21

Bronchiolitis obliterans with organizing pneumonia (BOOP), also called organizing pneumonia, refers to a nonspecific pattern of acute lung injury characterized by a distinctive form of patchy intraluminal proliferation of fibroblasts and myofibroblasts. BOOP occurs as a primary pathologic abnormality in a variety of clinical settings with multiple associations and potential etiologies (Table 21–1). Bronchiolitis obliterans organizing pneumonia was the term proposed in 1985 by Epler and colleagues for a unique clinicopathologic syndrome of idiopathic lung disease first described at the beginning of the 20th century in the German literature.^1–3 Prior to Epler’s description other reports had used a variety of terms for the same syndrome, such as cryptogenic organizing pneumonitis,⁴ bronchiolitis obliterans with classical interstitial pneumonia (BIP),⁵ bronchiolitis obliterans,⁶ and organizing pneumonia-like process.⁷ Since 1985 still other synonyms have been offered, including proliferative bronchiolitis⁸ and idiopathic intraluminal organizing pneumonia.⁹ Using the modifier “idiopathic” is helpful in distinguishing idiopathic BOOP, a specific clinical entity, from the relatively nonspecific histologic lesion described below. A recently published classification scheme for the idiopathic interstitial pneumonias adopts the term cryptogenic organizing pneumonia (COP).¹⁰ Numerous reviews have summarized clinical, radiologic, and pathologic features of idiopathic BOOP.^8,11–23

Clinical Features

Idiopathic BOOP is uncommon, with age- and sex-adjusted annual incidence of less than 1 per 100,021 person years in southeast Minnesota for the decade from 1984 to 1994.²⁸ Adult men and women are affected equally, with a peak incidence in the sixth decade of life. Underlying connective tissue disease has been identified in less than 10% of reported patients.^{3,4,24,25,28,82,114–116} Most patients with idiopathic BOOP present with cough, often with associated shortness of breath, of several weeks’ duration. Fever accompanies the respiratory complaints in about half; malaise and weight loss are present in a minority of patients. A more fulminant course has been described in a few patients,^113,117,118 although the clinical, radiologic, and pathologic findings overlap with those seen in acute interstitial pneumonia (Hamman-Rich disease) (see Chapter 20).^119–121 The classical description has been expanded by recognition of seasonal variation in a subset of patients from the United Kingdom who develop respiratory illness from late February to early May (“seasonal cryptogenic organizing pneumonia”).¹²² Physical findings in the majority of patients are limited to tachypnea and fine inspiratory crackles. Digital clubbing is rare. Laboratory findings show inconsistent and nonspecific abnormalities including mild leukocytosis and mild elevation in erythrocyte sedimentation rate and C-reactive protein.^4,28,115 Cholestatic abnormalities in liver function tests occur uncommonly, and have been linked to the seasonal variant.^116,122 Pulmonary function studies typically show mild to moderate restriction of lung volumes accompanied by a diminished diffusion capacity for carbon monoxide (DL_CO).

The terms BOOP and cryptogenic organizing pneumonia have also been applied to patients with underlying malignancies, most of whom received various forms of immunosuppressive therapy including patients status post–bone marrow transplantation.^28,36,82 Although many reported patients have respiratory syndromes analogous to otherwise idiopathic illness, the term idiopathic BOOP should probably be avoided in patients with underlying malignancies and immunocompromised patients because their lung diseases are often related to infection or other iatrogenic factors.^28,36 Most patients in this category survive their respiratory illnesses but have higher overall mortality rates compared with patients without underlying diseases.^28,36

Radiologic abnormalities in patients with BOOP are heterogeneous. Conventional chest roentgenograms typically show patchy bilateral airspace opacities, often described as having a “ground-glass” or consolidated appearance (Fig. 21–1).^3,21,123,124 The radiographic appearance is not specific and frequently mimics infectious pneumonia. Peripheral migratory infiltrates that tend to wax and wane over time are seen in some patients and overlap with radiographic findings classically associated with chronic eosinophilic pneumonia.^115,123,125 Conventional computed tomography (CT) and high-resolution CT (HRCT) scans demonstrate patchy areas of consolidation or ground-glass opacity in a peribronchovascular or peripheral subpleural distribution (Fig. 21–2).^126–130 Areas of opacity are often characterized as nodular or mass-like in appearance.^129–131 Cavitation has been observed in only occasional patients and when present should raise concerns for other possibilities, such as infection, carcinoma, or Wegener’s granulomatosis.^132–135 Localized airspace opacities represent another radiologic manifestation of idiopathic BOOP and may be indistinguishable from various lung neoplasms.28,132,136,137 Patients with localized opacities are usually asymptomatic without the nonspecific laboratory abnormalities more commonly observed in patients with patchy bilateral disease.²⁸ Bibasilar interstitial opacities that mimic those seen in idiopathic pulmonary fibrosis are uncommon.¹¹⁴ This latter radiographic pattern may be more common in patients with associated collagen vascular diseases and tends to be associated with a poorer prognosis.¹¹⁴

Clinical and radiologic features of idiopathic BOOP are characteristic but not specific. For that reason, lung biopsy is usually a key element in evaluation and diagnosis of patients with this syndrome. Surgical lung biopsy has been highlighted as the preferred diagnostic method,3,138 but transbronchial biopsies are also a reliable diagnostic tool if carefully interpreted in an appropriate clinical and radiologic context.^{116,123,139,140}

The prognosis for patients with idiopathic BOOP is excellent, with disease-specific mortality rates of just over 6%.^{3,4,24,25,28,114–116} Corticosteroids are standard therapy, although some patients recover without treatment. Relapses are common and develop in over half of patients, most within the first year of the presenting episode.¹¹⁶ Risk of relapse increases with increasingly severe hypoxemia at presentation and delays in treatment initiation.^116,141 Relapse often occurs after treatment cessation or with tapering low-dose therapy. Most patients who relapse respond to corticosteroid treatment.

Pathologic Features

A distinctive pattern of intraluminal fibrosis involving distal airways, alveolar ducts, and peribronchiolar airspaces is the histopathologic abnormality that defines BOOP. Filling of airways and airspaces results in patchy consolidation (Fig. 21–3) corresponding to the findings described on imaging studies. The intraluminal fibrosis consists of polypoid intraluminal plugs of connective tissue rich in spindle cells (Fig. 21–4). Intraluminal fibroblastic plugs are distributed within distal airways and alveolar ducts, resulting in a characteristic low magnification appearance (Fig. 21–5). Larger terminal bronchioles and peribronchiolar alveolar spaces also show varying degrees of involvement. At higher magnification intraluminal fibrosis consists of concentrically arranged spindle cells associated with a pale-staining basophilic matrix (Fig. 21–6). Chronic inflammatory cells and capillaries may be present within areas of fibrosis, thus resembling granulation tissue. Fibrinous exudates may accompany the luminal fibrosis (Fig. 21–7). An acute and chronic bronchiolitis is often present away from the areas of airspace fibrosis and consists of a nonspecific peribronchiolar infiltrate of acute and chronic inflammatory cells.

Fibrosis in the form of interstitial collagen deposition is distinctly uncommon in BOOP. The presence of collagen fibrosis, particularly when it is accompanied by architectural distortion in the form of scarring or honeycomb change, signifies a worse prognosis likely related to the presence of some other underlying process such as usual interstitial pneumonia.142,143

Bronchiolitis obliterans with organizing pneumonia, a term synonymous with organizing pneumonia, is a relatively nonspecific reaction to acute lung injury that can occur as a secondary finding adjacent to, or as a minor component of, other pathologic processes. This is particularly important to bear in mind when interpreting small biopsy specimens. For example, cryptococcosis (see Chapter 10), Wegener’s granulomatosis (see Chapter 15), eosinophilic pneumonia, and lung carcinoma are four important conditions in which organizing pneumonia can be a prominent secondary feature.^{36,106,135,144} Focal areas of organizing pneumonia resembling BOOP also occur frequently in nonspecific interstitial pneumonia (NSIP) and hypersensitivity pneumonia, and occasionally in other conditions such as usual interstitial pneumonia and Langerhans’ cell histiocytosis. Recognition of histopathologic features diagnostic of the underlying process is the key to distinguishing secondary organizing pneumonia from cases in which BOOP represents the primary pattern of injury.

