2009 Decker Intellectual Properties Inc Scientific American Surgery

THORAX SOLITARY PULMONARY NODULE 1

SOLITARY PULMONARY NODULE

Taine T.V. Pechet, MD, FACS*

Assessment of a Solitary Pulmonary Nodule

The solitary pulmo- Table 1 Differential Diagnosis of Solitary
nary nodule (SPN) is Pulmonary Nodule
a common finding
Behavior Category Disease
that is observed in
more than 150,000 Benign Vascular disease Arteriovenous malformations
persons each year in Pulmonary artery aneurysm
the United States.1 An Infection Mycobacterium avium
SPN is defined as a complex infection
single radiographically Aspergilloma
Histoplasmosis
visible pulmonary
Echinococcosis
lesion that is less than 3 cm in diameter, is completely sur- Blastomycosis
rounded by pulmonary parenchyma, and is not associated Cryptococcosis
with atelectasis or adenopathy.2 Any pulmonary lesion larger Coccidioidomycosis
than 3 cm is considered a mass and as such has a greater Ascariasis
likelihood of being malignant.3,4 SPNs are detected on Dirofilariasis
routine chest radiography at a rate of 1 in 500 x-rays, but with Inflammatory Rheumatoid nodule
the growing use of computed tomographic (CT) scanning, condition Sarcoidosis
they are now being diagnosed with increasing frequency. Wegener granulomatosis
The differential diagnosis of an SPN is broad and includes Congenital Foregut duplication cyst
vascular diseases, infections, inflammatory conditions, con- abnormality
genital abnormalities, benign tumors, and malignancies [see Other Rounded atelectasis
Table 1]. Although most SPNs are benign, as many as one Pulmonary amyloidosis
third represent primary malignancies, and nearly one quarter Benign tumor Hamartoma
may be solitary metastases.1,5,6 Various approaches have been Lipoma
developed to aid in the characterization and identification Fibroma
of SPNs. Certain clinical characteristicssuch as greater age,
Malignant Primary lung Nonsmall cell lung cancer
history of tobacco use, and previous history of cancerhave cancer Squamous cell carcinoma
been shown to increase the likelihood that the SPN is Adenocarcinoma
malignant.7 Some authors have attempted to use the Bayes Large cell cancer
theorem, logistic regression models, or neural network analy- Bronchoalveolar carcinoma
sis to predict the likelihood of malignancy.79 Such methods Small cell lung cancer
Carcinoid
are highly sensitive and specific, but they are cumbersome Lymphoma
and of limited clinical applicability.
Metastatic cancer Colon cancer
Testicular cancer
Clinical Evaluation Melanoma
Sarcoma
Once an SPN has been identified, it is necessary to Breast cancer
determine whether the lesion is benign or malignant and what
further investigations should be pursued. Evaluation should
generally be governed by the dictum malignant until proven factors influencing probability of malignancy
otherwise. The basis for an initial assumption of malignancy
is the observation that the overall 5-year survival rate is low A number of factors influence the probability that an SPN
(10 to 15%) once a diagnosis of lung cancer is established.10 is malignant. Those most strongly associated with lung cancer
Appropriate evaluation involves careful assessment of the are age, smoking history, and occupational history. Pulmo-
patients history and risk factors for malignancy in conjunc- nary function test results indicative of a severe obstructive
tion with the results of radiographic studies [see Investigative ventilatory impairment are also associated with an increased
Studies, below] to develop an individualized care plan. likelihood of malignancy.11 In addition, the presence of
endemic granulomatous disease has been shown to increase
* The authors and editors gratefully acknowledge the con- the probability that an SPN is harboring cancer.7
tributions of the previous author, Shamus Carr, MD, to the The radiographic appearance of an SPN, particularly on
development and writing of this chapter. a CT scan, also influences the probability of malignancy

DOI 10.2310/7800.S04C05

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THORAX SOLITARY PULMONARY NODULE 2

SPN is seen on chest x-ray or CT scan

Obtain history and perform thorough physical

examination. SPN
Assessment of a Solitary Review previous diagnostic images (if available). or n
Pulmonary Nodule
Obta

SPN is < 1.0 cm and patient is at low risk SPN is 1.03.0 cm

Obtain follow-up CT scan at 3 mo. Assess probability of malignancy on the basis of

salient characteristics (age, smoking history, lesion
size, lesion margin).

Probability of cancer is low P

Consider PET.

