1. Endoscopic biopsies are usually submitted in a single cassette. The fragments are small; use of a nylon mesh bag or a filter paper wrap is preferable to submission on biopsy sponges since tissue can be compressed or lost in the pores of sponges. The number of fragments, range of size, and color should be recorded. Three hematoxylin and eosin stained levels should be examined. For smaller biopsies, additional unstained levels may be cut at the time of initial sectioning in case special stains are needed.

Core biopsies of nodules presumed to represent neoplasms are obtained under CT guidance. They should be processed as for endoscopic biopsies.

2. Wedge resections are performed for either non-neoplastic or neoplastic processes. The specimen should be measured in three dimensions and weighed. Assessment of alveolar architecture may be improved by gently inflating the specimen by injection of formalin at multiple sites. If the specimen is inflated, the gross description should include this fact. Wedge biopsies generally have multiple staple lines, which should be cut off as close to the staples as possible; ideally, sections are taken perpendicular to the staple line. The entire specimen should be submitted in non-neoplastic cases; levels are usually not necessary. If the specimen is obtained for diagnosis of a neoplasm, the presence and dimensions of any masses should be described, as well as the distance to the staple line(s).

3. Lung resections should be described as lobectomy, bilobectomy, or right or left pneumonectomy. The specimen should be measured in three dimensions and weighed. Any additional designation by the surgeon (e.g., sutures) should be described. If a portion of chest wall is attached to the specimen, its size in three dimensions and the number of ribs or other attached structures should be noted. For lobectomy and pneumonectomy specimens, insufflation by injection of formalin into the bronchial orifices improves fixation and visualization of changes. Occasionally, obstruction of bronchi by tumor makes this technique ineffective, in which case the lung can be expanded by injection of formalin at multiple sites. The pleural surface should be described; areas of puckering, dullness, or adhesions should be noted, as should adhesions of lobes together in multilobe resections. Areas of pleural distortion over a mass should be marked with ink. The hilar area should be examined and the number and size of bronchial stumps noted. The lung can be sectioned in either parasagittal or in coronal planes; it is important to choose planes to highlight the extent of tumor, pleural invasion, invasion of adjacent structures, proximity to the hilum, and relationship to major airways and vessels. At least four sections of tumor should be taken, including one or two with the closest pleural surface (which may be at the hilum). If tumor is invading structures such as a rib, chest wall, or mediastinal soft tissue, a section that shows tumor in the lung in continuity with the involved structure should be taken. Other sections should include normal appearing lung, areas distal to the tumor that show obstructive pneumonia, and any additional nodules or lesions. Vascular and bronchial margins, hilar lymph nodes, and peribronchial lymph nodes should be submitted as well.

1. A description of small biopsies includes the number of pieces and their constituent elements: alveolar tissue, bronchial wall, alveolar tissue, and superficial detached fragments of epithelium. The number of fragments is not insignificant; six fragments are considered to be representative of lung. The low power impression of normal or abnormal alveolar architecture should be included. Expansion of the alveolar septa may be by inflammatory tissue, cellular tissue, or acellular fibrosis. Alveolar spaces may be
empty, or filled with blood, histocytes, or exudates. The vasculature may be unremarkable, thickened, show inflammation or vasculitis, or contain tumor or thromboemboli. The bronchial epithelium can be columnar, squamous, or dysplastic. The absence or presence and type of granulomas should be described. Inflammatory cells should be noted and characterized as to type and distribution, whether alveolar, septal, peribronchial, perivascular, or diffuse. The results of special stains for organisms or fibrosis should be reported.

Biopsies for a neoplasm should include the same quantitation of the biopsy fragments as for non-neoplastic samples, as well as a description of the neoplasm. An in situ or dysplastic component should be described, if present. Detectable vascular space invasion should be noted.

2. The pathology report of wedge resections for non-neoplastic processes should contain the same information as for smaller biopsies, but should also include additional assessment of larger airways and vessels, and distribution of any non-neoplastic processes. Fibrosis, for example, can be diffuse, peripheral, or sparing the periphery. Similarly, inflammation or granulomas can be perivascular, peribronchial, or distributed along septa.

3. Definitive resections of neoplasms, from wedge resections to pneumonectomies, should provide as much information as possible. Prior sampling (endoscopic biopsy, mediastinoscopies, or previous wedge resections) and prior treatment (chemotherapy or irradiation) should be included in the pathology report. Margins should be evaluated, and the non-neoplastic lung should be described.

