Diagnostic Evaluation and Management of the Solitary Pulmonary Nodule

06-04-2015 Diagnostic evaluation and management of the solitary pulmonary nodule

http://www.uptodate.com/contents/diagnostic-evaluation-and-management-of-the-solitary-pulmonary-nodule?source=search_result&search=nodulo+pulmonar& 1/21

Official reprint from UpToDate www.uptodate.com 2015 UpToDate

AuthorSteven E Weinberger, MD

Section EditorsNestor L Muller, MD, PhDTalmadge E King, Jr, MDJames R Jett, MD

Deputy EditorGeraldine Finlay, MD

Disclosures: Steven E Weinberger, MD Nothing to disclose. Nestor L Muller, MD, PhD Nothing to disclose. Talmadge E King,Jr, MD Consultant/Advisory Boards: InterMune [pulmonary f ibrosis (pirfenidone)]; ImmuneWorks [pulmonary f ibrosis]; BoehringerIngelheim [IPF (nintedanib)]; GlaxoSmithKline [pulmonary f ibrosis]; Daiichi Sankyo [pulmonary f ibrosis]. James R Jett, MDGrant/Research/Clinical Trial Support: Oncimmune Inc [Biomarkers of cancer (Early CDT lung)]. Geraldine Finlay, MD Nothing to

Diagnostic evaluation and management of the solitary pulmonary nodule

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2015. | This topic last updated: Feb 10, 2015.

INTRODUCTION A solitary pulmonary nodule (SPN) is a common clinical problem, with lung cancer screening

studies of smokers at high risk for malignancy reporting the prevalence of SPNs as high as 50 percent. The major

question that follows detection of a SPN is the probability of malignancy, with subsequent management varying

accordingly.

The definition, differential diagnosis, initial evaluation, and management of a SPN are reviewed here. Radiographic

evaluation of pulmonary nodules and differential diagnosis of multiple pulmonary nodules is discussed in greater

detail separately. (See "Computed tomographic and positron emission tomographic scanning of pulmonary

nodules" and "Differential diagnosis and evaluation of multiple pulmonary nodules".)

DEFINITIONS A solitary pulmonary nodule (SPN) is classically defined as a single, small (30 mm), usually

well-circumscribed, radiographic lesion that is surrounded completely by pulmonary parenchyma [1-3]. Patients are

usually asymptomatic, and there are typically no associated features on imaging (eg, hilar adenopathy, atelectasis,

or pleural effusion) [4,5]. SPNs are further subclassified as solid or subsolid, as discussed separately. (See

'Computed tomography' below.)

Radiographically, lesions that measure 30 mm are considered nodules and those >30 mm are considered

masses. The distinction between a SPN and a mass is important because it determines further work-up. When

patients present with a SPN, the focus of the evaluation is the assessment of the probability of malignancy and the

selection of patients for computed tomography (CT) scan surveillance, nonsurgical biopsy, or surgical biopsy. In

contrast, when symptoms or associated imaging abnormalities occur in patients with a nodule or mass, work-up

should proceed for suspected cancer, as discussed separately. (See "Overview of the initial evaluation, diagnosis,

and staging of patients with suspected lung cancer".)

The increased use of CT scanning for benign pathologies has led to the identification of multiple pulmonary nodules

(arbitrarily defined as



Malignant etiologies Common causes of a malignant SPN include primary lung cancer, lung metastases, and

carcinoid tumors.

Benign etiologies Common causes of a benign SPN include infectious granulomas and benign tumors such as

a hamartoma. Less common causes include vascular and inflammatory lesions (table 1).

Primary lung cancer Adenocarcinoma is the histologic subtype of primary lung cancer that most commonly

presents as a SPN, followed by squamous cell carcinoma and large cell carcinoma. Both adenocarcinoma

and large cell carcinoma share a tendency to originate as a peripheral lesion, whereas squamous cell

carcinoma presents more frequently as a central lesion than as a peripheral nodule. In one review, most of the

malignant SPNs were adenocarcinoma (50 percent) and squamous cell carcinoma (20 to 25 percent); each of

the other pathologic categories accounted for less than 10 percent of malignant SPNs [2]. Rarely, primary

extranodal lymphomas can present as a SPN. (See "Overview of the initial evaluation, diagnosis, and staging

of patients with suspected lung cancer".)

Metastatic cancer Although most metastases present as multiple pulmonary nodules, some present as a

SPN, including malignant melanoma, sarcoma, and carcinomas of the colon, breast, kidney, and testicle

(image 1) [13]. In a patient with a history of extrathoracic malignancy, the probability of metastasis is

approximately 25 percent when a SPN is detected on a chest radiograph [14].

Carcinoid tumors Although carcinoid tumors are typically endobronchial, approximately 20 percent present

as a peripheral, well-circumscribed SPN. (See "Bronchial neuroendocrine (carcinoid) tumors: Epidemiology,

risk factors, classification, histology, diagnosis, and staging".)

Infectious Infectious granulomas cause approximately 80 percent of benign nodules [1,9,10]. Endemic fungi

(eg, histoplasmosis, coccidioidomycosis) and mycobacteria (either tuberculous or nontuberculous

mycobacteria) (image 2) are the most frequently recognized causes of infectious granulomas presenting as a

SPN. While not pathognomonic, they classically appear as a well-demarcated and fully-calcified SPN (image

3). However, more frequently, they are not diagnosed until the lesion is resected as a presumed cancer [15].

Less commonly, infection with abscess-forming bacteria (eg, Staphylococcus aureus) and Pneumocystis

jirovecii (previously called Pneumocystis carinii) can present as a SPN, which may cavitate [16-19]. Rarely,

dirofilariasis, a mosquito-borne disease, presents as a SPN. Injected larvae embolize to the lungs and induce

a granulomatous response, typically resulting in a noncalcified, pleural-based nodule that is mistaken for

cancer. (See "Miscellaneous nematodes".)

Benign tumors Hamartomas cause approximately 10 percent of benign nodules found in the lung [1,9,10].

They typically present in middle age, grow slowly over years, and are histologically heterogeneous. Cartilage

(with scattered calcification), fat, muscle, myxomatous tissue, and fibroblastic tissue may all exist (picture 1

and picture 2A-B and image 4) [20]. The characteristic appearance of a hamartoma on a chest radiograph is a

SPN with "popcorn" calcification, although this pattern is observed in less than 10 percent of cases (image 5).