Risk of surgical complication is high

Consider PET, or obtain tissue diagnosis via TTNB
or bronchoscopy, as warranted by clinical situation

SPN is unchanged SPN has grown

Consider PET scanning if Tissue diagnosis is obtained

nature of lesion is indeterminate.
Otherwise, assume malignancy
and resect lesion via VATS
or thoracotomy after staging Pathology is indeterminate
investigations.
Consider PET, or proceed to metastatic evaluation,
as warranted by clinical situation.

PET scan is obtained PET scan is not obtained

PET scan is negative PET scan is positive and

lesion is suspicious

Obtain follow-up CT scans at 3-, 6-, or 12-month intervals.

SPN has remained unchanged for > 2 yr SPN has grown

Lesion is probably benign; treat appropriately. Consider PET scanning if nature of lesion is indeterminate. Otherwise,
assume malignancy and resect lesion via VATS or thoracotomy
after staging investigations.
SPN = solitary pulmonary nodule; CT = computed tomography; PET = positron emission tomography; VATS = video assisted thoracic surgery; TTNB =
trans-thoracic needle biopsy.

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THORAX SOLITARY PULMONARY NODULE 3

SPN has arisen or grown since previous images, SPN has remained unchanged for > 2 yr
or no previous images are available for review
Obtain CT scan. Lesion is probably benign; treat appropriately.

SPN is > 3.0 cm

sis of Lesion is considered a mass and thus is more
y, lesion likely to be malignant.

Probability of cancer is intermediate Probability of cancer is high

Risk of surgical complicatons is low

via TTNB
situation.
Obtain tissue diagnosis via TTNB or bronchoscopy,
or proceed to metastatic evaluation and resection,
as warranted by clinical situation.

ined Tissue diagnosis is not obtained

Pathology is malignant
on,

ained

Carry out metastatic evaluation. If results are negative,

resect lesion via VATS or thoracotomy. If results are
positive, treat appropriately.

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THORAX SOLITARY PULMONARY NODULE 4

[see Investigative Studies, Imaging, Computed Tomography, Investigative Studies

below]. The size, contour, internal characteristics, and growth
imaging
rate of the nodule are all potentially significant indicators of
malignant disease [see Table 2]. Chest Radiography
(X-Ray)
Age
Whereas the pre-
Lung cancer is rare before the age of 40 years, but its inci-
valence of lung cancer
dence steadily increases from that point until the age of 80.5
is low in comparison
Above the age of 70, the likelihood that an SPN is malignant
with that of breast
increases.8 After the age of 80, the incidence of malignancy
or prostate cancer, the
in an SPN seems to level off or even decrease.12 mortality for lung cancer exceeds that for breast, prostate,
Environmental Exposures and colon cancer combined. As noted [see Clinical Evalua-
tion, above], the overall 5-year survival rate for lung cancer
The link between cigarette smoking and lung cancer has
patients is poor, in part because lung cancer is frequently
been well established since the 1950s, and the incidence of
diagnosed at a more advanced stage than other forms of
lung cancer in smokers is directly correlated with the number cancer. Several trials performed before the advent of CT
of pack-years of smoking.13 The surgeon generals report from scanning evaluated chest radiography for early screening
2004 states that the evidence is sufficient to infer a causal of lung cancer but were unable to demonstrate that such
relationship between smoking and lung cancer.14 There is screening yielded better survival.1820 One explanation for