Diffuse alveolar damage in the organizing phase demonstrates significant morphologic overlap with BOOP, prompting Katzenstein145 to consider both under the general heading of acute lung injury patterns. Intraluminal fibrosis virtually indistinguishable from that seen in BOOP can occur as a focal or dominant finding in organizing diffuse alveolar damage (Fig. 21–8). Lung tissue away from areas of intraluminal fibrosis differs, however, in showing expansion and distortion of alveolar septa by fibroblasts and myofibroblasts often with associated hyaline membranes. Other markers of acute lung injury, such as fibrin thrombi in small muscular arteries and squamous metaplasia of bronchiolar epithelium, are uncommon in BOOP and when present should prompt a search for histologic features diagnostic of diffuse alveolar damage. In especially difficult cases correlation with clinical and radiologic findings is helpful in that diffuse alveolar damage typically occurs in the context of the acute respiratory distress syndrome (ARDS).

The term bronchiolitis obliterans has been applied to patients with BOOP as well as patients with a form of primary fibrosing airway disease now more commonly referred to as constrictive or obliterative bronchiolitis (see Chapter 22).¹⁴⁶ Patients with this disorder more commonly have significant airflow limitation on pulmonary function tests and nearly normal radiologic findings. The pathologic changes consist of patchy and sometimes subtle peribronchiolar fibrosis that encroaches on airway lumina, eventually reducing them to collagenized scars. Constrictive bronchiolitis lacks the intraluminal fibrosis typical of BOOP.

Pathogenesis

Ultrastructural and immunohistochemical studies show significant morphologic overlap between BOOP and other forms of acute lung injury, mainly diffuse alveolar damage.^147–150 Necrosis of bronchiolar, alveolar duct, and alveolar septal epithelium results in denudation of epithelial basement membranes. Fibroblasts migrate from the interstitial compartment into airways and airspaces through gaps in damaged basement membranes. Activated fibroblasts within areas of intraluminal fibrosis differentiate into myofibroblasts capable of collagen synthesis.¹⁵¹ Within airways and airspaces fibroblasts and myofibroblasts organize into compact connective tissue plugs composed of glycosaminoglycans, other matrix proteins, and inflammatory cells.^{148,149,151,152} Alveolar macrophage-derived interleukin-8 (IL-8), fibronectin, and platelet-derived growth factor (PDGF) may play important roles in migration and activation of fibroblasts and in recruitment of inflammatory cells including T lymphocytes and mast cells.153–156 Capillaries eventually populate the luminal connective tissue polyps. Proliferating reparative epithelial cells, mainly type 2 pneumocytes, eventually incorporate the polypoid plugs of intraluminal fibrosis back into the interstitial compartment where mechanisms not yet fully understood restore normal lung architecture.¹⁵⁷

Despite morphologic and phenotypic overlap between intraluminal fibrosis in BOOP and interstitial fibroblast foci in usual interstitial pneumonia (UIP) (see Chapter 20), there are also important differences that are likely key to differences in pathogenesis.¹⁵⁸ Compared with fibroblast foci in UIP, areas of intraluminal fibrosis in BOOP demonstrate more orderly reepithelialization linked to differences in expression of various cytokines, cell cycle regulatory proteins, and extracellular matrix proteins.^159–163 Matrix metalloproteinases (MMPs), particularly MMP-2, are expressed more commonly in BOOP and are associated with collagen fibril phagocytosis.^164,165 Intraluminal fibrosis in BOOP is more highly vascularized than fibroblast foci in UIP related to differences in vascular endothelial growth factor (VEGF) expression.^166,167 Apoptotic activity within areas of fibroblast and myofibroblast proliferation is also higher in BOOP.¹⁶⁸

Langerhans’ Cell Histiocytosis (LCH) (Eosinophilic Granuloma)

Pulmonary LCH affects primarily young and middle-aged men and women with a peak incidence in the third and fourth decades. Nearly all reported patients have been former or current cigarette smokers, prompting many authors to consider LCH a form of smoking-related interstitial lung disease.169–171 Respiratory symptoms are common at presentation and include nonproductive cough and dyspnea. About a third of patients also have constitutional complaints such as fever, weight loss, night sweats, and anorexia.^172–175 About one in four patients is asymptomatic at the time of diagnosis.^173–175 Spontaneous pneumothorax is a commonly reported complication, but probably occurs in less than 25% of patients.¹⁷⁶ A smaller percentage of patients experience symptoms secondary to extrapulmonary involvement, mainly isolated bone pain or diabetes insipidus. Pulmonary function studies are variable and may be normal or instead show mild airflow limitation, mild restriction, or a combination of the two.^{173–175,177–180} A reduced DL_CO is the most consistent abnormality and is present in as many as 90% of patients.¹⁷⁵ Patients with LCH may be at increased risk for developing pulmonary hypertension compared with other forms of diffuse lung disease.^180,181

Several authors have noted a relationship between LCH and bronchogenic carcinoma, a relationship likely explained by a common risk factor (i.e., cigarette smoking) rather than true cause and effect.^182–184 Patients with pulmonary LCH may be at increased risk for developing other extrapulmonary neoplasms, including hematologic malignancies.^184,185

Conventional chest roentgenograms are nearly always abnormal at the time of diagnosis and show micronodular and reticulonodular opacities, with or without cystic (“honeycomb”) change, involving middle and upper lung zones with sparing of the costophrenic angles (Fig. 21–9).^{173,177,178,186,187} CT and HRCT show a combination of nodules, usually less than 10 mm in diameter, and thin-walled cysts involving predominantly middle and upper lung zones (Fig. 21–9).^187–192 Cavitation within the nodules is uncommon.^188,189,192 The centrilobular nodular opacities predominate in early disease, whereas thin-walled cysts are characteristic of more advanced stage disease (Fig. 21–10).^{188,189,191,192} Concomitant ground-glass attenuation is seen in some patients.¹⁹³ This distinctive combination of findings allows a confident radiologic diagnosis in a high percentage of cases. Rarely reported manifestations of LCH include solitary macroscopic nodules, obstructing intratracheal or endobronchial tumors, and synchronous mediastinal lymph node involvement.^194–198

The natural history of pulmonary LCH is difficult to predict and ranges from spontaneous regression to progressive respiratory insufficiency and death. Disease-specific mortality is between 10% and 20% with median survivals of about 13 years.^185,199 Older age at diagnosis, significant airflow limitation with air trapping, and severely reduced DL_CO may imply a worse prognosis.^185,199 Smoking cessation is the mainstay of therapy and should be strongly encouraged in all affected patients.^200,201 Corticosteroids are often used in symptomatic patients, but there is only limited anecdotal evidence of efficacy.²⁰² Transplantation is a therapeutic option for patients with advanced disease, although LCH can recur within lung allografts.²⁰³

Pathologic Features

The gross appearance of lung specimens with LCH includes a combination of patchy nodular fibrosis and cystic change corresponding to the findings described on CT and HRCT scans (Fig. 21–11). In advanced disease, the extent of cystic change may rival that seen in emphysema, but the middle and upper lung zone distribution and the degree of associated fibrosis are helpful clues to the diagnosis.

