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 criteria³⁰; roughly two thirds of patients are older than 60 years of age at diagnosis.^5,31 For this reason, caution should be exercised when 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 (greater than 100 mm/hour). 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 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.³² When present, these usually are bilateral and often asymmetrical. Lung volumes are typically decreased at presentation except in cases with severe upper lobe (centriacinar) emphysema.³³ Unfortunately, a normal chest radiograph does not exclude the diagnosis.³⁴ 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.³⁵ 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. 7-1). Ground-glass opacities are not typical and, if present, should be limited in extent.^36–38 Subpleural cysts—ranging from a few millimeters to a centimeter or more in diameter (“radiologic honeycombing”)—increase in prominence as the disease advances (Fig. 7-2). In areas of more severe involvement, traction bronchiectasis often is 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 when relying on high-resolution CT diagnosis alone (low sensitivity).^24,39

Figure 7-1 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 7-2 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), that increase in prominence as the disease advances.

Histopathologic Findings

UIP cannot be diagnosed with the bronchoscopic or transbronchial biopsy specimen. Surgically derived wedge lung biopsies (3–5 cm in length by 2–3 cm in breadth), obtained from video-assisted thoracoscopic surgery (VATS) or open thoracotomy, are the appropriate samples for diagnosis (see Chapter 2 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, mid-lung and lower lung are preferable to upper and mid-lung, and samples from the lower lobe should be taken above the most advanced areas of fibrosis.

The characteristic histopathologic findings of UIP have been referred to as being “temporally heterogeneous” or having a “patchwork quilt” appearance,^32,40–43 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. 7-3). The remodeled lung is present mainly beneath the pleura and at the periphery of the secondary lobule, adjacent to interlobular septa (Fig. 7-4). When UIP is recognizable as a distinct pathologic entity, the pleural fibrosis contains smooth muscle proliferation in disorganized fascicles (Fig. 7-5) and foci of microscopic honeycombing are evident, even when the overall process appears to be mild or early in its evolution (Fig. 7-6). 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 0.5–3 cm or larger) as a localized manifestation of advanced lung remodeling (Fig. 7-7). Microscopic honeycomb cysts are considerably smaller (in the range of 1–3 mm) and typically are present subpleurally (Fig. 7-8). The cysts are lined by columnar ciliated epithelium and typically are filled with mucus, with variable amounts of acute inflammation and inflammatory debris (Fig. 7-9). When dense chronic inflammation is present in UIP, it is seen around these localized inflammatory lesions.

Figure 7-3 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).

Figure 7-4 Usual interstitial pneumonia. 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 7-5 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 7-6 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 often is 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.

Figure 7-7 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 7-8 Usual interstitial pneumonia. Microscopic honeycomb cysts are considerably smaller (in the range of 1–3 mm in diameter) than those identified radiologically.

Figure 7-9 Usual interstitial pneumonia (UIP). Microscopic honeycomb cysts are lined by columnar ciliated epithelium and typically are 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.

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 also would 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 (see Fig. 7-3). 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.⁴⁴ 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.⁴⁵

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 probably is 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 air space (Fig. 7-10), as though they were aborted “Masson polyps” of the type seen in organizing pneumonia (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 7-10 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 air space 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.⁴⁶ Acute exacerbations of IPF can manifest as other patterns of acute lung injury, such as organizing pneumonia, and despite the implication of the term, the “acute” exacerbation tends to evolve over several weeks, rather than a few days.⁴⁷ The mixed histopathologic changes can be confusing to the surgical pathologist examining the lung biopsy (and to the radiologist) because the background older fibrosis with microscopic honeycombing of UIP is often overshadowed by diffuse acute lung injury (Fig. 7-11).

Figure 7-11 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 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.⁴⁶ 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.⁴⁸ 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.^47,49

Differential Diagnosis

The differential diagnosis for the UIP pattern includes a number of diseases that produce lung fibrosis. When this is a diffuse bilateral process, the main entities in the differential diagnosis are listed in Box 7-5. There are cases showing coexistence of histopathologic patterns of NSIP and UIP in the same patient in multiple lobe biopsies.⁵⁰ Such cases can be considered “discordant” UIP.⁵¹ The clinical course of discordant UIP is still more like that of “non-discordant” UIP, however, with possibly longer survival.⁵²

Clinical Course

The most common causes of death among patients with IPF are listed in Box 7-6. As defined clinically, IPF patients have a median survival time of less than 3 years.⁵³ 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 use of human recombinant interferon γ-1β, the antifibrotic compound pirfenidone, the antioxidant N-acetylcysteine, and several endothelin receptor antagonists (e.g., bosentan, ambrisentan). To date, no trial has revealed a successful cure for the disease. However, perfenidone has emerged as a candidate for slowing functional loss in IPF patients and is approved for the treatment of IPF in Japan.^54,55

Essential Requirements for Accurate Diagnosis

For pulmonary physicians, a pathologic diagnosis of UIP implies clinical IPF; accordingly, UIP should never be diagnosed in the absence of clinical and radiologic correlation. The gravity of the prognosis and the lack of current available therapy 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 7-7. This approach provides an opportunity for further correlation by clinical colleagues and radiologists in solidifying the diagnosis.

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 (that is, an NSIP pattern) tend to be younger than patients with UIP^61–63; 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.^16,62

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.⁶⁴ Less than 40% of the lung volume is typically involved. Patchy parenchymal (alveolar) opacification is a commonly reported abnormality,⁶⁴ but reticular (interstitial) changes have also been identified.¹⁶ High-resolution CT findings are variable and nonspecific.⁶⁵ 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.^61,62 As might be anticipated, some of the findings described for NSIP overlap with those in other ILDs, such as hypersensitivity pneumonitis and COP. In 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. 7-12), 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. 7-13) and variably affecting the bronchovascular sheaths (Fig. 7-14) and pleura¹⁶ (Fig. 7-15). In some patients, infiltrates are predominantly peribronchial, whereas in others, germinal centers may be seen along with chronic pleuritis. When air space organization (the organizing pneumonia pattern) is present, it is not uniformly distributed (Fig. 7-16) as might occur in organizing infectious pneumonia.¹⁶ When fibrosis occurs in NSIP, it is usually mild and preserves lung structure (Fig. 7-17). Peribronchiolar metaplasia of variable extent may be seen, but microscopic honeycombing is characteristically absent.^16,66

Figure 7-12 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 7-13 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.

Figure 7-14 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 also typically are involved by the inflammatory process, to a variable degree.

Figure 7-15 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 7-16 Nonspecific interstitial pneumonia. When air space organization (organizing pneumonia pattern) is seen (center), it is not diffusely or uniformly distributed, as might occur in organizing infectious pneumonia.