also ample evidence of a causal relationship between environ- these disappointing results may be that fewer than 10% of
mental tobacco exposure, termed secondhand smoke, and lung cancers are stage I at presentation.18
lung cancer.15 Although chest radiography is ineffective as a screening
Radon exposure is the second leading cause of lung cancer tool for early-stage lung cancer, it remains a valuable investi-
in America, and cigarette smoking further increases the gative tool in the evaluation of SPNs. If an SPNs appearance
risks associated with radon exposure.16 Asbestos exposure in on chest x-rays has not changed for more than 2 years, the
combination with cigarette smoking also places patients at SPN will be benign in more than 90% of cases. In such cases,
significantly increased risk for lung cancer. Patients with only yearly follow-up is typically required; additional diag-
a history of workplace exposure to a radioactive substance nostic tests are usually unnecessary.21,22 Therefore, an effort
(e.g., uranium or plutonium) are at increased risk for lung should always be made to obtain old chest radiographs if they
cancer, but this association is not as well documented as the are known to exist.
association of lung cancer with tobacco use. Miners of heavy
metals (e.g., nickel, cadmium, and silica) are also at increased Computed Tomography
risk, and a variety of other environmental toxins, from The advent of CT scanning has led to an increase in the
diesel exhaust through vinyl, have been associated with the number of SPNs detected.23 But, of course, it has also led to
development of lung cancer.15 There is some evidence to an increase in the number of benign SPNs found. Advocates
suggest that patients with idiopathic pulmonary fibrosis and of CT scanning for assessment of SPNs base their argument
pneumoconiosis are at increased risk for bronchoalveolar cell on two central points. First, as many as 83% of CT-detected
carcinoma.17 stage I malignancies are not visible on chest x-ray.24 Second,
nonsmall cell lung cancer (NSCLC) is the malignancy most
commonly identified, and the survival rate for stage I NSCLC
is relatively high in comparison with more advanced disease
Table 2 Factors Affecting Malignant Probability of
stages. In patients whose SPN proves to be NSCLC, the
Solitary Pulmonary Nodule8
5-year survival rate is 67% for stage IA disease. This figure
Likelihood Ratio for falls rapidly as the disease stage rises: the 5-year survival rate
Factor Malignancy
is 55% for stage IIA NSCLC and only 10% for stage IIIA
Spiculated margins on CT scan 5.54 NSCLC with mediastinal nodal metastasis.25
Age > 70 yr 4.16 Numerous studies have evaluated the use of screening
Lesion size 2.13.0 cm 3.67
CT both in the general population and in at-risk groups
consisting of older patients with a smoking history.24,26,27 The
Doubling time < 465 days 3.40 greatest drawback to screening CT is the high false positive
History of smoking 2.27 rate: nodules are identified on 23 to 66% of all CT scans,
Age 5069 yr 1.90 depending on the thickness of the slices,12,24 and nearly 98%
of these nodules are eventually determined to be benign.
Lesion size 1.12.0 cm 0.74
Sequential CT scanning is often required to determine
Lesion size < 1 cm 0.52 whether an SPN is benign or malignant. In 10 to 15% of
Smooth margins on CT scan 0.30 patients, however, this determination cannot be made even
No history of smoking 0.19 when two CT scans are compared. Such patients may be
assessed with other imaging modalities (e.g., positron emis-
Doubling time > 465 days 0.01 sion tomography [PET]) or may be referred for transthoracic
CT = computed tomographic. needle biopsy (TTNB) or other invasive diagnostic tests.

