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Transbronchial biopsy interpretation in the patient with diffuse parenchymal lung disease.

* Context.--The most common lung tissue samples seen by pathologists worldwide are obtained with the flexible bronchoscope. Specimens taken for examination of diffuse or multifocal parenchymal lung abnormalities pose special challenges for the general surgical pathologist, and these challenges are often compounded by high clinical expectations for accurate and specific diagnosis.

Objective.--To present and discuss the most common histopathologic patterns and diagnostic entities seen in transbronchial biopsy specimens in the setting of diffuse or multifocal lung disease. Specifically, acute lung injury, eosinophilic pneumonia, diffuse alveolar hemorrhage, chronic cellular infiltrates, organizing pneumonia, alveolar proteinosis, sarcoidosis, Wegener granulomatosis, intravenous drug abuse-related microangiopathy, Langerhans cell histiocytosis, and lymphangioleiomyomatosis are presented. Clinical and radiologic context is provided for the more specific diagnostic entities.

Data Sources.--The published literature and experience from a consultation practice.

Conclusions.--The transbronchial biopsy specimen can provide valuable information for clinical management in the setting of diffuse or multifocal lung disease. Computed tomographic scans are useful for selecting appropriate patients to undergo biopsy and in limiting the differential diagnosis. Knowledge of the clinical context, radiologic distribution of abnormalities, and histopathologic patterns is essential. With this information, the surgical pathologist can substantially influence the diagnostic workup and help guide the clinician to an accurate clinical/radiologic/pathologic diagnosis.

(Arch Pathol Lab Med. 2007;131:407-423)


The flexible bronchoscope was introduced in the United States in the late 1960s and allowed pulmonologists and surgeons access to the lung as never before. (1,2) The small biopsy samples obtained with this instrument present special challenges to the general surgical pathologist, not the least of which is knowledge of the clinical and radiologic context that prompted the biopsy. In the case of diffuse or multifocal parenchymal disease, the transbronchial biopsy (TBB) approach is used, often with fluoroscopic guidance. The technique is not perfect, as the efficacy of any biopsy depends highly on the question being asked and the circumstances of the patient. For example, knowledge that the patient is immunocompromised raises the possibility of infection above all others, and requires both the use of special stains to exclude infection and a careful review of every section on the slide(s). In the normal host, knowing whether a radiologic abnormality is localized or diffuse is essential. Mild chronic inflammatory changes in a biopsy specimen taken in the setting of a spiculated mass lesion suspicious for carcinoma may be entirely incidental, whereas those same changes in a patient with diffuse parenchymal abnormalities could be a harbinger of a chronic inflammatory lung disease, or even cellular rejection in the biopsy specimen from a lung transplant recipient. Several excellent reviews of the challenges, strengths, and limitations of the TBB are available for the interested reader (3-19) and a recent overview is concisely presented by Churg. (20)


Computed tomography (CT), with scans often performed at high resolution, is very useful in predicting the yield of TBB based on the anatomic distribution and appearance of any abnormalities. In select instances, CT enables a specific diagnosis in the appropriate clinical context, particularly in patients with sarcoidosis, usual interstitial pneumonia, subacute hypersensitivity pneumonitis, acute eosinophilic pneumonia, Langerhans cell histiocytosis (LCH), and lymphangioleiomyomatosis (LAM). (21) Even when CT is nonspecific, peribronchovascular and central abnormalities are much more amenable to specific TBB diagnosis than is peripheral or nonsegmental disease. Transbronchial biopsy is also often diagnostic in patients in whom the CT findings are those of centrilobular nodules of ground-glass attenuation. (22) Unfortunately, there is still considerable variability in the performance and interpretation of thoracic CT, and the pathologist may receive tissue from a TBB in the absence of CT images or informative reports.


The main utility of the TBB rests on the possibility of making a specific diagnosis in a patient with diffuse lung disease and avoiding a surgical lung biopsy. Although the surgical lung biopsy provides substantially more material for pathologic study, the procedure requires general anesthesia, and one or more days in the hospital with a chest tube in place. Moreover, there have been reports that this surgical procedure may be associated with excess mortality in certain disease states. For example, one study reported that 10 of 60 patients with usual interstitial pneumonia died within 30 days of the surgical lung biopsy. (23) In contrast, bronchoscopy can be done as an outpatient procedure, usually with minimal morbidity and mortality. (24) Even with the limited size of the biopsy specimen obtained with the bronchoscope, the clinician can often combine the information gained with other clinical, radiologic, microbiologic, and cytologic information to arrive at a diagnosis.

The main complication of TBB is bleeding; less frequent complications are pneumothorax, hypoxemia, or cardiac arrhythmias during the procedure. Bleeding occurs to some degree in virtually all TBB procedures and in some cases can be substantial. The risk of bleeding is the main limiting factor in obtaining more or larger biopsy samples. Bleeding is a major concern to the bronchoscopist because of the limited options available to manage excessive bleeding through the flexible bronchoscope. The suction channel of the typical bronchoscope is only 2 mm in diameter, and the volume of blood that can be suctioned through the channel is hence limited. One drop of blood can obscure the small lens of the bronchoscope and eliminate vision through the scope. Moreover, because the entire tracheobronchial tree is only about 150 mL in volume, a relatively small amount of blood can produce major problems with oxygenation.

Evaluation of the patient prior to the procedure is crucial. Even though inspection of the airways and possibly bronchoalveolar lavage can be done in patients with bleeding abnormalities or in those receiving anticoagulation therapy such as warfarin, TBB is contraindicated in the presence of bleeding abnormalities. An international normalized ratio (INR) greater than 1.5 is an absolute contraindication; successful TBB can be done if the INR is less than 1.5. If a patient is taking warfarin, it can usually be withheld for 4 to 5 days to allow the INR to slowly decrease to a safer range. If the warfarin cannot be withheld--for example, if the patient has a mechanical heart valve--then TBB will likely not be possible. Fresh-frozen plasma can be administered to reverse warfarin anticoagulation more quickly. Transbronchial biopsy is also contraindicated if the platelet count is less than 50 000/[micro]L but the platelet count can be increased relatively quickly with platelet transfusions prior to the procedure. Also, platelet dysfunction is a relative contraindication to biopsy. There are insufficient data on antiplatelet agents such as clopidogrel, but most bronchoscopists are hesitant to perform a TBB if the patient is using this agent. Other contraindications for bronchoscopy and TBB are severe hypoxemia, uncontrolled cardiac arrythmias, unstable angina, and severe asthma or exacerbation of chronic obstructive pulmonary disease. The patient on mechanical ventilation support is at very high risk of pneumothorax, and TBB is not done in this circumstance, nor when extensive bullous disease, such as emphysema, is present.

