Sputum

Sputum consists of a mixture of cellular and noncellular elements that are cleared by the mucociliary apparatus. It was once the most common respiratory tract specimen because it is relatively easy to obtain, with little discomfort to the patient. Sputum cytology is generally reserved for symptomatic individuals: As a screening test (e.g., in asymptomatic smokers), sputum cytology is not effective in decreasing mortality from lung cancer. With the advent of bronchoscopy and FNA, its use as the mainstay in respiratory cytology has declined significantly.

Collecting multiple sputum samples over several days optimizes sensitivity. Early morning, deep cough specimens are preferred.⁶ If the patient is not able to expectorate adequately, expectoration can be induced by having the patient inhale nebulized water or saline. Sputum induction increases the detection of lung cancer.⁷ When prompt preparation of sputum is not possible, the patient can expectorate into a 70% ethanol solution, which prefixes the specimen.

A simple method of sputum preparation is known as the “pick and smear” technique, whereby fresh sputum is examined for tissue fragments, blood, or both. Smears are prepared from areas that contain these elements and immediately fixed in 95% ethanol. A modification of this is the Saccomanno method, which calls for sputum to be collected in 50% ethanol and 2% carbowax.⁸ The specimen is then homogenized in a blender and concentrated by centrifugation. Improved sensitivity has been demonstrated by the use of dithiothreitol (DTT) for homogenization.⁹ Smears are made from the concentrated cellular material. The Saccomanno method must be performed in a biologic safety hood due to the risks of infection from aerosolization. Sputum can also be processed using thin-layer methods or embedded in paraffin for cell block sections.¹⁰

The adequacy of a sputum sample is established by finding numerous pulmonary macrophages.⁶ Specimens consisting merely of squamous cells, bacteria, and Candida organisms are unsatisfactory because they represent only oral contents. Even ciliated cells, which also line the sinonasal passages, do not guarantee that a sample is from the lower respiratory tract. The presence of numerous macrophages indicates that a satisfactory, deep cough specimen of the lower respiratory tract has been obtained. In an adequate sample they should not be difficult to find: If they are absent or few in number, the sample should be reported as unsatisfactory.

The sensitivity of sputum cytology for the diagnosis of malignancy increases with the number of specimens examined, from 42% with a single specimen to 91% with five specimens.¹¹ The specificity of sputum examination is high, ranging from 96% to 99%, and the positive and negative predictive values are 100% and 15%, respectively.¹² Thus, negative sputum results do not guarantee the absence of a malignancy, especially in a patient suspected of having lung cancer. The sensitivity of sputum cytology depends also on the location of the malignant tumor: 46% to 77% for central lung cancers but only 31% to 47% for peripheral cancers.^13,14 Surprisingly, sensitivity is independent of tumor stage and histologic type. Accuracy in tumor classification is 75% to 80%¹⁵ and is tumor type-dependent.¹⁶

Bronchial Specimens

A pivotal improvement in sampling the lower respiratory tract occurred with the development of the flexible bronchoscope in the late 1960s. Today, any part of the respiratory mucosa can be sampled with this device.

Complications of bronchoscopy are rare (0.5% and 0.8% for major and minor complications, respectively)¹⁷ and include laryngospasm, bronchospasm, disturbances of cardiac conduction, seizures, hypoxia, and sepsis. The incidence of major complications is higher for transbronchial biopsy (6.8%).¹⁷

Transbronchial Fine-Needle Aspiration (‘Wang Needle’)

Transbronchial FNA is especially useful for the diagnosis of primary pulmonary lesions that lie beneath the bronchial surface and for staging lung cancer patients by sampling mediastinal lymph nodes.35–37 In these settings, the need for additional surgical procedures is eliminated in 20% of patients, and the cost is one-third that of mediastinoscopy.³⁸ The lesion is aspirated with a retractable (Wang) needle passed through a flexible catheter that is sent down the bronchoscope.

