younger cellular lesions admixed with older ones; in most surgical biopsy specimens, however, one form of the disease seems to predominate.³⁷⁷ Often the fibrotic lesions of the disease are not recognized because of the paucity or absence of Langerhans cells, and the proliferative lesions are typically mistaken for neoplasm.

Clinical Presentation

The true incidence and prevalence of PLCH are unknown. Most patients are between 20 and 50 years of age at the onset of symptoms; women may be more commonly affected than men.^377,379,382 Chronic cough and dyspnea are typical presenting complaints. However, a significant percentage of patients are asymptomatic. Rarely, hemoptysis or pneumothorax can occur.

Radiologic Findings

PLCH is a disease of the upper lung zones. Small nodules and cysts are present to a variable degree as seen on plain films of the chest.^382-385 the nodules range in size from 0.2 to 1 cm. When fibrosis occurs, it is best seen on high-resolution CT scans and appears as reticular opacities.^384,386 When significant fibrosis occurs in PLCH, the disease may simulate IPF 383,384,386

Histopathologic Findings

Proliferative (Cellular) Phase. At scanning magnification, the nodules of PLCH have a stellate appearance and are centered on the small airways (Fig. 8.95). Cysts are formed at the periphery of nodules by traction on surrounding alveolar walls or the central terminal airway, resulting in variably sized spaces typically lacking distinctive lining cells (Fig. 8.96).

Figure 8.96 Pulmonary Langerhans cell histiocytosis. The characteristic cysts are formed by traction on surrounding alveolar walls or the central terminal airway, resulting in variably sized spaces typically lacking distinctive lining cells.

Figure 8.97 Pulmonary Langerhans cell histiocytosis. The characteristic stellate cellular nodules may be as large as 1.5 cm in diameter.

Stellate cellular nodules may be as large as 1.5 cm,³⁸¹ and the confluence of nodules affecting adjacent airways may impart a serpentine outline to the lesions (see Case 5 and Fig. 8.97). As suggested by a three-dimensional reconstruction study, the lesions of PLCH seem to form a sheath around the small airways exclusively and extend proximally and distally in a continuous fashion.³⁸⁷ In many cases, lightly pigmented brown macrophages (“smoker’s macrophages”) are present in and around the nodules (Fig. 8.98). Eosinophils in variable numbers occupy the next innermost layer of the nodules (Fig. 8.99); this is the location in which aggregated Langerhans cells are most easily found in the thickened interstitium (Fig. 8.100). The Langerhans cells have a pale basophilic nucleus with characteristic sharp nuclear infoldings, imparting a “crumpled tissue paper” nuclear contour (Fig. 8.101). The cytoplasm of the Langerhans cell is granular and mildly eosinophilic, with indistinct margins. In these cellular lesions of PLCH, immunohistochemical stains for S100 protein and CD1a can be used to highlight the presence of Langerhans cells (Fig. 8.102), but in most instances the morphology of the lesions is compelling enough for a definitive diagnosis to be established without the aid of special stains. In some cases patchy interstitial and airspace organization (Fig. 8.103) may be seen, and RB is typically present. Other smoking-related lung changes may be present, adding further complexity to the morphologic picture (e.g., DIP/RBILD, small-airway disease with mucostasis, areas of bronchiolization).

Figure 8.98 Pulmonary Langerhans cell histiocytosis. (A and B) In many cases, a rim of lightly pigmented, brown macrophages (“smoker’s macrophages”) is present within and around the nodules.

Figure 8.99 Pulmonary Langerhans cell histiocytosis. Eosinophils in variable numbers occupy the next innermost layer of the nodules.

Figure 8.100 Pulmonary Langerhans cell histiocytosis. Aggregates of Langerhans cells are most readily found in the thickened interstitium of the stellate ramifications of the lesions.

Figure 8.101 Pulmonary Langerhans cell histiocytosis. The Langerhans cells have a pale nucleus with characteristic sharp nuclear infoldings' imparting a "crumpled tissue paper” outline. The cytoplasm is variably eosinophilic and indistinct.

Figure 8.102 Pulmonary Langerhans cell histiocytosis (PLCH). In the cellular lesions of PLCH, immunohistochemical stains for S100 protein (A) and CD1a (B) can be used to highlight the presence of Langerhans cells (immunohistochemical stains; red chromogen). In most cases, however, the morphology of the lesions is sufficiently compelling that a definitive diagnosis can be established without the aid of special stains.

Fibrotic Lesions. With aging of the lesions of PLCH, Langerhans cells become progressively depleted and overshadowed by fibrosis (Fig. 8.104). The mechanism for this transformation is unknown. In some patients, only residual stellate parenchymal scars are found. In these patients, pulmonary function may be significantly compromised (by a process analogous to constrictive bronchiolitis). Lung function and radiologic studies may suggest a diffuse lung disease, but biopsy tissue may exhibit only stellate fibrotic lesions centered on the terminal airways without an identifiable interstitial inflammatory disease (Fig. 8.105). Another scenario in which such scars can be seen is in portions of lung removed for other reasons (e.g., bronchogenic carcinoma). Presumably these footprints of previous PLCH are incidental findings and do not necessarily imply active disease elsewhere in the lung.

Figure 8.103 Pulmonary Langerhans cell histiocytosis. In some cases, patchy airspace organization may be present, but it is not a particularly characteristic feature of the disease.

Differential Diagnosis

Nodular infections and neoplasm are common in the differential diagnosis radiologically, the latter especially in the setting of known breast carcinoma in a young woman undergoing screening for metastatic disease to the lungs. Pathologically, the proliferative lesions may be mistaken for neoplasm as well, but careful attention to the layered or zonal composition of the nodules and the distinctive morphology of the Langerhans cells will typically bring the diagnosis of PLCH to the forefront. When cysts are prominent, lymphangioleiomyomatosis (LAM) enters the differential diagnosis (see further on). In this setting, immunohistochemical stains may be useful in establishing the correct diagnosis (S100 protein immunoreactivity in Langerhans cells vs. HMB45 and actin in LAM cells). Other nodular lung diseases are occasionally confused with PLCH, including GPA, Hodgkin disease, and certain metastatic low-grade sarcomas. When fibrotic lesions are dominant, UIP (clinical IPF) and other fibrosing lung disorders may be suggested. Helpful distinguishing features include the stellate appearance of the PLCH lesion, the tendency for lesions to spare the pleura and immediate subpleural lung, and the association of scars with the airways. Rarely, pneumothorax (from any cause) can produce subpleural fibrosis with sheets of tissue eosinophils (so-called reactive eosinophilic pleuritis').^388,39 Such lesions are not usually confused with PLCH but on occasion may be the only pathologic change identified on biopsy following pneumothorax (sometimes during surgical intervention for the pneumothorax), raising concern of undersampled or “upstream” PLCH. Radiologic correlation may be very helpful in this setting.

Clinical Course

Smoking cessation is the most effective management approach and is the “treatment” of choice³⁷⁷; however, a prospective study showed no significant effect of smoking cessation.³⁹⁰ Immunosuppression with corticosteroids, with or without the addition of a cytotoxic agent, has met with variable success. Pulmonary hypertension is one of complications, and the development of hypertension is associated with a poor prognosis.³⁹¹ In larger reviews, the median survival time is 12 years,³⁷⁷’³⁹² with 5- and 10-year survival rates of 70% and 60%, respectively. The most frequent cause of death is the respiratory complications associated with neoplasms of hematologic, pulmonary, or other organs. Survival rates are worse for patients with poorer respiratory function at diagnosis.³⁷⁷

Erdheim-Chester Disease

Erdheim-Chester disease (ECD) is a rare, nonfamilial, non-Langerhans cell, systemic histiocytosis affecting middle-aged adults; it has no gender predilection.^393-395 the disease is characterized by xanthogranulomatous infiltration of the long tubular bones, resulting in symmetrical osteo- sclerosis.³⁹³’^396-399 Extraskeletal involvement is relatively common, occurring in approximately half of patients. Of the reported extraskeletal sites, the pituitary area, skin, orbit, pericardium, and retroperitoneum are most often involved.

Figure 8.104 Pulmonary Langerhans cell histiocytosis (PLCH). As the lesions of PLCH age, they become progressively fibrotic (A), and Langerhans cells become depleted and replaced by fibrosis (B).

Clinical Presentation

Pulmonary involvement occurs in approximately one third of patients with ECD and is associated with significant morbidity and mortality.^393,400-404 Progressive breathlessness is the typical presentation.