In the hands of an experienced bronchoscopist, the procedure is quite tolerable for most patients. Following informed consent, conscious sedation is achieved, typically with a short-acting benzodiazepine and a narcotic, such as fentanyl or meperidine. A topical anesthetic, such a lidocaine, is applied to the upper airway mucosa. The bronchoscope can be passed through the nose or the mouth, depending on the preference of the bronchoscopist, and then through the vocal cords into the trachea. An endotracheal tube can be passed over the bronchoscope and into the trachea to achieve control of the airway. Topical lidocaine is administered to the bronchial mucosa during the procedure to reduce coughing. A complete endobronchial inspection of all segments of both lungs is performed to exclude significant endobronchial abnormalities. Often, bronchoalveolar lavage is obtained for culture and cytology specimens prior to the TBB.

The TBB is almost always done with fluoroscopic guidance as the rate of pneumothorax is reduced when fluoroscopy is used. The bronchoscope is directed to the segment desired for the biopsy and is wedged into that segmental bronchus as far as the scope will go. This "wedge" technique then isolates that segment in the case of bleeding, and also allows tamponade of that segment. Biopsy samples are then obtained repeatedly from this segment without removing the scope. A forceps is passed through the bronchoscope and into the segment as far as it will pass. The patient is asked to inhale and the forceps are opened. The patient is then asked to exhale and, at endexpiration, the forceps jaws are closed. If the patient experiences pain at this point, the forceps is opened and withdrawn because the only pain-sensitive structure in the area is the visceral pleura. Another location is selected. Approximately four to six biopsies are ideal (Figure 1). The bronchoscope is held in the wedge position until no further blood is visualized through the suction tubing. Biopsies from two different segments from the same lung can be obtained, but it is contraindicated to obtain biopsy specimens from both lungs because of concern for bilateral pneumothorax.


Transbronchial biopsies are obtained most commonly for the evaluation of mass lesions or localized infiltrates, in which neoplasm or infection leads the differential diagnosis. Patients with diffuse parenchymal lung disease (more than one lobe involved, and often bilateral abnormalities) undergo biopsy by this method, hoping to secure a definitive diagnosis, thus avoiding more invasive diagnostic procedures as discussed previously. Neoplasm and infection are still considerations when infiltrates are diffuse, but more often, inflammatory parenchymal disease is the primary clinical concern, and the TBB is the nonsurgical biopsy method of choice. The samples derived are typically only 2 to 3 mm in size but they hold a wealth of potentially useful information for the care of the patient.

A helpful general approach to the interpretation of the TBB is presented in Figure 2. Knowledge of the patient's immune status is an essential early key discriminator. For diffuse parenchymal diseases, histopathologic patterns of inflammatory disease are very helpful. Included in these patterns are (1) acute or subacute injury (infection, drug toxicity, systemic autoimmune disease); (2) chronic interstitial inflammation; (3) granulomatous inflammation and its differential diagnosis; (4) vascular diseases (including vasculitis/diffuse alveolar hemorrhage, pulmonary hypertension, and intravenous drug abuse microangiopathy); and (5) alveolar-filling processes such as alveolar proteinosis. In addition, rare distinctive lesions such as pulmonary LCH, LAM, and alveolar microlithiasis are amenable to sampling by TBB.


In this article we will focus on 10 examples of useful histopathologic findings and specific diagnostic entities observable in TBBs in the setting of diffuse parenchymal disease. For specific named entities, we have provided some clinical and radiologic context. Localized neoplasms and transplant-related pathology will not be discussed because of space constraints.


Acute and Subacute Lung Injury

In the setting of acute onset lung disease, infection always leads the differential diagnosis, and the TBB, bronchial washings, and bronchoalveolar lavage play a crucial role in the clinical evaluation. Computed tomographic scans typically show ground-glass attenuation and consolidation to a variable degree, although the imaging does not discriminate between edema, acute injury, or hemorrhage (see "Immunologically Mediated Diffuse Alveolar Hemorrhage" for a CT image of acute infiltrates in Good-pasture syndrome). Both acute and subacute lung injury are grouped under one heading in this article because they often occur together (areas of acute injury adjacent to areas of early repair with fibroblasts in the alveolar spaces). When fibrin, hyaline membranes, and/or organization in alveolar spaces are identified, the differential diagnosis is always the same: infection, drug toxicity, systemic connective tissue diseases manifesting in the lung, and idiopathic forms. (25,26) The potential causes of acute lung injury with hyaline membranes (diffuse alveolar damage) are presented in Table 1.

Special stains for organisms must be performed on any TBB that has more than a microscopic focus of fibrin in the alveolar spaces, hyaline membranes, or necrosis without evident neoplasm. Acid-fast and silver stains (Fite acid-fast and Grocott methenamine silver) should always be performed when fibrin or granulomas are present in a TBB. When necrosis is seen in the context of acute clinical disease, the battery of stains should be extended to include a tissue Gram stain and at least one special silver impregnation technique (Warthin-Starry or Dieterle). These latter techniques will stain some organisms that can be negative on acid-fast, silver, and Gram stains and, furthermore, tend to make bacteria more visible even when the Gram stain is positive. Keep in mind that the clinical management in the acute care setting aggressively targets infection before a biopsy is performed and it is unusual for the pathologist to be the first to discover bacterial infection as a cause of acute clinical disease. The most common unexpected infection diagnosed in our consult practice is Pneumocystis pneumonia, typically occurring in the mild-to-moderately immunocompromised host (often iatrogenic immunocompromise). Coccidioides, Aspergillus, Nocardia, Actinomyces, Histoplasma, Blastomyces, herpes simplex, and Cytomegalovirus are also identified on occasion. Rarely, we see fastidious organisms such as Legionella as a cause of acute suppurative bronchopneumonia before microbiological cultures have identified the organism (for a variety of reasons).