When transbronchial FNA is used to sample mediastinal lymph nodes, at least a moderate number of lymphocytes must be present to ensure the adequacy of the specimen and avoid a false-negative result.³⁹ Ciliated respiratory epithelial cells are common contaminants because the respiratory mucosa needs to be breached to reach the target. For this reason, ciliated cells should not be taken as evidence of adequate sampling. Complications from transbronchial aspiration are rare and include endobronchial bleeding, which is usually controlled by suctioning. Contraindications are coagulopathy, respiratory failure, and uncontrollable coughing.⁴⁰

Transbronchial FNA augments the diagnostic accuracy of bronchial washings, brushings, and endoscopic biopsies for the detection of primary pulmonary neoplasms.41,42 The sensitivity of transbronchial FNA by itself is 56% but increases to 72% when combined with bronchial brushing, washing, and biopsy. Specificity is 74%, and the positive and negative predictive values are 100 and 53% to 70%, respectively.

Transbronchial FNA is accurate in distinguishing small cell from non–small cell lung cancer.⁴³ For mediastinal staging of bronchogenic carcinoma, the negative predictive value of transbronchial FNA increases from 36% to 78% when negative specimens without sufficient lymphocytes are regarded as unsatisfactory for evaluation.³⁹ The most common cause of false negatives is sampling error.⁴²

Endobronchial Ultrasound-Guided (EBUS) Fine-Needle Aspiration

The accuracy of mediastinal staging by FNA improves with the use of ultrasound guidance.35,36 Endobronchial ultrasound-guided (EBUS) FNA is an enhanced procedure for sampling mediastinal and paratracheal lymph nodes and peribronchial lung or mediastinal lesions. Its primary indication is nodal staging of non–small cell lung cancer,^44–47 but it is also indicated for sarcoidosis and metastases from extrapulmonary primaries.⁴⁸ This minimally invasive procedure is a safer alternative to cervical mediastinoscopy in selected patients. Using a bronchoscope equipped with an ultrasound probe tip, the operator performs an FNA with real-time ultrasound imaging of a lymph node or central lung mass. Sensitivity and specificity are 78% and 99%, respectively.⁴⁹ To optimize sensitivity, a cytologist can assess the sample on-site for adequacy. In the absence of lesional cells, adequacy is defined as the presence of lymphocytes (if a lymph node is being sampled) or pigmented macrophages (in the case of a lung mass).⁴⁸ As with transbronchial (Wang needle) FNA, ciliated respiratory epithelial cells are common contaminants and should not be taken as evidence of adequate sampling. The advantage of EBUS is that it increases accessibility to lower station lymph nodes: transbronchial (Wang needle) FNA can sample station 2 to 4 and 7 lymph nodes; transesophageal ultrasound-guided FNA can reach station 2 to 4 and 7 to 9 nodes; whereas EBUS can sample station 2 to 4, 7, and 10 to 12 nodes.⁴⁸ Thus, combining esophageal FNA with EBUS is often performed for full accessibility.

Although the EBUS FNA procedure itself is more expensive than transbronchial (Wang) FNA, it saves downstream costs due to its greater sensitivity, thus reducing any need for more surgical staging.⁵⁰

Transesophageal Fine-Needle Aspiration

Mediastinal lymph node sampling can also be done endoscopically by passing the needle through the esophagus.51–53 The addition of ultrasound guidance improves the accuracy of mediastinal lymph node sampling.⁵⁴ Like bronchoscopic FNA, endoscopic FNA realizes significant cost savings⁵³ and reduces the number of unnecessary thoracotomies.⁵²

The diagnostic yield for mediastinal staging is greatly improved when endoscopic transesophageal FNA is used in combination with transbronchial FNA, with an accuracy that approaches 100%.⁵⁵ As with transbronchial FNA, a moderate number of lymphocytes must be present to ensure the adequacy of the specimen and avoid a false-negative result.

Percutaneous Fine-Needle Aspiration

The ease, rapidity of diagnosis, and minimal morbidity of percutaneous FNA make it an attractive alternative to surgical biopsy in the evaluation of the patient with a peripheral pulmonary mass. FNA is of greatest benefit to patients for whom it spares a more invasive surgical procedure. Surgical intervention, in fact, can be avoided in up to 50% of patients with clinically suspected lung cancer.⁵⁶ There are some contraindications, however.