High-resolution CT scanning of the lesion is particularly useful because it may demonstrate focal areas of fat,

or calcification alternating with fat, which are virtually diagnostic of a hamartoma (image 6 and image 7) [21].

Less common benign neoplasms such as fibromas, leiomyomas, hemangiomas, amyloidoma (image 8), and

pneumocytoma do not have characteristic features on imaging (image 9) [22].

Vascular Pulmonary arteriovenous malformations (PAVMs) are common in hereditary hemorrhagic

telangiectasia but can also be idiopathic. A contrast-enhanced CT scan may demonstrate a feeding artery

and vein, which will distinguish vascular from soft tissue lesions. If a PAVM is suspected and the feeding

artery diameter is >2 to 3 mm, contrast-enhanced CT and pulmonary angiography are the imaging modalities

of choice and biopsy should be avoided. Rarer causes of SPNs that are vascular in nature include pulmonary

infarcts (image 10), pulmonary varices, and pulmonary contusion or hematoma (table 1). (See "Pulmonary

arteriovenous malformations: Diagnostic evaluation".)



INITIAL EVALUATION The initial evaluation should use clinical features, radiographic features, and occasionally

quantitative models to determine the likelihood of malignancy. The likelihood of malignancy then determines further

management (eg, computed tomography [CT] surveillance or biopsy).

Clinical features Clinical features associated with an increased probability of malignancy include advanced

patient age and underlying risk factors. However, young age and the absence of risk factors do not preclude a

diagnosis of malignancy [23].

Imaging The imaging tools used to evaluate a solitary pulmonary nodule (SPN) include chest radiography, CT,

and functional imaging (usually positron emission tomography [PET]). Although the vast majority of SPNs that

present to the clinician for evaluation are incidental findings on CT, occasionally nodules are detected on the chest

radiograph. While nodule characteristics can be appreciated by chest radiography, they are better defined by CT

scan. It is important to make every attempt to secure old imaging studies, including prior CTs and chest

radiographs, because size comparisons can be used to determine whether the nodule has been stable or growing

over time.

Computed tomography A CT scan of the chest, preferably with thin sections (1 mm slice), should be

obtained in all patients. Contrast enhancement is not typically required when imaging a SPN. CT features that can

be used to predict whether a nodule is malignant include size, border, calcification, attenuation, and growth. (See

"Computed tomographic and positron emission tomographic scanning of pulmonary nodules", section on 'Computed

tomography (CT)'.)

Other Inflammatory lesions (granulomatosis with polyangiitis [formerly known as Wegeners

granulomatosis], rheumatoid arthritis, sarcoidosis, amyloidosis, rounded atelectasis), perifissural pulmonary

lymph nodes, and developmental lesions (bronchogenic cyst) are unusual causes of benign nodules (table 1).

The presence of systemic disease elsewhere may increase the likelihood of an inflammatory nodule, but not

all patients will have such a history since nodules can occasionally be the initial presenting feature of the

underlying disease. Rarely are SPNs due to artifact such as pseudotumor (loculated fluid in the interlobar

fissure) or mucoid impaction; simple maneuvers such as diuresis and cough assistance may result in the

resolution of a SPN due to such entities on follow-up imaging.

Patient age The probability of malignancy rises with increasing patient age [6,8,23-26]. One study reported

a higher frequency of malignant nodules in patients >50 years of age compared with patients 50 percent

Risk factors The probability of malignancy is always higher when a nodule occurs in a patient with a history

of smoking, especially current smokers, because of the strong association between cigarette smoking and

lung cancer [27]. Other risk factors for lung cancer including family history, female sex, emphysema, prior

malignancy, and asbestos exposure should also be considered when evaluating a patient with a nodule [28].

(See "Overview of the risk factors, pathology, and clinical manifestations of lung cancer", section on 'Risk

factors' and "Cigarette smoking and other risk factors for lung cancer".)

Size Consistently among studies, size, usually measured as the maximum diameter of a nodule, is an

independent predictor for malignancy. Data from retrospective series and prospective screening trials all

confirm that the risk of malignancy rises with increasing size as follows [12,24,25,27,29-37]:

Nodules



Nodules 8 to 20 mm: 18 percent

Nodules >20 mm: >50 percent

Attenuation Nodule attenuation should be classified as solid or subsolid (pure and part-solid). Solid lesions

are more common, but part-solid lesions have a higher likelihood of being malignant [12,38,39].

Solid SPNs are typically dense and homogeneous on imaging. Solid nodules 8 mm (also known as

subcentimeter nodules) are unlikely to be malignant, are difficult to biopsy, not reliably characterized by

functional imaging, and more likely to be followed by CT scan surveillance. In contrast, solid nodules >8 mm

have a greater likelihood of malignancy, can be more reliably characterized by functional imaging, and are

more likely to be successfully diagnosed by biopsy.

Subsolid/non solid nodules have poor attenuation (ie, density) on imaging such that normal parenchymal

structures, including airways and vessels, can be visualized through them. They should be further assessed

for the absence (pure subsolid; ground glass nodules) or presence (part-solid) of a solid component.

Compared with solid nodules, they are often less amenable to functional imaging and biopsy.

The incidence of subsolid nodules is increasing, likely due to the rising incidence of adenocarcinoma

worldwide. The most common neoplastic histologies seen with ground glass morphology are atypical

adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA)

(picture 3) [40-45]. (See "Pathology of lung malignancies" and "Bronchioloalveolar carcinoma, including

adenocarcinoma in situ".)

The risk of malignancy in ground glass lesions that persist beyond three months by CT scan ranges from 10

to 60 percent and depends upon the size and presence of a part-solid component [2,12,40-43,45,46]. As

examples, malignancy is rare in small (10 mm) SPN that are pure ground glass and more common (10 to 50

percent) in larger lesions (>10 mm). In contrast, malignancy will be identified in at least half of ground glass

lesions that have a large (>50 percent) or newly developed solid component. This higher malignant potential of

part-solid lesions was demonstrated in CT screening studies where the identification of a solid component of

ground glass lesions was an independent predictor for malignancy [12].

Formal density measurement of SPNs was at one time considered to be a promising technique but is no

longer used as part of the routine evaluation of a SPN.

Growth CT is classically used as a diagnostic and management tool to assess nodule growth or stability. A

SPN that has clearly grown on serial imaging is at high risk for malignancy, often necessitating a tissue

diagnosis. Conversely, a solid nodule that has been stable for two years and a subsolid nodule that is stable

for three years are likely to be benign, and immediate tissue biopsy can be avoided. Consequently, in patients

who present with a SPN, every attempt should be made to obtain older imaging studies, preferably a CT.