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Controversy exists in both the literature and in clinical
practice around the optimal intervals for follow-up CT scan-
ning after initial identification of an SPN. In the literature,
the recommended interval between initial CT scanning and
repeat CT scanning has ranged from 1 month to 1 year.12,24,27
These varying recommendations are based on what is con-
sidered the doubling time for an SPN. In a study from 2000
that included 13 patients with a known diagnosis and lesions
less than 10 mm in diameter at initial evaluation, volumetric
growth rates were measured to establish the doubling times
of the nodules.10 The doubling times ranged from 51 days
to more than 1 year. For malignant lesions, the average dou-
bling time was less than 177 days, whereas for benign lesions,
it was more than 396 days. New volumetric modeling meth-
ods have been developed that may be capable of detecting
conformational changes over much shorter intervals, but they
remain infrequently used.28 Because the doubling time is con-
siderably shorter for malignant lesions than for benign lesions,
a repeat CT scan should typically be performed for most
lesions 3 months after the initial study. If the lesion is visibly
larger on the repeat scan, it is likely malignant, and diagnos-
tic evaluation should progress toward presumed resection.
If, however, the lesion has neither regressed nor progressed,
a follow-up CT scan closer to 12 months is warranted;
the precise timing remains controversial and should be
determined on the basis of individual patient and SPN char-
acteristics. The Fleischner Society Statement from the
Radiological Society of North America provides commonly
cited guidelines for the radiographic evaluation of nodules,
with recommendations divided into size categories and
recommendations that range from 3 to 12 months.29
The morphologic characteristics of an SPN visualized on a
CT scan can be extremely helpful in characterizing the prob-
ability of malignancy [see Differential Diagnosis, below]. Size,
margin appearance, cavitation, and attenuation are important
criteria. Air bronchograms, ground-glass opacity, and adja-
cent vascular distortion patterns can also help suggest malig-
nancy. Although an SPN with a spiculated margin is perhaps
most suspicious for malignancy, one fifth of lung cancers may
have well-defined margins.30,31 Within areas of ground-glass
opacity, characteristic changes, such as the development of
nodularity and solid attenuation, have been identified that
increase the probability of malignancy.3234 Other CT charac-
teristics may point more toward a benign condition. For
example, although cavitation may occur in either benign or
malignant lesions, SPNs with walls thinner than 4 mm are
much more likely to be benign, whereas those with walls
thicker than 16 mm are more likely to be malignant.35 Intra-
nodular fat is a reliable indicator of a hamartoma, a benign
lesion, and is seen in as many as 50% of hamartomas.36 In
addition, calcification is most commonly associated with
hamartomas and other benign nodules. Unfortunately,
between one third and two thirds of benign lesions visualized
are not calcified, and as many as 6% of malignant lesions
are calcified.31,37,38 Finally, increased enhancement (measured
in Hounsfield units [HU]) after injection with intravenous
contrast is strongly suggestive of malignancy and has been
included in the American College of Chest Physicians (ACCP)
consensus recommendations.39 Lesions that enhance by less
than 15 HU are most likely benign (positive predictive value
99%), whereas lesions that enhance by more than 20 HU
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SOLITARY PULMONARY NODULE 5
are typically malignant (sensitivity 98%; specificity 73%).40
Lesions that enhance by 15 to 20 HU should be considered
indeterminate.
Because most SPNs are benign and because the risk of
misdiagnosing a malignant lesion is so great, it is important
to make use of all of the data obtained from CT scanning in
the effort to make cost-effective, logical decisions regarding
further evaluation or treatment. Careful evaluation of the
size, contours, and internal characteristics of an SPN on
successive CT scans, balanced by the patients risk profile,
including age, smoking history, and environmental exposures,
provides the framework for developing an individualized
evaluation strategy
Positron Emission Tomography
PET is an imaging modality that employs radiolabeled
isotopes of fluorine, carbon, or oxygen; the most commonly
used isotope is 18F-fluorodeoxyglucose (FDG). The rationale
for FDG-PET scanning in the evaluation of SPNs is based
on the higher metabolic rate of most malignancies and the
preferential trapping of FDG in malignant cells.41 However,
increased FDG activity can also occur in benign SPNs,42,43
especially those arising from active granulomatous diseases44,45
or inflammatory processes.46 These benign diseases can
produce false positive PET scans and thereby reduce the
sensitivity of the test. Conversely, some malignanciesbron-
choalveolar carcinoma and carcinoid tumors, in particular
have low metabolic activity and commonly produce false
negative PET scans.4751 Thus, a negative PET scan is not a
particularly helpful result, and it is necessary to follow the
lesion with serial CT scans. Accuracy calculations for PET
scanning vary widely, with some of the highest sensitivity and
specificity figures reported in an early meta-analysis identify-