The most common complication of percutaneous FNA is pneumothorax. A radiographically detectable pneumothorax occurs in 21% to 34% of patients⁵⁸; only 10%, however, require intercostal drainage tubes.⁵⁸ The risk of a pneumothorax increases with the number of passes through aerated lung, and decreases if the path does not traverse aerated lung.⁵⁸ Transient hemoptysis occurs in 5% to 10% of patients. Other complications are rare and include hemopericardium, hemothorax, air embolism, tumor seeding, and death.^58,59

Percutaneous FNA is usually performed by a radiologist using computed tomography (CT) or ultrasound guidance, the latter best reserved for lesions that abut the pleura or chest wall. The needle gauge ranges from 18 to 25, and many different types of needle devices are available. Although many radiologists prefer 22-gauge Chiba needles, these require repuncture if more than one pass is needed. Another choice is the coaxial needle, with a large-bore outer needle serving as the guide for a small-bore inner needle. Once the outer needle is positioned, more than one aspiration can be performed using the inner needle.

It can be helpful if a cytotechnologist and/or cytopathologist attends the FNA procedure to assist with specimen handling and assess its adequacy on site. After smears are prepared, the needle is rinsed in a balanced electrolyte solution, Saccomanno’s fixative, 50% ethanol, or commercial preservative solution. The cellular suspension can be processed as a cytospin, thinlayer preparation, or cell block, and it can be apportioned for flow cytometric analysis if needed. Formalin-fixed cell blocks are ideal for histochemical and immunohistochemical stains. A decision regarding the need, if any, for special studies can be made by the cytotechnologist or cytopathologist after examination of the smears.

Percutaneous FNA is a reliable and accurate way to diagnose many pulmonary neoplasms.

In a study of more than 13,000 FNA specimens from 436 institutions, the diagnostic sensitivity was 89% for the procedure itself and 99% for the pathologist’s interpretation.⁶⁰ This difference indicates that most false-negative results are due to sampling error. About 15% of false-positive diagnoses and 5% of false-negative diagnoses have a significant, permanent, or grave influence on patient outcome.⁶⁰ The reliability of a negative FNA result is a matter of controversy, given that negative predictive values range from 34% to 88%.^61–64 For this reason, most investigators recommend a repeat aspiration or tissue biopsy when a specific benign diagnosis that accounts for the lesion cannot be made with certainty. The small, cutting (“core”) biopsy is no more accurate than FNA,^61,65–67 but it is performed instead of FNA in some centers.

With regard to the management of patients with primary lung cancer, it is important to discriminate small cell from non–small cell carcinoma, and adenocarcinoma (ACA) from squamous cell carcinoma (SQC). The distinction between small cell and non–small cell carcinoma is possible in more than 95% of cases,⁶⁸ and between ACA and SQC in 88% of cases diagnosed by FNA.⁶⁹

A variety of benign cells occasionally contaminate a percutaneous FNA. Such cells need to be recognized as contaminants and not misconstrued as lesional. In particular, mesothelial cells from the pleura are common, and in some cases they can be numerous (Fig. 2.3). They resemble the cells of a well-differentiated adenocarcinoma (see “Adenocarcinoma”) but are identified as benign mesothelial cells by their relative flatness, cohesion, and the characteristic slitlike “windows” that separate the mesothelial cells from each other.

If the specimen consists only of one (or more) of these contaminants, it should be interpreted as insufficient for evaluation (nondiagnostic) rather than negative, because there is no evidence that the lesion itself has been sampled.

Epidermal Growth Factor Receptor

EGFR amplification drives growth, invasion, and angiogenesis through activation of PI3K/AKT and RAS/RAF/MEK signaling and is seen in 30% to 60% of non–small cell lung cancers.72–74 It is mutated in its tyrosine kinase domain in greater than 30% of Asians and 10% of Caucasians with non–small cell lung cancer.⁷⁵ Erlotinib, a U.S. Food and Drug Administration (FDA)–approved receptor tyrosine kinase inhibitor, significantly improves overall survival of previously untreated non–small cell lung cancer patients.⁷⁶ Moreover, erlotinib and gefitinib, the latter currently in clinical trials, are much less toxic than conventional chemotherapy. EGFR-mutated tumors respond much better than nonmutated tumors,³⁸ but unfortunately, a majority develop resistance within a year. Resistance is due to the acquisition of additional mutations within the tyrosine kinase domain of EGFR, most often a T790M amino acid substitution in exon 20.^77,78 EGFR inhibitors are currently in development to overcome resistance.⁷⁹