Radiologic Findings

CT scans reveal thickening of the visceral pleura and interlobular septa, fine reticular and centrilobular opacities, and ground-glass attenuation.⁴⁰³

Histopathologic Findings

In surgical wedge lung biopsies, a distinctive interstitial infiltrate is observed consisting of xanthomatous histiocytes, lymphocytes, and scattered Touton-type giant cells (Fig. 8.106).⁴⁰² Prominent fibrosis is present in a characteristic subpleural and lymphatic distribution (Fig. 8.107). In immunohistochemical studies, the cells of ECD express histiocytic markers (CD68 and factor XIIIa) but typically lack CD1a immunoreactivity. S100 protein immunoreactivity occurs in a subset of patients.

Figure 8.105 Erdheim-Chester disease. (A) In surgical wedge lung biopsies or resected lung lobes, a distinctive pattern of pleural and septal fibrosis is evident, with a distinctive lymphatic distribution. (B) Admixed lymphoid aggregates are typical. The interface with surrounding lung is generally abrupt.

Figure 8.106 Erdheim-Chester disease. (A) On closer inspection, the characteristic fibrotic process is seen to contain xanthomatous histiocytes, lymphocytes, and scattered Touton-type giant cells. (B) These giant cells, along with other histiocytes in the infiltrate, can be highlighted with immunohistochemical stains for CD68 and factor XIIIa.

Differential Diagnosis

The differential diagnosis includes advanced lung fibrosis associated with pulmonary Langerhans cell histiocytosis and the exceedingly rare occurrence of lung manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy—see Chapter 19 for discussion). In advanced PLCH, the fibrosis tends to be more confluent and particularly bronchiolocentric, with blunt, stellate-shaped scars. In Rosai-Dorfman disease, the histiocytic nature of the process is often overshadowed by the inflammatory component (Fig. 8.108).

Clinical Course

Patients with pulmonary involvement by ECD typically follow a progressive downhill course, with respiratory compromise and death. The disease is unresponsive to therapy.

Lymphangioleiomyomatosis

LAM is a rare chronic lung disease characterized by the presence of cysts accompanied by bundles of distinctive smooth muscle cells.^405-410 In the latest WHO classification, LAM is categorized as a diffuse multicystic form of PEComatous tumors.⁴¹¹ LAM is a disease that affects women; it has a distinctive relationship to the genetic disorder known as the tuberous sclerosis complex (TSC).⁴¹² Recent experimental data have demonstrated loss of heterozygosity on 9p and 16p and mutation in the TSC gene (TSC2), suggesting that LAM is a neoplastic disease.^413-415 Nevertheless, debate continues as to whether LAM is a true neoplasm or represents hyperplasia of genetically aberrant cells. Although LAM was considered to be a disease unique to women, rare cases of LAM in males have been reported.⁴¹⁶ Likewise, we have seen an additional case in consultation (unpublished data) in a phenotypic male with TSC. LAM is included in this chapter because the disease typically presents clinically and radiologically as a chronic diffuse lung process.

Figure 8.107 Rosai-Dorfman disease. (A) Nodular expansion of interlobular septa, pleura, and bronchovascular sheaths is apparent at low magnification. (B) the mixed inflammatory composition of the process becomes more evident at higher magnification.

Figure 8.108 Rosai-Dorfman disease. (A) the histiocytic nature of the disease process is often overshadowed by the inflammatory component. (B) An S100 protein stain may be very useful in establishing the diagnosis. Emperipolesis, the typical finding in the more common lymph node manifestation of the disease, may be difficult to appreciate on routine hematoxylin and eosin-stained sections of lung tissue.

Clinical Presentation

LAM occurs most frequently in women of childbearing age, with a peak incidence in the fourth decade of life.⁴⁰⁵’⁴⁰⁹ Two forms of the disease occur, one sporadically and the other in association with the genetic marker for TSC. In both forms of the disease, extrathoracic (especially renal) angiomyolipomas are common.^417-422 Of note, the rare male patients reported to have LAM also had TSC.⁴¹⁶ LAM is often asymptomatic in its early stage, and many affected individuals are diagnosed by chest radiographs performed for other reasons. The most common clinical complaint is shortness of breath.⁴⁰⁵’⁴⁰⁹’⁴¹⁰ Pneumothorax occurs, and pleurocentesis may reveal a chylous effusion.

Radiologic Features

Plain films of the chest may be interpreted as normal,⁴²³ but with pneumothorax, air or fluid may be present in the pleural space. Small nodules and cysts may be detected and are typically present diffusely in the lungs, in contrast with the upper lobe distribution of lesions in PLCH. CT scans show diagnostic changes, with small nodules and thin-walled cysts seen throughout both lungs.^423-427

Figure 8.109 Lymphangioleiomyomatosis (LAM). LAM lesions may be difficult to appreciate at scanning magnification, particularly in cases where smooth muscle lesions are sparse or of small size.

Histopathologic Features

LAM lesions may be difficult to appreciate at scanning magnification, particularly in cases where smooth muscle lesions are sparse or of small size (Fig. 8.109). In most cases thin-walled cysts are easily visible (Fig. 8.110) and useful for identifying diagnostic smooth muscle bundles at higher magnification (Fig. 8.111). The smooth muscle of LAM is distinctive (Fig. 8.112). The LAM cell is fusiform and plump. The nucleus is larger than that of other smooth muscle cells in the lung (Fig. 8.113), and the nuclear-cytoplasmic ratio is typically higher. Smooth muscle bundles may be small or attenuated at the periphery of cysts (Fig. 8.114) or quite cellular and prominent (Fig. 8.115). In the lung lymphatics or pleural space, unattached aggregations of cells enveloped by lymphatic endothelium may be seen; these have been referred to as LAM cell clusters.⁴²⁸ These unattached cell clusters have been proposed as the mechanism for dissemination of the disease.⁴²⁸ LAM typically stains for HMB45, melan A, micropthalmiatranscription factor, and P-catenin.⁴¹¹’⁴²⁹

Differential Diagnosis

The differential diagnosis for LAM includes Birt-Hogg-Dubé syndrome,⁴³⁰ alveolar duct smooth muscle hyperplasia, pulmonary Langerhans cell histiocytosis, metastatic low-grade sarcomas in the lung, thin-walled cysts seen in so-called radiologic LIP or in Sjogren syndrome, and cystic terminal airways in small-airway disease, especially when these diseases occur in the setting of recurrent pneumothorax in a woman. LAM should always be considered in a middle-aged female patient with bilateral cystic lung disease by imaging studies. The spindle cell proliferation of LAM may be very focal within the cyst walls and is easily missed, especially on smaller biopsies such as traditional transbronchial biopsies. Screening immunohistochemical stains for HMB-45 and melan A may be helpful in suspicious clinical and radiographic settings.

Figure 8.110 Lymphangioleiomyomatosis (LAM). In most cases, thin-walled cysts are readily visible (A) and useful for searching out the characteristic smooth muscle of LAM (B).

Clinical Course

No effective therapy has emerged for LAM. Nevertheless antihormonal therapy^431-434 has been the mainstay of treatment based on the presence of estrogen and progesterone receptors in the abnormal smooth muscle cells.^294,410’⁴³³’⁴³⁵ There is no evidence of improvement with the use of estrogen antagonists.⁴³⁶ Currently several multicenter clinical trials are under way using agents such as the mTOR inhibitor, sirolimus, Rheb inhibitors, selective estrogen antagonists, tyrosine kinase inhibitors, angiogenesis inhibitors, and lymphangiogenesis inhibitors (anti-vascular endothelial growth factor D antibody).⁴³⁶ Lung transplantation may also be considered an effective option.⁴³⁷ Recurrence of LAM in transplanted lung has been reported.⁴³⁸ the median survival period is in the range of 10 years, with an early subset of deaths occurring within the first 5 years of diagnosis.^333,439

Hermansky-Pudlak Syndrome

The Hermansky-Pudlak syndrome (HPS) encompasses a group of genetic disorders of autosomal recessive inheritance that share features of oculocutaneous albinism, platelet storage pool deficiency, and variable tissue lipofuchsinosis.^440-442 the most common form of HPS arises from a 16-base pair duplication in the HPS1 gene at exon 15 on the long arm of chromosome 10 (10q23).⁴⁴³ This form is referred to as HPS type 1 (HPS-1) and is associated with progressive, lethal pulmonary fibrosis.⁴⁴⁴ HPS-1 affects between 400 and 500 individuals in northwestern Puerto Rico.^445,446 Pulmonary fibrosis typically begins in the fourth decade and results in death from respiratory failure within 1 to 6 years of onset.⁴⁴⁷ A granulomatous colitis may also occur in HPS patients.

