2 Respiratory Tract

2
Respiratory Tract
Christopher A. French
NORMAL ANATOMY, HISTOLOgY, AND Sporotrichosis

CYTOLOGY OF THE RESPIRATORY TRACT Invasive Fungi
Pneumocystis carinii
SAMPLING TECHNIQUES, PREPARATION
Strongyloidiasis
METHODS, REPORTING TERMINOLOGY, AND
Dirofilariasis
ACCURACY
Echinococcosis (Hydatid Disease)
Sputum
Bronchial Specimens NON-NEOPLASTIC, NONINFECTIOUS
Bronchial Aspirations and Washings PULMONARY DISEASES
Bronchial Brushings Sarcoidosis
Bronchoalveolar Lavage Wegener Granulomatosis
Transbronchial Fine-Needle Aspiration Pulmonary Amyloidosis
Transesophageal Fine-Needle Aspiration Pulmonary Alveolar Proteinosis
Percutaneous Fine-Needle Aspiration Common Inflammatory Processes
Capillary Wedge Samples
BENIGN NEOPLASMS OF THE LUNG
BENIGN CELLULAR CHANGE Pulmonary Hamartoma
Benign Squamous Cell Changes Inflammatory Myofibroblastic Tumor
Benign Bronchial Cell Changes Endobronchial Granular Cell Tumor
Bronchial Reserve Cell Hyperplasia
PRENEOPLASTIC CHANGES OF THE
Repair
RESPIRATORY EPITHELIUM
Type II Pneumocyte Hyperplasia
LUNG CANCER
NONCELLULAR ELEMENTS AND SPECIMEN
Squamous Cell Carcinoma
CONTAMINANTS
Adenocarcinoma
INFECTIONS Large Cell Carcinoma
Viral Infections Sarcomatoid Carcinoma
Herpes Simplex Pulmonary Neuroendocrine Neoplasms
Cytomegalovirus Typical Carcinoid
Measles Virus and Respiratory Syncytial Virus Atypical Carcinoid
Adenovirus Small Cell Carcinoma
Bacterial Pneumonias
UNCOMMON PULMONARY TUMORS
Tuberculosis
Adenoid Cystic Carcinoma and Other Bronchial
Pulmonary Fungal Infections
Gland Tumors
Cryptococcosis
Clear Cell Tumor (“Sugar Tumor”)
Histoplasmosis
Sarcomas
Blastomycosis
Lymphomas and Leukemias
Coccidioidomycosis
Paracoccidioidomycosis METASTATIC CANCERS TO THE LUNG
Exfoliative cytology was first used to study cells of the of direct sampling methods via bronchoscopy and fine-
respiratory tract in 1845.1 The ability to diagnose pulmo- needle aspiration (FNA),3 resulting in an armamentar-
nary diseases cytologically was appreciated as early as ium of sampling techniques. Since then, the improved
1919,2 but it was not until the 1950s and 1960s that pul- sensitivity (and common application) of thoracic imag-
monary cytology came into its own as a diagnostic disci- ing has created an ever-increasing need for the cytologic
pline. Its emergence was bolstered by the introduction evaluation of pulmonary lesions.
65
66 Respiratory Tract
Normal Anatomy, Histology,

and Cytology of The
Respiratory Tract
The respiratory tract can be categorized into upper and
lower compartments. The upper airway extends from the
sinonasal region to the larynx. The cells of the upper air-
way are occasionally seen in lower respiratory tract spec-
imens. The lower respiratory tract, which is the major
focus of diagnostic respiratory cytopathology, extends
from the trachea to the lungs. The tracheobronchial tree
divides into progressively smaller units: bronchi, bron-
chioles, and respiratory acini.
Anatomy and cellular components of the Figure 2.1 Normal ciliated bronchial cells (bronchial brush-
ing). These columnar cells have oval nuclei and finely stippled
respiratory tract:
chromatin. Numerous cilia project from the apical surface.
Upper respiratory tract:
• ciliated columnar cells
thin and cover the gas exchange portion of the alveolar
• squamous cells
surface. The type II pneumocyte is more conspicuous:
Lower respiratory tract: plump and cuboidal rather than flat. It secretes pulmo-
• trachea and bronchi nary surfactant, seen ultrastructurally as osmiophilic
• ciliated columnar cells lamellar bodies. After lung injury, these cells function
• goblet cells as reserve cells for the delicate type I pneumocyte. On
• basal or reserve cells cytologic preparations, type II pneumocytes are round
• neuroendocrine cells and have vacuolated cytoplasm; they can be difficult to
• terminal bronchioles distinguish from macrophages.
• nonciliated cuboidal or columnar cells (Clara cells) Alveolar macrophages vary in appearance depend-
• alveoli ing on the amount and type of phagocytosed cytoplas-
• type I and II pneumocytes mic material. In general, they have one or more round
• alveolar macrophages to oval nuclei and lacy or bubbly cytoplasm (Fig. 2.2).
Numerous alveolar macrophages must be identified for
The trachea and bronchi are lined by a pseudostrat- a sputum sample to be judged adequate. Under normal
ified epithelium. The predominant cell is the ciliated
columnar cell, which has a basally placed nucleus and
finely textured chromatin. The luminal surface has
a thick terminal bar with cilia (Fig. 2.1). Goblet cells,
present in a ratio of approximately one per six cili-
ated cells, also have basally located nuclei, but they
lack cilia and their cytoplasm is distended by mucus.
The goblet cells secrete mucus, and the ciliated cells
move the mucus and entrapped contaminants up
the airway. Adjacent to the basement membrane are
basal or reserve cells: small, undifferentiated cells that
are the presumed forerunners of the ciliated and gob-
let cells. Neuroendocrine cells, or Kulchitsky cells, are
also present in the respiratory epithelium, but they are
identified only with special stains or ultrastructural
examination; they are argyrophil-positive and possess
dense-core granules.
The terminal bronchioles are lined by nonciliated
cuboidal to columnar cells called Clara cells, usually not Figure 2.2 Pulmonary alveolar macrophages (sputum).
Pulmonary macrophages have abundant foamy cytoplasm that
recognized as such on cytologic preparations. The alveo- often contains black carbon particles, as seen here. These mac-
lar lining consists of type I and type II pneumocytes. Type rophages fill with hemosiderin pigment following pulmonary
I pneumocytes, which are more numerous, are paper hemorrhage. Hemosiderin is golden brown rather than black.
Sampling Techniques, Preparation Methods, Reporting Terminology, and Accuracy 67
circumstances, a few white blood cells, such as neutrophils A simple method of sputum preparation is known as
and lymphocytes, are also found within the alveolar com- the “pick and smear” technique, whereby fresh sputum is
partment. An increased number of inflammatory cells is examined for tissue fragments, blood, or both. Smears are
abnormal: Abundant neutrophils indicate an acute pneu- prepared from areas that contain these elements and are
monia, and numerous lymphocytes are usually associ- immediately fixed in 95% ethanol. A modification of this is
ated with chronic inflammation. the Saccomanno method, which calls for sputum to be col-
lected in 50% ethanol and 2% carbowax.8 The specimen is
then homogenized in a blender and concentrated by cen-
trifugation. Improved sensitivity has been demonstrated
Sampling Techniques, by the use of dithiothreitol (DTT) for homogenization.9
Preparation Methods, Smears are made from the concentrated cellular material.
Reporting Terminology, The Saccomanno method must be performed in a biologic
and Accuracy safety hood as a result of the risks of infection from aero-
solization. Sputum can also be processed using thinlayer
Familiarity with the variety of sampling and preparation methods or embedded in paraffin for cell block sections.10
methods is crucial for cytologic interpretation because The adequacy of a sputum sample is established by
cytomorphology is different depending on the sampling finding numerous pulmonary macrophages. They indicate
and preparation method. The accuracy of respiratory that a deep cough specimen of the lower respiratory tract
cytology also varies depending on the specimen type. has been obtained. Specimens consisting merely of squa-
As with other nongynecologic cytology specimens, mous cells, bacteria, and Candida organisms are unsat-
respiratory tract diagnoses are typically reported as “nega- isfactory because they represent only oral contents. Even
tive for malignant cells,” “positive for malignant cells,” or ciliated cells, which also line the sinonasal passages, do not
“non-diagnostic (unsatisfactory),” followed by a descrip- guarantee that a sample is from the lower respiratory tract.
tive diagnosis. Inconclusive diagnoses are commonly The sensitivity of sputum cytology for the diagnosis
reported as “atypical cells present” (usually connoting a of malignancy increases with the number of specimens
lower degree of suspicion) or “suspicious for malignancy examined, from 42% with a single specimen to 91% with
(connoting a high degree of suspicion),” depending on the five specimens.11 The specificity of sputum examination
degree of suspicion. Cancer is confirmed in 40% of “atyp- is high, ranging from 96% to 99%, and the positive and
ical” respiratory specimens and in almost 70% of those negative predictive values are 100% and 15%, respec-
diagnosed as “suspicious.”4 Atypical or suspicious cases tively.12 Negative sputum results do not guarantee the
remain inconclusive even after careful retrospective reex- absence of a malignancy, especially in a patient suspected
amination, which fails to reveal any morphologic features of having lung cancer. The sensitivity of sputum cytology
to reliably distinguish benign from malignant specimens.5 depends on the location of the malignant tumor: 46%
to 77% of central lung cancers but only 31% to 47% of
peripheral cancers are diagnosed by sputum cytology.13,14
Sputum Surprisingly, sensitivity is independent of tumor stage
Sputum consists of a mixture of cellular and noncellu- and histologic type. Accuracy in tumor classification is
lar elements that are cleared by the mucociliary appa- 75% to 80%15 and is tumor type dependent.16
ratus. It was once the most common respiratory tract
specimen because it is relatively easy to obtain and
causes little if any discomfort. Unfortunately, screen-
Bronchial Specimens
ing asymptomatic smokers with sputum cytology does A pivotal improvement in sampling cells from the lower
not decrease mortality from lung cancer. Today, sputum respiratory tract occurred with the development of the
cytology is generally reserved for symptomatic individ- flexible bronchoscope in the late 1960s. Today, any part
uals. Even here, with the advent of bronchoscopy and of the respiratory tract can be sampled with this device.
FNA, its use as the mainstay in respiratory cytology has Complications of bronchoscopy are rare (0.5% and
declined significantly. 0.8% for major and minor complications, respectively),17
Collecting multiple sputum samples over several days and include laryngospasm, bronchospasm, distur-
optimizes sensitivity. Early morning, deep cough speci- bances of cardiac conduction, seizures, hypoxia, and
mens are preferred.6 If the patient is not able to expecto- sepsis. The incidence of major complications is higher
rate adequately, expectoration can be induced by having for transbronchial biopsy (6.8%).17
the patient inhale nebulized water or saline. Sputum
induction increases the detection of lung cancer.7 When
Bronchial Aspirations and Washings
prompt preparation of sputum is not possible, the
patient can expectorate into a 70% ethanol solution, Bronchial secretions can be aspirated directly from the
which prefixes the specimen. lower respiratory tract through the bronchoscope, but
an alternative (and more common) method is to “wash” Cryptococcus.26 The frequency and distribution of infec-
the mucosa by instilling 3 to 10 mL of saline and aspirate tions has changed since the widespread use of highly
the washings. The fluid is centrifuged and the concen- active antiretroviral therapy (HAART) to treat HIV.27
trate used to make smears, thinlayer preparations, or Among individuals who are HIV-seropositive with non-
cell blocks; the latter are particularly useful when special specific cytologic results, 27% prove to have pathogens,
stains are needed. usually bacterial or fungal, by either culture or biopsy,28
which emphasizes the importance of a multimodal
Bronchial Brushings approach to diagnosis in this setting.
BAL is also used for the diagnosis of malignancy, with
Fiberoptic bronchoscopy allows direct visualization
sensitivity that ranges from 35% to 70%.29,30 The sensitiv-
and sampling of the tracheobronchial tree. A brush is
ity of BAL for detecting malignancy is higher for multifo-
applied to the surface of an endobronchial lesion, and
cal or diffuse tumors like bronchioloalveolar carcinoma.31
the entrapped cells are either smeared onto a glass slide
False-positive results are occasionally encountered as a
or rinsed in a collection medium for thinlayer or cell
result of atypical type II pneumocytes in the setting of
block preparation. If smears are made, immediate fixa-
pneumonia, diffuse alveolar damage,32 bone marrow
tion (by immersion into 95% ethanol or spray fixation) of
transplantation,33 and chemotherapy.34
the smears is essential to preserve morphologic detail.6
The diagnostic accuracy of bronchial washing or
brushing cytology is comparable to that of bronchial Transbronchial Fine-Needle
biopsy.18 Brushings with cell block preparation some- Aspiration
times detect malignancy more reliably than bronchial
Transbronchial FNA is especially useful for the diagno-
biopsies.19 Accuracy improves when clinical history is
sis of primary pulmonary lesions that lie beneath the
provided with the specimen.20 The diagnostic yield also
bronchial surface and for staging lung cancer patients by
improves when several different sampling methods are
sampling mediastinal lymph nodes.35-37 In these settings,
used in concert.21,22
the need for additional surgical procedures is eliminated
in 20% of patients, and the cost is one third that of medi-
Bronchoalveolar Lavage
astinoscopy.38 The lesion is aspirated with a retractable
The choice between using bronchoalveolar lavage (BAL) (Wang) needle passed through a flexible catheter that is
and bronchial washing depends on the location of the sent down the bronchoscope.
airway one desires to sample. With BAL, the broncho- When used to sample mediastinal lymph nodes, at
scope is wedged into position as far as it will go, and least a moderate number of lymphocytes must be pres-
distal airways are flushed with several aliquots of sterile ent to ensure the adequacy of the specimen and avoid
saline. The first aliquot is more representative of the cel- a false-negative result.39 Complications from transbron-
lular material from larger airways, whereas subsequent chial aspiration are rare and include endobronchial
aliquots reflect the alveolar compartment. bleeding, which is usually controlled by suctioning.
BAL is particularly useful for the diagnosis of oppor- Contraindications are coagulopathy, respiratory failure,
tunistic infections in patients who are immunocompro- and uncontrollable coughing.40
mised. The specimen can be examined cytologically and Transbronchial FNA augments the diagnostic accu-
a portion also submitted for microbiologic studies. The racy of bronchial washings, brushings, and endoscopic
distinction between oral contamination and a real bac- biopsies for the detection of primary pulmonary neo-
terial infection can be difficult, but an abundance of nor- plasms.41,42
mal squamous cells usually indicates contamination by
oral flora, whereas neutrophils imply a real infection.23 Accuracy of transbronchial fine-needle
In patients who are immunocompromised, the diag- aspiration:
nostic yield for infectious pathogens is 39%, the sen-
• sensitivity (FNA alone): 56%
sitivity 82%, and the specificity 53%.24 In patients with
• sensitivity (combined with bronchial brush, wash,
acquired immune deficiency syndrome (AIDS), BAL has
and biopsy): 72%
a sensitivity for documenting infection that is compara-
• specificity: 74%
ble to that for transbronchial biopsy (86%); when used
• positive predictive value: 100%
in combination with biopsy, the sensitivity increases to
• negative predictive value: 53% to 70%
98%.25 Historically, the most common pulmonary patho-
gens that were detected by BAL in individuals who were
human immunodeficiency virus (HIV) seropositive Transbronchial FNA is accurate in distinguishing small
were Pneumocystis carinii (78%) and bacteria (19%); the cell from non–small cell lung cancer.43 For mediastinal
remaining infections were the result of Mycobacterium staging of bronchogenic carcinoma, the negative pre-
tuberculosis, atypical mycobacteria, Histoplasma, and dictive value of transbronchial FNA increases from
Sampling Techniques, Preparation Methods, Reporting Terminology, and Accuracy 69
36% to 78% when negative specimens without sufficient passes through aerated lung and decreases if the path
lymphocytes are regarded as unsatisfactory for evalu- does not traverse aerated lung.53 Transient hemoptysis
ation.39 The most common cause of false-negatives is occurs in 5% to 10% of patients. Other complications
sampling error.42 The accuracy of mediastinal staging are rare, and include hemopericardium, hemothorax, air
improves with the use of ultrasound guidance.35,36 embolism, tumor seeding, and death.53,54
Percutaneous FNA is usually performed by radiolo-
Transesophageal Fine-Needle gists using computed tomography (CT) or ultrasound
guidance. The needle gauge ranges from 18 to 22, and
Aspiration many different types of needle devices are available.
Mediastinal lymph node sampling can be performed not Although many radiologists prefer 22-gauge Chiba nee-
only bronchoscopically, but also endoscopically by pass- dles, these require repuncture if more than one pass
ing the needle through the esophagus.44-46 The addition is needed. Another choice is the coaxial needle, with a
of ultrasound guidance improves the accuracy of medi- large-bore outer needle serving as the guide for a small-
astinal lymph node sampling.47 Like bronchoscopic FNA, bore inner needle. Once the outer needle is positioned,
endoscopic FNA realizes significant cost savings46 and more than one aspiration can be performed using the
reduces the number of unnecessary thoracotomies.45 inner needle.
Endoscopic transesophageal FNA has a diagnostic It can be helpful in some cases if a cytotechnologist
accuracy (70% to 80%)48,49 that approaches that of ultra- or cytopathologist attends the FNA procedure to assist
sound-guided transbronchial FNA (84% to 96%).37,44,45,47 with specimen handling and assess its adequacy on-site.
When used in combination with transbronchial FNA, After direct smears are prepared, the needle is rinsed
the diagnostic yield for mediastinal staging is greatly in a balanced electrolyte solution, Saccomanno’s fixa-
improved, with an accuracy that approaches 100%.50 As tive, 50% ethanol, or commercial preservative solution.
with transbronchial FNA, a moderate number of lym- The cellular suspension can be processed for microbio-
phocytes must be present to ensure the adequacy of the logic analysis, cytospins, thinlayer preparations, filters,
specimen and avoid a false-negative result. cell blocks, cytogenetic analysis, flow cytometric analy-
sis, or electron microscopy. Formalin-fixed cell blocks
Percutaneous Fine-Needle are indispensable for histochemical and immunohisto-
chemical stains. A decision regarding the need, if any, for
Aspiration special studies can be made by the cytotechnologist or
The ease, rapidity of diagnosis, and minimal morbid- cytopathologist after examination of the direct smears.
ity of percutaneous FNA make it an attractive alterna- Percutaneous FNA is a reliable and accurate way to
tive to surgical biopsy in the evaluation of the patient diagnose many pulmonary neoplasms.
with a pulmonary mass. Thus, FNA is of greatest benefit
to patients for whom it spares a more invasive surgical Accuracy of percutaneous fine-needle
procedure. Surgical intervention, in fact, can be avoided aspiration:
in up to 50% of patients with clinically suspected lung
• sensitivity: 89%
cancer.51 There are some contraindications, however.
• specificity: 96%
• positive predictive value: 98%
Relative contraindications to percutaneous
• negative predictive value: 70%
fine-needle aspiration:
• false-positive rate: 0.85%
• chronic obstructive pulmonary disease (COPD) • false-negative rate: 8%
• emphysema
• uncontrollable coughing
In a study of more than 13,000 FNA specimens from
• uncooperative patient
436 institutions, the diagnostic sensitivity was 89% for
• bleeding diathesis (i.e., anticoagulant therapy)
the procedure itself and 99% for the pathologist’s inter-
• severe pulmonary hypertension
pretation.55 This difference indicates that most false-
• arteriovenous malformation
negative results are the result of sampling error. About
• cardiac disease
15% of false-positive diagnoses and 5% of false-negative
• suspected echinococcal cyst52
diagnoses have a significant, permanent, or grave influ-
ence on patient outcome.55 The reliability of a negative
The most common complication of percutaneous FNA result is a matter of controversy, given that negative
FNA is a pneumothorax. A radiographically detectable predictive values range from 34% to 88%.56-59 For this rea-
pneumothorax occurs in 21% to 34% of patients;53 only son, most investigators recommend a repeat aspiration
10%, however, require intercostal drainage tubes.53 The or tissue biopsy when a specific benign diagnosis that
risk of a pneumothorax increases with the number of accounts for the lesion cannot be made with certainty.
The small, cutting biopsy method is no more accurate

