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