Once bacterial, fungal, and mycobacterial infections have been reasonably excluded, a careful search for viral cytopathic changes is warranted, mainly if the patient is known to be immunocompromised and especially if necrosis is present. In our experience, in the absence of necrosis in the specimen, we rarely confirm a viral cause for a given acute process. Caution must be taken in regard to "pseudoviropathic" changes, such as large reactive nucleoli or globular cytoplasmic debris that can be seen in many acute inflammatory conditions.

As mentioned previously, the two other detectable causes of acute lung injury include toxic reaction to drug (27) and acute manifestations of systemic autoimmune diseases. (28) Regarding drug-related injury, no histopathologic changes are specific for any drug, despite any claims in the literature to the contrary. Identifying a direct relationship between initiation of a drug and onset of clinical symptoms is essential. For drugs commonly known to produce lung injury as a side effect (eg, amiodarone), unexplained acute injury of noninfectious origin must be considered as drug-related until proven otherwise. Every named rheumatic disease (except Sjo"gren syndrome) has been implicated as a cause of acute injury in the lung. (28-30) Moreover, acute lung injury may be the initial manifestation in a subset of rheumatic diseases (eg, polymyositis/dermatomyositis (31,32)), so this is worth keeping in mind.

Depending on when the biopsies are performed relative to onset of symptoms, acute lung injury patterns may be dominated by organizing pneumonia in the TBB. Potential causes of the organizing pneumonia pattern are presented in Table 2. In this setting it is tempting to refer to this pathologically as bronchiolitis obliterans organizing pneumonia. We would discourage this because, to our clinical colleagues, this name implies idiopathic bronchiolitis obliterans organizing pneumonia, a disease that is expected to respond to corticosteroid therapy. (33-35) Clearly, many causes of organizing pneumonia may be resistant to corticosteroid therapy. The term airspace organization or organizing pneumonia pattern is preferable as a more accurate descriptor of this phenomenon. When airspace organization is accompanied by nodular aggregations of fibrin in the alveolar spaces (but no hyaline membranes), the term acute fibrinous and organizing pneumonia is appropriate, as long as it is recognized that this diagnosis as an idiopathic condition has a guarded prognosis if the patient requires mechanical ventilation around the time of biopsy. (36) Also, idiopathic diffuse alveolar damage (referred to clinically as acute interstitial pneumonia) may be a manifestation of the adult respiratory distress syndrome in the setting of a ventilator-dependent patient. Given the appropriate clinical scenario and time course, no further cause for this histopathologic finding need be sought by the clinician. Many of the acute lung injury histopathologic changes are recapitulated in acute eosinophilic pneumonia and diffuse alveolar hemorrhage (see later discussion). A diagnostic TBB in diffuse alveolar damage is presented in Figure 3, A and B.


Eosinophilic Pneumonia

Clinical Scenario.--Eosinophilic pneumonia encompasses a number of disorders centered around increased eosinophils in lung parenchyma. The original description of "pulmonary eosinophilia" in 16 patients reported by Crofton and colleagues (37) proposed a classification to include simple pulmonary eosinophilia (few symptoms and transient infiltrates), prolonged pulmonary eosinophilia with persistent radiographic shadows persisting for more than a month (and sometimes other organ involvement), tropical eosinophilia, and pulmonary eosinophilia in the setting of asthma. In 1969, Liebow and Carrington (38) questioned the value of this mainly clinical classification and proposed that all eosinophilic pneumonia be described in relation to an etiology whenever possible (eg, eosinophilic pneumonia related to helminthic infestation or eosinophilic pneumonia induced by chemical agents). An excellent overview of eosinophilic lung disease can be found in a 1994 review by Allen and Davis. (39)

The most common pulmonary symptom is dyspnea, which can be severe. In acute forms, the condition has sudden onset, and clinical presentation is generally immediate. 40 Without a bronchoscopic diagnosis, acute eosinophilic pneumonia is frequently mistakenly treated as an infectious pneumonia, needless to say without success. In chronic forms, evolution during weeks to a few months is common and breathlessness is less severe. Night sweats with fever and chills occur to variable extent. Peripheral blood eosinophilia as well as increased eosinophil counts in pulmonary lavage samples are useful diagnostic findings, but may not be identified for a variety of reasons.

Radiologic Findings.--Peripheral consolidation is the most common appearance of eosinophilic pneumonia, whether idiopathic or related to a known antigen. Minimal architectural distortion, such as traction bronchiolectasis and lobular distortion in the areas of the consolidation, can occur in chronic cases. Areas of consolidation are most common in the middle and lower zones and are frequently bilateral. Although the distribution can be peribroncho-vascular, this is not a consistent finding. (41) If the distribution is peripheral and nonsegmental, TBB is less likely to be diagnostic.

The radiographic differential diagnosis typically includes infection in acute cases and cryptogenic organizing pneumonia in the more subacute or chronic course. Acute eosinophilic pneumonia is exquisitely steroid-responsive and areas of consolidation often resolve within 24 hours of treatment. A trial of steroids, without the need for a tissue sample, is most common in patients in whom a bronchoscopic lavage was negative for infection by direct smear and culture. Transbronchial biopsy (and surgical biopsy), therefore, is more commonly performed in patients with a subacute or chronic presentation in whom steroid responsiveness is less dramatic and the diagnosis is less certain clinically.

Bronchoscopic Approach.--In the patient with unexplained pulmonary infiltrates, especially if migratory, bronchoalveolar lavage with a differential cell count is an important adjunct to the diagnosis. Transbronchial biopsies are diagnostic in most cases if one or more infiltrates is sampled.

Histopathology.--Eosinophilic pneumonia is a histopathologic subtype of acute lung injury. Eosinophilic pneumonia is characterized by the triad of reactive type 2 cell hyperplasia, eosinophils free in the alveolar spaces accompanied by densely eosinophilic macrophages, and variable amounts of fibrin. (38,40) The differential diagnosis of increased tissue eosinophils in the lung is presented in Table 3. Sometimes the tissue eosinophils are sufficiently pronounced so that eosinophilic microabscesses can be seen. Also, the dense eosinophilic macrophages tend to aggregate and produce "pseudogranulomas" in the alveolar spaces. In the TBB, eosinophilic pneumonia is easily diagnosable when the requisite features are present. A differential diagnosis is always appropriate for eosinophilic pneumonia, recognizing that this can occur as a consequence of certain infections (particularly fungal infections such as coccidioidomycosis), as a manifestation of asthma, in allergic bronchopulmonary fungal disease (again, most commonly in asthma), and as a consequence of drug toxicity. Unfortunately, not all patients with eosinophilic pneumonia will recover, despite corticosteroid administration. Also, whether acute or chronic, the histopathology is similar. A diagnostic TBB in eosinophilic pneumonia is presented in Figure 4, A and B.