than FNA.56,60-62
Capillary Wedge Samples
With regard to the management of patients with pri- Pulmonary capillary blood samples are an uncommon
mary lung cancer, the most important consideration is specimen type. They are obtained using a vascular cath-
to discriminate between small cell and non–small cell eter in the wedge position and are useful in diagnosing
carcinoma of the lung, which is possible in more than disorders restricted to the pulmonary microvasculature.
95% of cases diagnosed by FNA.63 These include lymphangitic spread of carcinoma, amni-
It is important to recognize that a variety of benign otic fluid embolism, and fat embolism.64 Blood is collected
cells can occasionally contaminate a percutaneous in a heparanized tube to prevent clotting, and diagnostic
FNA. Such cells need to be recognized as contaminants cells are concentrated using a Ficoll-Hypaque gradient.65
and not misconstrued as lesional. In particular, meso- Megakaryocytes, normally present in the pulmonary cap-
thelial cells from the pleura are common and in some illaries, confirm the proper site and are useful to deter-
cases they can be numerous (Fig. 2.3). They resemble mine specimen adequacy.66 Because these are large, they
the cells of a well-differentiated adenocarcinoma, but may be mistaken for tumor cells, but their characteristic
are identified as benign mesothelial cells by their rel- multilobulated nuclei permit correct identification.
ative flatness, cohesion, and the characteristic slitlike
“windows” that separate the mesothelial cells from
each other.
Benign Cellular Change
Contaminants of percutaneous fine-needle
aspiration:
Benign Squamous Cell Changes
Benign squamous cells from the oral cavity often con-
• cutaneous squamous cells
taminate sputum and bronchial cytology specimens.
• mesothelial cells
Inflammatory conditions of the mouth caused by
• skeletal muscle
trauma, candidiasis, or pemphigus can exfoliate mildly
• fibroconnective tissue
atypical squamous cells (ASC) with hyperkeratinization
• hepatocytes (transdiaphragmatic needle path)
and nuclear degeneration, usually in small numbers.
Such minimal changes should not be misinterpreted as
If the specimen consists only of one (or more) of these squamous cell carcinoma (SQC). More marked (but still
contaminants, it should be interpreted as insufficient benign) squamous cell atypias occur adjacent to cavi-
for evaluation (nondiagnostic) rather than negative tary fungal infections and stomas, and with almost any
because there is no evidence that the lesion itself has injury to the lung (e.g., infarction, radiation, chemother-
been sampled. apy, sepsis, diffuse alveolar damage), and might result
Figure 2.3 Mesothelial cells (fine-needle aspiration [FNA]). Benign mesothelial cells are occasionally seen in transthoracic fine-
needle aspirates. They are arranged in flat, cohesive sheets. The cells have round or oval nuclei, small nucleoli, and a moderate
amount of cytoplasm, and space between cells—windows—can be appreciated.
Benign Cellular Change 71
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.67
Benign Bronchial Cell Changes

Benign bronchial cell changes occur in response to nox-
ious 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. 2.4). Large clusters of bronchial cells
known as “Creola bodies” (named after the first patient
in whom they were recognized) are commonly seen in Figure 2.6 Goblet cell hyperplasia (bronchial brushing). In
this group of benign bronchial cells, goblet cells, which have
chronic airway diseases like asthma (Fig. 2.5). Goblet
abundant mucin-filled cytoplasm, outnumber ciliated cells. The
cells can also proliferate and exfoliate as large sheets or normal ratio of goblet cells to ciliated cells is altered in chronic
diseases such as asthma and chronic bronchitis.
rounded clusters composed almost exclusively of goblet

cells (Fig. 2.6). Goblet cell hyperplasia is a particularly
notorious mimic of bronchioloalveolar carcinoma.
Marked benign bronchial cell changes (anisonucleo-
sis, Creola bodies, goblet cell hyperplasia) mimic those of
adenocarcinoma. Malignancy can be excluded if the atyp-
ical cells have cilia 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.
Figure 2.4 Reactive bronchial cells (bronchial brushing). Bronchial Reserve Cell Hyperplasia
Reactive bronchial cells may show marked nuclear size variation.
Note that cilia—evidence of their benign nature—are retained. 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. 2.7).
Cytomorphology of reserve cell

hyperplasia:
• tightly packed cells
• small cells
• smudged dark chromatin
• nuclear molding
• scant cytoplasm
• no mitoses or necrosis
Reserve cell hyperplasia (RCH) is a mimic of small

cell carcinoma but is usually easily distinguished from it.
The cells of reserve cell hyperplasia show greater cohe-
siveness; they are smaller; have smudged chromatin;
and there are no mitoses or necrosis.
Figure 2.5 Reactive bronchial cells (Creola body; bronchial
washing). In chronic lung diseases, as in this case of asthma,
clusters of reactive bronchial cells may assume a spherical shape Repair
and resemble adenocarcinoma. Normal nuclear features and
cilia indicate their benign nature. Eosinophils, a common find- Repair represents reepithelialization of an ulcer created
ing in patients with asthma, are also present. by trauma, radiation, burns, pulmonary infarction,
Figure 2.7 Reserve cell hyperplasia (bronchial brushing).

These clusters of benign cells have hyperchromatic nuclei with
nuclear molding. They are distinguished from small cell carci-
noma (SMC) by their extremely small size and lack of necrosis. Figure 2.8 Type II pneumocyte hyperplasia (bronchoal-
Compare these cells with the adjacent bronchial columnar cells. veolar lavage [BAL]). In patients with acute lung injury, type
II pneumocytes are markedly enlarged and may mimic adeno-
carcinoma, as seen here. This patient had diffuse infiltrates and
and infections. Typical (and “atypical”) repair of the marked respiratory distress resulting from diffuse alveolar dam-
respiratory tract is similar to that seen in the cervix and age. In this clinical setting, an unequivocal diagnosis of malig-
gastrointestinal (GI) tract. nancy should be avoided, inasmuch as most patients with lung
cancer are not acutely ill at presentation.
Cytomorphology of repair:
When floridly hyperplastic, as in diffuse alveolar
• flat, cohesive sheets
amage, the cells of type II pneumocyte hyperplasia
d
• abundant cytoplasm
resemble those of adenocarcinoma (Fig. 2.8).
• enlarged, often hypochromatic nuclei
• enlarged nucleoli
Cytomorphology of type II
• mitoses
pneumocyte hyperplasia:
• single cells and three-dimensional clusters
• large nuclei
Reparative epithelium is most commonly seen
• coarse chromatin
in tracheobronchial brushings and washings. The
• prominent nucleoli
differential diagnosis of repair includes malignancy:
• scant to abundant cytoplasm
the non–small cell lung cancers, a metastasis, and
other less common tumors. Malignant cells are usually
less cohesive and orderly than reparative epithelium, The only clue to avoiding an incorrect diagnosis of
and malignant cells are usually more numerous. malignancy in a patient with type II pneumocyte hyper-
Correlation with clinical history can be helpful; a con- plasia may be the clinical history of respiratory distress
servative approach is recommended if the findings and diffuse infiltrates. Thus, in a patient who is acutely ill
are not conclusive, and there is a history of mucosal with diffuse pulmonary infiltrates, markedly atypical cells
trauma or other lung injury. should be interpreted cautiously.33 Sequential respiratory
specimens can be helpful, inasmuch as hyperplastic
Type II Pneumocyte Hyperplasia pneumocytes are not present in BAL specimens more
than 1 month after the onset of acute lung injury.32
Because type II pneumocytes function as alveolar
reserve cells, they proliferate after lung injury.
Noncellular Elements and
Causes of type II pneumocyte hyperplasia: Specimen Contaminants
• pneumonia
• sepsis (diffuse alveolar damage) Noncellular and extraneous elements in respiratory
• pulmonary embolus with infarction material can be inhaled, produced by the host, formed
• chemotherapeutic drugs as a host response to foreign material, or introduced as
• radiation therapy laboratory contaminants.
• inhalant damage (e.g., oxygen toxicity) Curschmann spirals are coiled strands of mucus. With
• interstitial lung disease the Papanicolaou stain, they appear as distinctive purple
helices (Fig. 2.9). In the past they have been associated
Noncellular elements and specimen contaminants 73
architecture, like primary pulmonary adenocarcinoma,