Figure 7-17 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.

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. An American Thoracic Society project concluded that idiopathic NSIP is likely a distinct clinical entity with characteristic radiologic and pathologic features.⁶⁶ 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 on). Cellular NSIP and LIP may be difficult to distinguish from one another on histopathologic grounds, so they might be considered synonymous from the pathologist’s perspective, once lymphoproliferative disease has been rigorously excluded. Kinder and associates hypothesized that a majority of NSIP cases fall into the category of undifferentiated connective tissue disease manifesting in the lung. Because of significant overlap between NSIP and ILD in CVD, careful follow-up with serologic testing is recommended.⁶⁷ 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.

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.⁶⁶ 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.^61,68 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 connective tissue diseases that manifest in the lung with fibrosis.

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.^71,72 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. Mild to moderate restrictive pulmonary function studies are identified in a majority of patients.^72–74 Hemoptysis and wheezing typically are absent. Often there is a marked increase in the erythrocyte sedimentation rate (ESR). Digital clubbing is not a feature of the disease.

Radiologic Findings

Chest radiography and CT show a number of abnormalities, none of which are specific for one disease. Patchy air space consolidation (loss of visible structure underlying opacification) is the most consistent finding and is present in 90% of cases.^75,76 Air bronchograms can be seen in areas of consolidation. Ground-glass attenuation accompanies consolidation in more than one half of the patients. The disease involves the lower lung zones more often than the upper lung zones.⁷⁷ Small nodular opacities can be seen in 10% to 50% of patients.⁷⁸

In a small percentage of patients, large nodules may be seen⁷⁸; rarely, reticulonodular infiltrates occur.⁷⁴ It is speculated that this latter finding identifies a subset of COP that may not respond to therapy. Opacities may be recurrent and/or migratory.^79,80 Lung volumes are normal in most patients, and pleural effusions rarely occur.^75,76,81

Histopathologic Findings

The organizing pneumonia pattern is characterized by variably dense air space aggregates of fibroblasts in ground substance (immature collagen matrix) (Fig. 7-18). This alveolar filling process can be seen to extend into or from terminal bronchioles (Fig. 7-19). Typically, the lung architecture is preserved in COP, and lymphocytes, plasma cells, and histiocytes are present in variable numbers within the interstitium^17,82,83 (Fig. 7-20). Fibrin may be seen focally in association with air space organization (Fig. 7-21). Alveolar macrophage accumulation may be present, attesting to some degree of airway obstruction. ^17,82,83 When air space 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 organizing pneumonia. ^17,82,83

Figure 7-18 Organizing pneumonia pattern. This histopathologic pattern is characterized by variably dense air space 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 7-19 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.

Figure 7-20 Organizing pneumonia pattern. In cryptogenic organizing pneumonia (COP), the lung architecture typically is 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 7-21 Organizing pneumonia pattern. Fibrin (center right) may be seen focally in association with air space organization (center left) in cryptogenic organizing pneumonia.

Treatment and Prognosis

The expected response to systemic corticosteroid administration therapy is excellent.^17,79,84 Because relapses may occur if therapy is stopped abruptly, patients with COP generally require extended corticosteroid tapering, sometimes over a year or more.^17,79,84

Differential Diagnosis

As mentioned previously, the differential diagnosis for the organizing pneumonia histopathologic pattern 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 connective tissue diseases, hypersensitivity pneumonitis, and idiosyncratic reaction to drug or medication, rather than a “cryptogenic” disease. Rarely, air space organization may ossify and produced so-called “racemose” or “dendriform” ossification (Fig. 7-22).

Figure 7-22 Racemose (dendriform) alveolar calcification. A and B, Rarely, air space organization may ossify, producing so-called “racemose” or “dendriform” ossification.

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.^86,88 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,^87,89 but men and women were equally affected in one study.⁸⁸ Mild breathlessness and cough are the most common initial complaints.^86,88 Clubbing of the digits is unusual in RBILD.^88,90,91 Pulmonary function abnormalities parallel the mild clinical symptoms and may show evidence of both obstruction and restriction, with mild reduction in the diffusing capacity.⁸⁹

Radiologic Findings

The chest x-ray appearance of RBILD reflects the presence of disease centered on the airways, mainly with thickening of airway walls.⁸⁷ 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.⁸⁷

Histopathologic Findings

RB is a common reactive process in the lungs of cigarette smokers; its presence alone does not imply the diffuse lung disease manifestation.⁹¹ 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, 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. 7-23), (2) metaplastic bronchiolar epithelium extending out from terminal airways to involve alveolar ducts (Fig. 7-24), and (3) variable numbers of lightly pigmented, dusty brown air space macrophages within bronchiolar lumens and in immediate surrounding alveoli (Fig. 7-25). Scant peribronchiolar fibrosis may be present and may extend to involve contiguous alveolar walls (Fig. 7-26). When bronchiolocentric scarring is prominent, an alternative diagnosis, such as chronic hypersensitivity pneumonitis, should be considered. Dense collagenous thickening of the alveolar septa without inflammation can be seen in RBILD. Such fibrosis does not appear to progress to honeycomb fibrosis.⁹² Presence of fibroblastic foci or destruction of the lung architecture should always raise the possibility of an alternative diagnosis, especially undersampled UIP.

Figure 7-23 Respiratory bronchiolitis. This pathologic process is characterized by the presence of scant inflammation around the terminal airways.

Figure 7-24 Respiratory bronchiolitis. Metaplastic bronchiolar epithelium extends out from terminal airways to involve alveolar ducts.

Figure 7-25 Respiratory bronchiolitis. Variable numbers of lightly pigmented (dusty brown) air space macrophages are seen within bronchiolar lumens and in immediate surrounding alveoli.

Figure 7-26 Respiratory bronchiolitis. Scant peribronchiolar fibrosis may be present; this may extend to involve contiguous alveolar walls, with or without prominent smooth muscle bundles.

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 8 for a discussion of small airways disease).

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.⁹³

Clinical Presentation

As currently defined, DIP is a very rare smoking-related lung disease. Patients with DIP are typically older than those with RBILD⁸⁷ and roughly a decade younger than those with UIP.^91,94 Most patients with DIP are cigarette smokers; men are more frequently affected than women. Like UIP, the clinical presentation is dominated by insidious onset of dyspnea and dry cough over several weeks or months.^91,95 Digital clubbing is present in 50% of patients with DIP, a finding in sharp contrast with RBILD. The symptoms of DIP are usually more pronounced and more severe than those of RBILD,⁸⁷ supported by pulmonary function testing showing mild restriction and moderate reduction in diffusing capacity.⁹⁵

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.^87,96,97 On CT scans, ground-glass opacification is universally present, mostly in a bibasilar distribution.⁹⁶ 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,⁹⁶ but when prominent and associated with more pronounced reticular abnormalities, an alternate diagnosis should be considered (probably UIP).