1. DAD is the prototypical pattern of acute lung injury (e-Fig. 8.1).^* It is the pattern of histologic changes underlying the clinical syndrome of acute respiratory distress syndrome (ARDS), the clinical triad of diffuse lung infiltrates, hypoxemia, and decreased pulmonary compliance. DAD has myriad causes, as detailed in Table 8.1. DAD is caused by cellular injury to pulmonary epithelial and endothelial cells. The initial insult causes edema from leaky capillaries, and the sloughed cellular material and fibrinous exudate form hyaline membranes; there is often surprisingly little inflammation in this early phase, known as the exudative stage. By six to seven days after the initializing injury, the edema and hyaline membranes begin to disappear, and hyperplastic and regenerative type 2 pneumocytes are prominent. By seven days, the process of organization is well underway, with interstitial and airspace fibroblastic proliferations; this stage is known as the proliferative or organizing phase. During organization, the alveolar exudates may be incorporated into the alveolar wall if proliferating type 2 pneumocytes grow on top of the exudate rather than along original alveolar basement membrane. Likewise, alveolar collapse may lead to further remodeling of prior
airspaces. This process of organization and fibrosis may resolve at some point, or can continue along the path of fibrosis leading to the appearance of honeycomb lung within 3-4 weeks.

The hallmark of biopsies with DAD is spatial and temporal uniformity; that is, the process is similar across all areas of the tissue because the inciting injury is diffuse. By the time most patients are sick enough to come to biopsy, this process has been present for at least several days, and hence is in the organizing phase. A search for such etiologic clues as viral inclusions or fungus by silver stains is important, but the identification of the etiology for DAD is generally a clinicopathologic correlation exercise. When patients recover, they may be essentially normal, or may be left with some degree of lung impairment. Trichrome or similar stains may be helpful when reviewing these biopsies. Cases that show cellular fibrosis but in which trichrome stains do not show significant collagen deposition are thought to be reversible; however, once significant collagen is present in the areas of fibrosis, the process is not likely to resolve.

2. AIP is histologically similar to DAD, but has no definable cause and could thus also be considered as idiopathic DAD. The patients, often young adults, present with rapid onset of respiratory failure. There is often a history of a flu-like illness, and some studies have suggested that a Herpes-like virus may be present in some cases. By the time patients come to biopsy, the lung almost always shows a picture identical to that of organizing phase DAD. Most patients die of disease within 2 months. This rapid form of interstitial lung disease was classically described as Hamman-Rich syndrome.

3. Bronchiolitis obliterans-organizing pneumonia (BOOP) is another manifestation of acute lung injury (e-Fig. 8.2). Some authors now advocate the substitution of the term cryptogenic organizing pneumonia (COP). Causes are detailed in Table 8.2. Idiopathic cases tend to present in older adults with fever, cough, and some dyspnea; there may be an antecedent respiratory infection. Radiographs show patchy, peripheral air-space filling opacities that may appear in different areas of the lung over time. Histologic sections show a very distinctive pattern of immature fibroblastic tissue within
terminal bronchioles and alveolar ducts, which often has an elongated or hook-like configuration; these are often referred to as Masson bodies and can also be seen in peribronchiolar alveolar spaces. Because of the luminal filling of terminal bronchioles, there is often an associated localized obstructive pneumonia in the form of accumulation of lipid-filled macrophages. Since BOOP is centered on terminal airways, low-power views of wedge biopsies show a somewhat nodular configuration in contrast to the diffuse nature of injury in DAD. Thus, BOOP shares the temporal uniformity of DA, but not the homogeneous spatial appearance; nonetheless, the basic lesion of epithelial and endothelial cell injury is identical to that seen in DAD. It is important to emphasize that many, if not most, cases of BOOP are secondary to some other process. Consequently, the finding of a pattern of BOOP on a biopsy should lead to a careful search of the tissue for lesions that can be associated with BOOP, such as granulomas, vasculitis, or viral inclusions indicative of viral infection.

While the distinction between nodular versus diffuse involvement (and consequently, distinction between BOOP and DAD/AIP) may be obvious in wedge biopsies, transbronchial biopsies may show features such as organizing airspace fibrosis and type 2 pneumocyte hyperplasia without a clear indication of the spatial distribution of the process. In such cases, a more generic diagnosis of “organizing acute lung injury” may be used. This conveys the essential information for patient care—that is, the diagnosis defines the patient as having an acute injury with attendant lung response, as opposed to a chronic idiopathic interstitial lung disease.