mesothelioma, metastatic thyroid or ovarian cancer.
They are also seen in benign conditions like pulmonary
tuberculosis and alveolar microlithiasis.
Corpora amylacea are spherical structures with cir-
cumferential and radiating lines. They measure between
30 and 200 mm and are indistinguishable from those seen
in the prostate. They have no known significance but are
more commonly seen in older individuals (Fig. 2.11).
Amorphous protein in respiratory specimens may
be a clue to the diagnosis of amyloidosis or alveolar
proteinosis.
Specimen contaminants include vegetable matter
Figure 2.9 Curschmann spiral (sputum). These coils of inspis- (Fig. 2.12), pollen, and the pigmented fungus Alternaria
sated mucus are commonly seen in respiratory specimens and (Fig. 2.13A and B).
are a nonspecific finding.
with chronic respiratory diseases, but they are, in fact,

a nonspecific finding and not worth mentioning in the
report. (Mentioning them might only cause puzzlement.
Like some Hollywood celebrities, they are strikingly
beautiful and equally irrelevant.)
Ferruginous bodies are mineral fibers encrusted with
ferroproteins. Dumbbell-shaped, ranging from 5 to 200
mm in length, they stain golden-yellow to black with
Papanicolaou stains. Some but not all ferruginous bod-
ies contain a core of asbestos. So-called asbestos bodies
are distinguished from other ferruginous bodies by their
clubbed ends and thin, straight, lucent core. Asbestos
fibers are not visible by light microscopy but are usually Figure 2.11 Corpora amylacea (bronchoalveolar lavage
much more numerous than asbestos bodies. Patients [BAL]). These large acellular bodies are somewhat variable in
with known asbestos exposure usually have high num- appearance. They may be spherical, as seen here, or angulated.
bers of ferruginous bodies in BAL fluid.68 They have fine radial striations and may have concentric lamina-
tions. Occasionally, there may be a central pigmented core. They
Charcot-Leyden crystals are rhomboid-shaped, orange- are produced in the lung and other organs and have no known
ophilic structures derived from degenerating eosinophils significance. Pulmonary corpora amylacea are not calcific, dis-
in patients with severe allergic disorders like asthma tinguishing them from psammoma bodies and the laminated
(Fig. 2.10). spheres of pulmonary alveolar microlithiasis.
Psammoma bodies are concentrically laminated cal-
cifications seen in malignant tumors that have papillary
Figure 2.12 Vegetable cells (sputum). Some vegetable cells

have elongated shapes and large nuclei, resembling the cells of
Figure 2.10 Charcot-Leyden crystal (bronchial washing). keratinized squamous cell carcinoma (SQC). Their rectangular
This needle-shaped crystal from a patient with asthma is a by- shape, uniform size, and refractile cellulose wall, however, help
product of eosinophil degranulation. identify them as vegetable cells.
A B
Figure 2.13 Alternaria (bronchoalveolar lavage [BAL]). This pigmented fungus is rarely pathogenic. It can contaminate virtually
any cytologic specimen, including cervicovaginal smears, cerebrospinal fluid, and urine. A, The slender septate stalks (conidiophores)
are occasionally branched (not shown). B, The conidia are snowshoe-shaped and have both transverse and longitudinal septations.
Infections endothelial cells, and fibroblasts (see Table 2.1). The

diagnosis can be confirmed by viral culture, immuno-
Cytology plays an important role in diagnosing infectious histochemistry, in situ hybridization, or the polymerase
diseases, particularly those in patients who are immuno- chain reaction.69-71
compromised, and is being used more frequently than
ever because of improved sampling methods. It is impor-
Measles Virus and Respiratory
tant to know that conventional inflammatory responses
Syncytial Virus
can be much reduced, absent, or greatly altered in
patients with immune deficiencies. Measles is a highly contagious, usually self-limited dis-
ease caused by the rubeola virus. The incidence has been
curtailed as a result of the widespread use of a vaccine.
Viral Infections However, measles pneumonia occurs as an opportu-
Herpes Simplex nistic complication in children who are immunocom-
promised as a result of premature birth, cystic fibrosis,
Herpes simplex virus (HSV) pharyngitis, laryngotrache-
malignancy, or an immunologic disorder. Infection
itis, and pneumonia most commonly affect patients and
causes a giant cell pneumonia characterized by enor-
neonates who are immunocompromised, and HSV-1 is
mous multinucleated cells with cytoplasmic and nuclear
the most common serotype to involve the respiratory
inclusions (see Table 2.1, Fig. 2.14).72 Similar findings are
tract. Ulcerative or necrotizing infections can involve the
seen with infection by the respiratory syncytial virus
pharynx, larynx, tracheobronchial tree, or pulmonary
(RSV). The diagnosis is usually confirmed by detecting
parenchyma, and cytopathic changes are identical to
respiratory syncytial virus antigen in BAL specimens.
those seen in other sites: multinucleation, nuclear mold-
ing, chromatin margination, and large nuclear (Cowdry A)
inclusions (Table 2.1). The cytopathic changes of herpes Adenovirus
simplex virus are identical to those of herpes zoster. If
Adenovirus infection usually produces only a minor
the cytomorphologic changes are equivocal, the diag-
febrile illness, but adenovirus pneumonia can be severe
nosis can be confirmed by viral culture, immunohisto-
and fatal, particularly in patients who are immunocom-
chemistry, or in situ hybridization.69
promised. The virus causes two types of nuclear inclu-
sions. One is the smudge cell, in which a large basophilic
Cytomegalovirus
inclusion usually fills the entire nucleus and obscures
Cytomegalovirus (CMV) is one of the most common of chromatin detail. The other is eosinophilic inclusions
opportunistic infections. Patients with cytomegalovirus that resemble the Cowdry A inclusion of herpes simplex
pneumonia often present with fever, dyspnea, cough, virus infection. A curious morphologic decapitation of the
and diffuse nodular or reticular interstitial infiltrates. ciliated columnar cells, called ciliocytophthoria, can be
Viral cytopathic changes (cytomegaly, large basophilic prominent.73 The detached cell apex, represented by only
nuclear and small basophilic cytoplasmic inclusions) are the terminal bar and cilia, without its nucleus, resembles
found in bronchial cells, pneumocytes, macrophages, a floating tuft of hair or eyelash (see Table 2.1).
Infections 75
Table 2.1 Pulmonary Viral Infections

Virus Nuclear Features Inclusions Other Changes
Herpes simplex Multinucleation; molding; Eosinophilic, intranuclear —
and herpes peripheral margination (Cowdry type A)
zoster of chromatin
Cytomegalovirus Enlargement Large intranuclear, basophilic, Cytoplasmic enlargement
with halo; small cytoplasmic,
basophilic
Measles virus Multinucleation Eosinophilic, intranuclear; Giant cells

multiple eosinophilic
intracytoplasmic
Respiratory Multinucleation Cytoplasmic, basophilic, Giant cells; necrosis

syncytial virus with halo
Adenovirus Smudged appearance as a Large intranuclear, basophilic Ciliocytophthoria

result of large inclusion
that fills entire nucleus
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. Actinomy
ces species are a common inhabitant of the tonsil-
lar area and thus a common contaminant of sputum
and bronchial specimens (but not FNAs). Infection
by Actinomyces, however, is surprisingly 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 neutro-
Figure 2.14 Measles virus cytopathic effect (bronchoalve- philic response.When they appear in cytologic specimens
olar lavage [BAL], cell block). Measles virus infection causes as just an oral contaminant, Actinomyces bacteria are
pneumonia with giant multinucleated epithelial cells that have
large blue “cotton balls” often associated with squamous
eosinophilic intranuclear and intracytoplasmic inclusions. These
cells are pathognomonic. cells, with no neutrophilic infiltrate, similar to what is
occasionally encountered in Pap specimens (see Fig. 1.23).
A true thoracopulmonary actinomycosis should be con-
Bacterial Pneumonias sidered if the bacteria are associated with abundant
Bacterial pneumonias are caused by a large number of neutrophils.
bacteria, but most are characterized by a neutrophilic Nocardia are aerobic, filamentous bacteria that
exudate. Common organisms include Streptococcus inhabit the soil and are acquired by inhalation. N.
pneumoniae (pneumococccus), other Streptococci, asteroides accounts for 80% of nocardial infections.
Staphylococcus aureus, Haemophilus influenzae, Most patients are immunocompromised and have a
Klebsiella pneumonia, Pseudomonas sp., Legionella subacute presentation. Cavitary nodules are seen in
sp., Nocardia sp., Actinomyces sp., and some anaero- one third of patients. The organisms are found among
bic bacteria. Many but not all bacteria can be seen with abundant neutrophils. They are thin, filamentous, and
routine stains and with the Gram stain. Cytologic exam- beaded, with such extensive, predominantly right-
ination is not usually employed for the diagnosis of a angle branching that they resemble Chinese charac-
bacterial pneumonia, which is typically established by ters. They are gram-positive and stain with silver stains,
correlating clinical findings with microbiologic studies. but are only weak acid-fast and thus require modified
Bacterial pneumonias often have a characteristic lobar acid-fast stains like the Fite-Faraco for visualization.
or lobular distribution, but some pneumonias appear The diagnosis is established by culture of a biopsy or
as round and circumscribed masses on imaging studies BAL fluid.
Legionella pneumonia is caused by the aerobic gram- be an abundance of acid-fast organisms but few well-
negative bacteria Legionella sp., of which the most formed granulomas. If Romanowsky-type stains are used
common is L. pneumophila. The organisms are seen in such cases, the abundant acid-fast organisms can be
well with silver stains like the Steiner, Warthin-Starry, or identified as negative images.
Dieterle stains. A specific identification of L. pneumoph-
ila can be made in BAL samples using immunohisto-
chemical or immunofluorescent methods.
Pulmonary Fungal Infections
Pulmonary fungal infections are readily diagnosed by
cytology, particularly in transthoracic FNAs, and should
Tuberculosis be suspected whenever there is granulomatous inflam-
Infection by M. tuberculosis commonly results in granu- mation or necrosis. Cell block material can be used for
lomatous inflammation (Fig. 2.15). Cytologic specimens silver or periodic acid-Schiff (PAS) stains. Many fungi
contain aggregates of epithelioid histiocytes, lympho- have a characteristic microscopic appearance that
cytes, and Langhans giant cells. Necrosis may or may not enables a rapid, specific diagnosis (Table 2.2).
be evident. Granulomas by themselves, however, are a
nonspecific finding and can be seen in other conditions
Cryptococcosis
like fungal infections and sarcoidosis. A definitive dia
gnosis of tuberculosis rests on identifying the organ- Cryptococcus neoformans is an inhabitant of the soil and is
isms with the help of a special stain (Ziehl-Neelsen) or found in bird droppings. It can act as both a primary and
by microbiologic culture. Cell block preparations are an opportunistic pathogen and may involve numerous
particularly useful for special stains, but rarely are more body sites. Pulmonary invasion by this fungus is heralded
than one or just a few organisms identified. (By contrast, clinically by a productive cough, fever, and weight loss.
infection by M. avium intracellulare, as seen in patients
who are immunocompromised patients, often yields
Histoplasmosis
innumerable acid fast organisms.) A sensitive (93%)
and specific (99%) assay called the Mycobacterium Histoplasma capsulatum, another soil inhabitant, is con-
Tuberculosis Direct Test (MTD) is also available for the tracted by the inhalation of spores and more commonly
detection of M. tuberculosis and can be applied to respi- affects patients who are immunocompromised. The dis-
ratory specimens like sputum.74 The assay amplifies ease can mimic tuberculosis clinically, in that peripheral
M. tuberculosis ribosomal ribonucleic acid (RNA) by the nodular lesions and mediastinal lymphadenopathy are
polymerase chain reaction. relatively common. The organism, often present within
In countries where M. tuberculosis is prevalent, the the cytoplasm of macrophages, is so small that it may be
yield of acid-fast bacteria among all clinically suspi- overlooked if silver stains are not used.
cious lung masses can be quite high.75,76 In patients who
are immunocompromised with tuberculosis, there may
Blastomycosis
Blastomyces dermatitidis inhabits wooded terrain.
Although the lung is the primary target of infection,
there may be distant spread to other organs, such as
skin, bone, and the urinary tract.
Coccidioidomycosis
Coccidioides immitis infection is quite common in
endemic areas of the Southwest and Western United
States, giving rise to positive skin tests in more than
80% of individuals in these areas. It produces a respira-
tory infection that usually resolves spontaneously, but
persists as a pulmonary mass in about 2% of patients.
Multiorgan dissemination is more common in the
patient who is immunocompromised. Because BAL
Figure 2.15 Granuloma (fine-needle aspiration [FNA], or bronchial washings detect less than 50% of culture-
M. tuberculosis infection). The nodular aggregate of epithe- positive cases,77 cytologic diagnosis is best documented
lioid histiocytes, which defines the granuloma, has a syncytial
appearance because individual cell borders are indistinct. Note by transthoracic FNA. The organisms appear as mature
the curved and elongated, boomerang shape of some of the (sporulating) or immature spherules, often with a frac-
histiocytic nuclei. Interspersed lymphocytes can also be seen. tured (broken ping-pong ball) appearance, and free
Infections 77
Table 2.2 Pulmonary Fungal Infections