Microscopically, LCH comprises patchy interstitial nodules that often have a stellate configuration at low magnification (Fig. 21–12).^{172,173,177,178,204} The nodules are centered on bronchioles and occasionally show central cavitation corresponding to ectasia of the central airway lumen.^204,205 At higher magnification, the nodules contain a mixed inflammatory infiltrate including eosinophils, lymphocytes, plasma cells, histiocytes, and histiocyte-like Langerhans’ cells amidst a variably fibrotic background (Fig. 21–13). The nodules are frequently fibrotic centrally, the most cellular zones being in the peripheral tentacles formed by peribronchiolar interstitium tethered to contiguous alveolar septa. Enlargement of adjacent airspaces (i.e., paracicatricial airspace enlargement) is common as the nodules become more fibrotic. Eventually nodules become completely fibrotic, leaving only stellate collagenized scars as testimony to the likely underlying diagnosis (Fig. 21–14).^177,206

Accurate diagnosis of LCH hinges on recognition of Langerhans’ cells in the appropriate background. Abnormally increased numbers of Langerhans’ cells can occur in other pathologic conditions, but in other circumstances are usually distributed as single cells rather than the small groups, clusters, and sheets characteristic of LCH.207,208 Langerhans’ cells are distinguished by convoluted and folded nuclei with bland evenly dispersed chromatin, absent or inconspicuous nucleoli, and abundant pale-staining eosinophilic cytoplasm with indistinct borders (Fig. 21–15).²⁰⁹ The presence of highly convoluted nuclear contours is the single most helpful cytologic feature in distinguishing Langerhans’ cells from conventional histiocytes. Identification of Langerhans’ cells in the context of the previously described low-magnification features allows confident diagnosis of LCH on the basis of routinely stained sections in many cases. Immunohistochemical stains are helpful in difficult biopsies, particularly small transbronchial specimens.^178,210 Langerhans’ cells stain with a variety of antibodies easily applied in routinely processed paraffin-embedded tissues, including antibodies directed against S-100 protein, CD1a, and fascin.^{209,211–220} Electron microscopy demonstrates unique pentilaminar inclusions (Birbeck or Langerhans’ granules) within the cytoplasm of Langerhans’ cells (Fig. 21–16).^177,209,219

Secondary histologic changes are common in LCH and nearly always include pigmented alveolar histiocytes within airspaces immediately adjacent to diagnostic lesions. Pigmented histiocytes reflect the effects of cigarette smoking and are identical to those described in respiratory bronchiolitis and desquamative interstitial pneumonia (DIP), two other forms of smoking-related interstitial lung disease (see Chapter 20). The combination of pigmented alveolar histiocytes and expanded peribronchiolar alveolar septa closely mimics the appearance of DIP and has been referred to as a “DIP-like” reaction.^173,193,221 DIP-like changes may be sufficiently prominent to produce patchy ground-glass attenuation on HRCT scan in some patients.¹⁹³ Indeed, the possibility of underlying LCH should always be considered before making a clinicopathologic diagnosis of DIP. Small foci of intraluminal fibrosis resembling BOOP is another commonly seen secondary finding in LCH, but is rarely a prominent feature.¹⁷⁸

Differential Diagnosis

As the lesions of pulmonary LCH become less cellular they become more fibrotic and may be confused with the chronic interstitial pneumonias, especially UIP. It is imperative to distinguish these conditions because of marked differences in prognosis and treatment. At low magnification the first clue to the diagnosis of LCH is the stellate configuration and bronchiolocentric distribution of the interstitial nodules. This contrasts with the diffuse, random, and peripheral subpleural distribution of the interstitial fibrosis in UIP. The presence of pigmented alveolar histiocytes may result in histologic features resembling DIP, the key diagnostic features being the presence of bronchiolocentric nodules in LCH as opposed to the diffuse uniform interstitial pneumonia required for a diagnosis of DIP.

Eosinophilic pneumonia is predominantly an airspace rather than an interstitial process and is detailed elsewhere in this chapter. Briefly, eosinophilic pneumonia is characterized by a patchy airspace exudate rich in eosinophils and macrophages. An associated interstitial pneumonia is common, but without the bronchiolocentric nodules required for recognition of LCH. Reactive eosinophilic pleuritis is a form of visceral pleural inflammation that occurs after spontaneous pneumothorax of any cause.222 Although this unique form of pleuritis may occur in patients with LCH who experience pneumothorax prior to lung biopsy,^178,223 the vast majority of patients with reactive eosinophilic pleuritis have no evidence of underlying LCH.222

LCH is the consequence of a nonneoplastic accumulation of Langerhans’ cells linked to cigarette smoke. Langerhans’ cells accumulate in respiratory epithelium of distal airways in response to cigarette smoke constituents such as tobacco glycoprotein.175,224–226 Langerhans’ cells within the lesions of LCH show only low levels of proliferation and are instead recruited locally in response to various cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF).^227,228 Recruitment may be facilitated by a switch in expression of certain chemokines (CCR6 and CCR7) important in activation and migration of Langerhans’ cells to target tissues, in this case the lung.²²⁹ Tumor necrosis factor-α (TNF-α)–induced synthesis of membrane-associated MMP, particularly MMP-2 and MMP-9, by Langerhans’ cells is an autocrine loop and is another factor important in recruitment and migration of Langerhans’ cells.^230–232 Oligoclonal expansion contributes to maintenance of Langerhans’ cell at sites of disease and is accompanied by low levels of genetic instability, but without the features of neoplasia demonstrated in other forms of multifocal or systemic histiocytosis X.^233–236 Transforming growth factor-β (TGF-β) derived from respiratory epithelium and alveolar macrophages contributes to accumulation of extracellular matrix components in the fibrotic stage of LCH.²³⁷ MMPs and their inhibitors also participate in the pathogenesis of fibrosis and architectural distortion.²³⁸ Paracicatricial airspace enlargement is the result of epithelial necrosis, basement membrane damage, and intraluminal fibrosis combined with the effects of elastolytic proteins.²³⁹

Hypersensitivity Pneumonia (Extrinsic Allergic Alveolitis)

Hypersensitivity pneumonia (-itis), also called extrinsic allergic alveolitis, is a diffuse interstitial lung disorder that results from sensitization to a variety of inhaled organic dusts or aerosols. Offending agents are typically derived from thermophilic bacteria, molds, and various plant or animal proteins. Farmer’s lung was the first described and is perhaps the best-known example of this condition.240 A growing number of similar syndromes have been described and often are named according to the circumstances of exposure (Table 21–2). Other occupational lung diseases, such as asthma, organic dust toxic syndrome, and chronic airway disease (e.g., byssinosis), also result from inhalation of organic dusts and are unrelated to the interstitial disease referred to as hypersensitivity pneumonia.^241–246

Criteria for diagnosis of chronic hypersensitivity pneumonia are controversial but generally include an appropriate exposure history, subjective and objective evidence of lung disease temporally linked to antigen exposure, and the presence of serum antibodies directed against the suspected antigen.^247–249 Confirming the diagnosis is difficult, in part because the presence of precipitating antibodies reflects exposure and not necessarily disease. For example, precipitating antibodies are present in a sizable minority of exposed farmers and pigeon breeders as well as unexposed office workers and hospitalized patients who lack evidence of respiratory disease.^250–259 In addition, antibodies may persist for decades after cessation of exposure.²⁶⁰ False-negative results are common relating to inadequately characterized antigens, methodologic problems with laboratory antigen preparation, and the presence of complex bioaerosols containing multiple antigens.^261–263 Use of enzyme-linked immunosorbent assays (ELISA) in populations for which target antigens have been well characterized may increase diagnostic sensitivity.²⁶⁴ Given the absence of a diagnostic “gold standard,” recognition of characteristic histologic findings in lung biopsies often plays a pivotal role in diagnosis.²⁶¹

Prevalence of hypersensitivity pneumonia is highly variable depending on the specific circumstances of exposure, the diagnostic criteria employed, and the complex interplay of geographic, climatic, and seasonal factors. In farmers and pigeon breeders, for example, prevalence rates hover between 1 and 10%.²⁴⁸ The incidence and prevalence of nearly all forms of hypersensitivity pneumonia is lower in cigarette smokers compared with nonsmokers; smokers account for only 10 to 40% of reported patients in several large series.^{247,250,263,265–268} Precipitating antibodies against environment antigens are also less frequent in smokers compared with similarly exposed nonsmokers.^269,270 These differences likely reflect an inhibitory effect of cigarette smoke on immune regulation in the lung.²⁷¹

Clinical Features

Hypersensitivity pneumonia is often divided into acute, subacute, and chronic—or more simply acute and chronic—forms. The terms have been inconsistently applied, reflecting significant overlap between these interrelated categories. In general, the term acute hypersensitivity pneumonia is applied to patients suffering from a first attack with symptom duration of less than 1 month. Subacute hypersensitivity pneumonia refers to patients with periodic symptoms for less than 1 year, and chronic hypersensitivity pneumonia refers to patients with progressive respiratory complaints for at least 1 year. Chronic hypersensitivity pneumonia need not be preceded by acute disease, and only a small number of patients with acute disease develop chronic hypersensitivity pneumonia.