1. Usual interstitial pneumonitis (UIP) is the prototypical chronic interstitial pneumonitis. It is so named because it represents the underlying pathology in at least 80% of cases that fall under the clinical term of idiopathic pulmonary fibrosis. UIP is most often a disease of older adults, but has been reported in all age groups, including children. By the time of diagnosis, patients have often had several years of slowly developing shortness of breath. Pulmonary function tests show restrictive disease corresponding to the small lungs seen by chest X-ray examination. CT scans demonstrate honeycombing, most commonly at the lung bases and lung periphery, as well as traction bronchiectasis (e-Fig. 8.3). Gross examination shows coarse sponge-like lung corresponding to the honeycombing seen on radiograph. Microscopically, the disease is characterized by spatial and temporal heterogeneity. Temporal heterogeneity refers to the coexistence of old honeycomb scars (defined as cystic spaces lined by bronchiolar type epithelium) with areas of ongoing fibrosis (fibroblastic foci). The fibroblastic foci represent small areas of developing fibrosis, consistent with the insidious progression
of this disease. Acute inflammation is often restricted to the honeycomb areas, which may contain mucoid debris. Spatial heterogeneity refers to the finding that the most severe fibrosis is in the subpleural areas and along lobular septa; more central parts of the pulmonary lobule typically show less severe disease. Chronic inflammation is mild and patchy within areas of fibrosis; autoimmune or connective tissue disorders (CTDs) should be considered in cases with more extensive chronic inflammation. Related changes in the lung include secondary pulmonary hypertension and type II pneumocyte hyperplasia. The clinical course both before and after diagnosis is variable; most patients die within five years of diagnosis, although some patients have a more protracted course. In the process known as acute exacerbation of UIP, histologic sections show DAD superimposed on a background of UIP; the precise etiology for acute exacerbation of UIP is not known (which parallels the fact that the etiology of UIP itself is generally unknown).

2. Non-specific interstitial pneumonitis (NSIP) is the second most common form of idiopathic interstitial pneumonitis. As with UIP, patients tend to be middle aged or older adults. Many patients have underlying CTDs such as rheumatoid arthritis or lupus. Pulmonary function tests show a restrictive pattern. CT scans disclose significant differences from those in UIP; honeycombing is rarely a prominent feature in NSIP, but ground glass opacities, linear opacities, and small nodular infiltrates are frequently present (e-Fig. 8.4).

Microscopically, the process has a more homogeneous appearance than UIP. Biopsies usually lack subpleural accentuation, but instead show more uniform involvement of both central and peripheral parts of the lobule. The process is generally more cellular than UIP with a mixed interstitial acute and chronic inflammatory infiltrate. Cases may show features of organizing pneumonia or BOOP, and small non-descript granulomas may be seen in some cases. Honeycombing, if seen on microscopic sections, is usually more focal and should not be a dominant pattern. The forgoing findings are characteristic of the cellular or mixed patterns of NSIP; since they bear significant resemblance to processes such as chronic hypersensitivity pneumonia or unresolved or slowly resolving organizing pneumonia, it is not clear that cases labeled as NSIP do not represent some unusual variants of the latter groups. A third pattern of NSIP, namely the sclerotic variant, consists of hyaline-like interstitial fibrosis. Although the full characterization of NSIP is still evolving, the one unifying feature of NSIP is that the patients survive longer, and with less disability than those patients whose biopsies show UIP.

3. Desquamative interstitial pneumonia and related lesions (DIP) is a rare form of interstitial pneumonia characterized by abundant macrophage exudates that fill the alveolar spaces. In most patients, this process is related to cigarette smoking, although rare examples have been reported in nonsmokers; most patients are middle aged to older adults. Radiographic studies are dominated by ground glass opacities reflective of the filling of alveolar spaces, and microscopic sections feature dramatic filling of the alveolar spaces by macrophages, which tend to be light brown due to smokingrelated pigment (e-Fig. 8.5). DIP is spatially homogeneous in that virtually any microscopic field from involved lung will show identical features. The alveolar walls may be thin and delicate, or may show some mild inactive hyaline fibrosis. Honeycomb changes are rare. DIP has an excellent prognosis; in cases related to cigarette use, the primary therapy is smoking cessation.