Disease Organism Demographics Morphology Size Immunocompetent Appearance
Response
Cryptococcus Cryptococcus Worldwide Yeast; variably sized; 4–15 μm Granulomatous

neoformans narrow-based (diameter)
budding; mucin
capsule (immuno
competent);
refractile center
Histoplasmosis Histoplasma Americas, Small budding yeast; 1–5 μm Granulomatous
capsulatum especially intracellular (diameter)
Ohio and
Mississippi
river valleys
Blastomycosis Blastomyces North Broad-based 8–20 μm Neutrophilic/
dermatitides America budding yeast; (diameter) granulomatous
thick cell wall
Coccidioido- Coccidioides North Spherules; 15–60 μm; Granulomatous
mycosis immitis American endospores 1–2 μm
deserts (diameter)
Paracoccidioido- Paracoccidioides Central and Yeast with multiple 4–40 μm Neutrophilic/
mycosis braziliensis South budding (diameter) granulomatous
America (“mariner’s
wheel”)
Sporotrichosis Sporothrix Worldwide Intracellular ovoid 2–4 μm Neutrophilic/
schenkii yeast with slight (diameter) granulomatous
halo
Aspergillosis Aspergillus Worldwide Hyphae septate; Hyphae Tissue/vascular
fumigatus; 45-degree angle 10–30 μm invasion;
A. flavus branching; (width) colonization;
occasional fruiting fungus balls
bodies in cavities
Phycomycosis Mucor; Absidia; Worldwide Hyphae variably Hyphae Tissue/vascular
(Zygomycosis) Rhizopus; sized, ribbon- 10–30 μm invasion
Cunninghamella like nonseptate; (width)
90-degree angle
branching
Candidiasis Candida albicans; Worldwide Budding yeast 2–10 μm Respiratory space
C. tropicalis; forming (width) colonization;
C. glabrata pseudohyphae tissue invasion
(“sausage links”)
endospores (see Table 2.2). These are present on a back- erroneous diagnosis of SQC in cytologic material (see
ground of granular eosinophilic debris with little inflam- Fig. 2.25).80 There is a high sensitivity (50% to 90%) for
mation. Hyphae are seen in 5% of cases. FNA cytology the detection of the organism in cell block preparations
is diagnostically far superior to the culture of aspirated of sputum.81
materials.78
Sporotrichosis
Paracoccidioidomycosis
Pulmonary infection caused by Sporothrix schenckii
Paracoccidioidomycosis, also known as South American is uncommon and occurs mainly in patients who are
blastomycosis, is caused by the dimorphic fungus immunocompromised, including diabetics and alcohol-
Paracoccidioides brasiliensis (Fig. 2.16) and is the most ics. The clinical symptoms are nonspecific. Though often
common systemic mycosis in Latin America.79 It fre- self-limited, these infections can become chronic, with
quently involves the lungs and mucocutaneous areas mass lesions or cavitary nodule formation. The yeasts
of healthy individuals, and clinically simulates tubercu- resemble Cryptococcus, Histoplasma, and Candida, and
losis. There may be a hyperplasia of the bronchial epi- therefore culture or fluorescent antibody staining is
thelium overlying granulomas, which may lead to the necessary for definitive diagnosis.82
dry cough, fever, and dyspnea. Pulmonary infiltrates are

usually bilateral.
The organisms are well demonstrated in BAL mate-
rial, which has a sensitivity that compares favorably
with transbronchial biopsy.86 They can also be detected
in bronchial washings and induced sputum.87 With
Papanicolaou stains, the organisms themselves are not
visible, but masses of organisms enmeshed in protein-
aceous material result in green, foamy alveolar casts
that are more circumscribed than debris or lysed red
blood cells (Fig. 2.17A). The cysts are visualized with sil-
ver stains. They are cup-shaped, measure 5 to 7 μm in
diameter, and often have a central dark zone (Fig. 2.17B).
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
Figure 2.16 Paracoccidioidomycosis. This silver stain high- or trophozoites are stained as discrete blue dots either
lights the ship’s wheel appearance of yeast forms budding off of
within the cysts or as free organisms (Fig. 2.17C). In some
the central parent yeast. The resemblance of the broad-based
budding pattern to that of Blastomyces species is the reason for cases, the foamy alveolar casts are absent, and the organ-
its alternative term, South American Blastomycosis. isms may be present only in vacuolated macrophages.88
Direct immunofluorescence has higher sensitivity
(up to 92%) than the Giemsa, toluidine blue, and silver
Invasive Fungi
stains.89,90 Application of this method to induced spu-
This subgroup of fungi characteristically invades pul- tum (Fig. 2.17D) is the preferred initial diagnostic step
monary tissue, especially blood vessels, of patients who because it is noninvasive and highly accurate.
are immunocompromised. These organisms are readily
diagnosed by transthoracic FNA.
Aspergillosis. Aspergillus species can cause a vari-
Strongyloidiasis
ety of pulmonary disorders. Bronchopulmonary asper- Pulmonary strongyloidiasis is caused by the nematode
gillosis is characterized by the expectoration of mucus Strongyloides stercoralis. It can affect persons who are
plugs containing fungal organisms, numerous eosino- immunocompetent but is more common in patients
phils, and Charcot-Leyden crystals. When invasive, there who are immunosuppressed and presents as a pneumo-
may be hemorrhagic necrosis caused by mycelial inva- nitis with hemoptysis. Infection of the lungs is caused by
sion of vessels. In cavitary lesions, the organisms sporu- the hematogenous migration of the infective larva (filar-
late, producing fruiting heads, and are associated with iform larva) from the gut or skin. Histologically, there is
polarizable calcium oxalate crystals. There may be an a hemorrhagic pneumonia. This organism is identified
associated squamous cell atypia (Fig. 2.25) that can be in sputum or bronchial material by its large size and is
indistinguishable from carcinoma, making clinical cor- differentiated from other hookworms by its notched tail
relation imperative.34 and short buccal cavity (Fig. 2.18).
Zygomycosis. Zygomycosis is caused by several
mycelia-forming fungi, including Mucor, Absidia,
Cunninghamella, and Rhizopus. They are angioinvasive
Dirofilariasis
and often cause infarctions in patients who are debilitated. Dog heartworm (Dirofilaria immitis) infection of the
Candidiasis. Candida pneumonia is a common oppor human lung has been documented by FNA.91 This micro-
tunistic infection. An elevated level of Candida antigen in filarial disease is transmitted from dogs to humans via
BAL fluid suggests true infection rather than colonization.83 mosquitos, resulting in entrapment within small pul-
monary vessels and subsequent pulmonary infarction.
Diagnosis is made by aspiration of the discrete periph-
Pneumocystis carinii
eral nodule, which shows necrotic material, fragments
The taxonomy of this organism has been debated, but of infarcted pulmonary tissue, chronic inflammation, a
microbiologists favor classifying it as a fungus, based granulomatous response, and rarely the worm itself.
in part on molecular evidence.84,85 The pneumonia
caused by Pneumocystis carinii is particularly common
in individuals who are immunocompromised but has
Echinococcosis (Hydatid Disease)
decreased in frequency in these patients since the advent The clinical and cytologic features of Echinococcosis
of novel therapies.27 The clinical presentation includes are described in Chapter 12 (see Fig. 12.4). Sputum
Non-Neoplastic, Noninfectious Pulmonary Diseases 79
A B
C D
Figure 2.17 Pneumocystis carinii (bronchoalveolar lavage [BAL]). A, With the Papanicolaou stain, the pneumocystis organisms
are not seen, but foamy proteinaceous spheres characteristic of this infection are identified. B, The cysts, which have a cup-shaped
configuration and a central dark zone, are seen with the methenamine silver stain. C, The Giemsa stain outlines the cysts as nega-
tive images, and stains the intracystic bodies or trophozoites. Each cyst, as seen here, contains eight intracystic bodies. D, The direct
immunofluorescence test is highly sensitive, revealing green fluorescent-stained organisms and their extracellular products.
may contain scoleces if pulmonary hydatid cysts rup-

ture. Because of the risk of anaphylactic shock, aspi-
ration of a clinically suspected hydatid cyst may be
hazardous.52,92
Non-Neoplastic,
Noninfectious Pulmonary
Diseases
Sarcoidosis
This common disease of unknown etiology is character-
Figure 2.18 Strongyloides (sputum). These large round- ized by noncaseating granulomas in many organs, most
worms are distinguished by their short buccal cavities (arrow). commonly the lung.
helpful to substantiate the diagnosis with serologic stud-

Cytomorphology of sarcoidosis:
ies. The serum immunofluorescent antineutrophil cyto-
• aggregates of epithelioid histiocytes plasmic antibody (ANCA) test greatly aids in establishing
• multinucleated giant cells the diagnosis of Wegener granulomatosis. Although the
• lymphocytes classic (cytoplasmic) pattern (c-ANCA) is considered
more specific, neither the c-ANCA nor the perinuclear
Cytologic specimens show noncaseating granulo- (p-ANCA) pattern is entirely sensitive or specific for the
mas comprised of epithelioid histiocytes, with scattered diagnosis of Wegener granulomatosis.94
lymphocytes and multinucleated, giant histiocytes (see
Fig. 2.15).93 The epithelioid histiocytes have round,
oval, curved (boomerang-shaped), or spindle-shaped
Pulmonary Amyloidosis
nuclei, with translucent, vacuolated cytoplasm. The Pulmonary amyloidosis can be limited to the lung or
epithelioid histiocytes are haphazardly arranged in a represent a localized manifestation of systemic disease.
pseudosyncytial pattern. Although it can affect a wide age range, most patients are
in their 50s and 60s. Pulmonary amyloidosis can manifest
itself as nodular parenchymal amyloidosis (a mass lesion
Wegener Granulomatosis whose imaging characteristics mimic those of a neoplasm
This necrotizing vasculitis may present clinically as a lung or granulomatous disease, hence “amyloid tumor”);
mass with or without involvement of other organs like the tracheobronchial amyloidosis (in which the deposits are
nasal passages and kidneys. The histologic diagnosis of mostly submucosal and result in dyspnea, wheezing, and
Wegener granulomatosis (WG) rests on the identification recurrent pneumonia); or diffuse parenchymal amyloido-
of necrosis, granulomatous inflammation, and vasculitis. sis (with diffuse or multifocal deposits).
FNA yields irregular, waxy, amorphous, hypocellular
Cytomorphology of Wegener material with a scalloped, occasionally cracked appear-
granulomatosis: ance (see Fig. 9.11). These deposits appear blue-green
on Papanicolaou stains and show apple-green dichro-
• neutrophils
ism under polarized light after staining with the Congo
• giant cells
red stain. In the nodular parenchymal type there may
• necrotic collagen (“pathergic necrosis”)
be multinucleated giant cells, and calcification and
• epithelioid histiocytes
ossification are common.
The cytomorphologic findings are nonspecific but

include chunks of necrotic tissue (Fig. 2.19), giant cells,
Pulmonary Alveolar Proteinosis
granulomas, and neutrophils. The differential diag- Pulmonary alveolar proteinosis (PAP) is a rare disease
nosis includes a necrotizing infection (e.g., tubercu- characterized by an accumulation of a lipid-rich mate-
lous, fungal), lymphomatoid granulomatosis, and other rial within alveoli. Pulmonary alveolar proteinosis is
uncommon pulmonary diseases. Thus, if suspected on most likely the result of impaired macrophage function
the basis of characteristic cytomorphology, it can be as a result of the production of neutralizing auto-anti-
bodies to granulocyte-macrophage-colony-stimulating
factor (GM-CSF).95,96 Pulmonary alveolar proteinosis can
also be secondary to a number of conditions like HIV
infection or lung transplantation.94
The onset is insidious, and one third of patients are
asymptomatic despite impressive radiologic abnormali-
ties. There can be a nonproductive cough, dyspnea, and
expectoration of gelatinous material. Examination of
BAL specimens can be helpful. The characteristic find-
ings include an opaque, milky gross appearance; large,
acellular, eosinophilic, blobs that are positive for periodic
acid-Schiff (Fig. 2.20); and pulmonary macrophages filled
with material that is positive for periodic acid-Schiff. The
differential diagnosis includes pulmonary edema, P. cari-
nii pneumonia, and alveolar mucinosis. The diagnosis
Figure 2.19 Wegener granulomatosis (fine-needle aspira- is made by correlating clinical findings with laboratory
tion [FNA]). A bend-like, granular background debris consisting results and characteristic cytologic findings. Symptomatic
of necrotic collagen without acute inflammation is characteristic. patients are treated with whole lung lavage.
Benign Neoplasms of The Lung 81
Figure 2.20 Pulmonary alveolar proteinosis (bronchoalveolar lavage [BAL]). Hematoxylin-eosin (H & E) stained cell block sections
show numerous acellular eosinophilic aggregates.
hamartomas are discovered incidentally as a solitary

Common Inflammatory Processes discrete, round mass in the lung periphery on thoracic
There is considerable overlap in the cytologic features of imaging studies. Less commonly, they are central and
common pulmonary diseases like organizing pneumo- endobronchial; multiple hamartomas are rare.
nia (Fig. 2.21A and B), bronchiolitis obliterans obstruct-
ing pneumonia, diffuse alveolar damage, and transplant Cytomorphology of pulmonary
rejection. All show variable numbers of inflammatory hamartoma:
cells such as macrophages, neutrophils, eosinophils,
• benign glandular cells
and lymphocytes.97-101 Reactive pneumocytes are espe-
• immature fibromyxoid matrix and bland spindle
cially prominent in organizing pneumonia and diffuse
cells
alveolar damage (see Fig. 2.8).
• mature cartilage with chondrocytes in lacunae
As pneumonias organize, they can mimic mass lesions.
• adipocytes
Occasionally, the granulation tissue in these lesions may
resemble Masson bodies (see Fig. 2.21B).
In the setting of lung transplantation, BAL is a FNA specimens show a mixture of mesenchymal
routine monitoring procedure, especially for detecting (mainly fibromyxoid and cartilaginous material) and epi-
infections, the most common of which are Candida, thelial elements (Figs. 2.22A and B). In some hands, FNA
cytomegalovirus, and herpes simplex.102 Neutrophils has a sensitivity of 78% and a specificity of 100% in the
are normally seen within the first 3 months of trans- diagnosis of a hamartoma.105 A nationwide self-assess-
plantation,101 and increased numbers of macrophages ment testing program, however, revealed a general lack of
for years after the transplant. familiarity with this lesion, with a troubling false-positive
rate (22%). The most common misdiagnoses were carci-
noid tumor, adenocarcinoma, and small cell carcinoma.106
Benign Neoplasms of Hamartoma should be considered for any well-circum-
scribed neoplasm that contains epithelial cells.
The Lung
Pulmonary Hamartoma Inflammatory Myofibroblastic Tumor