Acute hypersensitivity pneumonia follows exposure to relatively large doses of the responsible antigen and is the most easily recognized variant. Symptoms occur within 4 to 6 hours of exposure and include severe dyspnea and cough frequently associated with fever, chills, sweating, nausea, and anorexia.³⁸⁷ Weight loss may occur with frequent or severe attacks.^387,388 Conventional chest roentgenograms are abnormal in the majority of patients and show diffuse reticular or nodular opacities.³⁸⁹ HRCT scans are more frequently abnormal and demonstrate patchy areas of ground-glass attenuation, often with a bibasilar distribution and usually associated with small, ill-defined, centrilobular micronodules measuring less than 5 mm in diameter.^390–392 Small, ill-defined centrilobular nodules are present in about two thirds of patients and can be helpful in distinguishing hypersensitivity pneumonia from other conditions such as desquamative interstitial pneumonia (see Chapter 20).³⁹¹ Pulmonary function studies may be normal but in others demonstrate mildly restricted lung volumes with reduced DL_CO.³⁹³ Symptoms subside 24 to 48 hours after cessation of exposure, and in most patients are followed by radiographic resolution over a period of days or weeks.

Chronic hypersensitivity pneumonia results from intermittent exposure to the offending antigen and in some patients represents the cumulative effect of multiple acute episodes. Indeed, the natural history of chronic hypersensitivity pneumonia is sometimes punctuated by intermittent exacerbations temporally linked to antigen exposure. More commonly patients present with a slowly progressive respiratory syndrome of insidious onset indistinguishable from other diffuse lung diseases, most importantly usual interstitial pneumonia.³⁹⁴ Affected patients may be unaware of the environmental exposure responsible for their respiratory symptoms, further complicating diagnosis. Cough, often with associated dyspnea on exertion, is the most common presenting complaint. Fever usually accompanies respiratory symptoms during periods of acute exacerbation in patients with subacute disease.^387,388 Laboratory studies show nonspecific abnormalities, including mild leukocytosis occasionally associated with mild peripheral eosinophilia. Serum levels of angiotensin-converting enzyme are normal, a finding that may have value in those patients for whom sarcoidosis is a competing consideration.^395,396 Pulmonary function studies demonstrate restricted lung volumes and reduced DL_CO.

Radiologic findings in chronic hypersensitivity pneumonia are not specific. Conventional radiographs are normal in some patients but in most show a nonspecific pattern of ground-glass and reticular opacities, often with an upper lobe distribution.^387,397 Volume loss and honeycomb change are present in patients with longstanding disease. HRCT scans show a distinctive combination of ground-glass opacities, small centrilobular nodules, and mosaic attenuation (Fig. 21–17).^{392,398–400} Chronic hypersensitivity pneumonia differs from acute disease in that the ground-glass opacities are accompanied by irregular lines and architectural distortion in the form of traction bronchiectasis and bronchiolectasis. Associated honeycomb change is seen in about half of patients, and may be more common in those with pigeon breeder’s lung.³⁹² In patients with honeycomb change, the findings may be indistinguishable from usual interstitial pneumonia.^391,392,401 Emphysema has also been described in patients with advanced disease.³⁹²

Prognosis for hypersensitivity pneumonia is variable.²⁶⁸ Antigen avoidance is the cornerstone of therapy and is often curative in patients for whom a specific antigen source is identified, assuming the absence of established fibrotic lung disease at the time of diagnosis. Rapid recovery of pulmonary function is typical of acute hypersensitivity pneumonia, although rare fatal episodes have been documented.³¹¹ Corticosteroids are useful in accelerating the rate of recovery but do not affect long-term outcome independent of eliminating antigenic exposure.^250,393 Lung function improves over a period of months and years, but abnormalities may persist in as many as 20 to 40% of patients.^{250,255,260,265,267} Disease-specific mortality rates in chronic hypersensitivity pneumonia range from 10 to nearly 30%.^{255,260,261,263,388} Repeated symptomatic attacks, older age, cigarette smoking, and the presence of established fibrosis and honeycomb change at the time of diagnosis are associated with a more aggressive course.260,261,263,270

Lung biopsy is rarely necessary for diagnosis and management of patients with acute hypersensitivity pneumonia, and for that reason pathologic findings in this form of the disease are incompletely understood. Rare reports describe a patchy airspace-filling process resembling bronchopneumonia in which both neutrophils and eosinophils are present with an associated necrotizing small vessel vasculitis.311,402 A single report illustrates a bronchiolocentric granulomatous process, but details regarding the circumstances of exposure are lacking.⁴⁰⁰

Chronic interstitial pneumonia is the lesion most frequently described in subacute and chronic hypersensitivity pneumonia and is present in nearly all cases.^{249,388,403–411} At low magnification, alveolar septa are expanded by an infiltrate of mononuclear inflammatory cells accentuated around bronchioles (Fig. 21–18). The inflammatory infiltrate is composed mainly of lymphocytes, plasma cells, and histiocytes, which are occasionally admixed with eosinophils and neutrophils. Epithelioid histiocytes predominate only focally, usually around the airways, and impart a subtle and vaguely granulomatous appearance to the inflammatory infiltrate. Well-formed granulomas are rare. Isolated multinucleated giant cells occur frequently in hypersensitivity pneumonia and in a minority of cases may represent a striking feature (Fig. 21–19). Giant cells often contain various nonspecific cytoplasmic inclusions identical to those seen in sarcoidosis such as Schaumann bodies, asteroid bodies, cholesterol clefts, and birefringent calcium salts. Granulomatous features, although seen in the majority of patients with hypersensitivity pneumonia, may be absent in as many as 30% of surgical lung biopsies.⁴⁰⁷ In advanced cases the changes are less characteristic and consist mainly of bland interstitial fibrosis and honeycomb change.

Chronic bronchiolitis is a consistent finding in hypersensitivity pneumonia and is usually present in the form of a cellular peribronchiolar infiltrate, often accompanied by lymphoid aggregates.^410,412 The degree of airway inflammation is proportional to the associated interstitial pneumonia.⁴¹⁰ Bronchiolitis obliterans is present about half the time and is characterized by polypoid plugs of intraluminal fibroblastic tissue indistinguishable from that described earlier in BOOP (Fig. 21–20).^{388,404,407,408} Small airway dysfunction results in microscopic foci of obstructive pneumonia characterized by clusters of finely vacuolated, foamy alveolar macrophages within peribronchiolar interstitium and airspaces.

Differential Diagnosis

The differential diagnosis for hypersensitivity pneumonia includes other chronic interstitial pneumonias. Peribronchiolar accentuation of the interstitial inflammatory infiltrate, granulomatous inflammation, and BOOP-like changes are perhaps the most helpful features in distinguishing hypersensitivity pneumonia from the idiopathic interstitial pneumonias (see Chapter 20). Some cases may be indistinguishable from cellular variants of NSIP, indicating that hypersensitivity pneumonia should always be considered a potential etiology in patients with otherwise idiopathic NSIP.^261,413 Associated honeycomb change may cause confusion with UIP. The changes in UIP tend to be more peripherally distributed without the bronchiolocentric distribution characteristic of hypersensitivity pneumonia. Peribronchiolar inflammation without fibrosis and isolated multinucleated giant cells are additional features helpful in distinguishing hypersensitivity pneumonia from UIP.