Histopathologic Findings

On scanning magnification, the surgical lung biopsy in DIP has an eosinophilic appearance due to the presence of eosinophilic macrophages uniformly filling air spaces^11,88 (Fig. 7-27). Mild interstitial thickening by fibrous tissue is the rule and is uniform in appearance (Fig. 7-28). When chronic inflammation is evident at scanning magnification, it is centrilobular and associated with respiratory bronchioles (Fig. 7-29). Scant numbers of plasma cells and rare eosinophils may be seen within slightly thickened alveolar walls at high magnification (Fig. 7-30).

Figure 7-27 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 air spaces.

Figure 7-28 Desquamative interstitial pneumonia (DIP). Variable thickening of alveolar walls by fibrous tissue is the rule in DIP and typically is 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.

Figure 7-29 Desquamative interstitial pneumonia (DIP). When chronic inflammation is evident in DIP at scanning magnification, it is centrilobular and associated with respiratory bronchioles.

Figure 7-30 Desquamative interstitial pneumonia. Scant numbers of plasma cells and rare eosinophils may be seen within slightly thickened alveolar walls at high magnification.

Differential Diagnosis

Distinguishing DIP from RBILD is probably a useless exercise for pathologists; 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, giant cell interstitial pneumonia 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%.⁹⁵ Smoking cessation and corticosteroid therapy have proved effective in older studies.⁹⁴

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.¹⁰⁵ Interestingly, all of the “idiopathic LIP” patients described by Cha and colleagues were men, whereas most of secondary LIP patients were women.¹⁰⁴ 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.^105–107 Findings may include bibasilar crackles, cyanosis, and clubbing. Immunoglobulin abnormalities in serum are present in some patients.¹⁰⁸ More commonly, the LIP pattern is associated with a systemic condition that dominates the clinical presentation and clinical course (e.g., Sjögren syndrome, pernicious anemia, hypogammaglobulinemia).

Radiologic Findings

The published radiologic features of idiopathic LIP seem to describe more than one pattern of disease.¹⁰⁹ Bibasilar reticular opacities along with ground-glass attenuation and thickening of interlobular septa are frequently observed abnormalities.^{104,109–111} There may be mixed alveolar and interstitial infiltrates and thin-walled cysts, honeycombing, and changes suggesting pulmonary hypertension late in the disease.^112,113 Nodular patterns can also occur.¹¹⁴ 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.¹¹⁵ An association with Sjögren syndrome has been documented.¹¹⁶

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. 7-31). This definition helps exclude diseases with less intense cellular interstitial infiltrates, such as certain hypersensitivity reactions and systemic connective tissue diseases. 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. 7-32), can also be a part of idiopathic LIP. To a variable extent, germinal centers may be present along airways and lymphatic routes (Fig. 7-33). 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 hyperimmunoglobulinemia, or even MALT lymphoma, are the main considerations.¹¹⁷ When the idiopathic form of the LIP pattern is identified, immunophenotyping and gene rearrangement studies typically show an absence of clonality.¹¹⁸ When nodular lymphoid hyperplasia is prominent around bronchioles, typically accompanied by an interstitial infiltrate, Sjögren syndrome should be rigorously investigated as a potential etiology.

Figure 7-31 Lymphoid interstitial pneumonia. A, This histopathologic pattern is characterized by the presence of a dense and diffuse alveolar septal infiltrate made up of lymphocytes, plasma cells, plasmacytoid cells, and histiocytes. B, Multinucleate giant cells and small non-necrotizing granulomas are commonly present.

Figure 7-32 Lymphoid interstitial pneumonia (LIP). Microscopic honeycomb cystic remodeling (A), with some interstitial fibrosis (B), can also be components of idiopathic LIP.

Figure 7-33 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.

Differential Diagnosis

The LIP pattern is most consistently seen when systemic CVDs manifest in the lung.^105,119 The LIP pattern may also be seen in the setting of bone marrow transplantation¹²⁰ and has frequently been observed in both children and adults who have congenital or acquired immunodeficiency syndromes¹²¹ and in the setting of adult HIV infection including vertical transmission from mother to child.^122–124

Much of what has been written about the histopathology of LIP is similar to that written 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 15 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 7-9) in a “comment” section of the surgical pathology report.

Clinical Course

The clinical outcome and response to therapy for patients with the LIP pattern is largely dependant on whether systemic disease is present. In the idiopathic form, an accurate prognosis has not been forthcoming, although in the series reported by Cha and coworkers, three patients survived more than 10 years.¹⁰⁴ In symptomatic patients, corticosteroid administration may result in significant benefit,¹⁰⁵ 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 are present, the prognosis is less favorable, with as many as one third of patients succumbing to the disease.^105,114 Infection is a common complication, especially when LIP is associated with dysproteinemia.^105,106,125

Clinical Presentation

Diffuse lung disease in RA typically is noted in patients with diagnosed RA, but rarely, ILD may precede articular manifestations.^140,141 The clinical presentation is dominated by shortness of breath and cough. Adults are more commonly affected than children,¹⁴² 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.¹⁴⁰ 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.^25,140 When fibrosis and honeycomb remodeling accompany diffuse lung disease in RA, UIP enters into the differential diagnosis. Affected patients often are younger than those with idiopathic UIP. Cigarette smoking has been reported to be an independent predictor of lung disease in persons with RA.¹⁴³

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.¹⁴⁴ 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.^144,145

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, although not unique (Fig. 7-34) Most of the lymphoid aggregations are present around the terminal airways (“follicular bronchiolitis” when lymphoid germinal centers are prominent) (Fig. 7-35), 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 air space organization (Fig. 7-36), can be seen with cellular interstitial pneumonia (Fig. 7-37) and variable interstitial fibrosis (Fig. 7-38). 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 or Wegener granulomatosis. Intrapulmonary lymph nodes may become prominent in RA and typically show reactive lymphoid hyperplasia when subjected to biopsy.

Figure 7-34 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.

Figure 7-35 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.

Figure 7-36 Rheumatoid arthritis (RA) lung disease. Areas of subacute lung injury, attended by reactive type II cells and air space organization, can be seen. Fresh hemorrhage, probably related to the biopsy procedure, also is evident.

Figure 7-37 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).

Figure 7-38 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 Wegener granulomatosis.

Differential Diagnosis

RA lung manifestations are frequently confused with the idiopathic interstitial pneumonias (COP, NSIP, or even UIP), especially when the lung disease precedes the systemic disease. When patients with RA 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.