Less dramatic findings along the same spectrum of smoking-related changes include respiratory bronchiolitis (RB) and respiratory bronchiolitis associated interstitial lung disease (RB-ILD). RB shows similar macrophages
as in DIP, but limited to the lumen of terminal airways; it is often most prominent in the upper lobes and is thought to be the precursor of centriacinar emphysema (e-Fig. 8.6). RB-ILD is similar with the addition of mild interstitial fibrosis surrounding the terminal bronchioles.

4. Lymphoid interstitial pneumonitis (LIP) is another rare idiopathic form of interstitial pneumonitis. LIP can occur in patients of any age. When LIP occurs in children, it is often a harbinger of HIV infection; similarly, LIP has been described in immunocompromised patients as a manifestation of EBV infection. Some cases of LIP are related to Sjöogren syndrome. Chest radiographs demonstrate infiltrates of a variety of patterns. Microscopically, there is diffuse expansion of the pulmonary interstitium by a mixed inflammatory cell infiltrate that includes small lymphocytes, plasma cells, germinal centers, and histiocytes. There may be some associated interstitial fibrosis. Many cases previously described as LIP likely represent examples of pulmonary MALToma or related neoplasms. Immunostains should show a mixed pattern of CD3-positive T-cells and CD20-positive B-cells. In cases of suspected LIP, flow cytometry or molecular studies to assess clonality are very useful to exclude lymphoma.

5. Giant cell interstitial pneumonitis is very rare. Most cases are now known to represent a reaction to various heavy metals. Consequently, optimum diagnosis is made by the combination of accurate history and spectrophotometric analysis of lung tissue.

6. Smoking-related interstitial fibrosis (SRIF) is a recent addition to list of smoking-related lung diseases (Hum Pathol. 2010;41:316-325). SRIF is often found in lobectomy specimens of resected lung carcinomas, in patients with no pre-operative clinical symptoms or imaging diagnosis of interstitial lung disease. The fibrosis typically has a hyaline or sclerotic appearance that somewhat resembles the sclerotic form of NSIP. Also, the fibrosis is usually superimposed on significant emphysema.

1. Connective tissue disorders. Lung involvement in CTDs is extremely common and variable. Prominent patterns of involvement for selected disorders are summarized in Table 8.3. There is significant overlap among these entities and assignment to a specific entity should not be made on the basis of pulmonary findings. Also, many of the lung findings in CTDs overlap with the idiopathic interstitial lung diseases.

2. Drug-induced pulmonary changes. Prominent pathologic findings associated with drug reactions are listed in Table 8.4. It is clear from this list that drug reactions can mimic virtually any non-neoplastic condition, which emphasizes the need for accurate history and correlation with the clinical setting.

3. Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis (EAA), is a disease caused by exposure to organic antigens. Classically the
exposure is to thermophilic Actinomyces, but a variety of organic agents have been implicated (Table 8.5). Acute HP occurs with exposure to large amount of antigen; within 4-6 hours dyspnea, cough, fever, and diffuse infiltrates develop. Pulmonary function tests show moderate to severe restriction and decreased DLCO; severe hypoxemia is also present. Radiology studies show airspace disease, ground glass opacities, and some small nodular opacities. Symptoms improve in 12-18 hours, and within 2-3 days the radiographic findings resolve. Microscopically, acute inflammation, edema, and exudates may be seen, but because of the rapid course of the disease, it is rarely biopsied.

Chronic HP is due to repeated or prolonged exposure to small amounts of antigen; it is typically due to episodic exposure to some organic antigen, but the offending antigen is eventually identified in only 1/3 to 1/2 of cases. Chronic HP has several histopathologic characteristic (e-Fig. 8.8) including chronic interstitial inflammation with many CD8+ T-cells, vague granulomas or giant cells in the interstitium, and chronic bronchiolitis, sometimes with BOOP. Eosinophils are not part of the disease, despite the hypersensitivity label. Most patients respond to therapy or have stable disease, with a minority progressing to fibrosis and end-stage lung disease. There is overlap between chronic HP and some cases labeled as NSIP, and the two diseases may actually be the same process.

4. Sarcoidosis is a systemic disease of uncertain etiology. While some molecular genetic studies suggest that sarcoid represents a hypersensitivity-like reaction to mycobacterial infection, standard stains and cultures do not show organisms. There is frequent lung involvement, although it is usually mild and as many as 2/3 of patients are asymptomatic. Most cases involve the hilar and mediastinal nodes as well as the lung, but isolated involvement of either site can occur. In symptomatic patients, pulmonary function tests show mixed restriction and obstruction and decreased DLCO; lung volumes tend to be preserved.