Well-formed granulomas are rare in hypersensitivity pneumonia and if present should raise a suspicion of other entities. Hot tub lung is a syndrome that combines features of hypersensitivity pneumonia and atypical mycobacterial infection resulting from exposure to contaminated hot tubs, spas, Jacuzzis, or whirlpools (see Chapter 8).^{249,331–335} Lung biopsy findings are similar to those seen in other examples of hypersensitivity pneumonia except that the interstitial pneumonia tends to be less conspicuous and the granulomas are well formed and distributed within airway lumina rather than peribronchiolar interstitium.³³⁴ Sarcoidosis differs in that the granulomas are well formed, distributed in a “lymphangitic” pattern, and lack the associated interstitial pneumonia and bronchiolitis typical of hypersensitivity pneumonia. Finally, lymphoid interstitial pneumonia (LIP) is associated with granulomatous inflammation in as many as 40 to 50% of patients and thus can mimic the histology of hypersensitivity pneumonia (see Chapter 19).^414,415 Alveolar septa are usually more extensively expanded by lymphocytes, plasma cells, and lymphoid follicles in LIP (see Fig. 19–2 in Chapter 19). Correlation with clinical and radiologic findings may be helpful in difficult cases. Patients with LIP are more likely to have an underlying connective tissue disease or immunodeficiency syndrome, lack an exposure history suggestive of hypersensitivity pneumonia, and have findings on imaging studies that typically differ from those described in patients with hypersensitivity pneumonia.

Hypersensitivity pneumonia is the consequence of a complex humoral and cellular immune response to an inhaled antigen in vulnerable sensitized patients. Vulnerable patients are likely distinguished by underlying genetic factors not yet well understood, including specific human leukocyte antigen (HLA) class II alleles important in immune response regulation.248,416 Acute hypersensitivity pneumonia represents a type III hypersensitivity reaction linked to immune complex deposition and complement activation.²⁴⁹ Subacute and chronic hypersensitivity pneumonia are more closely affiliated with a cell-mediated type IV reaction in which activated T cells are primary participants. Lymphocytosis in bronchoalveolar lavage (BAL) specimens is characteristic of hypersensitivity pneumonia and can be a useful diagnostic adjunct.⁴¹⁷ CD8-positive T cells predominate in acute disease, whereas CD4-positive cells become dominant in longstanding or fibrotic disease.⁴¹⁸ BAL lymphocytosis also occurs in asymptomatic individuals who lack other evidence of active disease.²⁵¹ Other important participants in the inflammatory reaction include mast cells, alveolar histiocytes, and neutrophils.^419,420 Macrophage-derived cytokines, including TNF-α and IL-8, further modulate the immune response. Neutrophils may be important in promoting epithelial injury and collagen accumulation in patients with chronic hypersensitivity pneumonia.⁴²¹

Sarcoidosis

Sarcoidosis is a multisystem disorder of unknown cause with worldwide distribution and protean clinical manifestations. In the United States, African Americans are affected more frequently than whites, and women are affected more often than men.⁴²² The earliest reports published in the 19th century focused on cutaneous manifestations of what would be dubbed sarkoid by Boeck⁴²³ in 1899. Sarcoidosis is now known to be capable of involving any organ or tissue. Lung involvement occurs in over 90% of patients and is the dominant feature in most.^422,424 Diagnosis usually requires demonstration of a characteristic pattern of granulomatous inflammation in an appropriate clinical and radiologic context.

Clinical Features

Most patients with sarcoidosis present between the ages of 20 and 40 years. Onset before age 10 years or after age 60 is unusual, although 1% of patients are older than 70 at the time of diagnosis. Women tend to be somewhat older than men at the time of diagnosis.⁴²² All but around 10% of patients are symptomatic at presentation. Symptoms are dependent on disease distribution, but respiratory symptoms predominate and usually include a combination of dyspnea and cough. Chest pain and hemoptysis are uncommon but the latter can be massive and life-threatening.425 Nonspecific constitutional symptoms are seen in about a third of patients and include weight loss, low-grade fever, fatigue, and malaise. Cutaneous lesions are the most common extrathoracic manifestation of disease and are present in about 15 to 25% of patients at the time of diagnosis; erythema nodosum and lupus pernio are the most distinctive and correspond to acute and chronic disease, respectively. The combination of erythema nodosum and hilar adenopathy is referred to as Löfgren’s syndrome and is usually a self-limited form of disease.⁴²⁶ Laboratory abnormalities are common and in the majority of patients include elevated serum angiotensin-converting enzyme (ACE), abnormal liver function tests, and polyclonal hypergammaglobulinemia. Antinuclear autoantibodies, hypercalcemia, and hypercalciuria are less common findings, occurring in around 20 to 40% of patients. Pulmonary function tests are abnormal in about two thirds of patients, demonstrating mild restriction, airflow limitation, or a combination of the two. Bronchoscopic biopsy is a sensitive diagnostic tool in patients with lung involvement,^427–436 but biopsy of other tissues is useful in those who present with active disease involving extrathoracic sites.

Chest radiographic finding in sarcoidosis are variable. Disease distribution as judged by conventional posteroanterior (PA) chest roentgenograms is the basis for disease staging (Table 21–3).⁴³⁷ A small minority of patients present with normal chest radiographs despite having granulomas on lung biopsies. Hilar lymphadenopathy, with or without associated lung infiltrates, is the most common finding and is seen in as many as 80% of patients. Pulmonary infiltrates may be reticular, reticulonodular, or ground glass in character and often have a predilection for upper lung zones. Fibrotic disease is often associated with bronchiectasis and cystic changes resembling emphysema or honeycomb change.^438,439 Pleural effusion is seen in about 10% of patients. CT and HRCT scans typically show irregular linear and nodular opacities distributed along lymphatic routes, particularly bronchovascular bundles, involving mainly upper and middle lung zones (Fig. 21–21).^440–443 Irregular morphology of parenchymal opacities coupled with evidence of architectural distortion may occasionally mimic the radiologic appearance of UIP and are associated with chronic disease.^439,440,444

Nodular sarcoidosis refers to an uncommon variant characterized by large, well-circumscribed nodules measuring up to 5 cm in diameter.^445–447 Nodules are usually multiple and bilateral and mimic the appearance of metastatic disease or other nodular processes such as Wegener’s granulomatosis.⁴⁴⁷ Central cavitation and ring-shaped opacities have been demonstrated in only a few patients.^448,449 Isolated solitary pulmonary nodules are rare.^450,451

The natural history of sarcoidosis is variable and dependent on several factors including race, sex, age, and respiratory symptoms at diagnosis.^422,424,452 Spontaneous remissions occur within 2 years of diagnosis in a large majority of patients.^424,453 Chronic progressive disease develops in 10 to 30% of patients. Sarcoidosis-associated mortality is variable and is as high as 5% in referral populations.⁴⁵⁴ Mortality rates of less than 1% have been observed in population-based studies and may more closely approximate the natural history of disease.^454,455 Black race, pulmonary hypertension, and use of supplemental oxygen are associated with shorter survival in patients with fibrotic lung disease.^456,457 Lung and cardiac involvement are the two most common causes of death in autopsied sarcoidosis patients.⁴⁵⁸ Systemic corticosteroids are the standard of care for patients requiring treatment and are generally reserved for progressive disease with functional deterioration, especially when it involves the lungs, heart, central nervous system (CNS), or eye.^424,459 Cytotoxic agents are used in selected patients.^424,460,461 Novel therapies (e.g., pentoxifylline, thalidomide, and infliximab) that target TNF-α, an important participant in the pathogenesis of fibrosis, show mixed success as potential therapeutic alternatives.^460–464 Lung transplantation has been employed in some patients, but sarcoidosis recurs in lung allografts with greater frequency than other forms of interstitial lung disease.^465–468

Gross findings in classical pulmonary sarcoidosis comprise variably sized nodules with a distinctive predilection for bronchovascular bundles, interlobular septa, and visceral pleura (Fig. 21–22). In minimally affected cases, the gross appearance may be nearly normal or show only tiny white nodules corresponding to granulomas. In other cases, confluent and coalescent granulomas with associated fibrosis form macroscopic nodules measuring up to several centimeters in maximum dimension.