Clinical Course

As with other connective tissue diseases, therapeutic strategies in RA have focused on immunosuppression.¹⁴⁶ 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.¹⁴⁷ Needless to say, the development of pulmonary fibrosis with a UIP pattern has a significant negative impact on survival.^{141,143,148,149}

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.^128,152 Digital clubbing may be present but is uncommon. Pulmonary fibrosis and cor pulmonale may develop eventually.¹⁵³ As in other CVDs, lung involvement can precede the development of diagnostic systemic manifestations.^128,154

Radiologic Findings

Bibasilar interstitial infiltrates with relative sparing of the upper lung zones are typical radiologic features.^155,156 Loss of lung volume, honeycomb cysts, and findings consistent with pulmonary hypertension may also be seen. Mixed reticular and nodular infiltrates are common.^155,156 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. 7-39). This distinctive “collagenization” of the lung interstitium has been confused with the pattern of lung fibrosis seen in idiopathic UIP.¹⁵³ The lack of so-called “temporal heterogeneity” (see the earlier section, “Usual Interstitial Pneumonia”) is a useful finding and helps exclude UIP (of IPF) from the differential diagnosis. Pulmonary hypertensive changes (Fig. 7-40) may be present and merit careful attention because this is a major cause of death in patients with scleroderma and lung disease.¹⁵⁷ Because patients with PSS can also develop esophageal motility problems, subclinical chronic aspiration should be carefully excluded as a comorbid disease process.^158,159

Figure 7-39 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 7-40 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

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.¹⁶⁰ 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.¹⁶¹

Clinical Presentation

SLE rivals PSS as the leader in pleuropulmonary manifestations in CVD.^{131,163,168,169} The spectrum of lung disease in SLE is quite broad^{130,164,165,170} and includes pleuritis (Fig. 7-41), acute lupus pneumonitis (Fig. 7-42), NSIP with fibrosis (Fig. 7-43), and diffuse alveolar hemorrhage (Fig. 7-44). 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.

Figure 7-41 Systemic lupus erythematosus (SLE). The spectrum of lung disease in SLE is quite broad and includes pleuritis (A), sometimes accompanied by so-called “lupus erythematosis bodies” or simply, “LE bodies” (B,center).

Figure 7-42 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 7-43 Systemic lupus erythematosus (SLE). The second most common manifestation of SLE lung disease is nonspecific interstitial pneumonia pattern cellular interstitial pneumonia with variable interstitial fibrosis.

Figure 7-44 Systemic lupus erythematosus (SLE). Diffuse alveolar hemorrhage may occur in SLE, often without hemoptysis. In this specimen, prominent air space 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.

Radiologic Findings

The radiologic findings are similar to those in other connective tissue diseases: variable ground-glass attenuation, pleural thickening, pleural and pericardial effusions, and linear parenchymal opacities.^{130,171–174} Acute pneumonitis can produce more extensive changes, but, rarely, chest radiography and high-resolution CT may show normal findings.¹⁷⁵

Histopathologic Findings

Two general categories of pulmonary disease are described in SLE. The first is acute lupus pneumonitis (ALP). ALP is characterized by alveolitis with variable interstitial inflammation and edema (Fig. 7-45). Siderophages and capillaritis occur to a variable degree (Fig. 7-46). Pleuritis is commonly present. The second category of disease includes cellular interstitial pneumonia (lymphocytes and plasma cells) with variable interstitial fibrosis (Fig. 7-47). This 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.^176–178 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 7-45 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 7-46 Systemic lupus erythematosus (SLE). Siderophages and capillaritis may be present in the diffuse alveolar hemorrhage of SLE.

Figure 7-47 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 air space 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).

Clinical Presentation

Although most patients with PM-DM develop lung manifestations after the clinical diagnosis has been established, occasionally lung disease can precede the clinical and serologic diagnosis by months or even years.¹⁸⁴ Onset of pulmonary symptoms may occur at any age, with a mean occurrence in the sixth decade.^150,184,185 Women are more commonly affected than men. Digital clubbing is rare. In contrast with most other systemic connective tissue diseases (with the exception of SLE), patients with PM-DM can present with acute lung disease, typically manifesting as rapidly progressive DAD.^183,185 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.^186,187

Radiologic Findings

As with other CVDs manifesting in the lung, radiologic abnormalities in PM-DM predominantly affect the lung bases.¹⁸⁵ Ikezoe and colleagues reviewed the high-resolution CT findings in 23 of 25 patients with PM-DM who had high-resolution CT abnormalities.¹⁸⁸ These researchers identified ground-glass opacities in 92%, linear opacities in 92%, irregular interfaces in 88%, air space 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 air space consolidation associated with the development of DAD.^184,185

Histopathologic Findings

The most frequent lung manifestation of PM-DM is a cellular interstitial pneumonia (Fig. 7-48) with some fibrosis,^184,185 indistinguishable from nonspecific interstitial pneumonia (see the later section, “Idiopathic Interstitial Pneumonias”). The next most common pattern is DAD (Fig. 7-49). The fibrosis associated with PM-DM is distinguishable from that of idiopathic UIP based on a relative lack of peripheral accentuation (Fig. 7-50) 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 connective tissue disease.

Figure 7-48 Polymyositis-dermatomyositis (PD-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 7-49 Polymyositis-dermatomyositis (PD-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 7-50 Polymyositis-dermatomyositis (PD-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.

Clinical Presentation

Women are more commonly affected with lung disease in Sjögren syndrome than men; the most frequent presenting complaint is cough and dyspnea.^107,190 Positive results on rheumatoid factor and ANA assays are expected findings, as well as positive reactions to extractable nuclear antigens (anti-SSA, anti-SSB).¹⁹² These latter serologic tests are specific for the primary form of the disease.¹⁹³

Radiologic Findings

Mixed alveolar and interstitial infiltrates are characteristic in Sjögren syndrome; they usually have a finely reticular or nodular pattern.^191,194 The occurrence of pleural effusion or hilar/mediastinal adenopathy in patients with Sjögren syndrome should raise concern for lymphoma.¹⁹⁵

Histopathologic Findings

The histopathologic spectrum of pulmonary Sjögren syndrome includes bronchiolitis (Fig. 7-51) with or without air space organization, follicular lymphoid hyperplasia along airways (Fig. 7-52), diffuse NSIP or LIP pattern interstitial inflammation (Fig. 7-53), and rarely, interstitial fibrosis (Fig. 7-54), the last raising concern for an inflammatory version of UIP. Small, non-necrotizing granulomas, resembling those of hypersensitivity pneumonitis, are frequently identified in the interstitium (Fig. 7-55).¹⁹⁶ In some cases, more prominent granulomatous inflammation can be seen, especially in association with the LIP pattern of cellular infiltration. Patients with Sjögren syndrome are at risk of developing lymphoid hyperplasia and lymphoproliferative diseases; this predilection should be kept in mind in evaluating the lung biopsy in this setting.