Traditionally, a nodule that remained stable for two years or longer on a chest radiograph was considered

benign. However, retrospective studies suggest that lack of appreciable growth on a chest radiograph over a

two-year duration has a poor positive predictive value (65 percent) for a benign lesion [1,47,48]. Compared to

chest radiography, high-resolution CT scan can better appreciate changes in diameter (0.5 mm change versus

3 to 5 mm) [1]. As such, serial CT is preferred for growth assessment.

Studies that assess the volume doubling time (VDT) of cancers have been helpful in predicting the probability

of malignancy in a SPN. Most malignant nodules have a VDT between 20 and 400 days, with slower VDTs

(>400 days) observed in typical carcinoid and in preinvasive or low grade adenocarcinoma (eg,

adenocarcinoma in situ [AIS] and minimally-invasive adenocarcinoma [MIA]) [1,5,49-51]. Thus, a nodule that

has increased in size over a short period of time (two

years) is likely benign. These data largely apply to solid nodules. In contrast, subsolid nodules are more likely

to be seen with early or low grade adenocarcinoma, which has a slower average VDT. One retrospective study

reported median VDTs of malignant nodules according to their CT attenuation characteristics as: ground glass



Functional imaging Because cancers are more likely to be metabolically active, functional imaging is often

used to help distinguish benign from malignant nodules. Positron emission tomography (PET) is the most common

functional imaging modality used. Less common modalities include dynamic contrast-enhanced CT scan, dynamic

magnetic resonance imaging (MRI), and dynamic single photon emission CT scan. Although the sensitivity is

similar among all four modalities, PET is the preferred modality because it is best studied and widely available.

(See "Computed tomographic and positron emission tomographic scanning of pulmonary nodules", section on

'Positron emission tomography (PET)'.)

The decision to perform a PET depends upon the probability of malignancy, size, and attenuation:

FDG-avidity is measured by the standardized uptake value (SUV). The optimal cut-off point that distinguishes

benign from malignant lesions is unknown. The SUV correlates positively with the likelihood of malignancy and even

nodules with a low SUV (eg, 8 mm PET has a high sensitivity (72 to 94 percent) for

the diagnosis of malignancy and should be used to further evaluate a SPN in all patients in this category [55-

62].

High probability (>65 percent) solid SPN >8 mm Although PET scan is unlikely to change the indication for

biopsy in this population, in practice, it is frequently performed as part of the work-up for suspected cancer.

This is because it has the distinct advantage of confirming the clinical suspicion for malignancy as well as

acquiring staging data if the nodule is indeed malignant. (See "Overview of the initial evaluation, diagnosis, and

staging of patients with suspected lung cancer", section on 'Radiographic staging'.)

Low probability (10 to 15 mm), which are considered to have greater malignant potential

compared with smaller, purely subsolid nodules.



SUV >2.5 is typically used to distinguish SPNs that have a high probability of malignancy, reflecting the value

typically used in practice [2].

PET can have false-positive and false-negative findings:

Other functional imaging modalities are rarely used. Combined imaging with CT and PET (integrated PET/CT)

increases the amount of ionizing radiation exposure from 5 to 7 mSv (PET) to 10 to 25 mSv (PET/CT) [2,78-81].

Although earlier studies suggested that CT scan with dynamic contrast enhancement had a sensitivity of 98

percent, the high false-negative rate demonstrated in later studies has discouraged its use [2,82-84]. Despite

reports of high sensitivity for dynamic MRI and dynamic single-photon emission CT scan (94 and 95 percent,

respectively), they are poorly studied and not widely available [2,78].

Assessing the risk of malignancy The probability of malignancy in a SPN should be assessed either clinically

or by quantitative predictive models as the following [2]:

Many physicians estimate the probability of malignancy intuitively. Studies that have compared the accuracy of

clinician judgment with quantitative prediction models report modest to excellent agreement in estimating the

probability of malignancy, suggesting that clinical assessment and prediction models may be complementary

[85,86].

Although no single quantitative predictive model is superior, they all combine clinical and radiographic features to

estimate the probability of malignancy [24,25,37,86-90]. They are most useful for nodules that are 8 to 30 mm to

facilitate patient discussion and guide management choices [2]. Typically, nodules >30 mm are resected because

these lesions have such a high likelihood of malignancy that the benefit of resection outweighs the associated risk

of surgery. In contrast, nodules 8 mm (without documented growth) are usually followed by serial CT scan

because these lesions have a low likelihood of malignancy such that the benefits of resection do not justify the risk

of a technically-difficult resective surgery [2,27,29,35,40-43,46]. Thus, estimating the probability of malignancy in

both of these settings is unlikely to change the diagnostic strategy. However, the risk of malignancy and diagnostic

options are widely variable in nodules that are 8 to 30 mm. Thus, estimating the pretest probability of malignancy in

that setting will facilitate the selection and interpretation of subsequent diagnostic tests.

Quantitative predictive models that have been validated for use include the following [12,24,25,36,37]:

False-positive findings occur with infectious and inflammatory conditions, in particular, pneumonia,

mycobacterial disease, rheumatoid nodules, and sarcoidosis.

False-negative results can occur with less metabolically active tumors (adenocarcinoma in situ, minimally

invasive adenocarcinoma, mucinous adenocarcinoma, and carcinoid tumors) and uncontrolled hyperglycemia

(high serum glucose levels retard FDG uptake). In addition, smaller lesions (eg, 8 mm) and subsolid lesions

may be falsely negative on PET because a critical mass of metabolically active malignant cells is required for

detection by PET [2,62-64,77].

Low probability (65 percent)

A full and simplified version of one model was derived using data collected from the Pan-Canadian Early

Detection of Lung Cancer screening study and validated using data from the British Columbia Cancer Agency

study [12]. Predictors of cancer were identified in 2961 patients with nodules found on first screening CT and

included the following: older age, female sex, family history of lung cancer, emphysema, larger nodule size,

location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Both full

and simplified versions of the model showed excellent discrimination between benign and malignant nodules,

even when applied to nodules typically difficult to characterize (SPN 10 mm). While the negative predictive

value of this model was consistently high (99 percent), the sensitivity ranged from 60 to 86 percent when

different cut-off thresholds were used. The probability of malignancy can be calculated using the calculator



The use of biomarkers (eg, carcinoembryonic antigen, alpha-1 antitrypsin, squamous cell carcinoma antigen) to

stratify risk of malignancy in patients with SPNs has been reported but is not yet validated for use [91].