MET

MET is a proto-oncogene that encodes another receptor tyrosine kinase, HGFR (see Fig. 2.4), and its amplification is associated with resistance to EGFR inhibitors. The mechanism of resistance is beyond the scope of this chapter, but MET is amplified in 5% to 20% of EGFR-mutated, EGFR-resistant non–small cell lung cancers.^80–82 Therapeutic anti-MET antibodies are in development.⁷⁹

Vascular Endothelial Growth Factor and Receptor

Bevacizumab is a highly effective monoclonal antibody targeting VEGF, a ligand implicated in tumor angiogenesis, significantly improving the overall survival of patients with non-squamous, non–small cell lung cancer when combined with carboplatin and paclitaxel.⁸³

Sunitinib and sorafenib, tyrosine kinase inhibitors of VEGFR, are in development.⁷⁹

ERBB-2 (HER2)

HER2, a member of the EGFR family, is amplified or overexpressed in up to 23% of non–small cell lung cancers, but oddly, these patients do not benefit from anti-HER2 single-agent therapy.84,85 In a subset of lung cancers (3% to 10%), however, HER2 is mutated in its kinase domain^86,87; for these patients, anti-HER2 antibodies and kinase inhibitors are in development.

Echinoderm Microtubule–Associated Protein–Like 4-Anaplastic Lymphoma Kinase

ALK is yet another receptor tyrosine kinase that plays an important role in a subset of lung cancers. When fused through chromosomal translocation to EML4, ALK becomes constitutively active, resulting in the activation of the pro-growth PI3K/AKT and RAS/RAF/MEK pathways (see Fig. 2.4). An EML4-ALK translocation is present in 5% to7% of non–small cell lung cancers. These patients have a unique clinical and molecular profile: they are nonsmokers and relatively young (median age 52) males without EGFR or KRAS mutations.^88,89 EML4-ALK translocated tumors are exquisitely sensitive to crizotinib.⁹⁰ The translocation is identified by fluorescence in situ hybridization (Fig. 2.5).

BRAF

BRAF is a form of RAF, a serine-threonine kinase that activates MEK (see Fig. 2.4). Mutation of exons 11 or 15 in the kinase domain is implicated in the early development of lung cancer and is seen in 3% of non–small cell lung cancers.⁹⁰ These mutations are distinct from those seen in melanoma (V600E), raising concern that a BRAF-mutated lung cancer may not be responsive to the BRAF inhibitors currently used to treat melanoma.⁹¹ To circumvent this limitation, MEK inhibitors are in development.

Insulin-Like Growth Factor 1 Receptor

IGF-1R is a unique receptor tyrosine kinase in that deregulation of IGF-1R is associated with squamous lung cancers.⁹² Further, its amplification is associated with an improved prognosis.⁹³ Antibodies targeting IGF-1R are under clinical development.

PIK3CA

Amplification of PIK3CA occurs in 12% to 17% of non–small cell lung cancers and is believed to play a role in resistance to receptor tyrosine kinase inhibitor therapy.94,95 Moreover, activating mutations of the kinase or helix domain are seen in 2% to 13% of non–small cell lung cancers.^76,95,96 PI3K inhibitors are currently in clinical development.