The basic histologic lesion of sarcoid is a non-caseating granuloma with enveloping fibrosis (e-Fig. 8.9). The individual granulomas can coalesce to form larger nodules. The granulomas follow the lymphatic routes and so are present along airways; for this reason, transbronchial lung biopsies produce a diagnosis in up to 80% of cases. The giant cells in the granulomas may contain various structures, including Schaumann bodies, asteroid bodies, and oxalate crystals (the latter are produced endogenously by the giant cells, and thus polarizable material in the giant cells should not be taken as evidence of foreign body exposure). Sarcoid also includes varying degrees of interstitial lymphoid infiltrates. Stains for fungi and mycobacteria should be performed in all cases. Some cases otherwise typical for sarcoid show minimal central fibrinoid material in the granulomas; however, true caseation should raise concern about that the diagnosis is not sarcoidosis.

Unusual clinicopathologic features of sarcoid include massive pleural effusions associated with chest pain suggesting mesothelioma or pleural tumors, or one large nodule or multiple nodules with cavitation mimicking primary or metastatic tumor within the lung. Rare cases of sarcoidosis
produce peripheral infiltrates that simulate eosinophilic pneumonia, or granulomatous vascular impingement that can simulate veno-occlusive disease. End-stage cases often are dominated by the presence of apical bullous disease; the granulomas at this stage may be largely “burnt-out” and replaced by hyalinized fibrous tissue that tracks along the lymphatic routes.

The differential diagnosis of sarcoid is always granulomatous infection, and it is important to note that up to 10%-15% of biopsies with granulomas and negative special stains are culture-positive. Infection should always be suspected if the granulomas are necrotizing. The differential diagnosis also includes a drug reaction, berylliosis, and aluminum exposure.

5. Pulmonary eosinophilic granuloma (also called Langerhans cell histiocytosis, or histiocytosis X) is a disease of adults, with most cases presenting in the third and fourth decades of life. There is a history of cigarette smoking in almost 90% of cases, indicating that this disease should be considered as another facet of smoking-induced lung disease. Patients with pulmonary eosinophilic granuloma (EG) have disease limited to lung; although some are asymptomatic, most complain of cough, dyspnea, fever, or weight loss. Pneumothorax is another documented presentation of EG. Radiologic studies show an upper lobe predominance; cysts and small stellate nodules can be seen by high-resolution CT scans. Because of the smoking history, there is often co-existent emphysema, desquamative interstitial pneumitis, RB, or RB-ILD.

The characteristic histologic picture of EG (e-Fig. 8.10) is a stellate interstitial collection, often near small airways, of eosinophils and Langerhans cells. Langerhans cells feature a unique convoluted nucleus and a moderate amount of cytoplasm; some bi-nucleated forms may also be present. An admixture of pigmented alveolar macrophages (“smoker’s macrophages”) is also often present. Langerhans cells can be easily demonstrated by immunostains for S-100 and CD1a; alveolar macrophages stain for CD68 but not S-100 or CD1a. In contrast to the cellular lesions just described, resolved or “burnt out” lesions in chronic disease may consist only of hyalinized stellate scars in the upper lung zones; immunostains may highlight a few Langerhans cells in these scars, or may be completely negative. About 10%-20% of cases progress to fibrosis, but most patients improve with cessation of smoking; rare patients develop severe pulmonary hypertension. Eosinophilic pneumonia is one important differential consideration in small biopsies, but can be easily dismissed by correlation with radiographic and clinical features; in addition, the macrophages in eosinophilic pneumonia will be negative for S-100 and CD1a. Eosinophilic pleuritis may develop after pneumothorax, and may raise concern for EG in the lung, but reactive mesothelial cells are negative for S-100 and CD1a.