Figure 7-51 Sjögren 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 7-52 Sjögren syndrome (SS). Terminal airway and alveolar space organization commonly accompany the bronchiolitis and cellular interstitial pneumonia of SS.

Figure 7-53 Sjögren 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 multinucleate giant cells and poorly formed granulomas in this specimen. Prominent arteriopathic changes with marked adventitial fibrosis can be seen in the pulmonary artery at center right.

Figure 7-54 Sjögren syndrome (SS). Advanced interstitial fibrosis occurs rarely 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.

Figure 7-55 Sjögren syndrome (SS). A, Small, non-necrotizing 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.

Clinical Features

Patients with the “chronic” form of eosinophilic pneumonia often exhibit a typical clinical syndrome and radiographic appearance.¹⁹⁹ 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 absent altogether.

Radiologic Findings

Chronic eosinophilic pneumonia presents the most consistent radiologic pattern, with bilateral, poorly defined, subpleural air space 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.¹⁹⁹ CT scans detect the peripheral location of infiltrates even when this distribution is not apparent on the chest radiograph.²⁰⁰ 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.

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. 7-56), and there is an associated mild interstitial pneumonia. Type II hyperplasia is characteristic (Fig. 7-57), and fibrin often is present in the air spaces (Fig. 7-58). Angiitis of small vessels may be seen, and patchy air space and alveolar duct organization may be present. A vaguely granulomatous accumulation of dense macrophages may be seen within the alveolar spaces (Fig. 7-59), sometimes accompanied by multinucleate giant cells whose nuclei and cytoplasm closely resemble those of adjacent macrophages (Fig. 7-60). 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 7-56 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.

Figure 7-57 Eosinophilic pneumonia. Highly atypical type II hyperplasia is characteristic in acute eosinophilic pneumonia, often raising concern for viral cytopathic changes.

Figure 7-58 Eosinophilic pneumonia. A, Fibrinous air space exudates are commonly present, typically with admixed eosinophils, as seen in this specimen. B, Organizing pneumonia pattern repair may also occur.

Figure 7-59 Eosinophilic pneumonia. A vaguely granulomatous accumulation of dense macrophages may be seen within the alveolar spaces, sometimes accompanied by plump multinucleate macrophages.

Figure 7-60 Eosinophilic pneumonia. The multinucleate 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.

Differential Diagnosis

When air space organization is prominent, disorders with the organizing pneumonia pattern must be considered in the differential diagnosis (see Box 7-8). 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 multinucleate 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 organizing pneumonia, because both patterns can be seen in acute eosinophilic pneumonia [AEP]; see Chapter 5) 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 acute onset eosinophilic pneumonia). As in all cases of eosinophilic pneumonia, it is always worthwhile to suggest the possibility of Churg-Strauss syndrome (see Chapter 10) because the pulmonary manifestations of that systemic vasculitic disease in the lung are most commonly those of eosinophilic pneumonia.

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.²³⁸ 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 Sjögren syndrome.²⁰¹

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 diffuse acute injury occurs.^224,263 Once fibrosis has occurred, changes are likely to be stable, with little improvement. Systemic corticosteroid therapy may be added when symptoms are severe.

Methotrexate

Methotrexate (MTX) lung toxicity is uncommon; when it occurs, it is predominantly a manifestation in women taking the drug.^264,265 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. 7-61) are common findings in the surgical lung biopsy.^239,266,267Giant cells and small non-necrotizing granulomas (Fig. 7-62) are the only relatively specific markers for MTX, in comparison with other drugs.²³⁹ Type II pneumocyte hyperplasia and tissue eosinophilia may be seen (Fig. 7-63). Hyaline membranes are rarely identified.²³⁹

Figure 7-61 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 comes into the differential diagnosis (e.g., rheumatoid arthritis).

Figure 7-62 Methotrexate toxicity. Giant cells and scattered small non-necrotizing granulomas (center) are the only relatively specific markers for lung injury due to methotrexate.

Figure 7-63 Methotrexate toxicity. Type II pneumocyte hyperplasia (A) and variable acute lung injury with air space 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.^268–271 High-resolution CT scans show diffuse infiltrates combined with basal or peripheral high-attenuation opacities and nonspecific infiltrates.^272,273 The most common pathologic manifestation is a cellular interstitial pneumonia (Fig. 7-64) associated with prominent intra-alveolar macrophages whose cytoplasm shows fine vacuolation.^{268,274–276} This vacuolation can also be seen in reactive type II pneumocytes (Fig. 7-65); published reports have described the presence of characteristic lamellar cytoplasmic inclusions ultrastructurally.²⁰⁰ 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.²⁷⁴ Pleural inflammation and pleural effusion have also been reported.²⁷⁷ Some patients with amiodarone toxicity may develop an organizing pneumonia (OP) pattern (Fig. 7-66), a nodular pattern,²⁷⁸ or even DAD.^274,279,280 A majority of patients with amiodarone-related pulmonary toxicity will recover once the drug is discontinued.^{268,269,274–276}

Figure 7-64 Amiodarone toxicity. The most common pathologic change seen in amiodarone toxicity is a cellular interstitial pneumonia associated with prominent intra-alveolar macrophages whose cytoplasm shows fine vacuolation.

Figure 7-65 Amiodarone toxicity. A and B, Amiodarone effect (fine cytoplasmic vacuolation; arrows) can be seen and in reactive type II pneumocytes. 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 7-66 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.

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 manifestationof acute BCNU pulmonary toxicity.^281–284 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.^281,285,286 The histopathologic features of BCNU toxicity can be generally grouped within the NSIP pattern (Fig. 7-67). In children, fibrosis develops in the upper lung zones, with peripheral accentuation.²⁸⁶ In adults, this upper lobe distribution is uncommon.²⁸⁷ Pleural disease can accompany pulmonary abnormalities in some patients.

Figure 7-67 BCNU (carmustine) toxicity. The histopathologic features of BCNU toxicity are those of a nonspecific cellular interstitial pneumonia with variable interstitial fibrosis.

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,^288–290 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 disease²¹² (Fig. 7-68).

Figure 7-68 Busulfan toxicity. A and B, The prognosis for patients with busulfan-induced acute lung disease is poor. In the subacute form of injury, air space organization is often accompanied by marked atypia of reactive type II cells.

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.^{210,291–293} The typical clinical presentation begins with dry cough and progresses to breathlessness. Chest imaging reveals areas of nodular consolidation or diffuse reticulation.²⁹⁴ 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.^295–298 In humans, toxicity results in acute lung injury with air space organization in the early phase and fibrosis as a late consequence (Fig. 7-69).