Figure 8.111 Lymphangioleiomyomatosis (LAM). (A and B) the smooth muscle of LAM more closely resembles a low-grade neoplasm than any normally occurring smooth muscle.

Figure 8.112 Lymphangioleiomyomatosis (LAM). The smooth muscle cells of LAM are distinctive in appearance. The LAM cell is fusiform and plump, with irregular pale vacuoles in its cytoplasm.

Radiologic Findings

Avila and coworkers⁴⁴⁸ reviewed chest radiographs and CT scans from 67 patients with HPS-1. CT scans with minimal abnormalities had normal corresponding chest radiographs. When abnormalities were present on the radiographs, these consisted of diffuse reticulonodular interstitial infiltrates, perihilar fibrosis, and pleural thickening. High- resolution CT findings included peribronchovascular thickening, ground-glass opacification, and septal thickening. Increasing severity of these changes, as assessed using a fibrosis scoring system, was inversely correlated with forced vital capacity.

Histopathologic Findings

Surgical biopsies and autopsy lungs from five patients with HPS were studied by Nakatani and colleagues.⁴⁴⁹ These researchers described alveolar septal thickening (Fig. 8.116) associated with prominent clear vacuolated type II pneumocytes (Fig. 8.117), patchy zones of fibrosis with an apparent bronchiolocentric distribution, some evidence of constrictive bronchiolitis, and haphazard microscopic honeycombing without a consistent peripheral lobular or subpleural distribution. Many giant lamellar bodies were present in the macrophages and type II cells on ultrastructural examination, and the phospholipid material in the vacuoles was weakly positive with antibodies directed against surfactant apoprotein by immunohistochemistry.

Clinical Course

No effective therapy has been identified for HPS patients with lung fibrosis, but newer antifibrotic therapies are being explored.⁴⁵⁰

Pulmonary Alveolar Microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare but distinctive lung disease of autosomal recessive inheritance, with approximately 300 cases reported in the literature.^451-455 A significant number of cases identified are familial (affecting siblings); however, PAM occurring in both a parent and a child is uncommon. The exact incidence of the disease is unknown, but in a 46-year period, the Mayo Clinic identified only eight cases.⁴⁵³ Patients are typically diagnosed in the fourth decade of life, but diagnosis can occur from childhood to 80 years of age.⁴⁵³ ttere appears to be an increased incidence in individuals of Turkish descent; a Turkish family with six affected members has been described.^{456 the} responsible gene mutation has been found in the SLC34A2 gene, which encodes the sodiumphosphate cotransporter in patients with PAM.⁴⁵⁷

Figure 8.113 Lymphangioleiomyomatosis (LAM). (A) the nucleus of the LAM smooth muscle cell is larger than that of other smooth muscle cells in the lung, and the nuclear/cytoplasmic ratio is typically higher. In this example, hemosiderosis is present in adjacent alveolar spaces. (B) Immunohistochemical stains for HMB45 are very helpful in establishing the correct diagnosis.

Figure 8.114 Lymphangioleiomyomatosis (LAM). Other positive stains in LAM smooth muscle include those for MelanA/ MART-1 (A), estrogen receptor (B), smooth muscle actin (C), and desmin (D).

Figure 8.115 Lymphangioleiomyomatosis (LAM). (A) Another distinctive lesion that may be seen in association with LAM, especially in those patients who also have tuberous sclerosis complex, is micronodular pneumocyte hyperplasia (MNPH). (B) MNPH lesions are epithelial and probably represent a hamartomatous proliferation. The cells of MNPH do not stain with antibodies directed against HMB45 or MelanA/MART-1 but rather with cytokeratin and surfactant apoprotein antibodies.

Figure 8.116 Hermansky-Pudlak syndrome. This genetic disease produces lethal lung fibrosis in affected persons. (A) the computed tomography findings are dramatic and characterized by diffuse reticular opacities. (B) Tissue sections show advanced lung remodeling with fibrosis, typically without an easily characterized distribution, but somewhat patchy and “UIP-like” at scanning magnification.

Figure 8.117 Hermansky-Pudlak syndrome. (A and B) At higher magnifications, prominent clear vacuolated type II pneumocytes can be seen embedded in chronic inflammation within patchy zones of fibrosis. The inset in part B shows the peculiar vacuolated cells of this disease, sometimes even confused for clear cell carcinoma.

Clinical Presentation

Most cases are diagnosed in adult life, but the disease can manifest at any age.^452-454 It is hypothesized that the condition results from a congenital metabolic disorder resulting in slowly progressive disease during life. The most common presentation is that of an asymptomatic patient. Some patients may experience various degrees of dyspnea, and death has been reported to occur after accelerated respiratory failure. Affected patients typically exhibit a restrictive pulmonary function defect,⁴⁵² but this is generally mild when compared with the dramatic appearance of the chest radiograph, especially in young patients. Associated nephrolithiasis and pleural calcification have been reported.⁴⁵⁸

Radiologic Findings

The chest radiograph is almost immediately diagnostic, with sandlike micronodular opacities present throughout both lungs diffusely. The lower lung zones tend to be more opacified than the upper lobes. Chest radiographs may remain static for many years.^452-454 High-resolution CT scans reveal intraalveolar microcalcifications bilaterally, with increased concentration of microliths along bronchovascular bundles and interlobular fissures and in the subpleural lung parenchyma.⁴⁵⁹

Histopathologic Findings

On gross examination, the lungs are firm and gritty; they rigidly maintain their shape before fixation. On microscopic examination, the airspaces contain innumerable tiny calcified bodies that are concentrically laminated and have radial striations (Fig. 8.118). These microliths are composed of calcium and phosphorus in concentrations similar to those in bone.⁴⁵⁴ Magnesium and iron are typically present in small amounts. Microliths may be as large as 1 mm or more in diameter, but usually they are of uniform size, with diameters in the range of 250 μm. Rarely, microlithiasis may involve the alveolar walls, often accompanied by some degree of interstitial thickening and chronic inflammation (Fig. 8.119).

Differential Diagnosis

The differential diagnosis includes corpora amylacea and alveolar calcification from any cause. The microliths of PAM can be distinguished from incidental corpora amylacea by the larger size of the former and the lack of calcification in the latter. Also, corpora amylacea typically have a small black pigment core, whereas the microliths of PAM lack this feature. The sheer number of alveolar microliths in PAM distinguish this condition from other forms of lung calcification.

Clinical Course

A majority of patients with PAM survive for many years with little disease progression. No effective therapy is currently available for symptomatic patients.

Pulmonary Alveolar Proteinosis

PAP is a diffuse lung process characterized by the presence of alveolar spaces filled with amorphous eosinophilic material. Recent data suggest that most patients with primary PAP develop this disorder as part of an autoimmune disease.⁴⁶⁰ In a recent series of PAP patients, 223 of 248 were seropositive for anti-granulocyte-monocyte colony-stimulating factor (anti-GM-CSF) autoantibody.⁴⁶¹ PAP is often multilobar, bilateral, and of subacute or chronic onset. Other subacute or chronic ILDs that include an alveolar component are considerations in the differential diagnosis for PAP (e.g., COP, RBILD/DIP, LIP, NSIP).⁴⁶² Recently a schema for categorizing PAP was proposed and included three domains, hereditary/congenital, secondary, and idiopathic/autoimmune.

Clinical Presentation

The disease occurs commonly as a primary idiopathic form, whether congenital or of adult onset. However, PAP may also be seen as a secondary phenomenon in the settings of occupational disease (especially dust-related), drug-induced injury, hematologic diseases, and in many settings of immunodeficiency.^463-467 the disease is commonly associated with exposure to crystalline material and silica, although other substances have also been implicated.^464,468 the idiopathic form is the most common presentation. Most PAP patients are male and range in age from 30 to 50 years. The usual presenting symptom is dyspnea on exertion, followed in frequency by insidious breathlessness, sometimes with cough.^461,467-469

Radiologic Findings

Chest radiographs show extensive bilateral airspace consolidation involving mainly the perihilar regions; often the symptoms belie the severity of the radiologic abnormalities. CT demonstrates smooth thickening of lobular septa that is not seen on the chest radiograph.