Immunologically Mediated Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage of immunologic origin can be diagnosed with the bronchoscope when the TBB shows hemosiderin-laden macrophages in alveolar spaces, fibrin admixed with siderophages, and organizing pneumonia. (42) Capillaritis or necrotizing vasculitis may be seen in this context and, as these findings may be harbingers of catastrophic hemorrhage, immediate notification of the clinician is imperative. Clinical context is essential. The patient typically presents with hemoptysis or anemia and the bronchoscopist will often describe the lavage samples as becoming progressively pink or red. The CT scan shows ground-glass attenuation and consolidation (Figure 5, A and B). Positional maneuvers may result in a change in distribution of the infiltrates (this also occurs for edema).


Without capillaritis or necrotizing vasculitis, the findings of pigment-laden macrophages accompanied by fibrin are less specific for immune-mediated hemorrhage, and a compelling clinical history is necessary (hemoptysis with positive serologic studies; see later discussion). In our consult practice, we diagnose cases showing good hemosiderosis, fresh alveolar hemorrhage, fibrin, and organization as "acute and organizing pulmonary hemorrhage consistent with immune-mediated diffuse alveolar hemorrhage (microscopic polyangiitis, Wegener granulomatosis, Goodpasture syndrome, systemic connective tissue disease, and drug toxicity are in the differential diagnosis)" and recommend serologic testing. Serologic studies (eg, antinuclear antibody, antineutrophil cytoplasmic autoantibody, antiglomerular basement membrane antibodies) are the preferred mode of confirming the diagnosis for purposes of therapy. We do not perform or recommend immunofluorescence studies on lung biopsies to support or refute a diagnosis of immune-mediated pulmonary hemorrhage, given the reliability of serologic studies and the technical challenges presented by diagnostic immunofluorescence in the lung. (43) Potential causes of diffuse alveolar hemorrhage are presented in Table 4. A diagnostic TBB in Goodpasture syndrome is presented in Figure 6, A and B.


Chronic Inflammation (Chronic Cellular Infiltrates)

The significance of chronic inflammation in the bronchoscopic biopsy depends largely on location of the inflammatory cells relative to the microanatomy of the sample. Sometimes the specimens received are entirely bronchial mucosa. Chronic inflammation of mild degree is a common nonspecific finding in this setting, especially in smokers. The same amount of chronic inflammation in a biopsy consisting entirely of alveolar parenchyma would be significant and would raise a differential diagnosis to include hypersensitivity pneumonitis (even without visible interstitial granulomas), low-grade infection, chronic drug reaction, systemic connective tissue disease manifesting in the lung, and so-called nonspecific interstitial pneumonia. (44) Naturally, this differential diagnosis presupposes that the patient has diffuse infiltrates on radiologic imaging. Conditions associated with chronic inflammation in alveolar walls (cellular interstitial infiltrates) are presented in Table 5.

For the group of diseases in the differential diagnosis of cellular interstitial infiltrates, the clinical presentation is typically subacute to chronic (weeks to months in evolution). Computed tomographic studies most often are dominated by ground-glass opacification (hazy increased attenuation with airways and arteries still visible through it). When the correct diagnosis is subacute hypersensitivity pneumonitis, fuzzy centrilobular nodules are present with a very suggestive appearance (22,45) (Figure 7, A and B). In such cases, TBBs may be diagnostic. The CT findings in subacute hypersensitivity pneumonitis are quite different than the findings in patients with nonspecific interstitial pneumonia or usual interstitial pneumonia or even chronic hypersensitivity pneumonitis. Also, chronic hypersensitivity pneumonitis is less likely to be confidently diagnosed with TBB. Patients with fibrotic lung disease that is not central or peribronchovascular should not have the procedure.


The TBB in subacute hypersensitivity pneumonitis typically shows airway mucosal chronic inflammation, either as subepithelial infiltration or lymphoid aggregates. Alveolar parenchymal samples will show increased numbers of lymphocytes and plasma cells involving the alveolar walls. Multinucleated giant cells with calcified bodies (Schaumann bodies) may be seen beneath the bronchial mucosa, but this is a nonspecific finding. If small non-necrotizing interstitial granulomas are also present, a more confident diagnosis of hypersensitivity pneumonitis can be made. (46-49) Tiny patches of organizing pneumonia are commonly present in hypersensitivity pneumonitis and other conditions in this category. If a diffuse lymphoid infiltrate of considerable density is present, low-grade lymphoma enters the differential diagnosis, similar to the classic diagnosis of lymphoid interstitial pneumonia. Other common findings when hypersensitivity pneumonitis is in the differential include prominent airspace macrophages with foamy cytoplasm. A diagnostic TBB in subacute hypersensitivity pneumonitis is presented in Figure 8, A and B.



Clinical Scenario.--Sarcoidosis is a chronic multisystem granulomatous disorder of unknown etiology characterized by the formation of granulomas composed of epithelioid histocytes. Different from infectious granulomas, the granulomas of sarcoidosis typically lack necrosis. Virtually any organ with lymphatics can be affected by the granulomatous inflammation of sarcoidosis, although lung, upper respiratory tract, lymph nodes, eye, and skin dominate the presentation. The peak incidence of the disease is young adulthood, with women affected more than men. African Americans, Asians, and Scandinavians have historically been considered to be at greater risk for developing sarcoidosis, but it is unclear how the previously reported incidence in these groups is related to genetic, geographic, socioeconomic, environmental, or differential access to medical care factors. (50-52)

General clinical manifestations include malaise, fatigue, fever, and weight loss in about one third of patients. Pulmonary symptoms include vague chest discomfort, to dyspnea on exertion and cough. Often the patient is entirely asymptomatic and the diagnosis becomes suspected from a chest radiograph or CT scan performed for some other reason. Upper respiratory tract involvement is characterized by nasal stuffiness and nasal blockage. Skin involvement in sarcoidosis is manifested most commonly by erythema nodosum (nodular panniculitis) and lupus pernio (violaceous papules and plaques). For a comprehensive review of sarcoidosis, the reader is referred to the joint statement of the American Thoracic Society, the European Respiratory Society, and the World Association of Sarcoidosis and other Granulomatous Disorders. (53) Potential causes of nodular granulomatous inflammation are presented in Table 6.