Figure 7-69 Bleomycin toxicity. Pulmonary changes may include acute lung injury with air space organization in the early phase (A) and fibrosis resembling that of usual interstitial pneumonia as a late consequence (B).

Histopathologic Findings

As the intravenous material becomes lodged in the pulmonary microvasculature, a perivascular interstitial foreign body–type granulomatous reaction is produced (Fig. 7-73) that may be associated with prominent vascular changes (including pulmonary hypertension and thrombotic lesions and others),³⁰⁶ as well as interstitial fibrosis (Fig. 7-74) that may be focal or diffuse and sometimes massive.³⁰⁷ Among the pathologic manifestations presented in Table 7-6, 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 been most frequently associated with methylphenidate (Ritalin) abuse.³⁰⁸ 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.³⁰⁸ The pathogenesis of panlobular emphysema associated with intravenous drug abuse is unknown. Some of the postulated mechanisms include synergism with cigarette smoke, direct toxic effects of the drug, and induced intravascular leukocyte sequestration causing proteolytic pulmonary injury.

Figure 7-73 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 7-74 Intravenous drug. One complication of intravenous drug abuse is lung fibrosis (A); sometimes this can be massive (B).

Table 7-6 Pathologic Lesions and Clinical Syndromes Related to Intravenous Drug Use

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.³⁰⁹

Clinical Presentation

Sarcoidosis is a systemic disease of uncertain etiology, with frequent lung manifestations.³¹¹ Lung disease is usually mild, accompanied by variable degrees of shortness of breath, chest pain, and cough.³¹¹ As many as two thirds of patients are asymptomatic.^270,312 Sarcoidosis is predominantly a disease of young adults but has been described in patients of all ages.^313–315 Sarcoidosis 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.²⁷⁰ The Kveim test²⁷⁰ is relatively specific for sarcoidosis, employing an injected antigenic extract derived from human sarcoid granulomas, but the test is not widely used today,³¹¹ 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 chest radiographic findings. 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.^270,311 When sarcoidosis involves the lung parenchyma, the disease is upper lobe predominant.³¹¹ CT scans are not usually necessary for the diagnosis but will show reticulonodular opacities along lymphatic routes, with or without alveolar infiltrates.^{270,316–318} Bullae with honeycombing may be seen in advanced disease, sometimes associated with progressive lung fibrosis.^319,320 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.”³²¹ 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 non-necrotizing (immune) granuloma, typically occurring within areas of sclerotic fibrosis (Fig. 7-75). In sarcoidosis, small granulomas have a tendency to coalesce to form larger nodular lesions, all embedded in refractile eosinophilic collagen (Fig. 7-76). A narrow rim of lymphocytic inflammation is typically seen at the periphery of these confluent nodules (Fig. 7-77). Granulomas are distributed along lymphatic routes in the pleura, within the intralobular septa, and along the bronchovascular bundles (Fig. 7-78). Multinucleate giant cells are characteristically present in the disease, often accompanied by a variety of distinctive cytoplasmic inclusions (e.g., Schaumann bodies, asteroid bodies) (Fig. 7-79). 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. 7-80).

Figure 7-75 Sarcoidosis. The characteristic pathologic lesion of pulmonary sarcoidosis is the non-necrotizing (immune) granuloma (A), typically occurring within sclerotic fibrosis (B).

Figure 7-76 Sarcoidosis. In sarcoidosis, small granulomas have a tendency to coalesce to form larger nodular lesions, all embedded in refractile eosinophilic collagen.

Figure 7-77 Sarcoidosis. A variable (but rarely intense) rim of lymphocytic inflammation is typically seen at the periphery of confluent granulomas.

Figure 7-78 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.

Figure 7-79 Sarcoidosis. Multinucleate 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 7-80 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 typically are present in the immediate subepithelial region of the airway.

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.³²² When five to six samples were obtained, the probability rose to 100% for patients with stage II and stage 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 microbiological cultures were identified in 11% of biopsies in which granulomas were present despite negative special stains of tissue sections.³²³ 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.

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 multinucleate giant cells, often containing foreign material (partially digested food, primarily).

Clinical Presentation

Hypersensitivity pneumonitis can occur as acute or subacute and chronic forms. The acute form occurs within hours of inhalational exposure to 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.³³⁵ Women are more commonly affected than men. Cigarette smoking seems to reduce the risk of developing hypersensitivity, although the mechanism for this protective effect is unknown.³³⁶

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.^335,337 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.^335,337 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.^{333–335,337,338}

Radiologic Findings

In acute hypersensitivity pneumonitis, a diffuse ground-glass appearance is seen on CT scans of the chest, sometimes accompanied by fine nodules.³³⁹ In subacute disease, abnormalities tend to be confined to the upper one half or two thirds of the lung and are characterized radiologically 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.²³ The presence of irregular linear opacities correlates with the presence of lung fibrosis.^335,338 In very-late-stage chronic hypersensitivity pneumonitis, honeycomb remodeling may be identified radiologically, mimicking UIP.^23,24 Interestingly, the CT appearance of subacute hypersensitivity pneumonitis may be indistinguishable from that in low-grade atypical mycobacterial infection occurring in the immunocompetent host as a result of bioaerosol exposure to non-tuberculous mycobacteria^340,341 (so-called “hot tub lung”; see Chapter 6).

Histopathologic Findings

The histopathologic features of hypersensitivity pneumonitis are typically those of a chronic inflammatory interstitial pneumonia associated with bronchiolitis, and small, indistinct, non-necrotizing interstitial granulomas^331,342,343 (Fig. 7-84). In early reports of farmer’s lung, acute inflammation and vasculitis were also observed.³⁴⁴ 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. 7-85). 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. 7-86). The interstitial “granulomas” of hypersensitivity pneumonitis are inconspicuous (Fig. 7-87) and may easily escape notice in many cases. Multinucleate giant cells (Fig. 7-88) 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. Air space organization (Fig. 7-89) with immature fibroblast and matrix (organizing pneumonia pattern) can be seen in as many as 60% of patients with hypersensitivity pneumonitis.³⁴² In general, this is not confluent organization, as seen in organizing pneumonia 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. 7-90). A mild perivascular lymphoid accumulation typically is present in hypersensitivity pneumonitis, but prominent germinal centers or dense lymphoplasmacellular infiltration along vascular sheaths (especially veins in the interlobular septa) are 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. 7-91). 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.³⁴⁵ Refractile oxalate crystals in giant cells may be sufficiently prominent to suggest aspiration pneumonia or even pneumoconiosis (Fig. 7-92).