Despite their time-honored name, pulmonary hamar- Inflammatory myofibroblastic tumor (IMT), once
tomas are, in fact, neoplasms. Recurrent clonal rear- known as inflammatory pseudotumor, is a neoplasm
rangements have been identified involving the HMGI(Y) of cytologically bland spindle cells that occurs in the
gene on chromosome 6p21.103,104 Most pulmonary lungs and at other sites. It is most common under the
A B
Figure 2.21 Organizing pneumonia (fine-needle aspiration [FNA]). Some pneumonias respond slowly to antibiotic treatment;
such lesions may mimic a neoplasm radiographically. A, Smears typically show an admixture of lymphocytes and foamy macrophages.
B, Cell block preparations show fragments of granulation tissue composed of loosely arranged fibroblasts admixed with chronic
inflammatory cells.
age of 40. IMT is usually a peripheral, discrete, solitary eosinophilic cytoplasm and are surrounded by a thick-
nodule. These tumors behave unpredictably: most patients ened basement membrane.
have an excellent prognosis, but some tumors are locally
aggressive.107 The neoplastic nature of this lesion was Cytomorphology of endobronchial
confirmed by the cloning of translocations involving the granular cell tumor:
anaplastic lymphoma kinase (ALK) gene (chromosome
• small clusters of macrophage-like cells
2p23) and the two tropomyosin genes, TPM3 and TPM4.108
• abundant granular cytoplasm
Anaplastic lymphoma kinase fusion partner variants
• small, uniform, round to oval nuclei
include the clathrin heavy chain gene109 and ATIC gene.110
Cytomorphology of inflammatory On cytologic preparations, the cells are easily over-

myofibroblastic tumor: looked because of their similarity to macrophages (see
Fig. 16.33).112,113
• spindle cells
• storiform pattern
• polymorphous inflammatory cells Preneoplastic Changes of
• minimal if any necrosis
The Respiratory Epithelium
Cytologic preparations show bland spindle cells SQC of the lung is preceded by a precursor lesion akin to
arranged as fascicles or in a storiform pattern.111 There that of cervical cancer, with a progression from benign
is little pleomorphism and few mitoses. Admixed with squamous metaplasia through dysplasia to invasive can-
the spindle cells is an impressive infiltrate of inflam- cer. Unlike cervical cancer, however, lung cancer is only
matory cells, including lymphocytes, plasma cells, his- rarely associated with human papillomavirus (HPV)
tiocytes, and Touton-type giant cells (defined as having infection,114 and there is no successful method to screen
a peripheral ring of nuclei). The differential diagnosis for and treat precursor pulmonary lesions. Aberrant
includes an organizing pneumonia and sarcomatoid expression of specific cancer-associated proteins like p53
carcinoma. and the epidermal growth factor receptor (EGFR) tyrosine
kinase in dysplastic respiratory epithelium precedes the
development of invasive carcinoma.115,116 Although the
precursor lesions are not as well defined as they are for
Endobronchial Granular Cell Tumor the uterine cervix, most authors acknowledge degrees (mild,
Endobronchial granular cell tumors account for a small moderate, severe) of dysplasia. While, the classification of
proportion of all granular cell tumors, which are thought dysplasia is subjective,117 the risk of developing broncho-
to originate from Schwann cells. They are usually covered genic carcinoma increases with the degree of atypia, which
by bronchial epithelium and are composed of clusters of is paralleled by the development of aneuploidy.118 More
tumor cells with small nuclei and abundant, granular, than 40% of patients with dysplasia are later diagnosed
lung cancer 83
B
Figure 2.22 Pulmonary hamartoma (fine-needle aspiration [FNA]). A, Smears from a pulmonary hamartoma show fragments of
myxoid material, chondroid material, or both. Chondrocytes in lacunae, which are green with Papanicolaou’s stain, but unstained on
hematoxylin-eosin (H & E) sections, are seen here. B, Epithelial cells and adipocytes (latter not shown) are also often present.
with SQC.119 Dysplastic changes have been demonstrated sure to tobacco smoking, and, as a result, lung cancer
to regress in experimental systems.120 is more common in developed countries. It is the most
common fatal malignancy in both men and women in
the United States, where it accounts for 31% of all cancer
Lung Cancer deaths in men and 26% in women.121
The causes of lung cancer are many. In men, 85%
Carcinoma of the lung is the most common cancer in the of lung cancers are attributed to cigarette smoking.122
world today. Its geographic distribution parallels expo- Tobacco smoke contains numerous carcinogens, tumor
initiators, and radioactive compounds, but the biologic more important as novel therapies are developed for
mechanism by which tobacco substances initiate lung specific lung cancer subtypes, like adenocarcinomas
cancer is not known. Genetic alterations play an impor- with EGFR mutations.
tant role. Chromosome 3p deletion (seen commonly Lung cancers often show histologic heterogeneity.
in neuroendocrine tumors)118 and p53, K-ras, and p16 Almost 50% of lung cancers contain more than one his-
mutations are common in lung carcinomas.123,124 p53 tologic type.122 Thus, careful examination of all cytologic
mutation, the most frequent mutation in human cancers, material for more than one histologic component is
likely occurs in lung cancer via a G-C to T-A transversion essential for correct classification.
induced by cigarette smoke.125 Exposure to asbestos has
a synergistic effect with smoking: Asbestos workers who
smoke increase their risk of developing pulmonary can-
Squamous Cell Carcinoma
cer by at least 50-fold. The development of lung cancer SQC of the lung accounts for approximately one third of
has been linked to exposure to other substances, includ- all primary pulmonary malignancies. Two thirds of these
ing radon, crystalline silica, nickel compounds, and tumors occur in a central location, and the remainder
organic compounds like benzene and vinyl chloride. arise in smaller bronchi. Postobstructive pneumonia
Universal screening for lung cancer with chest radio- and cavitation of the tumor are common. Of all the his-
graphs and sputum cytology is not cost effective. The tologic subtypes, SQC is the one most commonly asso-
most comprehensive trial in the United States was ciated with hemoptysis. Apical SQCs in the superior
undertaken by three medical centers under the aus- sulcus are called Pancoast tumors, characterized by pos-
pices of the National Cancer Institute. Approximately terior rib destruction and neural invasion, resulting in
30,000 men were screened, and the overall mortality of severe pain and Horner syndrome (enophthalmos, pto-
the screened group was no lower than that of the con- sis, miosis, and ipsilateral decreased sweating). Several
trol group.126 High-risk individuals might benefit from histologic variants (papillary, clear cell, small cell, basa-
periodic screening, however, like workers in the asbes- loid) have been described.122
tos or uranium industries, persons over the age of 65
with a 20-year history of smoking, and those whose Cytomorphology of well-differentiated
radiographs show a persistent abnormality.127 The use squamous cell carcinoma:
of low-dose spiral computed tomography with spu-
tum cytology has shown mixed results;128-132 early can- • abundant dyshesive cells
cer detection comes at the cost of unnecessary benign • polymorphic cell shapes: polygonal, rounded,
nodule detection and removal, and exposure to poten- elongated (fiber-like), tadpole shaped
tially harmful, repeated radiation exposures.128,133 Large, • dense cytoplasmic orangeophilia (Papanicolaou
prospective, multi-institutional trials with high-risk stain)
patients are needed to prove the efficacy of low-dose • pyknotic nuclei
spiral computed tomography with sputum screen- • frequent anucleate cells
ing.134,135 Detection of epigenetic or genetic aberrations
in frequently mutated lung cancer genes (p53, K-ras, The cytologic features vary depending on the degree
p16, HVAL2, FHIT, SFTPC) in sputum samples shows of squamous differentiation. In a well-differentiated
promise but is not yet widely applied.124,136,137 SQC, the malignant cells are dyshesive, come in a variety
Patients with lung cancer often present with shortness of shapes (polygonal, spindle, tadpole, Fig. 2.23A and B),
of breath, cough, chest pain, hoarseness, hemoptysis, or and have abundant smooth and dense cytoplasm that is
pneumonia. Some tumors, particularly adenocarcino- filled with keratin. The cytoplasm stains green, yellow,
mas, are detected incidentally in individuals who are or orange with the Papanicolaou stain and robin’s egg
asymptomatic. blue with Romanowsky stains. Nuclei are usually small,
Four histologic types account for 95% of all pulmo- hyperchromatic, and smudgy, and nucleoli are often
nary tumors: SQC, adenocarcinoma, large cell carci- inconspicuous.
noma (LCC), and small cell carcinoma. Because it is
usually metastatic at the time of detection, small cell Cytomorphology of moderately and
carcinoma is treated with systemic chemotherapy. The poorly differentiated squamous cell
treatment for the non–small cell carcinomas (SQC, carcinomas:
adenocarcinoma, and LCC) is essentially identical: • large, cohesive clusters of elongated cells
lobectomy or pneumonectomy for localized tumors. • rare to absent keratinization
The subclassification of the non–small cell carcinomas • large nuclei
is thus less important than the distinction between • coarse chromatin texture (“Idaho potato”)
non–small cell and small cell carcinoma. Finer distinc- • ± prominent nucleoli
tions (histologic and even molecular) are becoming
Lung Cancer 85
A B
Figure 2.23 Squamous cell carcinoma ([SQC]; fine-needle aspiration [FNA]). A, Well-differentiated SQCs are composed of cells
with dense, orangeophilic cytoplasm and hyperchromatic, often pyknotic nuclei, some with angular contours. B, Bizarre, elongated,
spindle-shaped cells are common. Often there is abundant granular debris, seen here, and inflammation.
In moderately and poorly differentiated SQCs, kera-

tinization is less apparent or absent altogether in the
cytologic sample. The cytoplasm may retain the char-
acteristic dense, smooth appearance of most SQCs, but
in some poorly differentiated SQCs it is scant and less
dense. The nuclei are larger and nucleoli are prominent.
Chromatin, rather than smudgy, is coarsely textured and
resembles the mottled and pitted surface of an Idaho
potato (Fig. 2.24). The basaloid variant of SQC shows
prominent palisading of nuclei around the perimeter of
cell groups.
Differential diagnosis of squamous

cell carcinoma: Figure 2.24 Squamous cell carcinoma ([SQC]; fine-needle
• squamous metaplasia aspiration [FNA]). Poorly differentiated squamous carcinoma
cells are often arranged in thick groups of pulled out, spindled
• degenerative changes cells, rather than as dissociated cells. The nuclei are enlarged,
• reactive squamous atypia (e.g., Aspergilloma) and chromatin is coarsely granular, in contrast to the dense, fre-
• vegetable cells quently pyknotic nuclei of keratinizing SQCs. Often it is impos-
• contamination from an upper airway cancer sible to make a definitive diagnosis of SQC because of lack of
• adenocarcinoma differentiation or excessive group thickness. These difficult cases
should be diagnosed as non-small cell carcinoma.
• LCC
• small cell carcinoma
• metastatic SQC alveolar damage).33,34 To avoid a false-positive, caution
is advised when the atypical squamous cells are few in
Squamous metaplastic cells (from chronic irritation number, poorly visualized, degenerated, or associated
to the bronchial epithelium) are recognizably benign with a stoma, fungal infection, or any manner of severe
because of their small, round, normochromatic nuclei. lung injury. Vegetable food particles occasionally res
In sputum samples, degenerative changes impart a pyk- emble keratinized squamous cells, but their cellulose
notic, condensed appearance to the nuclei of benign wall and the regularity of their shape usually permit cor-
squamous cells that mimics the pyknotic, smudgy rect identification (see Fig. 2.12). Occasionally, malignant
nuclei of SQC. Benign degenerated nuclei, however, cells from an SQC of the upper airway may contaminate
are small and do not vary in size and shape as much a specimen of the lower respiratory tract.67
as those of SQC. Reactive squamous cell atypias occur Most SQCs are easily distinguished from most ade-
adjacent to cavitary fungal infections (Fig. 2.25) and nocarcinomas of the lung based on the presence of
stomas, and with almost any injury to the lung (e.g., obvious keratinization, mucin, or gland formation.
infarction, radiation, chemotherapy, sepsis, and diffuse When these tumors are poorly differentiated, however,
Figure 2.25 Atypical squamous metaplasia (fine-needle aspiration [FNA]). Cavitary fungal infections, such as this one by
Aspergillus (inset), are among the causes of reactive squamous atypia, a mimic of squamous cell carcinoma (SQC).
the distinction becomes more difficult. In general,

nuclear chromatin is more finely textured in adenocar-
Adenocarcinoma
cinomas and coarse in SQCs. The cytoplasm is thinner Adenocarcinoma is the most common histologic sub-
and more vacuolated in adenocarcinomas, and denser type of lung cancer. The majority occur in the periphery
in SQCs. Histochemistry for mucin (mucicarmine and of the lung and are often associated with a desmoplas-
periodic acid-Schiff-D) and immunohistochemis- tic reaction and pleural puckering. Of all the histologic
try for p63 can be helpful. Although focal intracellular types, adenocarcinomas are most likely to be discov-
mucin can be seen in SQCs of the lung,122 more abun- ered incidentally in an asymptomatic individual. Some
dant mucin is diagnostic of adenocarcinoma, whereas are detected based on clinically evident metastases.
immunoreactivity for p63 is typical of SQC. The possi- Adenocarcinomas rarely show cavitation.
bility that both components are present (i.e., that the The significant morphologic heterogeneity of pul-
tumor might be an adenosquamous carcinoma) should monary adenocarcinomas is reflected in the number
be considered. If a definite distinction cannot be made, of histologic variants recognized by the World Health
the interpretation “Non–small cell carcinoma” may be Organization (WHO): acinar, papillary, bronchioloal-
most appropriate. This applies equally well to those veolar, solid with mucin production, fetal, mucinous
cases of poorly differentiated SQC that are difficult to (“colloid”), mucinous cystadenocarcinoma, and clear
distinguish from an LCC. cell.122 The most common (80%) is the mixed subtype,
The small cell variant of SQC is comprised of smaller which includes two or more of the histologic variants.
cells than the usual SQC. It is distinguished from small The bronchioloalveolar subtype, commonly called
cell carcinoma because the cells of the small cell variant bronchioloalveolar carcinoma (BAC), is defined by
of SQC have coarse or pale chromatin, more prominent its growth along alveolar septa (lepidic growth) with-
nucleoli, and distinct cell borders. out destruction of the underlying alveolar architec-
Metastatic SQCs are morphologically indistinguishable ture. There are two BAC subtypes: mucinous and
from primary SQCs of the lung. The distinction usually nonmucinous. Metastatic cancers like pancreatico-
relies on clinical impression. In some cases, molecular biliary and colorectal adenocarcinomas can mimic a
studies can be helpful; testing for human papillomavirus mucinous BAC.
can be helpful if there is a question of primary lung cancer The rare fetal adenocarcinoma resembles the epithe-
versus metastatic SQC of the cervix. lial component of the pulmonary blastoma.138
Lung Cancer 87
Less than 10% of pulmonary adenocarcinomas har-