ing sensitivity of 96% and specificity of 77%.52 More recent
pooled sensitivity and specificity figures were 87% and 83%,
with specificity ranging from 40 to 100%.39
Efforts have been made to improve the sensitivity and
specificity of PET scanning in the diagnosis of SPNs. One
such effort involves the use of the standardized uptake value
(SUV), which is a numerical indication of the activity con-
centration in a lesion, normalized for the injected dose.53
In many studies, an SPN is considered malignant when its
SUV is higher than 2.5. Because of the methodology used to
calculate SUV, however, small tumors (< 1.0 cm) may have
an SUV lower than 2.5 and still be malignant. Their small
volume causes their true activity concentration to be under-
estimated, with the result that their SUV drops below the
threshold value for malignancy. In one prospective study of
patients with SPNs, the overall sensitivity of FDG-PET scan-
ning was 79% and the overall specificity was 65%.54 When
the SPN was smaller than 1.0 cm, however, all of the scans
were negative, even though 40% of the nodules were malig-
nant. Another effort involves recent technology combining
PET and CT scans. CT-PET fusion imaging is clinically
available in many locales, and combination imaging has been
found to be particularly important for staging.55,56
In cases where the SPN is larger than 8 mm and no pre-
vious radiographs or CT scans are available for comparison,
PET scanning can provide information that may facilitate
the decision whether to follow the lesion closely or to proceed
with tissue acquisition. ACCP consensus recommendations
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include the use of PET scanning in select lesions greater than
8 mm identified in patients with low to moderate pretest
probability of malignancy.39 Cost analysis is also an important
criterion in considering PET scanning. One study that exam-
ined the cost-effectiveness of PET in the evaluation of SPNs
concluded that it was cost-effective for patients who had an
intermediate pretest probability of a malignant SPN and who
were at high risk for surgical complications.57 In all other
groups, PET was not cost-effective, and CT led to similar
outcomes (in terms of quality-adjusted life-years) and to
lower costs.
biopsy
If an SPN displays characteristics suggestive of malignancy,
a tissue diagnosis should be obtained. In many cases, the
appropriate form of tissue acquisition will be excisional biopsy
by wedge resection, often followed by anatomic lung resec-
tion. Traditionally, excisional biopsy was performed, accept-
ing the morbidity associated with thoracotomy. Especially for
peripheral lesions, however, video-assisted thoracic surgery
(VATS) has now supplanted thoracotomy as the procedure
of choice. However, several alternative biopsy techniques may
be performed in place of resection, including TTNB and
bronchoscopy.
Transthoracic Needle Biopsy
Lesions that are between 1.0 and 3.0 cm in diameter should
be considered for TTNB. The diagnostic yield of this pro-
cedure for SPNs is excellent, reaching 95% in some studies.
The reported sensitivity ranges from 80 to 95% and the
specificity ranges from 50 to 88%.5860 A study of 222 patients
who underwent TTNB for an SPN reported a positive
predictive value of 98.6% and a negative predictive value of
96.6%61; however, several other studies reported false nega-
tive rates ranging from 3 to 29%.58,62 The complication rate
associated with TTNB is relatively highpotentially as high
as 30% and rarely lower than 10%, in even the most experi-
enced hands.59,63 Most commonly, a pneumothorax results;
however, chest tube placement is required only if the patient
becomes symptomatic, a situation that occurs in approxi-
mately 50% of cases. In the absence of symptoms, obser-
vation with serial chest x-rays is generally appropriate. If
no increase in the size of the pneumothorax is observed,
the patient can be discharged with the expectation that the
pneumothorax will resolve.
For lesions smaller than 1.0 cm, the risk-to-benefit ratio of
TTNB rises to the point where other techniques are typically
preferred. The utility of TTNB depends primarily on the
characteristics of the SPNin particular, its location.
Nodules that are central or close to the diaphragm or the
pericardium are less well suited to this technique than those
at other sites.
Bronchoscopy
Bronchoscopy has a well-established role in the evaluation
of central SPNs, which are amenable to direct visualization
and biopsy. Most SPNs, however, are not central. Various
adjunctive measures, including transbronchial needle biopsy
and cytology brushings, are employed to improve the yield
of bronchoscopy. For SPNs between 2.0 and 3.0 cm in diam-
eter, the diagnostic yield of bronchoscopy ranges from 20 to
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SOLITARY PULMONARY NODULE 6
80%, depending on the size of the lesion, the incidence
of malignancy in the study population, and the proximity
of the lesion to the bronchial tree.64,65 For SPNs smaller than
1.5 cm, the yield drops to 10%.66 Even though bronchoscopy
has a low complication rate (about 5%), its low diagnostic
yield for malignancy limits its utility in the evaluation of
SPNs.
New technology has allowed the application of guidance
techniques to the field of bronchoscopy. Ultrasound trans-
ducers affixed to the tip of a bronchoscope, endobronchial
ultrasonography (EBUS), has become an important tool
in mediastinal staging, with EBUS-transbronchial needle