Figure 7-84 Hypersensitivity pneumonitis. This pathologic process manifests as a chronic inflammatory interstitial pneumonia associated with bronchiolitis (A) and small, indistinct, non-necrotizing interstitial granulomas (B).

Figure 7-85 Hypersensitivity pneumonitis. At low magnification, the surgical lung biopsy shows a moderately dense interstitial infiltrate, causing slight widening of the alveolar walls.

Figure 7-86 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 7-87 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 7-88 Hypersensitivity pneumonitis. Multinucleate 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 7-89 Hypersensitivity pneumonitis. Patchy air space organization can be seen in as many as 60% of affected patients.

Figure 7-90 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.

Figure 7-91 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 7-92 Hypersensitivity pneumonitis. Refractile oxalate crystals in giant cells may be sufficiently prominent to suggest aspiration pneumonia or even pneumoconiosis.

Clinical Course

The clinical course in hypersensitivity pneumonitis varies with the intensity and chronicity of exposure.^335,344,346 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.^347–351 Once lung fibrosis ensues, immunosuppressive therapy is of little benefit, especially if continued antigen exposure occurs.³⁵¹

Differential Diagnosis

Cellular interstitial pneumonias with or without small non-necrotizing 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 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 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 the latter 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.

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.^353,355,358 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.^358–361 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.^360,362 When significant fibrosis occurs in PLCH, the disease may simulate IPF.^359,360,362

Histopathologic Findings

Proliferative (Cellular) Phase

At scanning magnification, the nodules of PLCH have a stellate appearance and are centered on the small airways (Fig. 7-93). 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. 7-94). Stellate cellular nodules may be as large as 1.5 cm,³⁵⁷ and confluence of nodules affecting adjacent airways may impart a serpentine outline to the lesions (Fig. 7-95). 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.³⁶³ In many cases, lightly pigmented brown macrophages (“smoker’s macrophages”) are present in and around the nodules (Fig. 7-96). Eosinophils in variable numbers occupy the next innermost layer of the nodules (Fig. 7-97); this is the location in which aggregated Langerhans cells are most easily found in the thickened interstitium (Fig. 7-98). The Langerhans cells have a pale basophilic nucleus with characteristic sharp nuclear infoldings, imparting a “crumpled tissue paper” nuclear contour (Fig. 7-99). 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. 7-100), but in most instances, the morphology of the lesions is sufficiently compelling enough for a definitive diagnosis to be established without the aid of special stains. In some cases, patchy interstitial and air space organization (Fig. 7-101) 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 7-93 Pulmonary Langerhans cell histiocytosis. At scanning magnification, the characteristic nodules have a stellate appearance and are centered on the small airways.

Figure 7-94 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 7-95 Pulmonary Langerhans cell histiocytosis. The characteristic stellate cellular nodules may be as large as 1.5 cm in diameter.

Figure 7-96 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 7-97 Pulmonary Langerhans cell histiocytosis. Eosinophils in variable numbers occupy the next innermost layer of the nodules.

Figure 7-98 Pulmonary Langerhans cell histiocytosis. Aggregates of Langerhans cells are most readily found in the thickened interstitium of the stellate ramifications of the lesions.

Figure 7-99 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 7-100 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.

Figure 7-101 Pulmonary Langerhans cell histiocytosis. In some cases, patchy air space organization may be present, but it is not a particularly characteristic feature of the disease.

Fibrotic Lesions

With “aging” of the lesions of PLCH, Langerhans cells become progressively depleted and overshadowed by fibrosis (Fig. 7-102). The mechanism for this transformation is unknown. In some patients, only residual stellate parenchymal scars are found, and 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. 7-103). Another scenario inwhich 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 7-102 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).

Figure 7-103 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.

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 versus HMB45 and actin in LAM cells). Other nodular lung diseases are occasionally confused with PLCH, including Wegener granulomatosis, 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”).^364,365 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 choice.³⁵³ Immunosuppression with corticosteroids, with or without the addition of a cytotoxic agent, has met with variable success. In larger reviews, the median survival time is 12 years,^353,366 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.³⁵³

Clinical Presentation

Pulmonary involvement occurs in approximately one third of patients with ECD and is associated with significant morbidity and mortality.^{367,374–378} 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.³⁷⁷

Histopathologic Findings

In surgical wedge lung biopsies, a distinctive interstitial infiltrate is observed consisting of xanthomatous histiocytes, lymphocytes, and scattered Touton-type giant cells³⁷⁶ (Fig. 7-104). Prominent fibrosis is present in a characteristic subpleural and lymphatic distribution (Fig. 7-105). 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 7-104 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.

Figure 7-105 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.

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 18 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. 7-106).

Figure 7-106 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 Course

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

Clinical Presentation

LAM occurs most frequently in women of childbearing age, with a peak incidence in the fourth decade of life.^379,383 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.^390–395 Of note, the rare male patients reported to have LAM also had TSC.³⁸⁹ 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.^379,383,384 Pneumothorax occurs, and pleurocentesis may reveal a chylous effusion.

Radiologic Features

Plain films of the chest may be interpreted as normal,³⁹⁶ but with pneumothorax, air or fluid may be present in the pleural space. Small nodules and cysts may be detected and typically are 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.^396–401

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. 7-107). In most cases, thin walled cysts are easily visible (Fig. 7-108) and useful for identifying diagnostic smooth muscle bundles at higher magnification (Fig. 7-109). The smooth muscle of LAM is distinctive (Fig. 7-110). The LAM cell is fusiform and plump. The nucleus is larger than that of other smooth muscle cells in the lung (Fig. 7-111) and the nuclear-cytoplasmic ratio is typically higher. Smooth muscle bundles may be small or attenuated at the periphery of cysts (Fig. 7-112) or quite cellular and prominent (Fig. 7-113). 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.⁴⁰² These unattached cell clusters have been proposed as the mechanism for dissemination of the disease.⁴⁰²

Figure 7-107 Lymphangioleiomyomatosis (LAM). LAM lesions may be difficult to appreciate at scanning magnification, particularly in cases in which smooth muscle lesions are sparse or of small size.

Figure 7-108 Lymphangioleiomyomatosis (LAM). In most cases, thin-walled cysts are readily visible (A) and useful for searching out the characteristic smooth muscle of LAM (B).

Figure 7-109 Lymphangioleiomyomatosis (LAM). A and B, The smooth muscle of LAM more closely resembles a low-grade neoplasm than any normally occurring smooth muscle.

Figure 7-110 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.

Figure 7-111 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 7-112 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 7-113 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, stain with cytokeratin and surfactant apoprotein antibodies.