Measurement of biomarkers of benign diseases (eg, angiotensin converting enzyme, connective tissue disease

markers) has not been tested in the general setting of SPN but can be considered on a case-by-case basis.

Assessing nodule volume to increase the proportion of nodules correctly identified as malignant has been reported

but is not yet validated for routine use [36,92].

MANAGEMENT STRATEGY The optimal approach to a solitary pulmonary nodule (SPN) is unknown and the

approaches used in practice are often inconsistent with guidelines [93]. However, there is consensus that the

management be individualized to each patient.

Aggressive approaches that surgically remove nodules are more likely to result in the diagnosis of early stage lung

cancer, which is potentially curable and associated with a five-year survival of 70 to 80 percent [1,46,49,94-96].

However, they also result in the unnecessary removal of benign nodules of uncertain clinical significance. In

contrast, less aggressive approaches that leave most benign nodules intact will miss some cases of potentially

curable lung cancer, which may no longer be curable after progression. Many clinicians place a high value on

diagnostic certainty in the context of low operative mortality (



[2,63]. This approach maximizes the detection of early resectable lung cancer while minimizing the harm

associated with an excessively aggressive surgical approach and takes into consideration patient values and

preferences.

Selection of strategy Management options for SPNs include computed tomography (CT) surveillance and

nodule sampling or resection. Despite variation among institutions regarding optimal management strategy for

nodules, there is consensus that the management be individualized to each patient after consideration of the

following [2,63,97-99]:

Once this information is known, a strategy can be selected that is optimized to meet patient preferences (eg, for

diagnosis and safety) and institutional-related expertise. (See 'Values and preferences' below.)

Patients with adequate prior imaging This group of patients includes those in whom prior imaging is

sufficient for the assessment of growth or stability.

Growing nodule A solid or subsolid nodule that has clearly grown on serial imaging tests has a high

likelihood of being malignant and should be evaluated pathologically with excision or biopsy. This is discussed in

more detail separately. (See 'Surgical biopsy' below.)

Stable nodule Experts agree that the vast majority of solid SPNs that are unchanged on serial CT scan

over a two-year period and subsolid SPNs unchanged over a three-year period are likely benign and do not need

further diagnostic evaluation. Occasionally, patients in this category may require extended periods of CT

surveillance to ensure stability, especially if low grade adenocarcinoma or carcinoid is suspected.

Patients without adequate prior imaging This group of patients includes those in whom prior imaging is

insufficient for the assessment of growth or stability.

Solid nodules >8 mm In patients with solid SPNs >8 mm for which growth or stability cannot be

adequately determined, there is a consensus of opinion on the following (algorithm 1):

The probability of malignancy (low [65 percent]) (see

'Assessing the risk of malignancy' above)

Nodule characteristics (eg, size, attenuation, stability)

A nodule that has a low probability (



Solid nodules 8 mm A solid nodule 8 mm can be followed by serial CT scan. The rationale for this

strategy is based upon the low prevalence of malignancy as well as the procedural difficulty and high risk of tissue

biopsy in this population. Any increase in nodule size should prompt redirection of the management strategy toward

biopsy or excision.

Studies that report growth for nodules found on CT suggest that the detection of growth is dependent upon the

presence of risk factors in the study population. One retrospective review reported that in patients with no risk

factors for lung cancer who had SPNs


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The optimal management of persistent part-solid nodules is uncertain. Regardless of disagreement among

societies, the common goal is the selective removal of nodules at greater risk of being malignant, while avoiding the

removal of those that are more likely to be benign. For example, the Fleischner Society suggests management

based upon size of the solid component: CT surveillance when the solid component is 5 mm, surgical removal

when the solid component is >5 mm, and PET scanning for persistent part-solid nodules >10 mm. However, we

agree with the ACCP that suggests management based upon size of the part-solid nodule:

Multiple nodules The increased use of CT surveillance has led to the frequent identification of multiple

nodules of uncertain significance on serial imaging. Prospective studies of patients during evaluation for lung cancer

and screening studies suggest that the vast majority of these nodules are benign [29,30,104-109]. This suggests

that benign and malignant nodules can coexist in the same patient. Although one nodule may be dominant (size,

growth characteristics, PET avidity), each nodule should be assessed individually for the probability of malignancy

and followed by CT surveillance or biopsied accordingly [2]. As an alternative approach, the Fleischner Society has

developed detailed guidelines for the management of multiple nodules based upon size and appearance (table 6).

Values and preferences It is prudent to assess a patients desire for an extensive work-up as well as for

treatment in the eventuality that a nodule is cancer. Some individuals prefer no treatment or suboptimal therapy,

especially those with life-limiting comorbid conditions. For others who are risk averse, particularly to curative

lobectomy, discussion of alternative suboptimal therapies for lung cancer is reasonable. For patients who prefer no

therapy, monitoring clinically or with CT surveillance may be preferred for palliative purposes. In contrast, surgical

excision may be preferred by those who have a strong desire for diagnostic certainty, are noncompliant with follow-

up, and are willing to accept the risks associated with surgery.

Nonsurgical biopsy Nonsurgical biopsy can be performed by sampling the nodule through the airway

(bronchoscopic techniques) or through the chest wall (transthoracic needle biopsy). Nonsurgical biopsy is preferred

in patients who have a nodule at intermediate risk (5 to 65 percent) for malignancy or in patients who are at high

risk (>65 percent) who are not surgical candidates. Additional indications may include patients in whom a benign

diagnosis is suspected that requires therapy (eg, mycobacterial disease) or rarely, for patients at low risk of

malignancy who place a high value on diagnostic certainty.

The choice of sampling procedure varies according to the size and location of the nodule, the availability of the

procedure, and local expertise. Typically, bronchoscopic techniques (endobronchial ultrasound [EBUS] and

conventional bronchoscopy) are preferred for large, centrally-located lesions, and transthoracic needle biopsy

techniques are preferred for more peripheral lesions. EBUS-guided sheath transbronchial biopsy may also be used

in centers with expertise for peripheral nodules. Navigational tools (eg, virtual bronchoscopy or electromagnetic

navigation) hold promise as modalities that increase the diagnostic yield of bronchoscopy for small peripheral

nodules; their use depends on equipment availability and institutional expertise.