Discrete, well-formed, nonnecrotizing granulomas are the histologic hallmark of sarcoidosis (Fig. 21–23).^469–471 The granulomas are often associated with a peripheral infiltrate of lymphocytes and a distinctive pattern of lamellar fibrosis. Granulomas comprise a compact circumscribed aggregate of epithelioid and multinucleated histiocytes with minimal or no central necrosis. Giant cells in sarcoidosis frequently contain various nonspecific cytoplasmic inclusions such as asteroid bodies, basophilic Schaumann’s bodies, and birefringent crystalline particles corresponding to calcium oxalates and other calcium salts.^472,473 In some cases birefringent particles may be sufficiently prominent to raise concerns for occupational lung disease (Fig. 21–24). Aside from mild inflammation and variable degrees of fibrosis in the immediate vicinity of the granulomas in sarcoidosis, the remainder of the lung tissue is relatively unaffected without significant associated interstitial pneumonia.

Distribution of the granulomas in a lymphangitic pattern is a distinctive feature of sarcoidosis that can be extremely helpful in diagnosis. Granulomas are situated within the interstitium rather than the airspaces and involve predominantly bronchovascular bundles and interlobular septa (Figs. 21–25 and 21–26). Airway involvement is nearly universal and is occasionally associated with bronchial stenosis and airflow limitation.^474–476 Pleural involvement is somewhat less conspicuous but, in rare cases, is a dominant site of disease.^477–482 Nonnecrotizing granulomatous “vasculitis” is common in surgical lung biopsies and is consistent with involvement of bronchovascular bundles and interlobular septa (Fig. 21–27).^483–485 Vascular involvement only rarely results in pulmonary hypertension that mimics pulmonary veno-occlusive disease.486–489 Pulmonary hypertension in patients with sarcoidosis is more commonly a consequence of fibrosis and end-stage cystic change.

Granulomas occasionally coalesce and combine with hyalinizing fibrosis to form macroscopic nodules, corresponding to nodular sarcoidosis described earlier as a radiologic variant (Fig. 21–28). Over time fibrosis may obliterate the underlying granulomatous process and partially obscure the diagnostic features. Transformation of granulomas into broad zones of hyalinized sclerosis and scar also occurs in lymph nodes.

Differential Diagnosis

The main differential diagnosis in sarcoidosis is granulomatous infection. In addition, superimposed granulomatous infection can occur in patients with underlying sarcoidosis.^490–493 Special stains and cultures should be performed in all cases of suspected sarcoidosis to more confidently exclude infection. Extensive necrosis and intraluminal location of granulomas are features more typical of infection than sarcoidosis. Hypersensitivity pneumonia (see later) differs from sarcoidosis in that the granulomas are much less well formed, frequently consisting of only isolated multinucleated giant cells, and almost invariably associated with a cellular interstitial pneumonia in which lymphocytes predominate. The poorly formed granulomas of hypersensitivity pneumonia are also distinctly bronchiolocentric in distribution without the more widespread lymphangitic distribution characteristic of sarcoidosis. Berylliosis is associated with histologic findings indistinguishable from those described for sarcoidosis, the distinction depending on correlation with clinical and laboratory data.^470,494,495

Necrotizing sarcoid granulomatosis (NSG) was first proposed as a unique entity by Liebow496 in 1973. NSG overlaps clinically and histologically with nodular sarcoidosis. Indeed, most authorities consider NSG a subset of nodular sarcoidosis distinguished by broad zones of infarct-like parenchymal necrosis.^497,498 The combination of well-formed confluent granulomas coalescing to form nodules, infarct-like parenchymal necrosis, and granulomatous vasculitis are the histologic hallmarks of NSG.⁴⁹⁹ Granulomatous infection is a more important differential diagnosis than nodular sarcoidosis in such cases and should be vigorously excluded using a combination of special stains and cultures.

Pathogenesis

Sarcoidosis is the result of an abnormal immune response in which activated macrophages and CD4-positive T cells react to an as yet undiscovered environmental antigen in genetically susceptible hosts.⁴²⁴ Several environmental candidates have been proposed, including several infectious pathogens. The use of various molecular techniques has suggested a potential role for Mycobacterium tuberculosis, Propionibacterium, and other bacterial organisms, but the results are mixed and must be interpreted with caution.^500–506 There is no conclusive evidence that sarcoidosis is caused by an infectious agent, although certain microbes may serve as antigenic triggers in at least a subset of patients.^507,508

Sarcoidosis is propagated by activated macrophages and T lymphocytes whose effects are mediated through various cytokines.^424,507,509 CD4-positive helper cells predominate at sites of active disease. Lymphocyte-derived IL-2, IL-12, interferon-γ, and IL-18 are important in recruiting and maintaining local populations of immune effector cells with concomitant granuloma formation.424,507,509 Macrophage-derived cytokines and chemokines (e.g., IL-1, IL-6, IL-8, IL-15, interferon-γ, GM-CSF, TNF-α, TGF-β, and PDGF) further contribute to granuloma formation, fibroblast recruitment and activation, and extra-cellular matrix deposition.^{424,463,464,510–517}

Lymphangioleiomyomatosis and Tuberous Sclerosis

Pulmonary lymphangioleiomyomatosis (LAM), also called lymphangiomyomatosis, is a rare condition that affects young women almost exclusively. LAM occasionally involves extrapulmonary tissues (“lymphangioleiomyomas”), most commonly mediastinal and retroperitoneal lymph nodes.^518,519 Lung disease indistinguishable from sporadically occurring LAM occurs in 1 to 3% of patients with tuberous sclerosis complex (TSC), a multisystem autosomal-dominant disorder characterized by seizures, mental retardation, autism, and hamartomatous tumors in various organs (e.g., cutaneous angiofibroma, CNS subependymal giant cell astrocytoma, cardiac rhabdomyoma, and renal angiomyolipoma).⁵²⁰

Clinical Features

Sporadic LAM occurs in women with an average age at presentation in the fourth decade of life. Postmenopausal women are occasionally affected.^521,522 Breathlessness and pneumothorax are the most common presenting manifestations of lung disease (Table 21–4).^523–529 Cough and hemoptysis are uncommon as presenting symptoms, occurring in 19% and 9% of patients, respectively.^523–529 Nearly all patients experience shortness of breath during the course of their illness. Pneumothoraces eventually occur in two thirds of patients and commonly recur. Pulmonary function testing typically demonstrates normal lung volumes with airflow obstruction, disproportionately reduced DLco, and hypoxemia.