6. Lymphangioleiomyomatosis (LAM) is a disease that essentially occurs only in woman of reproductive age. Although classified as an interstitial disease, it features preserved lung volumes, unlike most fibrosing diseases. CT scans show diffuse involvement of the lung by cysts of rather uniform size that feature some mural thickening around the cystic spaces, a finding that serves to distinguish LAM from processes such as emphysema. In fact, high resolution CT images are so characteristic that the first pathologic specimen seen in many patients is explanted lungs. Patients present with obstructive lung symptoms or spontaneous pneumothorax, and also may demonstrate large chylous pleural effusions. Microscopic sections of LAM (e-Fig. 8.11) show a proliferation of abnormal smooth muscle-like cells in the lung. In many cases these cells seem to swirl away from the native smooth muscle of airways and vessels. Vascular compromise is linked to microhemorrhages, and so many cases show abundant hemosiderin within the lung. While
LAM is centered in the lung, it also involves lymph nodes in the pulmonary hilum, mediastinum, and abdomen in most cases. The smooth muscle-like cells stain with vimentin, desmin, and smooth muscle actin, and also may express estrogen and progesterone receptor. LAM also shows cross-lineage staining with melanoma markers including HMB-45 and melan-A. In this regard, the cells of LAM share the staining attributes of the members of the PEComa family (including the sugar tumor of lung), renal angiomyolipomas, and some soft tissue tumors (see Chap. 46). LAM also shows overlap with tuberous sclerosis (TS) in that some TS patients develop an identical cystic lung disease, and both LAM and TS share an association with angiomyolipomas in the kidney and elsewhere. The course of the disease is unpredictable; transplantation has been the only long term option for those with severe disease.

7. Alveolar proteinosis refers to a peculiar accumulation of intra-alveolar eosinophilic, granular PAS-positive protein and phospholipid. It was initially reported as an idiopathic process, but a relation to immune deficiency, hematologic malignancies, infections, and various exposures is now recognized. Classic exposure-related cases are associated with massive acute silica exposure, which is believed to poison the alveolar macrophages and thus inhibit their ability to clear alveolar debris.

Clinically, patients present with slowly progressive alveolar infiltrates and complain of dyspnea, cough, or sputum production with fever; CT scans show “crazy-paving” with alveolar infiltrates and septal line thickening. The diagnosis is often apparent from the milky appearance of lavage fluid; biopsies show complete filling of the alveolar spaces by granular eosinophilic debris that is PAS-positive and diastase-resistant (e-Fig. 8.12). Findings often include cholesterol clefts (acicular clefts), globular eosinophilic debris, and macrophages. In most cases the underlying alveolar structure appears normal, although some chronic cases may eventually show fibrosis. Secondary infection of the fluid by Nocardia, mycobacteria, and fungi has been reported. Pneumocystis infection can microscopically mimic alveolar proteinosis, although the material in alveolar proteinosis lacks the frothy appearance characteristic of Pneumocystis infection.

1. Eosinophilic pneumonia can be divided into acute and chronic forms. The acute forms include the “simple form” also known as Loeffler syndrome; this is an acute, self-limited process with fleeting infiltrates and peripheral blood eosinophilia and is rarely biopsied. The tropical form is usually linked to filaria infection, and also presents as an acute illness. The chronic form is more likely to require biopsy for diagnosis.

Chronic eosinophilic pneumonia (CEP) has a variable presentation from acute illness with fever, dyspnea, and weight loss, to vague respiratory complaints. Many patients have a history of asthma, and laboratory tests reveal elevated blood IgE and peripheral blood eosinophilia. Chest radiographs show patchy non-segmental infiltrates, often peripheral, that may cross fissures, a pattern that is sometimes described as the “photographic negative of pulmonary edema.” There are myriad underlying causes; major categories include drugs (antibiotics such as nitrofurantoin, sulfonamides, penicillins, anti-inflammatory agents, and chemotherapeutics), fungus (Aspergillus and Candida), parasites, nickel vapor, and idiopathic cases. Histologic sections of CEP (e-Fig. 8.13) show an alveolar-filling process consisting of a mixture of eosinophils and macrophages. Necrosis of eosinophils may be present, forming an eosinophilic abscess. Charcot-Leyden crystals will also be present, as well as interstitial and perivascular eosinophils, lymphocytes, plasma cells, and areas of BOOP.

2. Mucoid impaction of bronchi (MIB) is the filling of bronchi by viscous mucus, usually caused by another underlying disease such as asthma, cystic fibrosis, or chronic bronchitis. Patients present with evidence of lobar collapse or an irregular branching mass-like density. Histologic sections of the impacted material in most cases show “allergic mucin” that consists of laminated collections of eosinophils, eosinophil debris, and mucinous exudates. Fungal hyphae, most often Aspergillus (e-Fig. 8.14), may also be present in a pattern that overlaps with allergic bronchopulmonary aspergillosis (ABPA). A related process is plastic bronchitis which is impaction of airways by neutrophilic debris.