Bronchoscopic techniques The main bronchoscopic techniques that are used to obtain diagnostic material

from pulmonary nodules include conventional bronchoscopic-guided transbronchial biopsy (TBB), bronchoscopic-

transbronchial needle aspiration (bronchoscopic-TBNA), endobronchial ultrasound-guided sheath transbronchial

biopsy (EBUS-guided sheath TBBx), and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-

TBNA). Because these modalities biopsy nodules via the airway and are performed under conscious sedation, they

are preferred for patients who have nodules that are close to a patent airway and for those in whom the risk of

complications from surgery or transthoracic needle biopsy is high. Among the bronchoscopic modalities, EBUS-

A part-solid nodule 8 mm can be followed by CT surveillance at 3, 12, and 24 months. If the nodule or the

solid component is unchanged after 24 months of observation and clinical suspicion for low grade

adenocarcinoma or carcinoid exists, further CT yearly for an additional one to three years is preferred [2]. (See

'CT surveillance' below.)

A part-solid nodule >8 mm (especially those >15 mm) or those with a solid component >8 mm can be further

evaluated by PET, and when feasible, biopsy or surgical resection can be considered. (See 'Nonsurgical

biopsy' below and 'Surgical biopsy' below.)



TBNA or EBUS-guided sheath TBBx are the preferred procedures, when local expertise is available. Conventional

bronchoscopic-TBNA or TBB are alternatives when EBUS is not available.

EBUS-TBNA has been shown to surpass flexible bronchoscopy for the diagnosis of lung malignancies [110-112].

Its comparative performance for specific benign diagnoses is unknown but likely to also be superior to conventional

bronchoscopy. However, for both procedures, high operator proficiency and multiple passes with rapid onsite

cytologic evaluation (ROSE) may enhance the diagnostic accuracy [114-119].

The low negative predictive values for TBNA-associated techniques emphasize that a nondiagnostic or negative

finding does not rule out the possibility of malignancy. In such cases, when nonsurgical biopsy findings are

nondiagnostic, selecting a strategy that weighs the benefits of diagnostic certainty against the risks of surgical

resection is preferred.

Transthoracic needle biopsy Transthoracic needle biopsy (TTNB) is performed by passing a needle

percutaneously through the chest wall into the target nodule, usually under CT guidance. The needle frequently

traverses pleura and lung to either aspirate or biopsy tissue. Typically, the diagnostic yield of TTNB is >88 percent

for benign and malignant nodules [50,120-124]. However, the high diagnostic accuracy of TTNB should be weighed

against the risk of pneumothorax. The risk-benefit ratio is increased in patients with concomitant emphysema,

bullous disease, or chronic respiratory failure. Thus, TTNB is the preferred modality for biopsy of peripheral nodules

that are located close to the chest wall or for deeper lesions where fissures do not need to be traversed and are

without surrounding bullous disease.

One meta-analysis of 46 studies of TTNB detected malignant solitary pulmonary nodules (SPNs) with a sensitivity

and false negative rate of 90 and 22 percent, respectively [113]. However, the diagnostic sensitivity of TTNB is lower

for smaller SPNs (2 cm: 63 percent;



The most common complication of TTNB is pneumothorax (10 to 60 percent), with hemorrhage occurring less

commonly (1 to 9.5 percent) [123,124,130-132]. The risk of complications appears to be greatest in smokers, older

patients (>60 years), patients with chronic obstructive pulmonary disease or emphysema, and possibly in those

with ground glass nodules.

Surgical biopsy Surgical excision is the gold standard for the diagnosis of malignant SPNs. It is also the

definitive treatment for most malignant nodules, especially non-small cell lung cancer and carcinoid. For patients

that are surgical candidates, a diagnostic wedge resection by video-assisted thoracic surgery (VATS) is the

preferred procedure for SPNs at high risk of malignancy (>65 percent) or SPNs of intermediate risk when

nonsurgical biopsy is nondiagnostic or suspicious for malignancy [133,134]. Additional indications may include

patients in whom a benign diagnosis is suspected that requires therapy (eg, mycobacterial disease) in whom

nonsurgical biopsy was nondiagnostic or rarely for patients who place a high value on a diagnostic certainty.

During VATS, nodules targeted for resection are usually located by visual inspection, such that VATS is best

utilized for SPNs located close to the pleural surface [133,134]. However, for deeper lesions, digital palpation or

localization techniques can be performed to increase the diagnostic yield during thoracoscopy. Localization

techniques include preoperative placement of a hook wire and percutaneous injection of methylene blue or

microcoils; or intraoperative imaging with technetium-99 radioguidance, ultrasound, or fluoroscopy [135,136].

The diagnosis is typically established intraoperatively by frozen section analysis after wedge resection of the SPN.

When the diagnosis is consistent with non-small cell carcinoma (NSCLC), the surgery is preferably converted to a

VATS lobectomy with mediastinal node sampling, which is the optimal treatment for early stage NSCLC. The

advantage of this approach is that for SPNs that are malignant, diagnosis, staging, and therapy are performed in a

single operative procedure. However, frozen section pathology is less reliable for lesions



surveillance is most often performed in those at low risk for malignancy (eg, solid nodules



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REFERENCES

1. Ost D, Fein AM, Feinsilver SH. Clinical practice. The solitary pulmonary nodule. N Engl J Med 2003;

recommend diagnostic evaluation with surgical excision or nonsurgical biopsy rather than CT surveillance.

(See 'Growing nodule' above and 'Computed tomography' above.)

For patients with solid SPNs that have been stable over two years and subsolid SPNs stable over three years

on serial imaging, we suggest no further diagnostic testing. (See 'Stable nodule' above and 'Computed

tomography' above.)

For patients with a solid SPN >8 mm for which growth or stability cannot be determined, we suggest that the

diagnostic evaluation be determined by the probability of malignancy (algorithm 1). A SPN that has a low

probability (65 percent) of being malignant should be biopsied or surgically excised

rather than followed with serial CT. (See 'Solid nodules >8 mm' above.)

For patients with a solid SPN 8 mm for which growth or stability cannot be determined, we suggest non

enhanced serial CT scans rather than biopsy (table 5). The frequency of CT scanning depends upon the

individuals risk for cancer and nodule size. (See 'Solid nodules 8 mm' above.)

For patients with a pure subsolid (ground glass) SPN 5 mm, we suggest no additional diagnostic testing.

For patients with a pure subsolid SPN >5 mm, we suggest that a follow-up non enhanced CT scan be

performed at three months (table 6). A persistent nodule at three months that is 5 to 10 mm can be followed

by yearly CT for three years. A persistent nodule at three months that is >10 to 15 mm is preferably excised

or biopsied. (See 'Pure subsolid nodules' above.)