Figure 8.118 Pulmonary alveolar microlithiasis. The airspaces contain innumerable tiny calcified bodies that are concentrically laminated and have radial striations.

Figure 8.119 Pulmonary alveolar microlithiasis. Rarely, the calcifications may be present within the alveolar walls, often accompanied by some degree of interstitial thickening and chronic inflammation.

Thickened lobular septa sharply demarcate areas of ground-glass attenuation. These characteristics of alveolar proteinosis on CT are referred to as “crazy paving pattern.”⁴⁷⁰

Histopathologic Findings

PAP (i.e., alveolar lipoproteinosis) is characterized by an intraalveolar accumulation of lipid-rich eosinophilic material.⁴⁶³ In autoimmune PAP, it occurs as a result of impaired clearance of surfactant by alveolar macrophages due to the effects of an autoantibody directed against GM-CSF. The gross lung shows firm yellow-white nodules, some as large as 2 cm in diameter. Microscopically the scanning magnification appearance is distinctive if not diagnostic. Pink granular material fills the airspaces, sometimes with a rim of retraction that separates the alveolar wall slightly from the exudates (Fig. 8.120). Closer inspection of this material shows embedded clumps of dense globular material and cholesterol clefts (Fig. 8.121). Amorphous solid eosinophilic globules are frequently seen inside the pools of proteinaceous material. The PAS stain may be useful in demonstrating a diastase-resistant, positive reaction in the globular inclusions of PAP. By immunohistochemistry this material is immunoreactive with antibodies directed against surfactant. There may be few other associated changes in the lung biopsy, although patients with long-standing disease may develop some interstitial fibrosis and chronic inflammation. More dramatic inflammatory changes should suggest comorbid disease, such as infection. For example, Nocardia, Aspergillus, or mycobacterial infection can be associated with PAP.⁴⁶¹ PAP can be patchy in the lungs and even in biopsy specimens, so a high index of suspicion is required, coupled with good clinical and radiologic data.

Figure 8.120 Pulmonary alveolar proteinosis (PAP). The nearly diagnostic appearance of PAP at scanning magnification demonstrates pink granular material filling the airspaces, sometimes with a rim of retraction that separates the alveolar wall slightly from the exudate.

Differential Diagnosis

The differential diagnosis includes pulmonary edema and Pneumocystis pneumonia. Pulmonary edema does not feature the globular material and cellular debris seen in PAP. Pneumocystis pneumonia can be distinguished from PAP by a more dramatic clinical presentation, exudates that appear finely vacuolated or foamy, and significantly more inflammatory changes in background lung. When fibrotic change is prominent, it may be difficult to distinguish from UIP because focal PAP reaction can occur in and around areas of microscopic honeycombing in UIP.

Clinical Course

Despite significant radiologic abnormalities, the disease may be unusually silent, producing few if any clinical manifestations in the absence of superimposed infection. When patients have severe dyspnea and hypoxemia, treatment can be accomplished using one or more sessions of whole-lung lavage, which usually induce remission and excellent long-term survival.⁴⁷¹ Based on the recent evidence of a high incidence of anti-GM-CSF antibody in autoimmune PAP patients, clinical trials using aerosolized GM-CSF have been initiated with good results.^472,473

Lymphangitic Carcinomatosis

Metastatic carcinoma involving the lung, primarily within lymphatics, is known as pulmonary lymphangitic carcinomatosis (lymphangitis carcinomatosa). The tumor type is most often adenocarcinoma; it accounts for as much as 8% of all cases of metastasis to the lung. The most common sites of origin are the breast, lung, and stomach, although primary disease in the pancreas, ovary, kidney, and uterine cervix can also spread to the lungs in this manner.^474,475 Published reports on this subject are found predominantly in the radiology literature.^474-477

Figure 8.121 Pulmonary alveolar proteinosis. (A) Closer inspection of the material seen in Fig. 8.119 shows embedded clumps of dense globular material and cholesterol clefts. (B) the clumps may be variably prominent; in this example, they are less distinct.

Clinical Presentation

Patients often present with insidious onset of dyspnea, frequently accompanied by an irritating/nonproductive cough.

Radiologic Findings

On plain chest films, the changes are often subtle and nonspecific. In one study, the correct diagnosis was made in only 20 of 87 cases (23%), and 50% of the films were interpreted as normal.⁴⁷⁸ Abnormalities include linear opacities, horizontal linear lines abutting on the pleura mostly in the lower lobes (Kerley B lines), subpleural edema, and, commonly, hilar and mediastinal lymph node enlargement.⁴⁷⁶ By contrast, the high-resolution CT findings are highly characteristic and accurately reflect the macroscopic abnormalities in this disease. Because the major lymphatic vessels in the lung are located in the pleura, interlobular septa, and bronchovascular bundles, the abnormalities are found primarily in this distribution, thickening and accentuating these structures. High-resolution CT shows irregular thickening of the bronchovascular bundles and lobular septa, giving them a beaded appearance.^475,477 Distinction from sarcoidosis (another lymphatic disease) can be made by examining distribution (sarcoidosis is an upper lung zone disease).

Histopathologic Findings

Small aggregates of tumor cells are present within lymphatic channels of the bronchovascular sheath and pleura (Fig. 8.122). Because the lymphatics of the bronchi are involved in this process, lymphangitic carcinoma is one of the few diffuse lung diseases that can be diagnosed definitively by bronchial or transbronchial biopsy (Fig. 8.123).⁴⁷⁹ Variable amounts of tumor may be present throughout the lung, involving the interstitium of the alveolar walls, the airspaces themselves, and the lumens of small muscular pulmonary arteries. This finding (microangiopathic obliterative endarteritis) may be the origin of the edema, inflammation, and interstitial fibrosis that frequently accompany the disease and probably accounts for the clinical and radiologic impression of nonneoplastic diffuse lung disease.^474,476

Figure 8.122 Lymphangitic carcinomatosis. Few lung diseases are as dramatic (or as devastating to those affected) as lymphangitic carcinomatosis. The characteristic distribution of the disease is demonstrated here at scanning magnification' with peribronchial and septal lymphatics filled with metastatic tumor.

The pathogenesis of lymphangitic carcinoma is unknown. Seeding of the lung lymphatics from retrograde spread of microvascular tumor emboli has been postulated and supported by observations of intravascular tumor present in other organs at autopsy from patients so affected.^474,476

Differential Diagnosis

Lesions that may mimic lymphangitic carcinoma include intravascular lymphoma, thromboembolic disease, and foreign material from intravenous injection.

Clinical Course

The prognosis is grim, with most patients dying within 6 months of diagnosis. Rarely, long-term survivors are reported.⁴⁷⁴

Figure 8.123 Lymphangitic carcinomatosis. (A) At times the disease may be more subtle and manifest as an interstitial infiltrate in lung biopsies. (B) Lymphangitic carcinoma is one of the few diffuse lung diseases that can be diagnosed definitively by bronchial or transbronchial biopsy.

Figure 8.124 Diffuse pulmonary meningotheliomatosis (DPM). (A) From low power the lesions are distinctly nodular appearing and contrast with the normal appearing lung in the background. (B) the cells of DPM may be arranged in a whorled architecture with intranuclear inclusions.

Diffuse Pulmonary Meningotheliomatosis

Rarely innumerable meningothelial nodules may be encountered and manifest as an ILD clinically and radiographically, a syndrome known as diffuse pulmonary meningotheliomatosis (DPM).⁴⁸⁰

Clinical Presentation

DPM seems to be more common in females than males and is a disease of middle-aged to older patients. They often present with fatigue, dyspnea, and shortness of breath.⁴⁸¹ Pulmonary function testing typically shows a mild restrictive defect.

Radiographic Findings

Imaging studies show diffuse bilateral reticulonodular infiltrates and variable ground-glass infiltrates. The nodules do not show a site predilection and are typically smaller than 3 mm.

Histopathologic Findings

Histologically, the lesions are distinctively nodular from scanning magnification. The nodules are composed of small clusters and whorled nests of round to spindle cells with oval nuclei and occasional inclusions (Fig. 8.124A and B). Immunohistochemistry demonstrates positivity for CD56, EMA, vimentin, and PR, while antibodies to pancytokeratin and S100 are negative.

Differential Diagnosis

The major differential diagnosis is the distinction between a metastatic neoplasm and isolated meningothelial nodules. Distinction from a metastasis requires histologic and often immunohistochemical study. There is no consensus as to how many nodules are required for a diagnosis of DPM.

Clinical Course

There are insufficient studies to accurately predict the clinical course of DPM. Some cases have progressed.