Radiologic Findings.--The CT findings in sarcoidosis reflect the stage of the disease. (54,55) Early parenchymal findings reflect granulomatous inflammation in the axial and, to a lesser extent, peripheral and subfissural interstitium. A CT scan at this stage shows multiple, well-defined, tiny nodules with a middle and upper posterior lung predominance (Figure 9, A through D). Lymph node enlargement is variable and is not helpful in the differential diagnosis. Computed tomography is often diagnostic in such instances in the proper clinical context, but if tissue diagnosis is required, TBB has a yield approaching 100%. It should be noted that a normal CT does not exclude the diagnosis, and TBB can be positive in patients with a normal CT.


As the parenchymal findings evolve, increasing mass-like fibrosis occurs with architectural distortion and volume loss, especially in the posterior upper lung zones, often with paracicatricial emphysema (Figure 9, C and D). Nodules at this stage often are not present. Pulmonary hypertension may be evident. The CT findings often suggest the diagnosis, although TBB at this stage may be nonspecific. (56)

Bronchoscopic Approach.--The flexible bronchoscope is the mainstay of diagnosis, given the high incidence of pulmonary involvement in the disease. A high degree of diagnostic accuracy is achieved if more than 4 samples are taken. The distribution of granulomas along pulmonary lymphatic routes makes this possible because lymphatics travel along the bronchovascular bundles and are copiously sampled in the TBB specimen. Airway sarcoidosis should be suspected in patients with intractable cough. In this context, the lesions are often visible to the bronchoscopist as nodules or raised plaques and can be sampled directly with the cupped forceps. Transbronchial biopsy in sarcoidosis is especially important because diagnostic granulomas may be present even when the chest radiographs and CT scans fail to reveal lung parenchymal disease.

Histopathology.--Bronchoscopic biopsies are commonly used for a diagnosis of sarcoidosis in the appropriate clinical and radiologic context. (9,57,58) Multiple biopsies increase the likelihood of obtaining a diagnosis. The salient histopathologic features are well-formed nonnecrotizing granulomas, typically occurring as small confluences within hyalinized connective tissue. Minimal chronic inflammation may be present, but an alternate diagnosis is appropriate when abundant chronic inflammation is seen and granulomas are less well formed. (59) These latter changes typically herald low-grade infection, aspiration pneumonia, or hypersensitivity pneumonitis.

As an illustration of the problem of distinguishing sarcoid granulomas from those of infection in small tissue samples, Hsu et al (58) studied 92 cases in which granulomas were identified on TBB, but special stains on tissue sections were negative for organisms. In 83 of these cases, interstitial lung disease was present clinically and sarcoidosis was being considered. Subsequent microbiological cultures from tissue samples obtained at the initial bronchoscopy (cultures were obtained for all 92 cases), showed positive results in 10 (9 mycobacterial and 1 fungal), and these ultimately were diagnosed as granulomatous infection. The remaining cases were classified as sarcoidosis. Necrosis in the granulomas was observed in 20% of the cases of sarcoidosis, but in only 40% of the infectious cases. Interestingly, the granulomas in sarcoidosis tended to be present in greater number than those seen in the infectious cases. In this study, Schaumann bodies were also more likely to be present in association with sarcoidosis.

Unfortunately, the granulomas of sarcoidosis seen in bronchial mucosal biopsies may be less distinct than those seen in the lymph nodes or lung parenchyma. When the features are not compelling for the diagnosis ("naked" granulomas aggregated within dense sclerotic collagen), a broader differential is always appropriate. (59) Moreover, berylliosis can produce histopathologic changes identical to those of sarcoidosis, 60 so it is appropriate to include berylliosis in the differential diagnosis of sarcoidosis. A diagnostic TBB in sarcoidosis is presented in Figure 10, A and B.


Wegener Granulomatosis

Clinical Scenario.--Wegener granulomatosis (WG) is a multisystem disorder characterized by distinctive necrotizing granulomatous inflammation involving the upper and lower respiratory tract, generalized necrotizing vasculitis involving small arteries and veins, and renal disease in the form of necrotizing glomerulonephritis. (61 62) Limited forms may have only upper and lower respiratory tract pathology. Patients with lung disease (infiltrates or nodules) typically have pre-existing disease in the sinonasal region. Intranasal manifestations include thick mucosal crusts, septal perforation, and chondritis resulting in saddle deformity. A wide variety of ophthalmic manifestations are also well described, including uveitis, corneoscleral ulceration, and lacrimal duct damage. Pulmonary manifestations are varied and include acute onset shortness of breath and acute hemoptysis. (63) Serologic studies most frequently show antineutrophilic cytoplasmic antibodies of cytoplasmic type with reaction against proteinase 3.

Radiologic Findings.--There are no CT findings that are specific for WG. The most common CT appearance in patients who undergo TBB is that of multiple nodules, typically ill-defined, peribronchovascular, and often cavitary. (64) Endobronchial or endotracheal lesions may also occur. The differential diagnosis usually includes sarcoidosis (if no cavities are present) and infectious granulomatous disease. The association of peribronchovascular nodular consolidation with or without cavitation (Figure 11) in a patient with sinusitis or renal failure suggests the diagnosis, and if renal disease is present clinically, such patients often undergo renal sampling rather than TBB.


Bronchoscopic Approach.--Endobronchial biopsy may show perichondritis and mixed inflammatory infiltration, including lymphocytes, plasma cells, and eosinophils. (65) Cartilage destruction can result in catastrophic airway collapse. Transbronchial biopsies are useful when collagen microabscesses are present in a background of dense mixed inflammatory infiltration, with or without perichondritis (see later discussion).