3. ABPA is a related form of hypersensitivity to fungal organisms, most often Aspergillus. The disease almost always occurs in asthmatic patients, and is usually diagnosed by a combination of clinical features that include pulmonary infiltrates and proximal bronchiectasis, skin testing that shows reaction to fungal antigens, precipitating antibodies to fungal antigen, elevated IgE levels, and peripheral blood eosinophilia. Tissue sections show a combination of eosinophilic pneumonia, MIB, and bronchocentric granulomatosis (granulomatous destruction of bronchioles).

1. Wegener granulomatosis is the prototypical lung vasculitis. It most often presents in middle age with pulmonary symptoms including cough, hemoptysis, and fever. Other patients present with upper respiratory complaints or renal failure, depending on the dominant sites of disease. Chest radiographs may show alveolar filling due to hemorrhage, multiple nodules with cavitation, or even a single massive nodule. Microscopic features in the lung reflect a classic triad of findings (e-Fig. 8.17): (1) Vasculitis which involves arteries, veins, and capillaries (capillaritis). Acute vascular lesions show fibrinoid necrosis; chronic lesions may show only vascular scarring or perivascular chronic inflammation. Capillaritis consists of neutrophils, nuclear dust, and fibrin microthrombi in lung capillaries, analogous to leukocytoclastic vasculitis in the skin. (2) Necrosis that is often described as geographic necrosis, and classically has an abscess-like appearance with a hematoxyphilic hue, surrounded by palisaded histiocytes. (3) Granulomatous inflammation comprised of palisades of histiocytes, scattered giant cells, and poorly formed granulomas.

Other microscopic features can include acute or chronic alveolar hemorrhage; airway bronchocentric granulomatosis-like lesions, BOOP, chronic bronchitis, and bronchiolitis; interstitial lesions including fibrosis and nonspecific chronic inflammation; DAD; and pleural lesions such as fibrinous pleuritis, granulomas, or chronic inflammation. Serology studies in most cases reveal c-ANCA positivity; the anti-neutrophil antibodies will show a cytoplasmic pattern of staining, and PR3 is usually the antigen. Rarely, p-ANCA will be positive.

2. Microscopic polyarteritis is the lung equivalent of leukocytoclastic vasculitis. It is often associated with p-ANCA and has many other associations including drug-related cases, infection (e.g., hepatitis B, bacteria), Henoch-Schönlein purpura, collagen vascular disease, cryoglobulinemia, and idiopathic. The basic lesion is capillaritis, which has two main features: neutrophils in the alveolar septae and capillary walls with neutrophilic nuclear dust, and microscopic fibrin thrombi in capillaries (e-Fig. 8.18). Arteriolitis or venulitis is also often present. Since the differential diagnosis includes acute lung injury or acute pneumonia, microscopic polyarteritis is a diagnosis of exclusion.

3. Churg-Strauss syndrome (allergic angiitis and granulomatosis) is another ANCA-related vasculitis. Nearly all patients have a history of asthma. Many patients also have skin lesions, neuropathy, CNS disease, or heart failure; most cases are diagnosed by biopsy of sites other than lung. The histopathologic findings are a combination of two features: (1)Vasculitis that can affect both arteries and veins, with giant cell infiltration of vessel walls. There may also be transmural eosinophilia with fibrinoid necrosis and small palisaded
granulomas. (2) Eosinophilic infiltrates that resemble eosinophilic pneumonia consisting of a combination of histiocytes and eosinophils that fill alveoli.

1. Obliterative bronchiolitis (constrictive bronchiolitis, bronchiolitis obliterans), though it has a name that is similar to BOOP, is a completely different disease that is characterized by the progressive narrowing and luminal compromise of small airways by sub-epithelial fibrosis. Conditions associated with this process are listed in Table 8.8, many of which have some immunologic basis. Patients present with insidious onset of shortness of breath and obstructive pulmonary functions with air-trapping. Wedge biopsies are often required for diagnosis, and it is common to see a spectrum of small airway changes in such biopsies ranging from virtually normal, to partial scarring, to total luminal obliteration by fibrous tissue (e-Fig. 8.19). Inflammation is variable, and there will be mucus trapped distal to areas of severe luminal compromise. Although the disease may stabilize for some time, the changes are generally irreversible.

2. Cellular bronchiolitis is a descriptive name given to forms of bronchiolitis that feature marked acute and chronic bronchiolar inflammation. Conditions associated with this lesion are listed in Table 8.9.