Common Variable Immunodeficiency-Associated Interstitial Lung Disease

Common variable immunodeficiency (CVID) is the most common primary human immunodeficiency syndrome; up to 20% of patients with CVID may develop an associated interstitial lung disease (CVID-ILD).^482,483

Figure 8.125 Common variable immunodeficiency (CVID). Diffuse cellular interstitial infiltrates with marked chronic bronchiolitis and vague histiocytic aggregates in the alveolar spaces may be seen in CVID-associated interstitial lung disease.

Clinical Presentation

CVID-ILD patients present with dyspnea. Lung function testing reveals a restrictive pattern.

Radiographic Findings

A wide variety of imaging findings have been described in the setting of CVID-ILD, depending on the type of lung involvement. Described findings include ground-glass infiltrates, nodules, and bronchiectasis.⁴⁸⁴

Histopathologic Findings

A spectrum of histologic patterns of injury have been described, including NSIP, OP, follicular bronchiolitis, granulomatous disease, and sarcoid-like granulomatous inflammation (Fig. 8.125). Many cases may show an overlap of these patterns. Close scrutiny of dense lymphocytic infiltrates is warranted, as CVID patients are at increased risk of lymphoproliferative disorders. Granulomatous lymphocytic interstitial lung disease (GLILD) was proposed for a subset of CVID-ILD patients with evidence of lymphoproliferative disease and robust granulomatous inflammation.⁴⁸⁵

Figure 8.126 IgG4 related interstitial lung disease. (A) Note the intense fibroinflammatory process with numerous plasma cells. A venule at the center of the image is being overwhelmed by phlebitis. (B) Immunohistochemistry for IgG4 shows a marked increase in the overall number of IgG4-positive plasma cells.

Differential Diagnosis

There is a broad differential diagnosis for diffuse cellular interstitial infiltrates (reviewed further on). If There are associated granulomas and dense infiltrates, the possibility of CVID and GLILD should be raised in the pathology report.

Clinical Course

The majority of patients with CVID-ILD remain clinically stable over long periods of time. However, some may progress, and the standard treatment is steroids with a fairly high response rate.

IgG4-Related Interstitial Lung Disease

IgG4-associated disease is a recently described fibroinflammatory disease characterized by increased tissue IgG4 positive plasma cells and elevated serum levels of IgG4.⁴⁸⁶ Over the past decade, nearly every organ system has been implicated in IgG4-associated disease, including the lung.⁴⁸⁷

Clinical Presentation

IgG4-related ILD is mainly a disease of adults (The average age of presentation is 65 years) and is more common in men than in women (3 : 1). With pulmonary involvement There is often pain, cough, and dyspnea. Some patients have constitutional symptoms such as fever and weight loss.⁴⁸⁸

Radiographic Findings

Depending on the nature of involvement, the imaging studies may show solid to ground-glass nodules or more diffuse interstitial involvement in the form of ground-glass opacities with a mid- to lower lobe distribu- tion.⁴⁸⁸ Single nodules may be encountered and may mimic neoplastic lesions.

Histopathologic Findings

Pulmonary parenchymal IgG4-associated disease is encountered as either nodules or diffuse ILD. Classic features of IgG4 disease in the lung are similar to those found at other sites and include a dense, plasma-cell rich infiltrate, fibrosis, phlebitis, and an increased number of IgG4-positive plasma cells by immunohistochemistry (Fig. 8.126). The characteristic storiform fibrosis seen in other sites is only rarely encountered in the lung. It has become apparent that both the absolute number of IgG4-positive plasma cells as well as the IgG/IgG4 plasma cell ratio must be elevated. A recent consensus group proposed the following criteria to suggest IgG4-associated pulmonary disease: histologic features with greater than 20 IgG4-positive plasma cells per high-power field and an IgG4/IgG ratio of greater than 40%.⁴⁸⁹

Differential Diagnosis

ttere are a large number of fibroinflammatory diseases to consider in the differential diagnosis of IgG4-related lung disease, including reactive processes, neoplasm, recurrent aspiration, and CTD-ILD, among others. In practice, there should be a low threshold for ordering IgG and IgG4 stains.

Clinical Course

Accurate recognition of this disease is important, as it is quite steroid- responsive, usually within a few weeks. Relapses have been described, but There is insufficient clinical experience to comment on long-term outcome.⁴⁸⁸

Practical Approach to the Differential Diagnosis of Diffuse Lung Diseases

The preceding portion of this chapter has focused on presenting well-defined diffuse lung diseases along with their specific clinical presentation, radiologic findings, histology, differential diagnosis, and clinical course. Unfortunately the surgical pathologist is often left in the challenging position of interpreting lung biopsies with minimal access to clinical and radiographic information. In this setting, often a descriptive diagnosis must be rendered. But how can the surgical pathologist still add value to the pathologic assessment of the biopsy? the following paragraphs provide a practical approach to four of the more common general patterns encountered in surgical lung biopsies.

Figure 8.127 Different basic patterns of pulmonary fibrosis. (A) Usual interstitial pneumonia pattern. (B) Airway-centered fibrosis pattern. (C) Nonspecific interstitial pneumonia pattern.

Table 8.8 Clues to the Etiology of Pulmonary Fibrosis

General Fibrosis Pattern	Additional Pathologic Finding	Possible Causes
Usual interstitial pneumonia pattern	No additional findings Cellular interstitial infiltrates, chronic bronchiolitis, lymphoid follicles, and pleuritis	Idiopathic pulmonary fibrosis Connective tissue disease
	Rare giant cells or interstitial granulomas, chronic bronchiolitis, robust peribronchiolar metaplasia	Chronic hypersensitivity pneumonitis
Airway-centered pattern	Giant cells and granulomas	Chronic hypersensitivity pneumonitis, aspiration, infection
	Foreign material Chronic bronchiolitis Follicular bronchiolitis	Chronic aspiration Infection, aspiration, hypersensitivity pneumonitis, connective tissue disease Connective tissue disease, infection
	Respiratory bronchiolitis or Langerhans cells	Remote pulmonary Langerhans cell histiocytosis
Fibrotic nonspecific interstitial pneumonia pattern	Cellular interstitial infiltrates	Connective tissue disease, hypersensitivity pneumonitis, adverse drug reaction
	Giant cells and granulomas	Connective tissue disease, hypersensitivity pneumonitis
	Respiratory bronchiolitis and dense collagen	Smoking-related interstitial fibrosis

Data from Smith ML. Update on pulmonary fibrosis: not all fibrosis is created equally. Arch Pathol Lab Med. 2016;140(3):221-229.

Biopsies With Established Fibrosis

As a general rule, evaluating fibrosis on transbronchial biopsies should be avoided. Surgical lung biopsies with established fibrosis should be fairly obvious from scanning magnification as these biopsies often show distortion of the architecture of the lung, have a “pink” appearance due to the presence of fibrosis, and may have irregular pleural edges due to the underlying fibrosis. Three basic fibrosis patterns may be encountered: UIP, fibrotic NSIP, and airway-centered fibrosis (ACF) (Fig. 8.127A-C).^{16,32,490,491} Box 8.5 lists the differential diagnosis for cases involving advanced pulmonary fibrosis (Table 8.8).⁴⁹¹

The first and most clinically relevant step in assessing biopsies with established fibrosis is to decide if it represents the UIP pattern of fibrosis, because this limits the differential diagnosis significantly. The pathologic UIP pattern is described in the preceding text (Box 8.7). The established fibrosis of the UIP pattern is at the periphery of the lobules in the subpleural and paraseptal regions with sharp demarcations with normalappearing alveolar walls. This often leads to “windows” of spared lung and the bronchovascular bundle. Once a strict UIP pattern is identified, the differential diagnosis is limited to IPF, chronic hypersensitivity pneumonitis, CTD, and pneumoconioses.³² There are several histologic hallmarks of chronic hypersensitivity pneumonitis in the setting of a UIP pattern. These include rare, poorly formed granulomas and multinucleated giant cells; airway pathology in the form of chronic bronchiolitis and peribronchiolar metaplasia; and a component of ACF.⁴⁹² A combination of these features may allow a pathologist to suggest chronic hypersensitivity pneumonitis as a possibility. Histologic clues to CTD as an etiology of the UIP pattern include cellular interstitial inflammation in the nonfibrotic areas (think cellular NSIP), lymphoid follicles (especially if There are germinal centers), and chronic bronchiolitis. These biopsies typically have a “blue” appearance from scanning magnification owing to the cellular infiltrates. Finally, the histologic hallmark of pneumoconiosis as an etiology is the identification of the offending inhaled dust/foreign material in association with the fibrosis. Polarization microscopy can be helpful, but it is important to remember that nearly all adults will have some polarizable material. Pneumoconioses are covered extensively in Chapter 10.