For patients with part-solid nodules, we suggest CT surveillance once at three months (table 6). For

persistent part-solid lesions, CT surveillance (non enhanced) is preferred for small SPNs (eg, 8 mm, solid

component 5 mm). For larger persistent part-solid SPNs (eg, >8 mm or with solid component >8 mm), a

more aggressive strategy that incorporates PET scan and a low threshold for biopsy or excision is preferred.

(See 'Part-solid nodules' above.)

For patients with a SPN who are subsequently found to have multiple nodules on imaging on serial CT scan,

each nodule should be assessed individually for the probability of malignancy and followed by additional CT

surveillance or biopsied accordingly. (See 'Multiple nodules' above.)

Considerable variation in strategies occurs among clinicians. However, there is consensus that the

management be individualized and that patient values be assessed when discussing the advantages and

disadvantages for each management strategy. (See 'Values and preferences' above.)

The choice of sampling procedure (nonsurgical biopsy or surgical biopsy) varies according to the probability

of malignancy, size and location of the nodule, local expertise, and patient values. (See 'Nonsurgical biopsy'

above and 'Surgical biopsy' above.)

For patients in whom surveillance is chosen, CT imaging should be noncontrast, thin slice (1 mm),

contiguous sections, using a low-dose radiation technique [2,63]. Any increase in size or character of the

nodule is concerning for malignancy and warrants evaluation for tissue biopsy or excision, when feasible.

Informing the patient of the risks and benefits of CT surveillance is important when choosing this strategy.

(See 'CT surveillance' above.)



348:2535.

2. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lungcancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013; 143:e93S.

3. Tuddenham WJ. Glossary of terms for thoracic radiology: recommendations of the Nomenclature Committeeof the Fleischner Society. AJR Am J Roentgenol 1984; 143:509.

4. Lillington GA, Caskey CI. Evaluation and management of solitary and multiple pulmonary nodules. Clin ChestMed 1993; 14:111.

5. Midthun DE, Swensen SJ, Jett JR. Approach to the solitary pulmonary nodule. Mayo Clin Proc 1993; 68:378.

6. Toomes H, Delphendahl A, Manke HG, Vogt-Moykopf I. The coin lesion of the lung. A review of 955 resectedcoin lesions. Cancer 1983; 51:534.

7. Ost D, Fein A. Management strategies for the solitary pulmonary nodule. Curr Opin Pulm Med 2004; 10:272.

8. Trunk G, Gracey DR, Byrd RB. The management and evaluation of the solitary pulmonary nodule. Chest1974; 66:236.

9. Higgins GA, Shields TW, Keehn RJ. The solitary pulmonary nodule. Ten-year follow-up of veteransadministration-armed forces cooperative study. Arch Surg 1975; 110:570.

10. Ray JF 3rd, Lawton BR, Magnin GE, et al. The coin lesion story: update 1976. Twenty years' experience withthoracotomy for 179 suspected malignant coin lesions. Chest 1976; 70:332.

11. Rubins JB, Rubins HB. Temporal trends in the prevalence of malignancy in resected solitary pulmonarylesions. Chest 1996; 109:100.

12. McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on firstscreening CT. N Engl J Med 2013; 369:910.

13. Seo JB, Im JG, Goo JM, et al. Atypical pulmonary metastases: spectrum of radiologic findings.Radiographics 2001; 21:403.

14. Cahan WG, Shah JP, Castro EB. Benign solitary lung lesions in patients with cancer. Ann Surg 1978;187:241.

15. Gribetz AR, Damsker B, Bottone EJ, et al. Solitary pulmonary nodules due to nontuberculous mycobacterialinfection. Am J Med 1981; 70:39.

16. Barrio JL, Suarez M, Rodriguez JL, et al. Pneumocystis carinii pneumonia presenting as cavitating andnoncavitating solitary pulmonary nodules in patients with the acquired immunodeficiency syndrome. Am RevRespir Dis 1986; 134:1094.

17. Nicholson CP, Allen MS, Trastek VF, et al. Dirofilaria immitis: a rare, increasing cause of pulmonary nodules.Mayo Clin Proc 1992; 67:646.

18. Asimacopoulos PJ, Katras A, Christie B. Pulmonary dirofilariasis. The largest single-hospital experience.Chest 1992; 102:851.

19. Echeverri A, Long RF, Check W, Burnett CM. Pulmonary dirofilariasis. Ann Thorac Surg 1999; 67:201.

20. Gjevre JA, Myers JL, Prakash UB. Pulmonary hamartomas. Mayo Clin Proc 1996; 71:14.

21. Siegelman SS, Khouri NF, Scott WW Jr, et al. Pulmonary hamartoma: CT findings. Radiology 1986; 160:313.

22. Shin SY, Kim MY, Oh SY, et al. Pulmonary Sclerosing Pneumocytoma of the Lung: CT Characteristics in aLarge Series of a Tertiary Referral Center. Medicine (Baltimore) 2015; 94:e498.

23. Bourke W, Milstein D, Giura R, et al. Lung cancer in young adults. Chest 1992; 102:1723.

24. Swensen SJ, Silverstein MD, Ilstrup DM, et al. The probability of malignancy in solitary pulmonary nodules.Application to small radiologically indeterminate nodules. Arch Intern Med 1997; 157:849.

25. Gould MK, Ananth L, Barnett PG, Veterans Affairs SNAP Cooperative Study Group. A clinical model toestimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest 2007;131:383.

26. Yonemori K, Tateishi U, Uno H, et al. Development and validation of diagnostic prediction model for solitary



pulmonary nodules. Respirology 2007; 12:856.

27. Gohagan J, Marcus P, Fagerstrom R, et al. Baseline findings of a randomized feasibility trial of lung cancerscreening with spiral CT scan vs chest radiograph: the Lung Screening Study of the National Cancer Institute.Chest 2004; 126:114.

28. Neifeld JP, Michaelis LL, Doppman JL. Suspected pulmonary metastases: correlation of chest x-ray, wholelung tomograms, and operative findings. Cancer 1977; 39:383.

29. MacMahon H, Austin JH, Gamsu G, et al. Guidelines for management of small pulmonary nodules detectedon CT scans: a statement from the Fleischner Society. Radiology 2005; 237:395.

30. Midthun, DE, Swensen, SJ, Jett, JR, et al. Evaluation of nodules detected by screening for lung cancer withlow dose spiral computed tomography. Lung Cancer 2003; 41:40S.