KRAS

KRAS-mutated cancers carry a worse prognosis and are typically absent in patients with receptor tyrosine kinase mutations. These patients are usually smokers, and evidence suggests that they do worse when erlotinib is added to their chemotherapy,⁹⁷ once more underscoring the importance of molecular testing in lung cancer. Preliminary evidence suggests that sorafenib, a weak inhibitor of downstream RAF, has efficacy in this group of otherwise treatment-resistant tumors.⁹⁸

Reactive Squamous Cell Changes

Benign squamous cells from the oral cavity often contaminate sputum and bronchial cytology specimens. Inflammatory conditions of the mouth caused by trauma, candidiasis, or pemphigus can exfoliate mildly atypical squamous cells with hyperkeratinization and nuclear degeneration, usually in small numbers. Such minimal changes should not be misinterpreted as squamous cell carcinoma (SQC). More marked (but still benign) squamous cell atypias occur adjacent to cavitary fungal infections and stomas, and with almost any injury to the lung (e.g., infarction, radiation, chemotherapy, sepsis, diffuse alveolar damage) and might result in a false-positive interpretation of SQC.33,34 Another, uncommon source of false-positives is malignant cells from head and neck cancers that contaminate sputum and bronchial specimens.⁹⁹

Reactive Bronchial Cell Changes

Benign, reactive bronchial cell changes occur in response to noxious stimuli such as radiation, chemotherapy, and severe inflammation. Under such conditions, ciliated columnar cells can increase their nuclear area many times over, with multinucleation, coarsely textured chromatin, and large nucleoli (Fig. 2.6). Large clusters of bronchial cells known as Creola bodies (named after the first patient in whom they were recognized) are commonly seen in chronic airway diseases like asthma (Fig. 2.7).

Markedly reactive changes in benign bronchial cells mimic adenocarcinoma. Malignancy can be excluded if the atypical cells have cilia and/or demonstrate a spectrum of changes (from benign to markedly atypical) rather than the two distinct cell populations typical of a malignant sample obtained bronchoscopically. Note that in sputum and FNA specimens, a helpful dual cell population (malignant cells and bronchial cells) is usually not apparent.

Bronchial Reserve Cell Hyperplasia

As the surface epithelium of the respiratory tract is shed during lung injury, reserve cells proliferate and are seen in bronchial washings and brushings (Fig. 2.8).

Reserve cell hyperplasia (RCH) is a mimic of small cell carcinoma but is usually easily distinguished from it. The cells of RCH show greater cohesiveness; they are smaller; and there are no mitoses or necrosis.

Repair

Repair represents reepithelialization of an ulcer created by trauma, radiation, burns, pulmonary infarction, and infections. Typical (and atypical) repair of the respiratory tract is very similar to that seen in the cervix and gastrointestinal (GI) tract.

Reparative epithelium is most commonly seen in tracheobronchial brushings and washings. The differential diagnosis of repair includes malignancy: the non–small cell lung cancers, a metastasis, and other less common tumors. Malignant cells are usually less cohesive and orderly than reparative epithelium, and malignant cells are usually more numerous. Correlation with clinical history can be helpful; a conservative approach is recommended if the findings are not conclusive and there is a history of mucosal trauma or other lung injury.

Type II Pneumocyte Hyperplasia

Because type II pneumocytes function as alveolar reserve cells, they proliferate after lung injury.

When floridly hyperplastic, as in diffuse alveolar damage, the cells of type II pneumocyte hyperplasia resemble those of adenocarcinoma (Fig. 2.9).

The only clue to avoiding an incorrect diagnosis of malignancy in a patient with type II pneumocyte hyperplasia may be the clinical history of respiratory distress and diffuse infiltrates. Thus, in an acutely ill patient with diffuse pulmonary infiltrates, markedly atypical cells should be interpreted cautiously.³³ Sequential respiratory specimens can be helpful, inasmuch as hyperplastic pneumocytes are not present in BAL specimens more than 1 month after acute lung injury.³²

Viral Infections

Bacterial Pneumonias

Bacterial pneumonias are caused by a large number of bacteria, but most are characterized by a neutrophilic exudate. Common organisms include Streptococcus pneumoniae (pneumococccus), other streptococci, Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas sp., Legionella sp., Nocardia sp., Actinomyces sp., and some anaerobic bacteria. Many but not all bacteria can be seen with routine stains as well as with the Gram stain. Cytologic examination is not usually employed for the diagnosis of a bacterial pneumonia, which is typically established by correlating clinical findings with microbiologic studies.

Bacterial pneumonias often have a characteristic lobar or lobular distribution, but some pneumonias appear as round and circumscribed masses on imaging studies and thus mimic the appearance of a malignancy. In such cases, a cytologic specimen might be obtained, because the working clinical diagnosis is a suspected malignancy.