Histopathology.--Bronchial mucosal biopsies and TBBs can be diagnostic of WG, but the diagnosis requires considerable experience with the histopathologic manifestations of this disease. (66,67) Moreover, WG has a wide range of histopathologic manifestations, complicating further an accurate diagnosis in the limited biopsy sample obtained with the bronchoscope. In classic nodular WG, multiple bilateral nodules are the norm, often with some cavitation. In contrast, infectious granulomas are frequently solitary or localized. In the alveolar hemorrhage form of WG, acute and organizing pulmonary hemorrhage dominates the histopathology, often with prominent capillaritis. Organizing pneumonia can be the dominant appearance of WG in the so-called bronchiolitis obliterans organizing pneumonia-pattern WG.

As mentioned previously, the key findings that should suggest a diagnosis of WG are a dense mixed inflammatory infiltrate (including lymphocytes, plasma cells, and eosinophils), microscopic foci of collagen necrosis (with or without histiocytic palisading), perichondritis, capillaritis, hemosiderosis, and isolated osteoclast-like giant cells, the latter typically best seen at the edge of palisaded histiocytic reaction around necrosis. (61,62,68) If granulomas without necrosis are present anywhere in the sample, this argues strongly against a diagnosis of WG and in favor of infection. Necrotizing vasculitis may be present but is not a requisite for the diagnosis. A diagnostic TBB in WG is presented in Figure 12, A through C.


Intravenous Drug Abuse Microangiopathy

Drug abusers who crush analgesic tablets and inject them intravenously can develop pulmonary deposition of pill-binding agents (in previous years this was talc, (69,70) but today this is typically microcrystalline cellulose (71)). This refractile material accumulates as particles (often greater than 10 [micro]m in size) accompanied by, or within, giant cells in the perivascular sheath of small precapillary arteries. (72) Recognizing this histopathology is essential, especially in avoiding confusion with sarcoidosis. Polarization will reveal the particles, but keep in mind that polarizable particles (calcium oxylate and calcium carbonate) can be seen as a nonspecific finding in giant cells of granulomatous inflammation. Sometimes, morphologically distinctive pill components such as the disintegrant polymer crospovidone (blue) may be present, producing a deeply basophilic corallike particle. (73) Recognizing the location of refractile material deposits as being within the perivascular sheath is essential. A diagnostic TBB in "pill-crusher" intravenous drug abuse is presented in Figure 13, A and B.


Alveolar Proteinosis

Clinical Scenario.--Pulmonary alveolar proteinosis (PAP) is not one disease but rather a manifestation of a number of disparate diseases and conditions. (74,75) Environmental exposure to dust of varying composition, hematolymphoid neoplasms and their associated disorders, systemic immunologic disorders, dermatomyositis, and lung transplantation have all been implicated in the etiology of PAP, and, naturally, an idiopathic form is well described.

Surfactant, produced by pulmonary type 2 alveolar lining cells, is highly regulated in terms of production and clearance. Macrophages are known to participate in the clearance of surfactant and new data have shown a central role for granulocyte monocyte colony-stimulating factor in successful surfactant degradation and clearance. In PAP, abnormal surfactant metabolism presumably leads to the accumulation of this material within the alveolar spaces. In primary (idiopathic) PAP, autoantibodies directed at granulocyte monocyte colony-stimulating factor support the concept that this is an autoimmune disorder. (76)

Regardless of underlying etiology, patient complaints and physical findings are similar. Exertional dyspnea of gradual onset and accompanied by cough is typical. (77) Physical examination is frequently normal, but crackles and coarse breath sounds may be present, and clubbing has been reported in up to 25% of patients. (78) Pulmonary physiology often reflects restriction with exertional hypoxemia. Patients with PAP are at risk for secondary infections (mycobacteria and nocardia most commonly).

Radiologic Findings.--The CT findings are often diagnostic, with a pattern of normal lung alternating with sharply demarcated areas of ground-glass attenuation superimposed on a fine reticular pattern, the so-called crazy paving (Figure 14, A and B). Crazy paving is not specific for alveolar proteinosis. (79) The differential diagnosis includes Pneumocystis pneumonia, a cause of secondary alveolar proteinosis. In some instances, multifocal aspiration pneumonitis or organizing pneumonia/bronchiolitis obliterans organizing pneumonia can also mimic this pattern. Initially, the degree of intralobular line formation (the fine reticular pattern) is minimal, but this becomes more prominent, and the degree of architectural distortion and traction bronchiolectasis increases with the duration of the disease.


Bronchoscopic Approach.--The classic bronchoscopic description of PAP is the occurrence of a milky white bronchoalveolar lavage, a finding nearly unique to PAP. Although initially milky and opaque, after time, the fluid layers out, and a thick, proteinaceous material settles toward the bottom of the bottle. Periodic acid-Schiff histochemical staining of lavage fluid samples, following diastase digestion, can be helpful if abundant positive granular material is identified. (80)

Histopathology.--Few pulmonary diseases are as easily recognizable under the microscope as PAP. Many conditions can result in eosinophilic material accumulating in the alveolar spaces, but the granular appearance of PAP, with its scattered larger and darker "inclusions" and retraction at the interface with alveolar walls, is distinctive. (81) Table 7 lists conditions in which eosinophilic exudates or inclusions accumulate within alveoli. As mentioned previously, PAP occurs as primary (idiopathic) and secondary forms. (74,76,77,81,82) Because the secondary forms can occur in the vicinity of infection (often Nocardia sp) or as part of an immunologic phenomena in certain hematologic malignancies, these potential comorbidities should be considered during the histopathologic evaluation.

Under the microscope, PAP is immediately recognizable at scanning magnification by the presence of alveoli filled with eosinophilic material. The granular eosinophilic exudates within alveolar spaces are rich in surfactant and accompanied by randomly dispersed larger eosinophilic dense bodies. This material tends to pull away from nearby alveolar walls, producing a cleft or space. If in doubt, a periodic acid-Schiff stain with diastase digestion can be used for confirmation. Whenever abundant chronic inflammation is also seen, this may be a clue to the presence of the secondary form (infection or immune disorder). A diagnostic TBB from a patient with primary PAP is presented in Figure 15, A through C.