Chest radiographs are normal early in the course of the illness, but eventually show diffuse interstitial opacities, cystic spaces resembling honeycomb change, and paradoxical lung enlargement (Fig. 21–29). HRCT scans are more sensitive than conventional roentgenograms in detecting abnormalities in LAM and show sharply demarcated, rounded, thin-walled cysts uniformly distributed in the lungs (Fig. 21–30).^530–535 This characteristic radiologic appearance allows accurate diagnosis in a high percentage of cases, although distinction from other cystic lung diseases including emphysema and LCH can be difficult.^536–538 Abdominal CT scans are frequently abnormal, demonstrating renal angiomyolipomas in 50 to 60% of patients.^{525,539–541} Involvement of mediastinal, retroperitoneal, and mesenteric lymph nodes, usually in the form of one to three discrete masses, is observed in some patients.⁵¹⁸ Nearly all patients with extrapulmonary LAM also have pulmonary disease, but diagnosis of extrapulmonary lesions may precede recognition of lung involvement by months or years.⁵¹⁹

Patients with underlying TSC tend to be women of reproductive age without CNS disease and thus resemble patients with otherwise sporadic LAM.520 Reports suggest that the prevalence of LAM in women with TSC is higher than that reported in historical studies, affecting 30 to 40% of women with TSC.^542–544 LAM rarely occurs in men with TSC.^545,546 Respiratory involvement contributes disproportionately to morbidity and mortality and was the third most common cause of death in a review of 40 patients who died of TSC-related complications.⁵⁴⁷

The natural history of LAM is difficult to predict. A progressive course culminating in respiratory failure and death occurs in some patients.^524,527 Recent studies indicate that the prognosis may be better than that suggested in historical reports, with 10-year disease-specific survivals of 70 to 80%.528,529,548 Extent of disease on CT scan and rate of decline in lung function are helpful in predicting disease progression.^527,549 Progestogen or antiestrogen therapy is commonly used to treat LAM;^{525,528,550–553} other hormonal manipulations have been attempted with varying degrees of success.^529,554 Transplantation is another therapeutic alternative, but is occasionally complicated by recurrent disease in lung allografts.^{529,555–560}

The most consistent gross finding in lung specimens with LAM is the presence of cystic spaces diffusely involving pulmonary parenchyma (Fig. 21–31). Localized disease with gross and histologic characteristics of LAM is extraordinarily rare and has been described in association with a clear cell (“sugar”) tumor in only a single patient.⁵⁶¹ In early diffuse disease the cysts are discrete and separated by normal-appearing lung tissue. Advanced disease is characterized by confluent cystic spaces resembling emphysema or diffuse honeycomb change. Hemosiderin deposition results in brown discoloration of the lung parenchyma in later disease stages.

The presence of modified smooth muscle cells is the histologic hallmark of LAM.^{523,524,527,548} Cytologically distinct muscle cells are distributed along lymphatic pathways, focally expanding bronchovascular bundles and surrounding arteries, veins, and lymphatic channels (Fig. 21–32). Associated hyperplasia of alveolar pneumocytes is common.⁵⁶² LAM smooth muscle cells tend to be spindled in shape, although plump epithelioid forms also occur and predominate in some cases. The cytologic characteristics differ from normal smooth muscle in that LAM cells are more plump with larger rounded nuclei, small but sometimes conspicuous eosinophilic nucleoli, and pale-staining cytoplasm characterized by a slightly granular and finely vacuolated texture (Fig. 21–33). Spindled and epithelioid cells coalesce focally to form microscopic nodules that are often situated around or immediately adjacent to bronchioles.^523,563 Cystic “emphysematous” spaces are common and are a helpful clue to the diagnosis at low magnification (Fig. 21–34). Cystic spaces are centered on airways and contain bundles of specialized smooth muscles cells within at least a portion of their walls. Hemosiderin is frequently present within surrounding airspaces and is a striking feature in some cases (Fig. 21–35).

Semiquantitative assessment of histologic stage may provide prognostically useful information. The degree of cystic change and the extent of tissue infiltration by lesional smooth muscle cells in surgical lung biopsies correlates with other measures of disease severity.^527,548 Matsui and colleagues⁵⁴⁸ demonstrated 100% 10-year survival in patients whose biopsies showed involvement of less than 25% of the sampled lung tissue compared with 52% 10-year survival in patients whose biopsies showed cysts or smooth muscles cells in over 50% of the biopsy surface area.

Extrapulmonary LAM usually involves intrathoracic, retroperitoneal, or intraabdominal lymph nodes.⁵¹⁹ Involved nodes present as single or more commonly multiple well-circumscribed nodules averaging around 5 cm in greatest dimension. Masses as large as 20 cm have been reported. Spindle and epithelioid smooth muscles cells identical to those described in pulmonary lesions are arranged in ill-defined fascicles that surround and infiltrate lymph node sinuses and occasionally extend into perinodal soft tissues (Fig. 21–36). As in pulmonary LAM, mitotic figures are rare and there is no associated necrosis.

The modified smooth muscle cells of LAM are thought to be derived from perivascular epithelioid cells.564 Expression of melanogenesis-associated proteins, most commonly HMB45, is the most distinctive immunohistochemical feature of the specialized smooth muscle cells in both pulmonary and extrapulmonary LAM.^{519,525,564–570} Melanoma antigen recognized by T cells (MART-1) is a less sensitive marker for this condition.⁵⁶⁶ HMB45 is a useful diagnostic marker in difficult cases, including small transbronchial biopsies, although HMB45-staining is frequently focal and therefore subject to sampling bias.^525,565,571 Confocal microscopy and ultrastructural studies identify immunophenotypically distinct small spindle and larger epithelioid cells and suggest that HMB45 staining is confined to epithelioid cells.^570,572 LAM smooth muscle cells are also immunoreactive with antibodies directed against muscle-associated proteins (e.g., actin and desmin) and frequently stain for estrogen and progesterone receptor proteins.^{568,569,571–573} The unique staining characteristics of LAM are also typical of renal angiomyolipoma, a neoplasm derived from perivascular epithelioid cells and associated with TSC.^564,568 Clear cell (“sugar”) tumors are also immunoreactive for HMB45 and have been occasionally described in association with LAM.^561,574

Micronodular pneumocyte hyperplasia (MNPH) is an unusual epithelial proliferation that occurs in a subset of patients with sporadic LAM or TSC.545,574–579 MNPH comprises circumscribed proliferations of cytologically bland type 2 pneumocytes in a pattern resembling bronchioloalveolar adenocarcinoma (Fig. 21–37). Muir and colleagues⁵⁷⁸ reported a series of 14 patients with MNPH, including nearly all previously reported examples. Ten (71.4%) patients, all women, had associated LAM and seven of them had other manifestations of TSC. MNPH in association with LAM has also been described in a man with underlying TSC.⁵⁴⁵ Indeed, the combination of LAM and MNPH in a lung biopsy is strong evidence in support of a diagnosis of TSC in a patient of either gender. Intrapulmonary clear cell (“sugar”) tumor and intrapulmonary angiomyolipoma combined with MNPH are other rare manifestations of lung involvement in TSC.^574,579

The differential diagnosis of LAM is limited. So-called benign metastasizing leiomyoma is a rare condition characterized by the presence of multiple circumscribed nodules of cytologically bland smooth muscle cells within the lungs.580,581 The nodules differ from the lesions of LAM in that they are usually solid and well circumscribed, and frequently have a “biphasic” appearance due to the presence of entrapped alveolar epithelial cells. Hemosiderin pigment deposition can be a prominent feature of LAM and may lead to confusion with pulmonary hemorrhage syndromes, particularly idiopathic pulmonary hemosiderosis. The presence of cystic spaces coupled with foci of characteristic smooth muscle cells in LAM should serve to distinguish these conditions.