Several bacteria deserve special mention. Actinomyces species are a common inhabitant of the tonsillar area and thus a common contaminant of sputum and bronchial specimens (but not FNAs). Infection by Actinomyces, however, is uncommon. Pulmonary infection occurs by aspiration of oral contents or by direct extension from subdiaphragmatic abscesses. Actinomycosis is usually a chronic infection that may result in sinus tracts. The bacteria aggregate into grossly visible sulfur granules (so called because they look yellow on gross examination) and evoke a brisk neutrophilic response. When they appear in cytologic specimens as just an oral contaminant, Actinomyces bacteria are large blue “cotton balls” often associated with squamous cells, with no neutrophilic infiltrate, similar to what is occasionally encountered in Pap specimens (see Fig. 1.23). A true thoracopulmonary actinomycosis should be considered if the bacteria are associated with abundant neutrophils.

Nocardia are aerobic, filamentous bacteria that inhabit the soil and are acquired by inhalation. N. asteroides accounts for 80% of nocardial infections. Most patients are immunocompromised and have a subacute presentation. Cavitary nodules are seen in one third of patients. The organisms are found among abundant neutrophils. They are thin, filamentous, and beaded, with such extensive, predominantly right-angle branching that they resemble Chinese characters. They are gram-positive and stain with silver stains but are only weakly acid-fast and thus require modified acid-fast stains like the Fite-Faraco for visualization. The diagnosis is established by culture of a biopsy or BAL fluid.

Legionella pneumonia is caused by the aerobic gram-negative bacteria Legionella sp., of which the most common is L. pneumophila. The organisms are seen well with silver stains like the Steiner, Warthin-Starry, and Dieterle stains. A specific identification of L. pneumophila can be made in BAL samples using immunohistochemical or immunofluorescent methods.

Tuberculosis

Infection by M. tuberculosis commonly results in granulomatous inflammation (Fig. 2.16). Cytologic specimens contain aggregates of epithelioid histiocytes, lymphocytes, and Langhans giant cells. Necrosis may or may not be evident. Granulomas by themselves, however, are a nonspecific finding and can be seen in other conditions like fungal infections and sarcoidosis. A definitive diagnosis of tuberculosis rests on identifying the organisms with the help of a special stain (Ziehl-Neelsen) or by microbiologic culture. Cell block preparations are particularly useful for special stains, but rarely are more than one or just a few organisms identified. (By contrast, infection by M. avium-intracellulare, as seen in immunocompromised patients, often yields innumerable acid-fast organisms.) A sensitive (93%) and specific (99%) assay called the Mycobacterium Tuberculosis Direct Test (MTD) is also available for the detection of M. tuberculosis and can be applied to respiratory specimens such as sputum.¹⁰⁶ The assay amplifies M. tuberculosis ribosomal RNA by the polymerase chain reaction.

In countries where M. tuberculosis is prevalent, the yield of acid-fast bacteria among all clinically suspicious lung masses can be very high.107,108 In immunocompromised patients with tuberculosis, there may be an abundance of acid-fast organisms but few well-formed granulomas. If Romanowsky-type stains are used in such cases, the abundant acid-fast organisms can be identified as negative images.

Pulmonary Fungal Infections

Pulmonary fungal infections are readily diagnosed by cytology, particularly in transthoracic FNAs, and should be suspected whenever there is granulomatous inflammation and/or necrosis. Cell block material can be used for silver or periodic acid–Schiff (PAS) stains. Many fungi have a characteristic microscopic appearance that enables a rapid, specific diagnosis (Table 2.2).

Pneumocystis jirovecii

The taxonomy of this organism, formerly called Pneumocystis carinii, has been debated, but microbiologists favor classifying it as a fungus, based in part on molecular evidence, hence the change in name to Pneumocystis jirovecii.116,117 The pneumonia caused by P. jirovecii is particularly common in immunocompromised individuals but has decreased in frequency since the advent of novel therapies.²⁷ The clinical presentation includes dry cough, fever, and dyspnea. Pulmonary infiltrates are usually bilateral.