aspiration (EBUS-TBNA) sensitivities in the range of 92%
and specificities of 98% reported.67 Electromagnetic naviga-
tional bronchoscopy (ENB) uses three-dimensional CT
reconstructions to provide guidance for bronchoscopic sam-
pling of peripheral lesions. The diagnostic yield for peripheral
lesions is in the range of 70%,68 and experience within the
community is growing. ENB is a technique that can provide
tissue from central nodules as well as an alternative to TTNB
or VATS for peripheral lesions, and offers the ability to place
a fiducial marker for subsequent radiation therapy guidance.
Excisional Biopsy
The decision to proceed to excisional lung biopsy (open
or VATS) must be carefully considered. The risk-to-benefit
ratio of excisional biopsy for an individual patient is
determined by clinical characteristics affecting perioperative
morbidity and mortality, as well as by the expected risk of
malignancy in the SPN.
Resection is the reference standard for tissue acquisition.
The morbidity associated with VATS is less than that associ-
ated with thoracotomy; accordingly, when VATS lung biopsy
is technically feasible, it is preferable to open lung biopsy.
The overall morbidity is lower than 1% for VATS wedge
resection, compared with 3 to 7% for the equivalent open
procedure. Patients who have undergone VATS resection
experience less pain, have shorter hospital stays, and recover
sooner than those who have undergone open biopsy.6971
A technical consideration that must be contemplated when
VATS is planned is possible conversion to thoracotomy.
The conversion rate for VATS to thoracotomy has been
reported to be as high as 33%, but there is evidence to sug-
gest that this rate can be significantly reduced with careful
patient selection and increasing experience in minimally inva-
sive techniques.72,73 For example, modern experience with
VATS techniques has demonstrated a low conversion rate
of 2.5% in a series of 1,100 patients undergoing the more
complex VATS lobectomy procedure.74
Peripheral SPNs more than 1.0 cm in diameter are the
lesions best suited to VATS excision. As SPNs become
smaller and more central, they become harder to identify, and
the rate of conversion to thoracotomy or the need to perform
an anatomic resection increases. A wide variety of techniques
have been employed to improve the identification of SPNs
for VATS, ranging from dye staining through guide-wire
localization. One of the more recent developments has
been the use of technetium-labeled microalbumin combined
with a gamma probe to successfully resect 96% of lesions
using thoracoscopic techniques.75 Despite demonstrated
cost-effectiveness,76 however, none of these techniques have
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achieved wide acceptance, and most surgeons rely on digital
palpation combined with radiographic guidance.
Differential Diagnosis
malignant lesions
NonSmall Cell Lung Cancer
As noted, NSCLC is the malignancy most frequently
identified in an SPN. Most lung cancer patients are asymp-
tomatic, and those who are symptomatic usually have
advanced disease, including mediastinal lymph node involve-
ment. Arterial invasion has also been shown to have an
adverse effect on survival in patients with early-stage
NSCLC.77 The most common sites of metastases are the
lymph nodes, the brain, the bones, and the adrenal glands.
Accordingly, it is essential to perform a metastatic evaluation
that focuses on these areas before proceeding with resection.
Adenocarcinoma and squamous cell carcinoma remain
the most common types of NSCLC, but bronchoalveolar car-
cinoma is a well-differentiated subtype that has a prolonged
doubling time. Because of its slow growth rate, it may be
missed by PET scan.49 Bronchoalveolar carcinoma may pres-
ent as an SPN, particularly with a ground-glass appearance,
as airspace disease, or as multiple nodules.
Small Cell Lung Cancer
Small cell carcinoma accounts for approximately 20% of
lung cancers. Typically, it presents as a central mass in
association with significant nodal disease, often accompanied
by distant metastases.78 Small cell carcinoma typically has a
very short doubling time. Paraneoplastic syndromes are more
common with small cell lung cancer than with NSCLC.
Pulmonary Carcinoid Tumor
Pulmonary carcinoid tumors are uncommon neuroendo-
crine neoplasms that account for 1 to 2% of lung cancers.79
They are classified as either typical or atypical, depending on
their histology, but represent a spectrum of neuroendocrine
tumors.80 Either type of carcinoid may present as an SPN,
usually in the fifth or sixth decade of life. Typical carcinoid
tumors have a very long doubling timeup to 80 months
and thus may be mistaken for benign lesions.81 Atypical
carcinoid tumors have a much shorter doubling time and are
more likely to show an increase in size on serial CT scans.
Typical carcinoid tumors have an extremely low incidence
of recurrence and are not usually associated with nodal
metastasis.
Metastatic Malignancies
Metastases to the lung frequently appear as smooth, round,
well-demarcated lesions. They often are multiple, tend to be
found in the better vascularized lower lung zones, and rarely
are associated with mediastinal adenopathy. Most pulmonary
metastases derive from the lungs, the colon, the testicles,
the breasts, melanomas, or sarcomas. Treatment tends to be
palliative, based on the diagnosis of the primary tumor, but
it may be curative in cases of metastatic sarcoma or testicular