Pulmonary LCH

Clinical Scenario.--Pulmonary Langerhans cell histiocytosis (PLCH) is a smoking-related interstitial lung disease of unknown incidence and prevalence in the smoking population. (83,84) Pulmonary Langerhans cell histiocytosis occurs most commonly between the ages of 30 and 50 years, but can be seen in the older population. It has been unclear whether there is a gender bias in this disease process, although some recent studies suggest that PLCH is more common in women. Also, anecdotal cases suggest that heavy smoking is a predisposing factor, although no objective data are available to suggest a dose relationship.

The most common presenting complaint of patients with PLCH is breathlessness and nonproductive cough. Less commonly, the disease may be asymptomatic and discovered on chest imaging for other concerns. Pneumothorax occurs in a small percentage of patients (10%-15%) and as many as one third of patients will complain of generalized constitutional symptoms such as weight loss, fever, and night sweats. Superficial adenopathy, skin rash, hypothalamic manifestations, and bone pain occur in less than 15% of patients as manifestations of extrapulmonary involvement.

General physical manifestations are limited, with typically normal chest auscultation. Laboratory tests are typically unhelpful. Pulmonary function studies show reduced lung capacity most consistently, but may also show obstructive, restrictive, or mixed patterns depending on when in the course of disease patients are tested.

Radiologic Findings.--As is the case with many other diffuse or multifocal pulmonary disorders, the CT findings depend entirely on the stage of disease. (85) In the early stage, nodules measuring several millimeters in diameter dominate, usually in a centrilobular distribution with a middle and upper zonal predominance. The differential diagnosis at this stage includes granulomatous infection, sarcoidosis, and WG. Later, the nodules contain central lucencies caused by either tiny cavities or actual bronchiolar dilatation. Late disease is more cystic in nature, with variable size and shape of the cystic lesions. Costophrenic angle-sparing is a hallmark of this stage of the disease process. Although LAM is in the differential diagnosis of cystic disease, the CT findings in LAM usually are distinctive (see later discussion). Very advanced cases of LCH are indistinguishable from emphysema. Although CT can be diagnostic in mixed nodular and cystic disease with costophrenic angle-sparing in a young smoker (Figure 16, A and B), frequently the changes are suggestive, but not specific, and TBB is required.


Bronchoscopy.--Transbronchial biopsies and bronchial alveolar lavage may be diagnostic in PLCH, (86) although the sporadic occurrence of lesions makes the yield relatively low (less than 50%). (83) Exclusion of other diseases in the differential diagnosis appears to be the primary role (eg, infection, sarcoidosis, hypersensitivity pneumonitis, lymphangitic tumor). The use of immunohistochemistry on lavage material to secure a diagnosis is discouraged (CD1a and S100 protein), as Langerhans cells can be increased in the lungs of smokers (and a variety of inflammatory conditions), making a false-positive diagnosis a significant risk. Routine use of these stains on the TBB is also fraught with perils, simply because there are too many circumstances other than PLCH that may have a few Langerhans cells as a reactive phenomenon. That said, the presence of confluent S100 protein and CD1a immuno-stained Langerhans cells in a TBB would certainly be highly suggestive of or compatible with a diagnosis of PLCH in the proper clinical (ie, smoker) and radiologic context (see later discussion).

Histopathology.--Many of the patients who undergo flexible bronchoscopy are smokers. Smokers are at increased risk for a number of pulmonary diseases, including 3 forms of interstitial pneumonia: respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, and PLCH. (87,88) The incidence and prevalence of these 3 conditions in smokers is unknown. The former 2 conditions are probably not diagnosable with the TBB, although they can reasonably be suggested as a possibility when airspace macrophages of "smokers" type dominate the histopathology, the patient has ground-glass infiltrates, and no other findings are present to suggest an alternative diagnosis. Pulmonary LCH on the other hand is diagnosable on occasion if a characteristic lesion happens to be included in the sample. Langerhans cell histiocytosis is an airway-centered disease, so the occurrence of PLCH lesions is not unexpected in the TBB. (83,84,86,89) The difficult challenge is recognizing PLCH when lesions are only partially sampled. Knowledge of the CT findings is often helpful. We do not advise the performance of immunohistochemical stains for Langerhans cells (S100 protein and CD1a) unless the findings are compelling for PLCH, and in this setting, stains are not really required for the diagnosis. Langerhans cells may be present in a number of inflammatory conditions and increased in the lung parenchyma, potentially producing a false-positive result. A diagnostic TBB in LCH is presented in Figure 17, A and B.



Clinical Scenario.--Lymphangioleiomyomatosis is a rare disease of unknown etiology, characterized by the accumulation of morphologically and immunophenotypically distinctive smooth muscle along lymphatic channels in the lung and pleura, and in lymph nodes of the mediastinum, abdomen, and lower cervical chain. (90-96) Affected individuals are almost exclusively women in their childbearing years, although LAM has been reported rarely in men and can occur in postmenopausal women. The clinical presentation includes progressive breathlessness often accompanied by recurrent pneumothoraces and chylothorax. Because obstruction is almost invariably seen by pulmonary function testing, patients may be incorrectly diagnosed as having asthma. A genetic association with the tuberous sclerosis complex has been identified, but LAM can occur in the absence of this complex, and conversely, only a small fraction of individuals with tuberous sclerosis complex develop LAM. (97,98) The clinical course is variable and the current approach to therapy is hormonal.

Radiologic Findings.--Multiple thin-walled cysts in a uniform but perilymphatic distribution are most commonly present, with or without an associated pneumothorax (Figure 18). (99) The perilymphatic distribution, lack of costophrenic angle-sparing, thin walls of the cysts, and monotonous size and shape of the cysts all distinguish LAM from LCH. Smoking history favors the latter condition, and pneumothorax favors the former. The differential diagnosis is primarily that of idiopathic lymphoid interstitial pneumonia, which can also cause multiple cysts, and in a young woman, could indicate underlying connective tissue disease (eg, Sjogren syndrome) rather than LAM.


Bronchoscopic Approach.--Transbronchial biopsy can be diagnostic in LAM. (100-102) As in the case of sarcoidosis, several biopsies are more likely to be successful, given the sporadic and seemingly random distribution of diagnosable lesions. When clinical and radiologic findings are compelling for LAM, immunohistochemical staining (see following discussion) may be worthwhile, even if definite lesions are not seen. There is an increased risk for pneumothorax in LAM. This concern often tempers the desire on the part of the bronchoscopist for obtaining biopsies.