The organisms are well demonstrated in BAL material, which has a sensitivity that compares favorably with transbronchial biopsy.¹¹⁸ They can also be detected in bronchial washings and induced sputum.¹¹⁹ With Papanicolaou stains, the organisms themselves are not visible, but masses of organisms enmeshed in proteinaceous material result in green, foamy alveolar casts that are more circumscribed than debris or lysed red blood cells (Fig. 2.20A). The cysts are visualized with silver stains. They are cup-shaped, measure 5 to 7 μm in diameter, and often have a central dark zone (Fig. 2.20B). No budding occurs, which helps distinguish them from Histoplasma. The Giemsa stain highlights the cysts as negative images, but the eight 1.5 μm intracystic bodies or trophozoites are stained as discrete blue dots either within the cysts or as free organisms (Fig. 2.20C). In some cases, the foamy alveolar casts are absent, and the organisms may be present only in vacuolated macrophages.¹²⁰

Direct immunofluorescence has higher sensitivity (up to 92%) than use of Giemsa, toluidine blue, and silver stains.121,122 Application of this method to induced sputum (Fig. 2.20D) is the preferred initial diagnostic step because it is noninvasive and highly accurate.

Strongyloidiasis

Pulmonary strongyloidiasis is caused by the nematode Strongyloides stercoralis. It can affect immunocompetent people but is more common in the immunosuppressed patient and presents as a pneumonitis with hemoptysis. Infection of the lungs is caused by the hematogenous migration of the infective larva (filariform larva) from the gut or skin. Histologically, there is a hemorrhagic pneumonia. This organism is identified in sputum or bronchial material by its large size and is differentiated from other hookworms by its notched tail and short buccal cavity (Fig. 2.21).

Dirofilariasis

Dog heartworm (Dirofilaria immitis) infection of the human lung has been documented by FNA.¹²³ This microfilarial disease is transmitted from dogs to humans via mosquitos, resulting in entrapment within small pulmonary vessels and subsequent pulmonary infarction. Diagnosis is made by aspiration of the discrete peripheral nodule, which shows necrotic material, fragments of infarcted pulmonary tissue, chronic inflammation, a granulomatous response, and rarely the worm itself.

Echinococcosis (Hydatid Disease)

The clinical and cytologic features of echinococcosis are described in Chapter 12 (see Fig. 13.4). Sputum may contain scoleces if pulmonary hydatid cysts rupture. Because of the risk of anaphylactic shock, aspiration of a clinically suspected hydatid cyst may be hazardous.^57,124

Sarcoidosis

A common disease of unknown etiology, sarcoidosis is characterized by noncaseating granulomas in many organs, most commonly the lung.

Cytologic specimens show noncaseating granulomas composed of epithelioid histiocytes, with scattered lymphocytes and multinucleated giant histiocytes (see Fig. 2.16).¹²⁵ The epithelioid histiocytes have round, oval, curved (boomerang-shaped), or spindle-shaped nuclei, with translucent, vacuolated cytoplasm, and are haphazardly arranged in a pseudosyncytial pattern.

Wegener Granulomatosis

This necrotizing vasculitis may present clinically as a lung mass with or without involvement of other organs like the nasal passages and kidneys. The histologic diagnosis of Wegener granulomatosis rests on the identification of necrosis, granulomatous inflammation, and vasculitis.

The cytomorphologic findings are nonspecific but include chunks of necrotic tissue (Fig. 2.22), giant cells, granulomas, and neutrophils. The differential diagnosis includes a necrotizing infection (e.g., tuberculous, fungal), lymphomatoid granulomatosis, and other uncommon pulmonary diseases. If suspected on the basis of its characteristic cytomorphology, the diagnosis can be substantiated with serologic studies. The serum immunofluorescent antineutrophil cytoplasmic antibody (ANCA) test greatly aids in establishing the diagnosis of Wegener granulomatosis. Although the classic (cytoplasmic) pattern (c-ANCA) is considered more specific, neither the c-ANCA nor the perinuclear (p-ANCA) pattern is entirely sensitive or specific for the diagnosis of Wegener granulomatosis.¹²⁶

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