31. Swensen SJ, Jett JR, Sloan JA, et al. Screening for lung cancer with low-dose spiral computed tomography.Am J Respir Crit Care Med 2002; 165:508.

32. Henschke CI, Yankelevitz DF, Naidich DP, et al. CT screening for lung cancer: suspiciousness of nodulesaccording to size on baseline scans. Radiology 2004; 231:164.

33. Suzuki K, Nagai K, Yoshida J, et al. Video-assisted thoracoscopic surgery for small indeterminate pulmonarynodules: indications for preoperative marking. Chest 1999; 115:563.

34. Benjamin MS, Drucker EA, McLoud TC, Shepard JA. Small pulmonary nodules: detection at chest CT andoutcome. Radiology 2003; 226:489.

35. Piyavisetpat N, Aquino SL, Hahn PF, et al. Small incidental pulmonary nodules: how useful is short-terminterval CT follow-up? J Thorac Imaging 2005; 20:5.

36. Mehta HJ, Ravenel JG, Shaftman SR, et al. The utility of nodule volume in the context of malignancyprediction for small pulmonary nodules. Chest 2014; 145:464.

37. Cummings SR, Lillington GA, Richard RJ. Estimating the probability of malignancy in solitary pulmonarynodules. A Bayesian approach. Am Rev Respir Dis 1986; 134:449.

38. Henschke CI, Yankelevitz DF, Mirtcheva R, et al. CT screening for lung cancer: frequency and significance ofpart-solid and nonsolid nodules. AJR Am J Roentgenol 2002; 178:1053.

39. Li F, Sone S, Abe H, et al. Malignant versus benign nodules at CT screening for lung cancer: comparison ofthin-section CT findings. Radiology 2004; 233:793.

40. Kim HY, Shim YM, Lee KS, et al. Persistent pulmonary nodular ground-glass opacity at thin-section CT:histopathologic comparisons. Radiology 2007; 245:267.

41. Kodama K, Higashiyama M, Takami K, et al. Treatment strategy for patients with small peripheral lunglesion(s): intermediate-term results of prospective study. Eur J Cardiothorac Surg 2008; 34:1068.

42. Mun M, Kohno T. Efficacy of thoracoscopic resection for multifocal bronchioloalveolar carcinoma showingpure ground-glass opacities of 20 mm or less in diameter. J Thorac Cardiovasc Surg 2007; 134:877.

43. Nakata M, Sawada S, Saeki H, et al. Prospective study of thoracoscopic limited resection for ground-glassopacity selected by computed tomography. Ann Thorac Surg 2003; 75:1601.

44. Ohtsuka T, Watanabe K, Kaji M, et al. A clinicopathological study of resected pulmonary nodules with focalpure ground-glass opacity. Eur J Cardiothorac Surg 2006; 30:160.

45. Lim HJ, Ahn S, Lee KS, et al. Persistent pure ground-glass opacity lung nodules 10 mm in diameter at CTscan: histopathologic comparisons and prognostic implications. Chest 2013; 144:1291.

46. Allen MS, Darling GE, Pechet TT, et al. Morbidity and mortality of major pulmonary resections in patientswith early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann ThoracSurg 2006; 81:1013.

47. GOOD CA, HOOD RT Jr, McDONALD JR. Significance of a solitary mass in the lung. Am J RoentgenolRadium Ther Nucl Med 1953; 70:543.

48. Yankelevitz DF, Henschke CI. Does 2-year stability imply that pulmonary nodules are benign? AJR Am JRoentgenol 1997; 168:325.

49. Williams DE, Pairolero PC, Davis CS, et al. Survival of patients surgically treated for stage I lung cancer. J



Thorac Cardiovasc Surg 1981; 82:70.

50. Ost D, Fein A. Evaluation and management of the solitary pulmonary nodule. Am J Respir Crit Care Med2000; 162:782.

51. Song YS, Park CM, Park SJ, et al. Volume and mass doubling times of persistent pulmonary subsolidnodules detected in patients without known malignancy. Radiology 2014; 273:276.

52. Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CTscreening. Br J Radiol 2000; 73:1252.

53. Zerhouni EA, Stitik FP, Siegelman SS, et al. CT of the pulmonary nodule: a cooperative study. Radiology1986; 160:319.

54. Rigler LG. An overview of cancer of the lung. Semin Roentgenol 1977; 12:161.

55. Grgic A, Yksel Y, Grschel A, et al. Risk stratification of solitary pulmonary nodules by means of PET using(18)F-fluorodeoxyglucose and SUV quantification. Eur J Nucl Med Mol Imaging 2010; 37:1087.

56. Kagna O, Solomonov A, Keidar Z, et al. The value of FDG-PET/CT in assessing single pulmonary nodules inpatients at high risk of lung cancer. Eur J Nucl Med Mol Imaging 2009; 36:997.

57. Mizugaki H, Shinagawa N, Kanegae K, et al. Combining transbronchial biopsy using endobronchialultrasonography with a guide sheath and positron emission tomography for the diagnosis of small peripheralpulmonary lesions. Lung Cancer 2010; 68:211.

58. Mori T, Nomori H, Ikeda K, et al. Diffusion-weighted magnetic resonance imaging for diagnosing malignantpulmonary nodules/masses: comparison with positron emission tomography. J Thorac Oncol 2008; 3:358.

59. Ohba Y, Nomori H, Mori T, et al. Is diffusion-weighted magnetic resonance imaging superior to positronemission tomography with fludeoxyglucose F 18 in imaging non-small cell lung cancer? J Thorac CardiovascSurg 2009; 138:439.

60. Cronin P, Dwamena BA, Kelly AM, Carlos RC. Solitary pulmonary nodules: meta-analytic comparison ofcross-sectional imaging modalities for diagnosis of malignancy. Radiology 2008; 246:772.

61. Gould MK, Maclean CC, Kuschner WG, et al. Accuracy of positron emission tomography for diagnosis ofpulmonary nodules and mass lesions: a meta-analysis. JAMA 2001; 285:914.

62. Vansteenkiste JF, Stroobants SS. PET scan in lung cancer: current recommendations and innovation. JThorac Oncol 2006; 1:71.

63. Naidich DP, Bankier AA, MacMahon H, et al. Recommendations for the management of subsolid pulmonarynodules detected at CT: a statement from the Fleischner Society. Radiology 2013; 266:304.

64. Casali C, Cucca M, Rossi G, et al. The variation of prognostic significance of Maximum Standardized UptakeValue of [18F]-fluoro-2-deoxy-glucose positron emission tomography in different histological subtypes andpathological stages of surgically resected Non-Small Cell Lung Carcinoma. Lung Cancer 2010; 69:187.