carcinoma. In patients with these cancers, limited wedge
resection of a metastasis to the lung has been shown to confer
a survival advantage; this measure may also be beneficial for
Scientific American Surgery
SOLITARY PULMONARY NODULE 7
patients with metastatic head and neck cancer and, occasion-
ally, for those with metastatic melanoma.82 Recent reports
with modern chemotherapeutic strategies and resection
have suggested that prolonged survival is possible in colorec-
tal cancer metastatic to the lung, with 5-year survival of
67%.83 Improved outcomes are thought to be more likely
in colorectal cancer patients with less than two pulmonary
metastases.84
benign lesions
Pulmonary Hamartoma
Pulmonary hamartomas are the most common benign
pulmonary tumors and the third most common cause of
SPNs overall. Most (90%) arise in the periphery of the lung,
but endobronchial hamartomas are seen as well. Because they
are most common in the periphery, hamartomas are usually
asymptomatic. When a potential hamartoma appears as an
SPN on a chest x-ray, CT scanning is warranted for further
evaluation.
Certain typical CT findings suggest that the SPN is likely
to be a hamartoma. One such finding is a particular pattern
of calcification. Calcification is more common in benign
lesions than in malignant tumors. Four patterns of calcifica-
tion are considered benign: central, diffuse, laminated, and
popcornlike. The first three patterns are most commonly
associated with an infectious condition (e.g., histoplasmosis
or tuberculosis). The popcornlike pattern, however, indicates
that the lesion is probably a hamartoma. Unfortunately,
calcification is present in only about 50% of benign lesions,
and only about 50% of hamartomas are calcified.31 It is
important to remember that pulmonary carcinoid tumors and
metastases to the lung (especially those from osteosarcomas,
chondrosarcomas, or synovial cell sarcomas) may also have
calcifications. Another reliable marker of a hamartoma is the
finding of fat within the lesion on a CT scan; however, fewer
than 50% of hamartomas demonstrate this characteristic.
PET scanning, particularly the correlation between PET
and CT findings on PET-CT, has been suggested as a useful
diagnostic tool.85
Inflammatory Nodules
Sarcoidosis is known as the great mimicker, but it rarely
presents as an SPN.86 Most commonly, it presents as hilar
and mediastinal lymphadenopathy and diffuse parenchymal
involvement. When it does present as an SPN, it is almost
invariably a solid lesion, hardly ever a cavitary one. The inci-
dence of sarcoidosis is highest in African-American women
between 20 and 40 years of age. If sarcoidosis is suspected
during the evaluation of an SPN, an elevated angiotensin-
converting enzyme level supports the diagnosis, but a normal
level does not exclude it. If a biopsy is performed, the pres-
ence of noncaseating granulomas on pathologic evaluation
helps establish the diagnosis. If a diagnosis of sarcoidosis is
suspected, PET scanning has been suggested as an effective
method to identify extrathoracic sites of disease to target for
pathologic confirmation.87
Pulmonary rheumatoid nodules are present in fewer than
1% of patients with rheumatoid arthritis.88 They are usually
associated with rheumatoid nodules in other parts of the
body but may precede any systemic manifestations of the
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disease. Pulmonary rheumatoid nodules, although generally
asymptomatic in themselves, arise from underlying rheu-
matoid activity. When the underlying disease is active, the
nodules may grow, simulating malignancy. An elevated serum
rheumatoid factor level is typical and helps confirm the
diagnosis.
Wegener granulomatosis is a necrotizing vasculitis that
affects both the upper and the lower respiratory tract, as well
as the kidneys. It presents with an SPN in approximately 20%
of patients.89 If vasculitis is suspected during evaluation of
an SPN, laboratory studies should include testing for cyto-
plasmic antineutrophil cytoplasmic antibodies (c-ANCAs);
a positive result on this test is highly suggestive of Wegener
granulomatosis. Treatment includes the cytotoxic drug
cyclophosphamide, either alone or in combination with
corticosteroids.
Infectious Nodules
An SPN can also represent an infectious granuloma caused
by tuberculosis, atypical mycobacterial diseases, histoplas-
mosis, coccidioidomycosis, or aspergillosis. Such granulomas
frequently have a cavitary appearance on CT scans. Occa-
sionally, a chest x-ray taken with the patient in different
positions shows shifting of the position of the cavitys con-
tents or a crescent of air around the mass (the Monod sign).90
This radiographic finding is characteristic of a mycetoma,
usually aspergilloma. Depending on the circumstancesin
particular, on whether there has been significant hemoptysis
and whether pulmonary function is reasonably well pre-
servedmany of these lesions are best treated with resection.
Others are best diagnosed by noninvasive techniques and
treated with antimicrobial therapy.
Pulmonary dirofilariasis is a rare but well-attested cause of
SPNs that is the consequence of infestation of human lungs
by the canine heartworm Dirofilaria immitis. This organism is
transmitted to humans in larval form by mosquitoes that have
ingested blood from affected dogs.91 Because humans are not
suitable hosts for this organism, the larvae die and embolize
to the lungs, where they initiate a granulomatous response.
Typically, these lesions are pleura based, and the diagnosis is