Fibrotic NSIP is generally described as a diffuse homogenous process involving all of the alveolar walls evenly. Although this is true in concept, the reality is that many biopsies with a fibrotic NSIP pattern will have a heterogeneous appearance on scanning magnification. Furthermore, a minority of cases may show focal microscopic honeycomb remodeling and fibroblast foci.⁹ Because of these features, the distinction between UIP pattern and NSIP pattern may be more challenging. Careful scrutiny of fibrotic NSIP cases should show abnormally thickened alveolar walls throughout the biopsy, with minimal to no areas of normal alveolar walls. In the face of a fibrotic NSIP pattern, several possibilities should be entertained, and careful scrutiny of the biopsy can help to narrow the differential diagnosis. CTD leads the differential diagnosis, and features on the biopsy that could support CTD include associated cellular infiltrates, pleuritis or fibrosis, bronchiolitis, lymphoid hyperplasia, and associated OP. Poorly formed granulomas and giant cells, especially if located in the interstitium around the airways, are suggestive of chronic hypersensitivity pneumonitis. Smoking-related interstitial fibrosis can be identified by the dense collagenized fibrosis in the interstitium and the presence of prominent pigmented macrophages in the airspace.^{493 the} other possibilities—including drug reaction, infection, and healed acute lung injury—require clinical history and do not have distinguishing histologic features. Obviously, idiopathic fibrotic NSIP can be diagnosed only following exclusion of all the other potential etiologies.

ACF is characterized by fibrosis occurring in the centrilobular region, often with other features of airway injury including peribronchiolar metaplasia, chronic bronchiolitis, mucostasis, and airway fibrosis.⁴⁹⁰ Because of the central location of the fibrosis, the scars in ACF often show a “star” of fibrosis in the center of the lobule. The fibrosis is accentuated around the airway because most of the potential etiologies involve inhalational insults. The leading diagnostic consideration is chronic hypersensitivity pneumonitis and, as with the other patterns, poorly formed granulomas and giant cells in the interstitium are clues to the etiology. Some CTDs may target the airways, with resulting ACF. This is often associated with robust chronic bronchiolitis and even follicular bronchiolitis. Other features that support CTD include areas of cellular interstitial pneumonia and foci of OP. The identification of foreign material or associated granulomas is a clue to chronic aspiration as a diagnosis. Many patients with chronic subclinical aspiration predominately aspirate salivary contents and thus do not form large granulomas or have fragments of foreign material giving away the diagnosis. Recurrent infection, especially in patients with small airways disease, can lead to centrilobular fibrosis, but this is not usually a diffuse lung disease. Fibrotic PLCH can classically show centrilobular stellate scars and, if There is also smoking-related fibrosis, the biopsy may show quite advanced fibrosis. The numerous smoker’s macrophages are clues to the etiology. Finally, there is a possibility that an idiopathic form of ACF exists.¹⁸

Biopsies With Granulomas

Granulomas or granulomatous inflammation are commonly encountered in lung biopsy specimens and generate a long differential diagnosis (Box 8.12). This chapter reviews the common diffuse granulomatous lung diseases including sarcoidosis, berylliosis, and hypersensitivity pneumonitis. The chapters on infection (see Chapter 7) and vasculitis (see Chapter 11) also cover different granulomatous diseases. This section focuses on an approach to granulomatous lung diseases for the surgical pathologist.

Several key histologic features of granulomas—including the presence or absence of necrosis, size, anatomic distribution, and associated interstitial inflammation and OP—may help narrow the differential diagnosis and provide clues to the etiology (Table 8.9).⁴⁹⁴

Although the use of Table 8.9 in practice may help to narrow the differential diagnosis, close study reveals infection and aspiration as very common possibilities regardless of the histology. For this reason, stains for infectious etiologies should be performed (sometimes on multiple blocks) in the setting of granulomas, especially if they are necrotizing granulomas. The areas of necrosis are most likely to have infectious organisms and deserve close scrutiny in evaluating the stains. Aspiration is one of the most commonly overlooked etiologies by pathologists despite the frequency of aspiration in the population.⁴⁹⁵

One common diagnostic challenge is in the distinction between infection and GPA, as both diseases can show robust granulomatous vasculitis. Features that favor infection include a pink color to the necrosis, numerous large epithelioid giant cells at the edge of the necrosis, and a round shape. In contrast, the granulomas of GPA are blue in color; have rare, smaller hyperchromatic giant cells with angulated nuclei; and have a geographic shape (Fig. 8.128A and B). Clinical and serologic features may also help in making the distinction. Patients with GPA often have an impressive burden of disease by imaging and yet feel relatively well, whereas a similar disease burden in an infectious disease would likely result in admission to an intensive care unit. Patients with GPA commonly have renal involvement with an active urine sediment and a positive antineutrophil cytoplasmic antibody (ANCA). Without a positive ANCA, it may be prudent to follow culture studies to completion prior to aggressive immunosuppression.

Biopsies With Organizing Pneumonia

OP is one of the more common pathologic patterns encountered in daily surgical pathology practice. Unfortunately the presence of immature fibroblastic polyps within the airspaces is seen in a large number of diseases (Box 8.8), and their presence is rarely suggestive of a specific entity. Furthermore, OP is a finding often associated with other patterns of injury (fibrosis, cellular infiltrates, and fibrosis). When encountered in isolation, the leading diagnostic considerations include infection, adverse drug reaction, CTD, aspiration, and COP.² In this setting, the surgical pathologist must look for a variety of clues to help suggest one etiology over another and provide guidance to the clinician (Table 8.10).²

Owing to the limited treatment options, the most critical differential diagnosis is between infectious and noninfectious etiologies. Thus any patient with OP should have infectious stains performed. Histologic features often encountered in infection include the presence of abundant fibrin as well as granulomas, giant cells, necrosis, neutrophils, and viral cytopathic effect. The histologic characteristics of an adverse drug reaction can be exceedingly variable, but features that should raise the possibility of drug reaction include the presence of numerous eosinophils, finely vacuolated macrophages and pneumocytes, and markedly atypical pneumocytes. Patients with ILD secondary to CTD rarely show isolated OP alone. Instead, there is often a component of cellular interstitial lymphoplasmacytic inflammation, chronic bronchiolitis, or pleuritis. A temporal spectrum of injury (acute, subacute, and chronic) may also suggest CTD. Histologic features suggestive of aspiration as an etiology for OP include a centrilobular distribution and the presence of giant cells and foreign material. The OP pattern seen in COP is often a “clean” OP without significant additional pathology such as fibrin, inflammation, or giant cells. In this setting, a descriptive diagnosis with a differential diagnosis is the best a surgical pathologist can provide.

Table 8.9 Histologic Features That May Help Narrow the Differential Diagnosis in the Setting of Granulomatous Lung Disease

Necrosis	Size	Associated-Interstitial Inflammation and OP	Additional Features	Potential Causes
Necrotizing	Mass-forming	Present	Eosinophilic necrosis Basophilic necrosis, geographic	Infection, aspiration, lymphoma, rheumatoid nodule, eosinophilic granulomatosis with polyangiitis Granulomatosis with polyangiitis
		Absent		Nodular sarcoid, aspiration, infection, bronchocentric granulomatosis
	Small, microscopic finding			Infection, aspiration, sarcoid, drug reaction
Nonnecrotizing	Mass-forming Small, microscopic finding			Nodular sarcoid, infection, CVID
		Present Absent	Well formed Poorly formed Lympahngitic distribution No lymphangitic distribution	Infection, hot tub lung, CVID, IBD, CTD, drug reaction, aspiration HP, aspiration, immunodeficiency, IBD, CTD, drug reaction Sarcoidosis, drug reaction Infection, aspiration, drug reaction

CTD, Connective tissue disease; CVID, common variable immunodeficiency; HP, hypersensitivity pneumonitis; IBD, inflammatory bowel disease; OP, organizing pneumonia.