Diffuse pulmonary lymphangiomatosis (DPL) is a form of diffuse lung disease that occurs mainly in children and occasionally young adults, without the gender predilection characteristic of LAM.^582–587 DPL is characterized by a combination of arborizing lymphatic channels infiltrating visceral pleura, interlobular septa, bronchovascular bundles, and proliferation of perivascular smooth muscle cells. The degree of lymphatic proliferation resembles that seen in other forms of vascular neoplasia and is the single most helpful feature in distinguishing DPL from LAM. Cystic change is not seen in DPL and is another important clue in distinguishing these conditions.⁵⁸³ Immunostains can be helpful in difficult cases because smooth muscles cells in DPL fail to express HMB45.^582,584

Pathogenesis

TSC is linked to germline mutations affecting a single allele in either one of two (but not both) tumor-suppressor genes: TSC1 on chromosome 9q34 (encoding hamartin) and TSC2 on chromosome 16p13 (encoding tuberin).^588,589 Hamartin and tuberin form a cytosolic heteromer and regulate proliferation and migration of the smooth muscle-like cells in LAM and TSC. Approximately 80% of germline mutations affect TSC2. Microdissection studies have demonstrated somatic TSC2 mutations and loss of heterozygosity (LOH) resulting in inactivation of the wild-type allele in sporadic and TSC-associated LAM consistent with a two-hit tumor-suppressor gene model.^{588,590–592} Despite the prevalence of TSC2 mutations in sporadic and TSC-associated LAM, immunoreactive tuberin is preserved in LAM smooth muscle cells.⁵⁹³ Concordant TSC2 mutations and LOH patterns in cells from renal angiomyolipomas and pulmonary LAM suggest a common genetic origin in at least some patients.⁵⁹² Combined with two recent reports in which recurrent LAM cells in lung allografts were of recipient origin, these findings raise the possibility that aberrant smooth muscle cells “metastasize” to the lung rather than originating from a resident population of modified lung cells.^558,594,595

The precise mechanisms linking TSC1 and TSC2 mutations to the pathogenesis of LAM are still being worked out. Tuberin exerts an inhibitory effect on the S6 kinase signaling pathway.^589,596 Recent studies have suggested that telomerase and mast cell derived basic fibroblast growth factor also contribute to proliferation of smooth muscles cells in LAM.^597,598 Overexpression of serum response factor, a transcription factor normally expressed in immature smooth muscle cells, upregulates MMPs and downregulates their inhibitors and likely plays a role in elastic fiber degradation and cystic change.^599–601 Epithelial-derived TGF-β also participates in abnormalities of extracellular matrix deposition.602

Eosinophilic pneumonia refers to an airspace-filling process in which alveolar spaces contain an inflammatory exudate rich in eosinophils. Eosinophilic pneumonia is often associated with peripheral eosinophilia. Eosinophilic pneumonia as a histopathologically defined entity can occur as either a primary or a secondary finding in several different clinical settings (Table 21–5). Lung biopsy is rarely required to diagnose many of the listed conditions. Tropical eosinophilia, Löffler’s syndrome, and chronic eosinophilic pneumonia are presumed to have similar pathologic abnormalities, the chief distinction depending on clinical findings. Acute eosinophilic pneumonia is characterized by unique histologic features.

Löffler’s Syndrome (Simple Pulmonary Eosinophilia)

Löffler’s syndrome, also called simple pulmonary eosinophilia, is an acute, self-limited form of eosinophilic pneumonia in which symptoms are mild or absent.^603–605 Peripheral eosinophilia is nearly always present. Chest radiographs show patchy airspace opacities that may migrate from one location to another. Most recover without treatment within a month of diagnosis. Many of the patients originally reported by Löffler likely had Ascaris infestations. Infestations with other parasites and drug reactions account for other examples, while a third represent a form of idiopathic eosinophilic pneumonia.603 Lung biopsies are rarely needed for diagnosis but are presumed to show findings identical to those described in chronic eosinophilic pneumonia (see later).

Acute Eosinophilic Pneumonia

Acute eosinophilic pneumonia is a febrile illness of unknown cause associated with abrupt onset and rapidly progressive hypoxemic respiratory failure, diffuse radiographic abnormalities, BAL eosinophilia of greater than 25%, absence of an identifiable etiology (e.g., infection, parasitic infestation, drug exposure), rapid response to corticosteroid therapy, and failure to relapse after treatment cessation.^606–610 Men and women are affected equally and usually present in the third decade of life. Peripheral eosinophilia occurs in about half of patients. Chest radiographs show nonspecific bilateral mixed interstitial and airspace infiltrates.^611,612 CT scans show a combination of thickened interlobular septa, ground-glass attenuation, and pleural effusion.^611–613 Most patients are diagnosed on the basis of clinical, radiographic, and BAL findings without resorting to lung biopsy. By definition, acute eosinophilic pneumonia is associated with an excellent prognosis, all patients recovering spontaneously or after corticosteroid therapy.^607–609

A syndrome identical to idiopathic acute eosinophilic pneumonia has been described in first-time cigarette smokers, and less commonly in those who resume smoking after a period of smoking cessation.^614–620 Exposures to other uncommon environmental dusts and smoke have been cited as additional rare causes of acute eosinophilic pneumonia.^621,622 Acute eosinophilic pneumonia has been reported in a patient with AIDS without evidence of either infection or a drug reaction.⁶²³

Acute eosinophilic pneumonia is characterized by histologic features that overlap diffuse alveolar damage and eosinophilic pneumonia (Fig. 21–38).⁶²⁴ Alveolar septa are expanded by an inflammatory infiltrate focally rich in eosinophils with associated fibroblasts and myofibroblasts and hyperplasia of alveolar lining cells. Well-formed hyaline membranes are present in the majority of cases. A patchy fibrinous airspace exudate with variable numbers of eosinophils is frequently present and resembles the changes described in chronic eosinophilic pneumonia.

Chronic Eosinophilic Pneumonia

Chronic eosinophilic pneumonia refers to a subacute form of eosinophilic pneumonia in which symptoms persist for weeks or months but without the fulminant course observed in acute eosinophilic pneumonia.606,625–628 Nearly half of patients have underlying asthma. Women, most commonly in the fourth or fifth decade of life, account for over two thirds of reported patients, although any age group can be affected.⁶²⁹ Cough, often accompanied by dyspnea, is the most common presenting complaint. Fever is also common and is frequently associated with weight loss and night sweats. Symptoms may spontaneously remit, or wax and wane over a period of months or years. Peripheral eosinophilia occurs in nearly 90% of patients. Chronic eosinophilic pneumonia is associated with an excellent prognosis. Patients respond rapidly to corticosteroid therapy, although relapses are common if treatment is tapered prematurely.

Chest radiographs classically show peripheral alveolar infiltrates involving upper lung zones in a pattern described as the “photographic negative of pulmonary edema” (Fig. 21–39).⁶³⁰ This classical pattern occurs in about half to two thirds of patients and, when present, is nearly pathognomonic. CT scans are helpful in confirming patchy peripheral zones of ground-glass attenuation, occasionally with a vaguely nodular appearance (Fig. 21–40).⁶¹³

Lung biopsy findings in chronic eosinophilic pneumonia are stereotypical of eosinophilic pneumonia in general. At low magnification the lesion is patchy and comprises an airspace-filling process in which alveolar spaces contain an inflammatory exudate resulting in zones of consolidation (Fig. 21–41). A fibrinous exudate often accompanies the inflammatory exudate. Eosinophils typically predominate, although the relative proportion of associated alveolar histiocytes, neutrophils, lymphocytes, and plasma cells is highly variable. Histiocytes are frequently a prominent component and invariably include multinucleated giant cells. Brightly eosinophilic Charcot-Leyden crystals are often present within the extracellular exudate or the cytoplasm of alveolar macrophages. Focal necrosis may be present within the airspace exudates, resulting in eosinophilic microabscesses (Fig. 21–42).

Several secondary changes occur in chronic eosinophilic pneumonia. Patchy intraluminal fibrosis resembling that seen in BOOP is present in about a third of cases.^625,626 Indeed, idiopathic BOOP and chronic eosinophilic pneumonia have overlapping clinical, radiologic, and histologic features.^129,626,628 Tissue eosinophilia is a more prominent feature in lung biopsy specimens from patients with chronic eosinophilic pneumonia, although in any individual patient the distinction may be arbitrary.¹⁴⁴ Well-formed, nonnecrotizing granulomas have been reported in about 15% of surgical lung biopsies and resemble those seen in sarcoidosis.^625,626 Eosinophilic pneumonia can occur as a secondary finding in occasional examples of granulomatous infection. For that reason, discovery of granulomas in an otherwise typical case of presumed eosinophilic pneumonia should prompt a vigorous search for potential pathogens using appropriate special stains and cultures. Perivascular inflammatory infiltrates (“angiitis”) are present in as many as two thirds of surgical lung biopsies.^625,628 True necrotizing vasculitis does not occur, however, and when present should prompt consideration of other entities such as Churg-Strauss syndrome (see Chapter 16).

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