made at the time of resection.92 Once the diagnosis is made,
no further therapy is required.
Echinococcosis is a hydatid disease caused by the tape-
worm Echinococcus granulosus. It is endemic to certain areas
of the world where sheep and cattle are raised. Normally, it
is ingested incidentally; the parasite penetrates the bowel wall
and travels to the lungs in 10 to 30% of cases.93,94 A complete
blood count usually demonstrates peripheral eosinophilia. If
echinococcosis is suspected, a hemagglutination test, which
has a sensitivity of 66 to 100% and a specificity of 98 to 99%
for Echinococcus, should be performed. TTNB should not be
performed because there is a risk that cyst rupture triggers an
anaphylactic reaction to the highly antigenic contents. Patients
may be treated with anthelmintic agents, but the incidence of
persistent or recurrent disease is high. Accordingly, surgical
resection should be considered.
other considerations
Pulmonary amyloidosis may present in either a diffuse or
a nodular form. The prognosis is most favorable when it
presents as an asymptomatic SPN. Typically, the nodule is
well defined and between 2 and 4 cm in diameter. Unless the
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SOLITARY PULMONARY NODULE 8
patient exhibits systemic manifestations of amyloidosis, the
diagnosis can be confirmed only by biopsy of the nodule.42
Rounded atelectasis usually presents as a pleura-based
nodular density that occurs secondary to pleural scarring and
thickening. An effort should be made to look for associated
pleural plaques resulting from asbestos exposure. The CT
scan usually demonstrates an SPN with a comet tail. Biopsy
is not required unless mesothelioma is strongly suspected or
the SPN is seen to have grown on successive CT scans.
Management
The ACCP attempted to provide evidence-based guide-
lines to direct the evaluation of patients with SPNs 8 to
10 mm in diameter in their 2007 consensus statement.39
Unfortunately, few, if any, randomized controlled trials exist
to direct management. Most clinicians rely on a combination
of single-institution studies, a few prospective trials, and clin-
ical acumen to assess a given patients risk profile to inform
decisions on invasive and noninvasive testing. The initial step
in decision making is to confirm that the lesion is, in fact,
new, and to compare current chest x-rays or CT scans with
any previous images that are available. An SPN whose size
has been stable for 2 years on diagnostic images will be benign
90 to 95% of the time. If no previous images are available for
comparison, the patient should undergo a clinical evaluation
to determine their risk profile. This evaluation must be
individualized according to the characteristics of the patient
and the lesion. On the basis of the patients age, exposure and
smoking history, the size of the SPN, and the characteristics
of the lesions borders, an SPN for which no previous
diagnostic images are available can be initially classified
as having a low, intermediate, or high probability of cancer
[see Table 3].7,95,96 This classification governs the subsequent
workup. Whereas a patient with a high-probability SPN needs
a complete evaluation progressing toward resection with min-
imal delay, the same strategy would not be cost-effective for
a patient with a low-probability SPN. It is important not to
subject a patient with a high-probability SPN to studies that
will not change clinical management or outcome: doing so
will delay diagnosis and treatment unnecessarily.
At this point in the evaluation, if the nature of the SPN is
still indeterminate and the lesion is larger than 1 cm, there
may be a role for PET or PET-CT scanning. If PET scanning
yields negative results, the SPN is likely benign, and follow-
up CT scanning is appropriate. If PET scanning yields
positive results and the patient is at high surgical risk, TTNB,
bronchoscopy, or guided bronchoscopy may be performed to
Table 3 Initial Assessment of Probability of Cancer in
Solitary Pulmonary Nodule
Characteristics Probability of Cancer
of Patient or
Lesion Low Intermediate High
Patient age (yr) < 40 4060 > 60
Patient smoking Never < 20 pack-yr g20 pack-yr
history smoked
Lesion size (cm) < 1.0 1.12.2 g2.3
Lesion margin Smooth Scalloped Spiculated
 2009 Decker Intellectual Properties Inc Scientific American Surgery
THORAX SOLITARY PULMONARY NODULE 9

establish a diagnosis. If, however, the patient is at reasonable
surgical risk, proceeding directly to VATS resection (and,
potentially, to lobectomy) offers the best chance of cure for a
probable carcinoma.
For patients with SPNs smaller than 1.0 cm, the optimal
approach may be to perform serial CT scanning at an initial
3-month interval for a minimum of 2 years. The rationale
for this approach is based on the difficulty of identifying
these lesions with VATS, the low likelihood of establishing a
diagnosis with TTNB, and the possibility that the lesion may
be benign. If the lesion has grown visibly between scans, it is
probably malignant, and proceeding with resection for diag-
nosis and treatment is appropriate. The likelihood that nodal
metastases will develop in a closely followed SPN smaller
than 1.0 cm is low.73 If the SPN proves to be malignant,
scanning at 3-month intervals is unlikely to alter the eventual
outcome. Society guidelines continue to be refined in an
effort to provide helpful recommendations.
Financial Disclosures: None Reported.

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