bor mutations of the EGFR, predominantly those in
patients who are Asian and nonsmokers.139-141 These
mutations lie within the adenosine triphosphate
(ATP)-binding pocket of this receptor tyrosine kinase
(RTK) and result in its ligand-independent constitutive
activation.142,143 Such mutations result in malignant
transformation.144 Because of the unique, extraor-
dinary sensitivity of EGFR-mutated lung carcino-
mas to RTK small molecule inhibitors145 like gefitinib
or monoclonal antibodies directed against mutated
EGFR, it is important to identify these tumors because
the existence of the mutation entitles patients to this
specialized and potentially less toxic treatment.146,147
Figure 2.26 Adenocarcinoma (bronchial washing). The glan-
Ultimately, resistance to RTK inhibitors by various
dular differentiation can be easily appreciated. Cells are colum-
mechanisms like point mutations146 and Met onco- nar, with polarized nuclei and single prominent nucleoli.
gene amplification148 is more the rule than the excep-
tion,149 however, and more work is needed to develop
lasting therapies. Cytologic preparations are suitable
for EGFR mutation analysis,150 and PCR methods like
direct sequencing or the more sensitive Scorpions
Amplified Refractory Mutation System (ARMS) have
been shown to be effective (up to 91% sensitivity) in
the identification of EGFR mutations in transbron-
chial FNA material.151 EGFR mutation-positive carci-
nomas are almost always adenocarcinomas,140 with
a tendency toward BAC morphology, but SQCs and
other types have been described.151
Cytomorphology of adenocarcinoma:
• honeycomb-like sheets, three-dimensional
clusters, acini, papillae Figure 2.27 Adenocarcinoma (bronchial washing). These
• eccentrically placed, round or irregular nuclei malignant cells have large, round nuclei with distinct nucleoli,
open chromatin, and lacy, clear cytoplasm, and form a honey-
• finely textured chromatin comb-like arrangement.
• large nucleoli
• mucin vacuoles
• translucent, foamy cytoplasm are prominent in many adenocarcinomas. Psammoma
bodies can be seen in the papillary and bronchioloal-
veolar variants.152,153
In cytologic preparations, adenocarcinoma cells can Cytologic preparations from a mucinous BAC show
be arranged in a variety of architectural patterns: three- uniform cells with pale, optically clear nuclei and incon-
dimensional clusters, flat sheets, acini, and papil- spicuous nucleoli. Grooves and nuclear pseudoinclu-
lae (Figs. 2.26 and 2.27). The clustered cells tend to sions are often present (Fig. 2.28). In some cases, the
be loosely cohesive, such that isolated cells and small cells of a mucinous BAC are dispersed and resemble
groups are also present. Cytoplasm is usually abundant, macrophages. A nonmucinous BAC is indistinguishable
with well-defined borders. It can be thin and translu- from an ordinary adenocarcinoma on cytologic prepa-
cent or foamy. Some tumors have cells with a promi- rations (Fig. 2.29). Neither the mucinous nor the non-
nent large mucin vacuole. Nuclei are often eccentrically mucinous subtype of BAC can be diagnosed reliably on
placed and usually have round, smooth contours, but cytologic specimens, because the diagnosis is based on
in some tumors the nuclear membranes can be highly architecture: the absence of stromal, vascular, or pleural
irregular. Chromatin is finely textured in most adeno- invasion.122 A mucinous BAC can be suspected, however,
carcinomas, but some poorly differentiated adenocar- when characteristic cytology is correlated with imaging
cinomas have coarsely textured chromatin. Nucleoli findings.122,154
The cells of a florid type II pneumocyte hyperpla-

Differential diagnosis of
sia resemble those of adenocarcinoma (see Fig. 2.8).
adenocarcinoma:
Attention to the clinical history (e.g., respiratory distress
• reactive bronchial cells and diffuse infiltrates) can provide a clue that the cells
• Creola bodies are reactive. In a patient who is acutely ill with diffuse
• goblet cell hyperplasia pulmonary infiltrates, markedly atypical cells should be
• reactive pneumocytes interpreted with caution. Sequential respiratory speci-
• mesothelial cells (FNA specimens) mens can help because hyperplastic pneumocytes are
• vegetable cells not present in BAL specimens more than a month after
• hamartoma the onset of acute lung injury.32
• SQC Mesothelial cells are common in percutaneous FNA
• large cell carcinoma specimens, and in some cases they can be numerous
• small cell carcinoma (see Fig. 2.3). They resemble the cells of a well-differen-
• epithelioid hemangioendothelioma and epitheli- tiated adenocarcinoma, particularly a mucinous BAC,
oid angiosarcoma but are recognized as benign mesothelial cells by their
• metastatic adenocarcinoma cohesion and the characteristic slitlike “windows” that
separate them from each other. Some inadequate per-
cutaneous FNAs contain only mesothelial cells. In such
cases it is important to identify the sample as insuffi-
Benign bronchial cell atypia and hyperplasia (aniso- cient (nondiagnostic) rather than representative of any
nucleosis as a result of inflammation or injury, Creola underlying lesion.
bodies, goblet cell hyperplasia) can be recognized as Vegetable cells and other contaminants can mimic
a harmless mimic of adenocarcinoma if the atypical the cells of an adenocarcinoma but are recognized as
or hyperplastic cells have cilia (see Figs. 2.4 and 2.5) contaminants because of their prominent capsule.
or demonstrate a spectrum of changes (from benign Some hamartomas have a conspicuous glandular
to markedly atypical). In a bronchial specimen, where component that resembles that of a well or even mod-
malignant cells are often intermixed with benign bron- erately differentiated adenocarcinoma. Fragments of
chial cells, it is usually straightforward to identify two chondromyxoid matrix in the background are essen-
distinct cell populations, one malignant, the other tial for establishing the diagnosis of a hamartoma and
benign. avoiding a false-positive interpretation.
Figure 2.28 Bronchioloalveolar carcinoma, mucinous type (fine-needle aspiration [FNA]). The crowded sheets of these tumor
cells, with their pale nuclei, small nucleoli, and occasional nuclear grooves, and intranuclear pseudoinclusions (arrows), are reminis-
cent of papillary carcinoma of the thyroid. Abundant extracellular mucin (not shown) is often present.
Lung Cancer 89
The differential diagnosis also includes metastatic

adenocarcinoma. In a patient with a history of a pre-
vious neoplasm, it is helpful to compare the current
specimen with the prior cytologic or histologic material
to exclude a metastasis (see Fig. 2.39). Some cytologic
features, such as the “dirty” necrosis and tall colum-
nar cells of colorectal cancer, may suggest a specific
primary site. Some metastatic tumors, however, are
virtually indistinguishable from a primary lung ade-
nocarcinoma. Metastatic papillary thyroid carcinoma
mimics BAC to perfection: both tumors have intranu-
clear cytoplasmic pseudoinclusions, nuclear grooves,
and optically clear nuclei. Immunohistochemistry can
be essential. Adenocarcinomas of the lung are typi-
Figure 2.29 Bronchioloalveolar carcinoma, nonmucinous cally positive for CK7 and negative for CK20, and 75%
type (fine-needle aspiration [FNA]). These tumors are impossible express TTF-1. BAC is an exception, as it is often pos-
to distinguish cytologically from a conventional adenocarcinoma.
itive for CK20 and negative for TTF-1. Organ-specific
antigens, such as thyroglobulin, prostate-specific anti-
gen (PSA), Hepar1, and renal cell carcinoma antigen,
Most adenocarcinomas are easily distinguished from are also helpful.
SQCs because of obvious keratinization, mucin, or aci-
nar formation. The cells of most adenocarcinomas
are more cohesive than those of an SQC. When these
Large Cell Carcinoma
tumors are poorly differentiated, however, the distinc- LCC is an undifferentiated non-small cell malignancy
tion becomes more difficult. In general, nuclear chro- that accounts for about 9% of all lung cancers.122 It is a
matin is more finely textured in adenocarcinomas and diagnosis of exclusion based on the absence of squa-
coarser in SQCs. The cytoplasm is thinner and more mous, glandular, or small cell differentiation. Histologic
vacuolated in adenocarcinomas and denser in SQCs. variants include basaloid carcinoma, lymphoepithe-
A stain for mucin can be helpful: abundant mucin is lioma-like carcinoma, clear cell carcinoma, LCC with
diagnostic of an adenocarcinoma. The possibility that rhabdoid phenotype, and large cell neuroendocrine
both components are present, (i.e., that the tumor carcinoma (LCNEC).122 Most tumors are located in the
might be an adenosquamous carcinoma) should be periphery of the lung, with the exception of the basaloid
considered. If a definite distinction cannot be made, subtype. The neuroendocrine nature of the LCNEC is
the interpretation “Non–small cell carcinoma” is confirmed by immunohistochemical and ultrastructural
appropriate. This applies equally well to those cases of studies.
poorly differentiated adenocarcinoma that are difficult
to distinguish from an LCC. Cytomorphology of large cell
The vascular tumors epithelioid hemangioendothe- carcinoma:
lioma (EHE) and epithelioid angiosarcoma (EAS) occur
as primary tumors in the lung and other sites. EHE is a • syncytial clusters and dispersed cells
low-to-intermediate grade tumor and EAS is high grade. • irregular nuclei
They can present as a solitary mass or as multiple, bilat- • striking chromatin clearing
eral pulmonary masses. Pleural involvement mimicking • prominent, often multiple nucleoli
mesothelioma is not uncommon (see Fig. 4.8), and liver • ill-defined, feathery cytoplasm
involvement is seen in 15% of cases. The cells of both
tumors mimic carcinomas because they are epithelioid
in shape. EHE is the more likely to be confused with ade- Cytologically, a diagnosis of malignancy is rarely diffi-
nocarcinoma because it is lower grade.155 The common cult (Fig. 2.30). LCC cells are often arranged in large, syn-
occurrence of intracytoplasmic vacuoles and intranu- cytial-like sheets of crowded, overlapped cells. There is no
clear inclusions in EHE (and EAS) only adds to the con- apparent cytoplasmic differentiation. The nuclei are large
fusion. The diagnosis of EHE and EAS is established by and either round or markedly irregular, with irregularly
immunohistochemistry for vascular markers like CD31 distributed, coarse chromatin. Nucleoli are usually quite
and CD34. About 30% are reactive for keratins, however, prominent. LCNEC shows nuclear palisading, nuclear
and might be misinterpreted as carcinomas if a wider molding, and rosettes156,157 (Fig. 2.31). Mitotic counts are
antibody panel is not used. high and there is usually necrosis. Confirmation of neu-
Differential diagnosis of large cell