Figure 8.128 Distinction between granulomatosis with polyangiitis (GPA) and infection. (A) Characteristic granuloma in GPA with geographic architecture, basophilic central necrosis, and surrounding rims of pink histiocytes. Inset of rare hyperchromatic multinucleated giant cells in GPA. (B) Typical granuloma seen in infection (histoplasmosis). Round eosinophilic central necrosis with a rim of basophilic lymphoplasmacytic inflammation. Inset of numerous plump multinucleated giant cells with hypochromatic nuclei.

Table 8.10 Clues to the Etiology of the Organizing Pneumonia Pattern

Finding	Possible Causes
Centrilobular distribution	Infection, aspiration
Giant cells and granulomas	Hypersensitivity pneumonitis, aspiration, infection, CTD, CVID
Fibrin and eosinophils	Eosinophilic pneumonia, infection, adverse drug reaction
Foreign material	Aspiration, intravenous drug abuse
Cellular interstitial infiltrates	Hypersensitivity pneumonitis, CTD, drug reaction, CVID
Pleuritis	CTD
Chronic bronchiolitis	CTD, hypersensitivity pneumonitis, aspiration, CVID
Interstitial fibrosis	Exacerbation of chronic interstitial lung disease
Markedly atypical pneumocytes	Infection (viral), adverse drug reaction
Necrosis and neutrophils	Infection, adverse drug reaction

CTD, Connective tissue disease; CVID, common variable immunodeficiency.

Biopsies With Diffuse Cellular Interstitial Infiltrates

The LIP pattern has been discussed previously; its distinction from the cellular NSIP pattern rests mainly on the density of the infiltrate. Regardless of the density, in the presence of a biopsy showing a diffuse cellular interstitial infiltrate, several etiologic possibilities should be considered (Table 8.11).

Table 8.11 Histologic Clues to the Etiology of the Dense Cellular Interstitial Infiltrate

Etiology	Diagnostic Clues
Infection	Presence of frothy eosinophilic material Cells with viral cytopathic effect Organisms on GMS stain Positive EBV-ISH
Connective tissue disease	Secondary lymphoid follicles Associated pleuritis Associated fibrosis and acute lung injury Associated chronic bronchiolitis Associated capillaritis
Subacute hypersensitivity pneumonitis	Poorly formed interstitial granulomas Multinucleated giant cells Associated organizing pneumonia
Drug reaction	No specific histology (giant cells, organizing pneumonia, eosinophils, granulomas, hyaline membranes may be seen)
Low-grade lymphoma	Monotony of infiltrate Destructive lymphoepithelial lesions Light-chain restriction Positive B-cell gene rearrangement studies
IgG4-mediated disease	Increased IgG4-positive plasma cells Associated fibrosis Vasculitis
CVID	Follicular bronchiolitis Granulomas Organizing pneumonia

CVID, Common variable immunodeficiency; ISH, in-situ hybridization.

Often additional histologic features can help narrow the differential diagnosis.² An exhaustive differential diagnosis is provided in the section titled Pattern-Based Approach to Diagnosis at the beginning of this book.

When confronted with a biopsy showing a diffuse cellular interstitial infiltrate, the possibility of an as yet to be identified CTD should not be underestimated. Approximately 20% of patients with CTD may present initially with pulmonary manifestations.⁴⁹⁶ On the biopsy, there are several findings that may help to support CTD as an etiology, including secondary lymphoid follicles, superimposed acute lung injury (hyaline membranes and OP), interstitial fibrosis, pleuritis, and chronic bronchiolitis. Regardless of the findings, a suggestion to screen the patient for the presence of autoantibodies is reasonable.

Although subacute hypersensitivity pneumonitis is classically thought of as a granulomatous disease, the presence of a diffuse cellular infiltrate is a diagnostic hallmark of the disease.⁴⁹⁷ This is underscored by the historic name “allergic extrinsic alveolitis" In practice, the poorly formed granulomas of subacute hypersensitivity pneumonitis should be difficult to identify. They are loose collections of histiocytes and occasional giant cells in the interstitium around the airway. Patchy foci of OP may also be present.

Exclusion of a low-grade lymphoproliferative process is one of the critical jobs of the surgical pathologist in biopsies with dense cellular infiltrates. Histologic features that should raise concern for lymphoma include a monotony of the cells, infiltration of the pleura, destructive lymphoepithelial lesions, and a striking plasmacytosis. There should be a low threshold to order CD3, CD20, kappa, and lambda studies to work up the infiltrates. Sending the block for B-cell gene rearrangement studies may also be necessary.

IgG4-mediated disease may present with a dense cellular interstitial infiltrate containing abundant plasma cells. Although it is classically lymphangitic in distribution, the infiltrate may spill out significantly into the interstitium, resembling NSIP. The presence of abundant plasma cells, vasculitis, and associated fibrosis should trigger IgG and IgG4 immunohistochemical stains.⁴⁹⁸ the infiltrate should be over 50% plasma cells and have greater than 20 IgG4-positive plasma cells per high-power field. Over 40% of the plasma cells should be IgG4-positive.⁴⁹⁸

Finally, infection and adverse drug reactions should be considered in a biopsy with cellular interstitial infiltrates. Pneumocystis jirovecii, Epstein-Barr virus, viral pneumonia, and human immunodeficiency virus are potential considerations. These diseases are discussed in depth in Chapter 7.

Without any clinical history of radiologic studies, these cases are often signed out descriptively with a long differential diagnosis unless more specific findings are identified.

Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.

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Multiple Choice Questions

1. Which of the following statements concerning the acronym ILD, which stands for interstitial lung disease, is/are TRUE?

A. ILD is a term not commonly used in practice.

B. ILD is not an accurate anatomical term because some “ILDs” have changes primarily in alveolar spaces rather than the interstitium.

C. ILD can be alternately termed “diffuse lung disease.”

D. ILDs are by definition never neoplastic conditions.

E. All of the above

ANSWER: C

2. Which of the following statements about patients with interstitial lung disease is FALSE?

A. They often present with dyspnea, abnormal pulmonary function, and chest imaging abnormalities.

B. They frequently improve spontaneously.

C. They may require lung biopsy for diagnosis.

D. Their disease presentation can be acute, subacute, or chronic.

E. None of the above

ANSWER: B

3. Which of the following statements about usual interstitial pneumonia (UIP) is/are TRUE?

A. UIP most commonly affects young adults.

B. UIP is a chronic lung disease that never improves after diagnosis.

C. UIP frequently has associated small sarcoid-like pulmonary granulomas, without necrosis.

D . UIP rarely ever occurs without renal involvement at presentation.

E. All of the above

ANSWER: B

4. Which of the following findings are typical of cryptogenic organizing pneumonia?

A. Asthma

B. Fatal cardiac disease

C. Peripheral blood eosinophilia

D. Perinuclear antineutrophilic cytoplasmic antibody (p-ANCA) serology

E. None of the above

ANSWER: E

5. A characteristic computed tomography manifestation of usual interstitial pneumonia is:

A. “Ground glass” infiltrates in upper lobes

B. Reticulation with subpleural sparing

C. Airway-centered nodules at the lung bases

D. “Honeycomb” cysts at the lung bases peripherally

E. “Honeycomb” cysts in the upper lobes

ANSWER: D

6. Which of the following statements about idiopathic lymphoid interstitial pneumonia (LIP) is FALSE?

A. Most causes are known.

B. LIP frequently presents with unilateral disease.

C. LIP must never be treated with antibiotics.

D. LIP always progresses to lymphoma if untreated.

E. None of the above

ANSWER: E

7. Which of the following is not included in the idiopathic interstitial pneumonias?

A. Lymphoid interstitial pneumonia

B. Usual interstitial pneumonia

C. Giant cell interstitial pneumonia

D. Cryptogenic organizing pneumonia

E. Desquamative interstitial pneumonia

ANSWER: C

8. Hypersensitivity pneumonitis has all of the following features EXCEPT:

A. Small, poorly formed, nonnecrotizing interstitial granulomas

B. Focal organizing pneumonia

C. Chronic bronchiolitis

D. Necrotizing vasculitis

E. Interstitial inflammation

ANSWER: D

9. Which of the following best characterizes lung involvement in rheumatoid arthritis?

A. It occurs more commonly in women.

B. It can produce a usual interstitial pneumonia pattern of fibrosis.

C. It mainly occurs as an acute lung disease.

D. It can manifest before the patient is diagnosed with rheumatoid arthritis.

E. b and d only

F. None of the above

ANSWER: E

10. Which of the following statements about sarcoidosis is/are TRUE?

A. Granulomas are confined to the airways.

B. It is most frequent in young adults.

C. Interstitial fibrosis is common and is accompanied by “honeycomb” cysts.

D. It is an aggressive clinical disease when the lungs are involved.

E. All of the above

ANSWER: B

11. TRUE or FALSE: Berylliosis is thought to be an infectious disease.

A. True

B. False

ANSWER: B

12. TRUE or FALSE: Avian antigens are the least likely causative exposure for hypersensitivity pneumonitis.

A. True

B. False

ANSWER: B

13. TRUE or FALSE: Langerhans cell histiocytosis is considered to be a smoking-related interstitial lung disease.

A. True

B. False

ANSWER: A

14. TRUE or FALSE: Late-stage lesions of Langerhans cell histiocytosis typically have few characteristic Langerhans cells.