Differential Diagnosis

The differential diagnosis for LAM includes Birt-Hogg-Dubé syndrome,⁴⁰³ 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 Sjögren syndrome, and cystic terminal airways in small-airway disease, especially when these diseases occur in the setting of recurrent pneumothorax in a woman.

Clinical Course

No effective therapy has emerged for LAM. Nevertheless, antihormonal therapy^404–407 has been the mainstay of treatment, based on the presence of estrogen and progesterone receptors in the abnormal smooth muscle cells in this disease.^{270,384,406,408} There is no evidence of improvement with the use of estrogen antagonists.⁴⁰⁹ 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).⁴⁰⁹ Lung transplantation may also be considered an effective option.⁴¹⁰ Recurrence of LAM in transplanted lung has been reported.⁴¹¹ 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.^309,412

Radiologic Findings

Avila and coworkers⁴²¹ 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.⁴²² These researchers described alveolar septal thickening (Fig. 7-114) associated with prominent clear vacuolated type II pneumocytes (Fig. 7-115), 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.

Figure 7-114 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 7-115 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. Inset in part B shows the peculiar vacuolated cells of this disease, sometimes even confused for “clear cell carcinoma.”

Clinical Course

No effective therapy has been identified for HPS patients with lung fibrosis, but newer antifibrotic therapies are being explored.⁴²³

Clinical Presentation

Most cases are diagnosed in adult life, but the disease can manifest at any age.^425–427 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,⁴²⁵ 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.⁴³¹

Radiologic Findings

The chest radiograph is almost immediately diagnostic, with sand-like 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.^425–427 High-resolution CT scans reveal intra-alveolar microcalcifications bilaterally, with increased concentration of microliths along bronchovascular bundles and interlobular fissures and in the subpleural lung parenchyma.⁴³²

Histopathologic Findings

On gross examination, the lungs are firm and gritty and rigidly maintain their shape before fixation. On microscopic examination, the air spaces contain innumerable tiny calcified bodies that are concentrically laminated and have radial striations (Fig. 7-116). These microliths are composed of calcium and phosphorus, in concentrations similar to those in bone.⁴²⁷ 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. 7-117).

Figure 7-116 Pulmonary alveolar microlithiasis. The air spaces contain innumerable tiny calcified bodies that are concentrically laminated and have radial striations.

Figure 7-117 Pulmonary alveolar microlithiasis. Rarely, the calcifications may be present within the alveolar walls, often accompanied by some degree of interstitial thickening and chronic inflammation.

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 while the microliths of PAM lack this feature. The shear 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.

Clinical Presentation

The disease occurs commonly as a primary idiopathic form, whether congenital or 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.^436–440 The disease is commonly associated with exposure to crystalline material and silica, although other substances have also been implicated.^437,441 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.^{435,440–442}

Radiologic Findings

Chest radiographs show extensive bilateral air space 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. Thickened lobular septa sharply demarcate areas of ground-glass attenuation. These characteristics of alveolar proteinosis on CT are referred to as “crazy paving pattern.”⁴⁴³

Histopathologic Findings

PAP (i.e., alveolar lipoproteinosis) is characterized by an intra-alveolar accumulation of lipid-rich eosinophilic material.⁴³⁶ In primary 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 air spaces, sometimes with a rim of retraction that separates the alveolar wall slightly from the exudates (Fig. 7-118). Closer inspection of this material shows embedded clumps of dense globular material and cholesterol clefts (Fig. 7-119). Amorphous solid eosinophilic globules are seen frequently inside the pools of proteinaceous material. The periodic acid/Schiff reagent (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.⁴³⁵ 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 7-118 Pulmonary alveolar proteinosis (PAP). The nearly diagnostic appearance of PAP at scanning magnification demonstrates pink granular material filling the air spaces, sometimes with a rim of retraction that separates the alveolar wall slightly from the exudate.

Figure 7-119 Pulmonary alveolar proteinosis (PAP). A, Closer inspection of the material seen in Figure 7-118 shows embedded clumps of dense globular material and cholesterol clefts. B, The clumps may be variably prominent; in this example, they are less distinct.

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 induces remission and excellent long-term survival.⁴⁴⁴ Based on the recent evidence of a high incidence of anti–GM-CSF antibody in primary PAP patients, clinical trials using aerosolized GM-CSF have been initiated with good results.^445,446

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.⁴⁵¹ Abnormalities include linear opacities, horizontal linear lines abutting on the pleura, mostly the lower lobes (Kerley B lines), subpleural edema, and commonly, hilar and mediastinal lymph node enlargement.⁴⁴⁹ 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 scanning shows irregular thickening of the bronchovascular bundles and lobular septa, giving them a beaded appearance.^448,450 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. 7-120). 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 biopsy⁴⁵² (Fig. 7-121). Variable amounts of tumor may be present throughout the lung, involving the interstitium of the alveolar walls, the air spaces themselves, and the lumens of small muscular pulmonary arteries. This latter 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 non-neoplastic diffuse lung disease.^447,449

Figure 7-120 Lymphangitic carcinomatosis. Few lung diseases are as dramatic (or as devastating to those affected) than lymphangitic carcinomatosis. The characteristic distribution of the disease is demonstrated here at scanning magnification, with peribronchial and septal lymphatics filled by metastatic tumor.

Figure 7-121 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.

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.^447,449

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.⁴⁴⁷

Clinical Presentation

IPFE patients range in age from 32 to 65 years. Most of the reported cases have been in women who present with dyspnea on exertion and cough. Pneumothorax has been reported in some patients. In a subset of reported cases of IPFE, the patients had a history of malignancy; however, many of them began to experience lung symptoms before their malignant neoplasm was diagnosed. There appears to be a familial association.

Radiologic Findings

Bilateral upper lung volume loss with marked apical pleural thickening is the most common finding on plain films. 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. 7-122A).

Figure 7-122 Idiopathic pleuroparenchymal fibroelastosis (IPFE). A, Biapical pleural fibrotic changes, more prominent on the right (CT image). Subcutaneous Port-A-Cath reservoir is present on the left anterior chest wall. B, An upper lobe biopsy from a patient with IPFE, seen at scanning magnification. Note the elastotic fibrosis (f) 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(6):784–787, Case 2, Figure 4.)

Histopathologic Findings

The histopathology of IPFE 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 (see Fig. 7-122B).

Differential Diagnosis

Apical cap should be excluded from the differential diagnosis. IPFE is a progressive scarring disorder that can affect survival through eventual loss of lung compliance. The presence of dense collagenous fibrosis should raise an alternative diagnosis, such as UIP/NSIP. Honeycomb fibrosis in the lower lung is not an expected finding in patients with IPFE.

Clinical Course

The expected clinical course varies considerably from case to case; however, three of the seven patients were dead within the follow-up period.^453,454

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