carcinoma:
• reactive changes (e.g., radiation reaction)
• adenocarcinoma
• SQC
• sarcomatoid carcinoma
• epithelioid angiosarcoma
• non-Hodgkin lymphoma
• metastatic carcinoma
• melanoma
Figure 2.30 Large cell carcinoma ([LCC]; bronchial wash- Various types of lung injury (e.g., irradiation, infarc-
ing). The cells of this tumor are loosely arranged in aggregates. tion) can result in highly atypical bronchial cells or pneu-
Nuclei are markedly enlarged with focal chromatin clearing and
mocytes that mimic LCC and other tumors. The cells of
multiple irregular nucleoli.
a florid type II pneumocyte hyperplasia can be large and
wildly pleomorphic, but most patients with this phe-
nomenon are acutely ill with diffuse alveolar damage.
roendocrine differentiation is required, with clear-cut In patients who are acutely ill or those with other injury
reactivity for at least one of the neuroendocrine mark- to the lung, a conservative approach to diagnosis is rec-
ers (synaptophysin, chromogranin, and CD56). Like ommended. When there is no question that the lesion
LCNEC, basaloid carcinoma shows nuclear palisading is malignant, adenocarcinoma and SQC are unlikely if
around the margins of cell groups. The rare lymphoep- there is no keratinization or mucinous or glandular dif-
ithelioma-like carcinoma contains interspersed lym- ferentiation, but because the entire tumor has not been
phoid cells. Clear cell carcinoma is comprised of large sampled, the possibility of an undersampled adenocar-
polygonal cells with abundant clear cytoplasm. The cells cinoma or SQC can never be entirely excluded. For this
of large cell carcinoma with rhabdoid features have reason, cytologic specimens with features of LCC are
large cytoplasmic globules. often resulted as “Non-small cell carcinoma.” One of the
A B
Figure 2.31 Large cell neuroendocrine carcinoma (LCNEC). A, Fine-needle aspiration (FNA). The key cytologic features include:
rosettes, prominent nucleoli, and carcinoid tumor-like nuclei with extreme atypia and enlargement. Mitoses (not seen) are fre-
quent. This constellation of findings is not always present, making distinction from non–small cell carcinoma sometimes impos-
sible. B, Lung, autopsy specimen, same patient as A. Note the organoid growth pattern, rosettes, and brisk mitotic activity in the
histologic material.
Lung Cancer 91
A B
Figure 2.32 Epithelioid angiosarcoma (EAS) of the lung. A, The large polygonal tumor cells resemble those of a large cell
carcinoma (LCC). B, Cell block sections show sheetlike growth.
sarcomatoid carcinomas should be considered if there is no differentiated spindle cell elements. Cytologic prep-
spindle or giant cell differentiation. arations show large malignant spindle cells with hyper-
EAS occurs as a primary tumor in the lung and other chromatic nuclei.
sites. EAS is a particularly good mimic of LCC because Giant cell carcinoma is composed of enormous,
it is a high-grade tumor, with large nuclei, prominent often multinucleated cells with no foci of adenocarci-
nucleoli, and brisk mitotic activity (Fig. 2.32). The diag- noma, SQC, or LCC. Cytologic preparations show dis-
nosis of EAS is established by demonstrating vascular persed, isolated, strikingly large, often multinucleated
differentiation with immunohistochemistry for CD31 or cells with round nuclei and prominent nucleoli (Fig.
CD34. About 30% are reactive for keratins, however, and 2.33). Neutrophils are often prominent. It is important to
thus a wider antibody panel is essential. recognize giant cell carcinoma because it is associated
Diffuse large B-cell lymphoma, anaplastic large cell with an aggressive clinical course.158
lymphoma, metastatic carcinoma, and melanoma can The diagnosis of a pleomorphic, spindle cell, or
usually be distinguished from LCC by an immunohisto- giant cell carcinoma can be suspected on a cytologic
chemical panel that includes CD20, CD3, ALK1, S-100, specimen, but precise classification depends on exten-
HMB45, keratins CK7 and CK20, and carcinoma-specific sive sampling and thus is best deferred to histologic
markers selected based on clinical correlation. examination.
The remaining two tumors are true biphasic neo-
plasms. Pulmonary blastoma, composed of primitive
Sarcomatoid Carcinoma glandular and stromal elements, is a malignant neo-
Sarcomatoid carcinoma is a family of poorly differenti- plasm named for its resemblance to fetal lung. It is
ated non–small cell carcinomas that show sarcomatoid slightly more common in males, and the mean age is in
or giant cell differentiation. The group includes pleo- the fourth decade.159 Histologically there is a spindle cell
morphic carcinoma, spindle cell carcinoma, giant cell component that can show myxoid, chondroid, osteoid,
carcinoma, carcinosarcoma, and pulmonary blastoma. or rhabdomyoblastic differentiation and an epithelial
These tumors are important to recognize because they component consisting of tubules of cuboidal to colum-
have a worse prognosis than the conventional non-small nar cells with frequent mitoses and subnuclear and
cell carcinomas. supranuclear vacuoles. The vacuoles contain glycogen
Pleomorphic carcinoma is defined histologically as a and impart a “piano key”–like, endometrioid appear-
poorly differentiated adenocarcinoma, SQC, or LCC, at ance to the epithelioid component. Solid nests of squa-
least 10% of which is a spindle or giant cell malignancy. moid cells (squamoid morulas) are sometimes present.
The spindle cell component shows no differentiated Tumors comprised of just the epithelial component of
sarcomatous elements. Cytologic preparations show, in the pulmonary blastoma are called fetal adenocarci-
addition to adenocarcinoma, SQC, or LCC, a population nomas.138 Pulmonary blastoma most likely arises from
of pleomorphic spindle or giant cells. Pleomorphic car- a totipotent precursor because identical p53 mutations
cinoma is often a large peripheral tumor with a tendency are present in both the epithelial and sarcomatous
to invade the chest wall. components within the same tumor.160 Immunohis
Spindle cell carcinoma is a non–small cell carcinoma tochemical demonstration of keratins in the epithelial
consisting only of spindle-shaped malignant cells with component and muscle-specific actin in the spindle
Typical Carcinoid
At one end of the spectrum of neuroendocrine tumors
is the typical carcinoid (TC), which accounts for 2%
to 3% of all pulmonary tumors. Typical carcinoids are
uniformly distributed throughout the lungs. Centrally
located tumors are often submucosal, with a promi-
nent endobronchial component. When submucosal,
the typical carcinoid is usually covered by intact respira-
tory epithelium, and as a result sputum cytology is often
negative. TCs have a low metastatic rate: 10% to 15% of
patients have regional lymph node involvement,122,162
and 5% to 10% eventually metastasize to distant sites,122
but the prognosis is excellent with surgery, and 5-year
Figure 2.33 Giant cell carcinoma (fine-needle aspiration survival is 90% to 98%.122
[FNA]). The huge multinucleated cells with striking nuclear Histologic examination reveals uniform polygonal
atypia of this tumor are obviously malignant. cells with a variable growth pattern that may include
nests, ribbons, papillae, and rosette-like arrangements.
Occasionally the cells and nuclei are elongated (spindle
cells helps to confirm the diagnosis.161 Pitfalls in the cell carcinoid).163
cytologic diagnosis of blastoma occur when one of the
components is poorly represented, as when the stromal Cytomorphology of typical
component is misinterpreted as a small cell carcinoma. carcinoid:
Carcinosarcoma differs clinically from blastoma in
the mean age of patients at presentation (65 rather than • loosely cohesive groups and single cells
40 years). Morphologically, the spindle cell component • rosette-like structures
includes differentiated elements like malignant carti- • round, plasmacytoid, or elongated cells
lage, bone, or skeletal muscle. • uniform nuclei with “salt and pepper” chromatin
• ample granular cytoplasm
• branching capillaries
• mitoses uncommon
Pulmonary Neuroendocrine • no necrosis
Neoplasms
This group of neoplasms encompasses a morphologic
and biologic spectrum, divided by the World Health Cytologic preparations usually show a uniform pop-
Organization into four distinct diagnostic categories: ulation of isolated cells and loose clusters (Fig. 2.34).
typical carcinoid, atypical carcinoid, LCNEC, and small Large vascularized tissue fragments are sometimes
cell carcinoma.122 By electron microscopy, all contain present. TCs are vascular tumors, and sometimes a
cytoplasmic dense-core, membrane-bound granules in mesh of branching capillaries is encountered. In cell
variable quantities. Neuroendocrine tumors are immu- block sections, solid nests, trabeculae (ribbons), papil-
noreactive for one or more of the neuroendocrine mark- lae, and rosettes can be appreciated. The tumor cells
ers, chromogranin A (most specific), synaptophysin, and are round, oval (plasmacytoid), or elongated (spindle
Leu-7 (CD57). Adrenocorticotropic hormone (ACTH), cell carcinoid) and have moderate or abundant granu-
insulin, calcitonin, gastrin, and vasoactive intestinal lar cytoplasm. Nuclei are round or oval, with smooth
peptide are less consistently present. contours, finely speckled (salt and pepper) chromatin,
The critical feature that separates typical and atypi- and inconspicuous nucleoli. In some cases there may
cal carcinoids from LCNEC and small cell carcinoma be nuclear atypia and pleomorphism, but this has no
is the mitotic rate (Table 2.3). Even if a tumor has mor- clinical significance.
phologic features of small cell carcinoma, if it lacks fre-
quent mitoses or necrosis, it should not be diagnosed as Differential diagnosis of typical
small cell carcinoma. LCNEC was previously discussed carcinoid:
in greater detail. • benign bronchial epithelial cells
Typical and atypical carcinoids are usually positive • adenocarcinoma
for keratins, but up to 20% can be negative.122 Conflicting • small cell carcinoma/atypical carcinoid
results have been obtained with thyroid transcription • lymphoma
factor 1 (TTF-1): carcinoids are either negative, or they • mesenchymal tumors
can be positive in one third of cases.122
Lung Cancer 93
Table 2.3 Cytologic Features of Pulmonary Neuroendrocrine Tumors*

Typical Carcinoid Atypical Carcinoid Large Cell Neuroendocrine Small Cell
Carcinoma Carcinoma
Image
Cell size Small to medium Medium Large Small to medium

Predominant pattern Tight clusters/rosettes Loose clusters/rosettes Loose clusters/rosettes Dispersed cells
Cytoplasm Moderately abundant Scant to moderate, lacy Scant or moderate, lacy Scant
Plexiform vascularity Common Common Not known Rare
Nuclear molding Rare Slight to moderate Slight to moderate Prominent
Chromatin Coarsely granular Coarsely granular Coarsely granular Finely granular
Nucleoli Small Occasionally prominent Prominent Inconspicuous
Mitoses (per 10 high Rare (<2) Uncommon (2–10) Abundant (≥11; median 70) Abundant (≥11;
power fields) median 80)
Nuclear pleomorphism Mild Moderate Marked Moderate
Necrosis Absent Moderate Marked Marked
Nuclear crush Absent Mild Moderate Marked
*Cytologic features extrapolated from Travis WD, Linnoila RI, Tsokos MG, et al.: Neuroendocrine tumors of the lung with proposed criteria for large-cell
neuroendocrine carcinoma: An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991;15:529–553, and
authors’ unpublished observations.
Atypical Carcinoid
In the hazy area between the typical carcinoid and small
cell carcinoma lies the atypical carcinoid (AT). It is more
aggressive than the typical carcinoid: the 5-year survival
rate is 61% to 73%.122
Cytomorphology of atypical
carcinoid:
• cells and architecture similar to typical carcinoid
• focal necrosis
• mitoses (moderate number)
• prominent nucleoli
Figure 2.34 Typical carcinoid (fine-needle aspiration [FNA]).
The tumor cells have a moderate amount of coarsely granular
cytoplasm and a “salt-and-pepper” chromatin pattern. Rosettes The cytomorphologic features of the neuroendocrine
are seen in some carcinoid tumors.
tumors are listed in Table 2.3. ATs share many of the mor-
phologic features of TCs (Fig. 2.35). They differ, however,
Because of their bland, monomorphous appearance, in several slight ways: the architectural arrangements may
the cells of the typical carcinoid may be mistaken for be looser; there is greater (but not brisk) mitotic activity;
benign bronchial cells. In contrast to bronchial cells, TC there may be focal necrosis.164 Although helpful, these fea-
cells are less cohesive and lack cilia. Because rosettes are tures do not always permit precise classification in cyto-
seen in some TCs, they are sometimes mistaken for an logic and bronchial biopsy samples. Precise classification
adenocarcinoma. In most adenocarcinomas, however, depends on thorough histologic sampling of a resected
there is greater variation in cell size and more group- specimen. In view of this, surgical excision should be con-
ing of cells into spheres and sheets than with carcinoid sidered for all localized neuroendocrine tumors.
tumors. Carcinoid tumors are distinguished from atyp-
ical carcinoids and small cell carcinomas by the lower Small Cell Carcinoma
mitotic rate and absence of necrosis (see Table 2.3).
There may be a resemblance to lymphoid cells, but lym- Small cell carcinoma (SMC) accounts for 20% to 25%
phoid cells have less cytoplasm and do not form clusters of all primary lung carcinomas, and 90% are centrally
or rosettes. located. The majority of patients are male smokers
Figure 2.35 Atypical carcinoid (fine-needle aspiration Figure 2.36 Small cell carcinoma ([SMC]; bronchial brushing).
[FNA]). All the features of typical carcinoid can be seen, but The cells of SMC are tightly packed and show nuclear molding.
greater pleomorphism, slight nuclear enlargement, an increased They are fragile and occasionally degenerated. Well-preserved
number of mitoses, and focal necrosis are important distinguish- cells have a powdery chromatin texture.
ing elements.
(80%), and their prognosis is poor (5-year survival intermediate in size. Cytoplasm is scant and incon-
<10%).165 A morphologic variant is the “combined spicuous, and adjacent nuclei show frequent mold-
small cell carcinoma” (e.g., small cell/SQC, small ing (Fig. 2.36). The cytoplasm can contain occasional
cell/adenocarcinoma). paranuclear blue bodies, solitary round, light to dark
Histologically, SMC consists of small, round to fusi- blue, homogeneous spheres that indent the nucleus.166
form cells with scant cytoplasm. The tumor often under- Nuclei are round, oval, or stretched out (carrot-
mines the bronchial mucosa, with extensive invasion shaped). Chromatin is finely textured, and nucleoli
of lung parenchyma and lymphatics. Necrosis, a high are absent or uncommon. The cytologic appearance
mitotic rate, and nuclear encrustation of vascular walls varies somewhat with the sampling method. In spu-
are characteristic features. In some cases the cells are tum, streams of small hyperchromatic cells form loose
larger, with more cytoplasm and vesicular nuclei. aggregates. In bronchial brushings and FNA speci-
mens, the cells are better preserved.
Cytomorphology of small cell

Differential diagnosis of small cell
carcinoma:
carcinoma:
• small cells (twice the size of lymphocytes), occa-
• reserve cell hyperplasia
sionally larger
• lymphocytes
• carrot-shaped nuclei
• typical carcinoid
• evenly dispersed, powdery chromatin
• atypical carcinoid
• nuclear molding
• non-small cell carcinomas
• small to indistinct nucleoli
• Ewing sarcoma
• paranuclear blue bodies
• neuroblastoma
• mitoses
• Wilms tumor
• scant cytoplasm
• rhabdomyosarcoma
• background of nuclear debris and crush artifact
• pulmonary blastoma
Cytologically, the cells are loosely aggregated and