A. True

B. False

ANSWER: A

15. What is this?

A. Acute bronchopneumonia

B. Usual interstitial pneumonia

C. Eosinophilic pneumonia

D. Desquamative interstitial pneumonia

E. None of the above

ANSWER: C

16. What is this?

A. Churg-Strauss syndrome

B. Histiocytosis X

C. Acute bronchopneumonia

D. Desquamative interstitial pneumonia

E. None of the above

ANSWER: D

17. What is this?

A. Nonspecific interstitial pneumonia

B. Desquamative interstitial pneumonia

C. Lymphoid interstitial pneumonia

D. Respiratory bronchiolitis-associated interstitial lung disease

E. Usual interstitial pneumonia

ANSWER: E

18. What is this?

A. Blue bodies

B. Behçet syndrome

C. Microscopic honeycombing

D. Giant cell interstitial pneumonia

E. None of the above

ANSWER: C

19. What is this?

A. Acute interstitial pneumonia

B. Usual interstitial pneumonia

C. Desquamative interstitial pneumonia

D. Nonspecific interstitial pneumonia

E. None of the above

ANSWER: D

20. What is this?

A. Sarcoidosis

B. Metastatic carcinoma

C. Langerhans cell histiocytosis

D. Intravenous talcosis

E. Pulmonary parasitosis

F. None of the above

ANSWER: A

Case 1

eSlide 8.1

A 71-Year-Old Man With Idiopathic Pulmonary Fibrosis

Clinical History

A 71-year-old man presents with a 4-month history of nonproductive cough followed by dyspnea on exertion. On admission, he did not have the symptoms or serologic autoantibodies suggestive of collagen vascular disease. A computed tomography (CT) scan of the chest revealed airspace consolidation with traction bronchiectasis in the subpleural area and irregular reticular shadows in both lower lobes.

Pathologic Findings

Surgical lung biopsies obtained from the left upper and lower lungs show patchy areas of marked dense fibrosis along with architectural distortion and microscopic honeycombing. Fibroblastic foci and a small area of preserved lung tissue are seen in the upper lobe. There are a few lymphoid aggregates along with only minimal inflammation.

Diagnosis

Usual interstitial pneumonia (IPF).

Discussion

The patient was diagnosed as having IPF after a multidisciplinary discussion. Histologically, the case met all four criteria for the UIP pattern according to the 2011 IPF guidelines. Pathologic judgment of UIP can be difficult. The absence of cellular infiltrates and airway-centered change helps to support the diagnosis of UIP.

Case 2

eSlide 8.2

A 61-Year-Old Man With Pleuroparenchymal Fibroelastosis

Clinical History

Four years after his chest x-ray was found to be abnormal, a 61-year-old man experienced pneumothorax. A CT scan of the chest showed atelectatic induration in both lung apexes and reticular shadows in the lower lobes.

Pathologic Findings

All surgical lung biopsies obtained from the right middle and lower lungs showed, histologically, subpleural and parenchymal interstitial fibroelastosis, which was highlighted by EVG stain. Through observation of the EVG staining, the framework architecture of lung parenchyma was seen to be fairly preserved. In addition to fibroelastosis, there was a mild degree of bronchiolitis as well as airway-centered fibrosis. Dense collagenous fibrosis as seen in UIP was absent. No honeycombing was observed.

Diagnosis

Pleuroparenchymal fibroelastosis (PPFE).

Discussion

PPFE is a recently recognized, rare form of interstitial pneumonia. PPFE characteristically shows subpleural and interstitial accumulations of fibrosis, predominantly with elastic fibers, in the upper lobes. PPFE can be seen as a secondary lung manifestation of other conditions, such as earlier bone marrow transplantation. The present case had no identifiable cause and was considered to be idiopathic PPFE.

Case 3

eSlide 8.3

A 62-Year-Old Woman With Collagen Vascular Disease-Related Interstitial Lung Disease

Clinical History

A 62-year-old woman who had had an abnormal chest x-ray 3 years earlier presents with a nonproductive cough. On admission, she experienced early-morning stiffness and joint swelling of her hands, wrists, knees, and both shoulders. Testing for anti-citric citrullinated peptides (CCP) antibody was positive, leading to the diagnosis of rheumatoid arthritis (RA). A CT scan of the chest revealed reticular shadows and honeycombing in both lower lobes.

Pathologic Findings

Surgical lung biopsies were obtained from the right middle and lower lobes. The major histologic process was a dense fibrosis along with marked lymphoid hyperplasia. Lymphoplasmacytic infiltration was present around airway and in the pleura. In addition, all specimens showed microscopic honeycombing. Abrupt changes between fibrotic and normal lung areas were seen in the middle lobe.

Diagnosis

The basic pattern was considered to represent UIP with lymphoid hyperplasia; etiologically, this case was considered to be a pulmonary manifestation of RA.

Discussion

RA manifesting in the lung is fairly common. Its distinction from idiopathic interstitial pneumonias is challenging but important in terms of differing clinical management. The UIP pattern is a frequent pathology for RA patients and, when present, may indicate a poor prognosis.

Case 4

eSlide 8.4

A 63-Year-Old Man With Hypersensitivity Pneumonitis

Clinical History

A 63-year-old asymptomatic man was found to have an abnormal chest x-ray. A CT scan of the chest showed centrilobular ground-glass changes with micronodules. Precipitating serum antibody testing against pigeon was positive. Bronchoalveolar lavage revealed lymphocytosis (35%).

Pathologic Findings

Surgical lung biopsies were obtained from the left upper and lower lungs. Histologically, all specimens showed a moderate degree of dense fibrosis distributed in the peripheral zone along with mild lymphocytic infiltration. Abrupt change is found between fibrotic and normal lung areas. Some fibroblastic foci and microscopic honeycombing are seen. Scattered nonnecrotizing, poorly formed granulomas and interstitial giant cells with cholesterol clefts are observed. Airway-centered changes such as peribronchiolar metaplasia and bronchiolitis are also noted.

Diagnosis

The basic histologic pattern is UIP but, based on the presence of the granulomas, chronic hypersensitivity pneumonitis would lead the histologic differential diagnosis. Following correlation with the clinical and laboratory studies, this case clearly proved to be chronic bird-related hypersensitivity pneumonitis (HP).

Discussion

Chronic bird-related HP is induced by the inhalation of bird-related antigens. Patients with chronic HP may develop extensive interstitial fibrosis clinically resembling IPF. The diagnosis of chronic HP should be carefully made through multidisciplinary discussion.

Case 5

eSlide 8.5

A 20-Year-Old Man With Pulmonary Langerhans Cell Histiocytosis Clinical History

A 20-year-old otherwise healthy man, a smoker, was found to have an abnormal chest x-ray. A CT scan of the chest showed multiple nodules with cavitation in both lungs. The nodules were seen predominantly in the upper lobe.

Pathologic Findings

Surgical lung biopsies were obtained from the left upper and lower lungs. Histologically, all specimens showed multiple nodular lesions

and stellate scars. The nodules consisted of cells with pale nuclei, simulating “crumpled tissue paper”; There were also numerous eosinophils. Some nodules were associated with cystic change. Lymphoid follicles, airspace macrophages, and anthracosis were found around the nodules. Immunohistochemically, the pale cells were positive for CD1a and S100, confirming Langerhans cells.

Diagnosis

Pulmonary Langerhans cell histiocytosis (PLCH), mixed proliferative and fibrotic phase.

Discussion

PLCH is one of the smoking-related diffuse lung diseases; it is considered to represent a reactive proliferation of Langerhans cells secondary to smoking. Immunohistochemical stain for CD1a often aids in making the diagnosis of PLCH, but it may not be helpful when disease shows only fibrotic lesions. The recognition of stellate centrilobular scars is helpful in establishing the diagnosis.