1. Cytomegalovirus typically affects immunocompromised patients; since most people are exposed to cytomegalovirus (CMV) in childhood, many cases represent activation of latent infection. Patients may develop fever, cough, or shortness of breath. Chest X-rays show diffuse infiltrates, and biopsies show interstitial pneumonitis as well as DAD or nodular inflammation. Enlarged cells with nuclear and/or cytoplasmic inclusions are pathognomic for CMV infection. In H&E stained sections, nuclear inclusions have an eosinophilic core (6 μm) with a surrounding cleared zone, while the cytoplasmic deposit
is basophilic (e-Fig. 8.20). Epithelial cells, vascular cells, and even stromal cells can exhibit inclusions. Immunohistochemistry for CMV will decorate the enlarged cells; electron microscopy demonstrates virions in the inclusions, while a PAS stain with diastase highlights the cytoplasmic deposits.

2. Herpesvirus (HSV). Both HSV types I and II can induce pneumonitis, and immunocompromised hosts are more prone to Herpes viral pneumonia. Clinically, HSV pneumonia may result from extension of upperway disease with primarily bronchiolar inflammation, or from systemic infection which presents as multiple small perivascular inflammatory nodules. Three findings are characteristic of HSV: necrosis, individual cells with inclusions (e-Fig. 8.21) (featuring eosinophilic nuclear inclusions with perinuclear clearing; amphophilic nucleoplasm in single cells may represent early inclusions or giant cell formation), and herpes viral giant cells (which contain two or more nuclei with ground glass central nuclear clearing and coarsely granular, sharply defined nuclear borders; the nuclei are often molded against one another). Immunohistochemistry using antibodies to HSV decorates the giant cells and the individual cells with inclusions.

3. Varicella zoster (VZV) is the causative agent for chicken pox and shingles. Primary infection in healthy adults and immunocompromised children can result in pneumonia. The underlying lung injury pattern can be either DAD with hyaline membranes and proteinaceous exudates, or nodular inflammation with central necrosis that calcifies and persists on chest radiographs. Biopsies of VZV infections show giant cells similar to those of HSV.

4. Adenovirus infection generally presents with symptoms typical of an upper respiratory infection; pneumonia develops in a small percentage of healthy and immunocompromised children and adults. Two patterns of infection evolve. Some patients develop necrotizing bronchiolitis and pneumonia, while others respond with DAD with hyaline membranes and exudates. In adenoviral infections both alveolar lining cells and bronchial epithelial cells may exhibit blurred and hyperchromatic nuclear chromatin (so-called smudge cells) (e-Fig. 8.22). The bronchial damage of adenovirus may result in fibrosis or constricting bronchiolitis.

5. Respiratory syncytial virus (RSV) affects primarily small children and infants; premature infants and immunocompromised children are particularly prone to infection. RSV infection exhibits some seasonality, and is more common in fall and winter. RSV can induce bronchiolitis with symptoms of cough, wheezing, and respiratory distress. Biopsies show necrotizing bronchiolitis and/or interstitial pneumonia.

6. Measles virus. With the advent of vaccination, infection by measles virus is rare, and evolution to pneumonia rarer. Most patients are immunocompromised, and the characteristic skin rash is present. The underlying pathology is DAD, with associated individual and giant cells with viral inclusions; the alveolar spaces may contain exudates, and necrosis may be present. Both eosinophilic intranuclear and cytoplasmic inclusions develop in both alveolar and vascular lining cells. Measles pneumonia features a distinctive multinucleate giant cell thought to derive from coalescence of type II pneumocytes, the Warthin-Finkeldey giant cell, which contains up to 60 nuclei.

7. Parainfluenza and influenza generate non-specific patterns, consisting of varying degrees of DAD, bronchial necrosis, and peribronchial inflammation.

1. Mycoplasma induces acute and chronic bronchiolitis, with necrosis and denudment of bronchial epithelium. The bronchial lumina may contain acute inflammatory cells admixed with denuded epithelium. Acute and
chronic inflammatory cells often traverse the bronchial wall. Alveolar spaces may exhibit bronchopneumonia, with BOOP or DAD.

2. Mycobacterial infections are typically grouped into tuberculosis and other (atypical) mycobacterial infections. The most common stain used to demonstrate organisms in tissue sections is the Ziehl-Neelsen stain; immunofluorescent (auramine-rhodamine) and immunohistochemical stains can also be used to identify mycobacteria. PCR based genetic methods can also be used to detect (and speciate) the organism in tissue sections.