dispersed as isolated cells. The cells of SMC are fragile. The cells of reserve cell hyperplasia can show mold-
Bare nuclei stripped of cytoplasm and crush artifact ing, but they are smaller and more cohesive than those
with smearing of nuclear DNA (chromatin streaks) of SMC; there is no necrosis, mitoses are absent, and
are common. Crush artifact can be so marked that nuclei have smudged, featureless chromatin (see Fig.
mitoses, which are abundant but delicate, may all be 2.7). Lymphoid cells, whether from an inflammatory
smeared and not identifiable. In such cases, apoptotic process, an intrapulmonary lymph node, or lymphoma,
cells and single cell necrosis are considered evidence can be mistaken for SMC. Lymphoid cells generally do
of rapid cell turnover and abundant mitotic activity. not form cell clusters, except artifactually on cytospin
Depending on the tumor, the cells may be small or or thinlayer preparations; they tend to be evenly spaced
Uncommon Pulmonary Tumors 95
rather than molded together; and they are one-half the include cough, dyspnea, and hemoptysis. Treatment is
size of SMC cells. surgical, but the long-term prognosis is poor, with 80% of
The distinction between an SMC and a TC is usually patients dead of disease within 20 years.169
straightforward, given that TC lack nuclear molding, These tumors are most often diagnosed by means of
necrosis, and mitotic activity. In addition, the chroma- bronchial brushings or transbronchial needle aspira-
tin texture of TC is more coarsely granular than that of tion. Cytologic preparations show cylinders or spheres
SMC. Some TC, like the spindle cell variant, however, of small, deceptively innocuous-appearing epithe-
bear a superficial resemblance to SMC. Therefore, care lial cells that surround basal lamina material (see Figs
must be taken not to make a diagnosis of SMC with- 10.20 to 22).
out abundant mitotic activity and necrosis. The distinc- Mucoepidermoid carcinomas of the trachea and
tion between TC and AC (see Fig. 2.35), and between bronchi are uncommon, representing only 0.2% of lung
AC and SMC, is more difficult; distinguishing features tumors. They are defined by the presence of squamous,
are summarized in Table 2.3. In general, ACs have more glandular, and intermediate cells, and by their origin
numerous mitoses than TCs, and SMCs have signifi- within cartilage-containing airways. The diagnosis “ade-
cantly more mitoses than either TCs or ACs, but a final nosquamous carcinoma” should be restricted to tumors
determination may not be possible without thorough arising at the lung periphery beyond a recognizable
histologic sampling. bronchus. Mucoepidermoid carcinomas can develop in
SMC is sometimes difficult to distinguish from the persons of all ages, including children. They are endo-
non–small cell carcinomas, particularly the small cell bronchial tumors like those of adenoid cystic carcinoma
variant of SQC and those adenocarcinomas composed and other salivary gland tumors, and the presenting
of relatively small cells. The most helpful features in symptoms are similar. Cytologically, the tumors are
making this distinction are the powdery chromatin tex- diagnosed by finding squamous cells, intermediate cells,
ture, inconspicuous nucleoli, prominent nuclear mold- and mucinous cells (see Figs 10.17, 10.18). High-grade
ing, and scant cytoplasm of SMC. Care should be taken tumors show marked nuclear atypia. Mucoepidermoid
not to misinterpret the solid paranuclear blue bod- carcinoma is another one of a growing number of neo-
ies as mucin vacuoles (which are clear), otherwise an plasms for which a recurrent and tumor-specific genetic
SMC might be misidentified as an adenocarcinoma.166 aberration is present: the t(11;19), forming the MECT1-
Immunohistochemistry for p63 can be quite helpful MAML2 fusion transcript.170
in distinguishing SQC, which is immunoreactive, from Other bronchial gland tumors include pleomorphic
SMC, which is negative.167,168 Even after careful examina- adenoma, acinic cell carcinoma, and oncocytoma.
tion and immunohistochemical study, not all tumors are
easily classified. In such cases, the possibility of a mixed
tumor, a common occurrence in the lungs, should be
Clear Cell Tumor (“Sugar Tumor”)
considered. The clear cell tumor is extremely rare and can occur in
Clinical history, particularly patient age, provides persons of all ages, most of whom are asymptomatic. It
clues to the diagnosis of the other small round cell is usually a peripheral mass and ranges from 1 to 7 cm
tumors. The sarcomatous component of pulmonary in greatest diameter. Clear cell tumors most likely arise
blastomas resembles a SMC; identifying the epithelial from perivascular epithelioid cells.122,171 Histologically
areas is crucial in making this distinction. and cytologically, the tumor consists of bland polygo-
nal and spindle-shaped cells with a central oval or elon-
gated nucleus and clear, glycogen-rich cytoplasm.172
Uncommon Pulmonary The differential diagnosis includes the clear cell vari-
Tumors ant of adenocarcinoma or SQC of the lung, granular cell
tumor, and metastatic tumors with clear-cell features
Adenoid Cystic Carcinoma and (renal cell carcinoma, adrenal cortical carcinoma, some
melanomas, and others).172,173 Immunohistochemistry
Other Bronchial Gland Tumors is helpful for most of these distinctions except with
The submucosal glands of the trachea and bronchi give melanoma: most clear cell tumors are positive for
rise to neoplasms that resemble those occurring in the HMB-45 and Melan-A and negative for cytokeratins
salivary glands. The most common of these is the adenoid and CEA.171,174
cystic carcinoma. This malignant tumor accounts for
20% to 35% of all cancers in the trachea but also occurs in
the major bronchi. The tumors grow as polypoid masses,
Sarcomas
undermining intact overlying respiratory epithelium. Primary malignant mesenchymal tumors of the lung
They often infiltrate the cartilage and soft tissues of the are rare, occurring in adults of either sex. They can be
major airways. Symptoms are related to obstruction, and large masses or small endobronchial lesions. One of the
most common primary sarcomas is leiomyosarcoma.175,176

Differential diagnosis of pulmonary
Others include fibrosarcoma, solitary fibrous tumor,
lymphoma and leukemia:
chondrosarcoma,177 Kaposi sarcoma, angiosarcoma,178
epithelioid hemangioendothelioma,155 rhabdomyosar- • inflammatory lesions
coma, malignant peripheral nerve sheath tumor, and • small cell carcinoma
synovial sarcoma. Care must be taken not to mistake • LCC
stromal and smooth muscle cells in ulcerative processes • melanoma
for sarcoma cells. Most sarcomas, both primary and
metastatic, can confidently be distinguished from carci-
nomas on FNA smears.179,180 MALT lymphoma can be particularly troublesome to
diagnose by cytology alone because it is indistinguish-
able from a reactive condition (Fig. 2.37). Identifying
Cytomorphology of sarcomas: a diffuse large B-cell lymphoma is much more reliable
because of the striking atypia of the large cells. Surface
• sheetlike, cellular aggregates marker analysis to demonstrate monoclonality, best
• single, highly atypical spindle cells determined by flow cytometric analysis185 is often essen-
tial to confirm the diagnosis of a MALT lymphoma. A
Differential diagnosis of sarcomas: diffuse large B-cell lymphoma, which is obviously cyto-
• spindle cell carcinoma logically malignant, need only stain for lymphoid mark-
• spindle cell carcinoid ers (e.g., CD20 or leukocyte common antigen)186 for
• spindle cell thymoma diagnostic confirmation.
• sarcomatoid mesothelioma Primary pulmonary Hodgkin lymphoma is exception-
• melanoma ally rare, though secondary involvement occurs in 40%
to 50% of patients.181,187 Primary pulmonary involvement
is two-fold more common in women, who present with
Whether the sarcoma is primary or metastatic is a cough and B-type symptoms. Radiologic findings are
distinction made mainly on clinical grounds. Immuno equally divided among solitary lesions, multiple masses,
histochemistry for keratins, CEA, desmin, smooth and a pneumonia-like infiltrate. Patients who present
muscle actin, CD31, CD34, calretinin, WT-1, S-100, and with pulmonary involvement have a poorer prognosis
HMB45 can be quite useful in the differential diagnosis. than those with nodal disease only. The cytologic diag-
nosis of Hodgkin lymphoma rests on identifying Reed-
Sternberg cells.187 Mononuclear variants and a mixed
Lymphomas and Leukemias background of lymphocytes, plasma cells, eosinophils,
Hodgkin and non-Hodgkin lymphomas occur as pri- and histiocytes are typically present.
mary tumors of the lung, but spread from an extrapul-
monary primary is more common. Primary pulmonary
non-Hodgkin lymphoma represents fewer than 10% of
all extranodal lymphomas. By contrast, secondary lung
involvement by non-Hodgkin lymphomas is noted in
20% to 50% of patients at some point in their clinical
course.181 The most common primary non-Hodgkin lym-
phoma of the lung (70% to 90%) is extranodal marginal
zone B-cell lymphoma of the mucosa-associated lymphoid
tissue (MALT lymphoma), followed by diffuse large B-cell
lymphoma. Much less common primary lymphoprolif-
erative disorders include lymphomatoid granulomato-
sis and peripheral T cell lymphoma.182 MALT lymphomas
are typically incidental solitary pulmonary masses and
have an indolent clinical course: the 5-year survival rate
is around 90%.122,182 By contrast, lymphomatoid gran- Figure 2.37 Lymphocytic interstitial pneumonia (bronchoal-
ulomatosis, an Epstein-Barr virus (EBV)-associated, veolar lavage [BAL]). This demonstrates a polymorphous pop-
T-cell-rich B-cell lymphoproliferative disorder, is often ulation comprised of small- and medium-sized lymphocytes.
Although this cytologic pattern suggests a reactive process, a
associated with chest pain, cough, dyspnea, and neu- mucosa-associated lymphoid tissue (MALT) lymphoma cannot
rologic symptoms,183,184 and the median survival is be excluded. Immunophenotyping is essential to confirm the
2 years. reactive or neoplastic nature of the lesion.
Metastatic Cancers To The Lung 97
Granulomatous inflammatory processes need to be Metastases are diagnosed in sputum in up to 70% of cases.192
distinguished from Hodgkin lymphoma. Histiocytes About 40% of metastatic tumors in exfoliative specimens
can mimic Reed-Sternberg cells, and granulomas can are squamous carcinomas from an adjacent site in the
occur in Hodgkin lymphoma. Reed-Sternberg cells are aerodigestive tract. The remainder of the cases includes
distinguished from histiocytes because RS cells have adenocarcinomas (34%)—most commonly of the breast, kid-
large, inclusion-like nucleoli and highly irregular nuclei. ney, and colon—and hematopoietic malignancies (8%).193
Melanoma and LCC can be excluded with immunohisto- Because confirming metastatic disease is a major indi-
chemical studies for keratins, S-100, and HMB45. cation for transthoracic FNA, metastatic tumors account
About 10% of diffuse pulmonary infiltrates in patients for between 14% and 26% of transthoracic FNA speci-
with leukemia result from leukemic involvement of the mens.194 In a study of more than 1000 cases, malignant
lung. At autopsy, infiltrates are seen in 25% to 65% of melanoma accounted for 27%, urinary and male geni-
cases, most commonly acute leukemia. Leukemic involve- tal tract neoplasms for 17%, breast carcinoma for 15%,
ment of the lung may also present as a mass lesion. The female genital tract neoplasms for 13%, and gastrointes-
cells are dispersed as isolated cells, as with lympho- tinal tract neoplasms for 10%.193 Another study reported
mas, and cellular monomorphism is characteristic. that the most common metastases (in decreasing fre-
BAL is useful for demonstrating leukemic involvement, quency) are those from breast cancer, colon cancer, renal
especially when biopsy is contraindicated because of coag- cell carcinoma, bladder cancer, and melanoma.195
ulopathy.188 The diagnosis can be confirmed using immu- Primary sites for some metastatic carcinomas can be
nohistochemistry on cell block, cytospin preparations, or inferred based on their characteristic cytologic features.
by flow cytometry (i.e., blasts are commonly CD34+). The cells of the usual type of colon carcinoma have a dis-
Other hematopoietic malignancies that can involve tinctive tall, columnar “picket fence” appearance, with
the lung include myeloma189 and mycosis fungoides.190 hyperchromatic nuclei and “dirty” necrosis. Malignant
melanoma often demonstrates a single-cell arrangement,
with cytoplasmic pigment, intranuclear cytoplasmic
Metastatic Cancers To invaginations, and classic “mirror-image” binucleation.
The Lung Breast carcinoma often shows a single-file arrangement of
cells, some with mucin-containing intracellular lumens
The lungs receive the entire cardiac output, so it is not surpris- (Fig. 2.38); renal cell carcinoma cells are large cells with
ing that they are a common site for metastasis; 30% to 50% abundant clear cytoplasm and poorly defined cell mem-
of extrapulmonary cancers involve the lungs at autopsy.191 branes; and metastatic papillary thyroid carcinomas have
A
Figure 2.38 Metastatic ductal carcinoma of the breast. This patient had a previous history of ductal breast carcinoma. A, Fine-needle
aspiration (FNA) of the lung. The smear shows clusters of tumor cells with prominent nucleoli and mucin-filled intracellular lumens.
Illustration continued on following page
B
Figure 2.38 (Continued) Metastatic ductal carcinoma of the breast. B, Breast lumpectomy. Comparison with the previously
resected tumor shows close similarity, supporting the diagnosis of metastasis to the lung from the breast primary.
nuclear grooves, nuclear pallor, and intranuclear pseu- cytopathologic diagnoses during the years 1970 to 1974. Acta
doinclusions, a morphologic appearance mimicked by Cytol 1982;26:759-766.
5. Wax TD, Coogan AC, Johnston WW: Clinical significance
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NORMAL ANATOMY, HISTOLOgY, AND Sporotrichosis

Normal Anatomy, Histology,

The small, cutting biopsy method is no more accurate

in a false-positive interpretation of SQC.33,34 Another,

Benign Bronchial Cell Changes

rounded clusters composed almost exclusively of goblet

Cytomorphology of reserve cell

Reserve cell hyperplasia (RCH) is a mimic of small

Figure 2.7 Reserve cell hyperplasia (bronchial brushing).

architecture, like primary pulmonary adenocarcinoma,

with chronic respiratory diseases, but they are, in fact,

Figure 2.12 Vegetable cells (sputum). Some vegetable cells

Infections endothelial cells, and fibroblasts (see Table 2.1). The

Table 2.1 Pulmonary Viral Infections

Measles virus Multinucleation Eosinophilic, intranuclear; Giant cells

Respiratory Multinucleation Cytoplasmic, basophilic, Giant cells; necrosis

Adenovirus Smudged appearance as a Large intranuclear, basophilic Ciliocytophthoria

and thus mimic the appearance of a malignancy. In such

Table 2.2 Pulmonary Fungal Infections

Cryptococcus Cryptococcus Worldwide Yeast; variably sized; 4–15 μm Granulomatous

dry cough, fever, and dyspnea. Pulmonary infiltrates are

may contain scoleces if pulmonary hydatid cysts rup-

helpful to substantiate the diagnosis with serologic stud-

The cytomorphologic findings are nonspecific but

hamartomas are discovered incidentally as a solitary

Pulmonary Hamartoma Inflammatory Myofibroblastic Tumor

Cytomorphology of inflammatory On cytologic preparations, the cells are easily over-

In moderately and poorly differentiated SQCs, kera-

Differential diagnosis of squamous

the distinction becomes more difficult. In general,

Less than 10% of pulmonary adenocarcinomas har-

The cells of a florid type II pneumocyte hyperpla-

The differential diagnosis also includes metastatic

Differential diagnosis of large cell

Table 2.3 Cytologic Features of Pulmonary Neuroendrocrine Tumors*

Cell size Small to medium Medium Large Small to medium

Cytomorphology of small cell

Cytologically, the cells are loosely aggregated and

most common primary sarcomas is leiomyosarcoma.175,176

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