Histopathology.--Morphologically, the lesions of LAM are distinctive and, under most circumstances, are not easily confused with normal anatomic structures (like alveolar duct smooth muscle hyperplasia). The difficulty in diagnosis arises from the broad spectrum of manifestations associated with LAM. Lesions of LAM can be exuberant, raising a differential diagnosis to include metastatic low-grade sarcoma, especially in the small biopsy sample. Lymphangioleiomyomatosis lesions can be subtle and easily missed, even in the surgical lung biopsy. These lesions can be associated with prominent hemosiderosis resulting from recurrent microhemorrhages. Also, LAM lesions are characteristically associated with cyst formation, and sometimes the cysts dominate the histopathologic picture.

In the TBB, clues to the diagnosis of LAM begin with the clinical history and CT findings. The radiologic findings can be diagnostic, but the rarity of the disease and the implications of the diagnosis make a tissue sampling almost a prerequisite. Without a clinical or radiologic suspicion of LAM, the pathologist must rely on recognizing the characteristic, slightly disorganized appearance of LAM smooth muscle and characteristic vacuolation of the cytoplasm. (96,103,104) Lymphangioleiomyomatosis lesions are eosinophilic on hematoxylin-eosin-stained sections and may be missed on cursory perusal of the TBB at scanning magnification. If one or more lesions are suspected, estrogen receptor and HMB-45 immunohistochemical stains can be performed to confirm the diagnosis. Smooth muscle of LAM also expresses actin, desmin, progesterone receptors, and MART1. Another lesion that can occur in association with LAM is so-called micronodular pneumocyte hyperplasia. This epithelial lesion resembles atypical adenomatous hyperplasia to some extent, and would be difficult to distinguish accurately in small biopsy samples. A diagnostic TBB in LAM is presented in Figure 19, A and B.



The transbronchial biopsy is a powerful tool for diagnosis when applied with realistic expectations on the part of both clinicians and pathologists and knowledge of the diseases and conditions that are likely to be successfully biopsied. Computed tomography context is often essential both for choosing appropriate patients to undergo biopsy and in the accurate interpretation of biopsy findings. An overview has been presented of the nonneoplastic conditions most commonly diagnosed using this procedure. Close interaction between pulmonologist, radiologist, and pathologist enhances the utility of the TBB and improves the quality of patient care.


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Accepted for publication October 23, 2006.

From the Departments of Laboratory Medicine and Pathology (Dr Leslie), Radiology (Dr Gruden), and Medicine (Dr Parish), Division of Pulmonary Medicine, Mayo Clinic Arizona, Scottsdale; and the Department of Pulmonary and Critical Care Medicine, University of Utah School of Medicine, Salt Lake City (Dr Scholand).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Kevin O. Leslie, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, 13400 E Shea Blvd, Scottsdale, AZ 85259 (e-mail:

Kevin O. Leslie, MD; James F. Gruden, MD; James M. Parish, MD; Mary Beth Scholand, MD
Table 1. Conditions Most Commonly Associated With
Diffuse Alveolar Damage

Infections (viral, fungal, bacterial, parasitic)
Toxic inhalants
Acute allergic reactions (eg, hypersensitivity pneumonitis)
Drug reactions
Systemic collagen vascular diseases
Radiation reactions (acute)
Alveolar hemorrhage syndromes
Idiopathic disease (acute interstitial pneumonia)

Table 2. Common Causes of the Organizing
Pneumonia Pattern

Organizing infections (any cause)
Organizing diffuse alveolar damage
Hypersensitivity pneumonitis
Aspiration pneumonia
Eosinophilic pneumonia
Drug and toxin reactions
Systemic collagen vascular diseases
Cryptogenic organizing pneumonia
Peripheral reaction around focal lesions
 Wegener granulomatosis
 Malignant tumors

Table 3. Potential Causes of Lung Tissue Eosinophils

Drug reaction
Some fungal infections (eg, coccidiodomycosis)
Parasitic infestation
Acute eosinophilic pneumonia (idiopathic)
Churg-Strauss syndrome
Hypereosinophilia syndromes
Cigarette smoking

Table 4. Causes of Diffuse Alveolar Hemorrhage

Goodpasture syndrome (antiglomerular basement membrane
 antibody disease)
Vasculitides (especially Wegener granulomatosis)
Mitral stenosis
Bronchiectasis (often unilateral, or unilobar)
Immunoglobulin A nephropathy
Behcet syndrome
Certain systemic collagen vascular diseases (especially systemic
 lupus erythematosus)
Antiphospholipid syndrome
Human immunodeficiency virus infection
Pulmonary veno-occlusive disease
Idiopathic pulmonary hemosiderosis
Drug reactions, including toxic reactions and anticoagulants
Acute lung allograft rejection
Isolated capillaritis

Table 5. Lung Diseases With Chronic Inflammatory
Interstitial Infiltrates

Resolving infection
Hypersensitivity pneumonitis
Systemic collagen vascular diseases manifesting in the lung
Certain toxic or hypersensitivity drug reactions
Nonspecific interstitial pneumonia
Lymphoid interstitial pneumonia (idiopathic type)
Lymphocytic interstitial pneumonia in human immunodefi-
 ciency virus infection
Lymphoproliferative diseases (typically low grade)

Table 6. Diffuse Diseases Associated With Nodular

Granulomatous Inflammation
Granulomatous infections
Intravenous talcosis
Pneumoconioses (eg, inhalation talcosis, berylliosis)
Aspiration pneumonia
Wegener granulomatosis

Table 7. Conditions Associated With Noncellular

Eosinophilic Alveolar Exudates and Eosinophilic
Intra-alveolar Inclusions
Edema: cardiogenic and noncardiogenic
Fibrin: acute lung injury
Hyaline membranes: diffuse alveolar damage
Necrosis: infection, infarction, tumor
Protein: alveolar proteinosis
Bone: dendriform calcification
Round calcifications: alveolar microlithiasis
Other: corpora amylacea
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Article Details
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Author:Leslie, Kevin O.; Gruden, James F.; Parish, James M.; Scholand, Mary Beth
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Clinical report
Geographic Code:1USA
Date:Mar 1, 2007
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