65. Divisi D, Di Tommaso S, Di Leonardo G, et al. 18-fluorine fluorodeoxyglucose positron emission tomographywith computerized tomography versus computerized tomography alone for the management of solitary lungnodules with diameters inferior to 1.5 cm. Thorac Cardiovasc Surg 2010; 58:422.

66. Herder GJ, Golding RP, Hoekstra OS, et al. The performance of( 18)F-fluorodeoxyglucose positron emissiontomography in small solitary pulmonary nodules. Eur J Nucl Med Mol Imaging 2004; 31:1231.

67. Nomori H, Watanabe K, Ohtsuka T, et al. Fluorine 18-tagged fluorodeoxyglucose positron emissiontomographic scanning to predict lymph node metastasis, invasiveness, or both, in clinical T1 N0 M0 lungadenocarcinoma. J Thorac Cardiovasc Surg 2004; 128:396.

68. Nomori H, Watanabe K, Ohtsuka T, et al. Evaluation of F-18 fluorodeoxyglucose (FDG) PET scanning forpulmonary nodules less than 3 cm in diameter, with special reference to the CT images. Lung Cancer 2004;45:19.

69. Chun EJ, Lee HJ, Kang WJ, et al. Differentiation between malignancy and inflammation in pulmonary ground-glass nodules: The feasibility of integrated (18)F-FDG PET/CT. Lung Cancer 2009; 65:180.

70. Raz DJ, Odisho AY, Franc BL, Jablons DM. Tumor fluoro-2-deoxy-D-glucose avidity on positron emissiontomographic scan predicts mortality in patients with early-stage pure and mixed bronchioloalveolarcarcinoma. J Thorac Cardiovasc Surg 2006; 132:1189.



71. Heyneman LE, Patz EF. PET imaging in patients with bronchioloalveolar cell carcinoma. Lung Cancer 2002;38:261.

72. Yap CS, Schiepers C, Fishbein MC, et al. FDG-PET imaging in lung cancer: how sensitive is it forbronchioloalveolar carcinoma? Eur J Nucl Med Mol Imaging 2002; 29:1166.

73. Maeda R, Isowa N, Onuma H, et al. The maximum standardized uptake values on positron emissiontomography to predict the Noguchi classification and invasiveness in clinical stage IA adenocarcinomameasuring 2 cm or less in size. Interact Cardiovasc Thorac Surg 2009; 9:70.

74. Okada M, Tauchi S, Iwanaga K, et al. Associations among bronchioloalveolar carcinoma components,positron emission tomographic and computed tomographic findings, and malignant behavior in small lungadenocarcinomas. J Thorac Cardiovasc Surg 2007; 133:1448.

75. Sim YT, Goh YG, Dempsey MF, et al. PET-CT evaluation of solitary pulmonary nodules: correlation withmaximum standardized uptake value and pathology. Lung 2013; 191:625.

76. Fletcher JW, Kymes SM, Gould M, et al. A comparison of the diagnostic accuracy of 18F-FDG PET and CTin the characterization of solitary pulmonary nodules. J Nucl Med 2008; 49:179.

77. Nair VS, Barnett PG, Ananth L, et al. PET scan 18F-fluorodeoxyglucose uptake and prognosis in patientswith resected clinical stage IA non-small cell lung cancer. Chest 2010; 137:1150.

78. Brix G, Lechel U, Glatting G, et al. Radiation exposure of patients undergoing whole-body dual-modality 18F-FDG PET/CT examinations. J Nucl Med 2005; 46:608.

79. Chang CY, Tzao C, Lee SC, et al. Incremental value of integrated FDG-PET/CT in evaluating indeterminatesolitary pulmonary nodule for malignancy. Mol Imaging Biol 2010; 12:204.

80. Kim SK, Allen-Auerbach M, Goldin J, et al. Accuracy of PET/CT in characterization of solitary pulmonarylesions. J Nucl Med 2007; 48:214.

81. Jeong SY, Lee KS, Shin KM, et al. Efficacy of PET/CT in the characterization of solid or partly solid solitarypulmonary nodules. Lung Cancer 2008; 61:186.

82. Swensen SJ, Viggiano RW, Midthun DE, et al. Lung nodule enhancement at CT: multicenter study.Radiology 2000; 214:73.

83. Yamashita K, Matsunobe S, Tsuda T, et al. Intratumoral necrosis of lung carcinoma: a potential diagnosticpitfall in incremental dynamic computed tomography analysis of solitary pulmonary nodules? J ThoracImaging 1997; 12:181.

84. Li Y, Yang ZG, Chen TW, et al. First-pass perfusion imaging of solitary pulmonary nodules with 64-detectorrow CT: comparison of perfusion parameters of malignant and benign lesions. Br J Radiol 2010; 83:785.

85. Swensen SJ, Silverstein MD, Edell ES, et al. Solitary pulmonary nodules: clinical prediction model versusphysicians. Mayo Clin Proc 1999; 74:319.

86. Balekian AA, Silvestri GA, Simkovich SM, et al. Accuracy of clinicians and models for estimating theprobability that a pulmonary nodule is malignant. Ann Am Thorac Soc 2013; 10:629.

87. Gurney JW, Lyddon DM, McKay JA. Determining the likelihood of malignancy in solitary pulmonary noduleswith Bayesian analysis. Part II. Application. Radiology 1993; 186:415.

88. Herder GJ, van Tinteren H, Golding RP, et al. Clinical prediction model to characterize pulmonary nodules:validation and added value of 18F-fluorodeoxyglucose positron emission tomography. Chest 2005; 128:2490.

89. Isbell JM, Deppen S, Putnam JB Jr, et al. Existing general population models inaccurately predict lungcancer risk in patients referred for surgical evaluation. Ann Thorac Surg 2011; 91:227.

90. Schultz EM, Sanders GD, Trotter PR, et al. Validation of two models to estimate the probability ofmalignancy in patients with solitary pulmonary nodules. Thorax 2008; 63:335.

91. Patz EF Jr, Campa MJ, Gottlin EB, et al. Biomarkers to help guide management of patients with pulmonarynodules. Am J Respir Crit Care Med 2013; 188:461.

92. Ko JP, Berman EJ, Kaur M, et al. Pulmonary Nodules: growth rate assessment in patients by using serial CTand three-dimensional volumetry. Radiology 2012; 262:662.

93. Wiener RS, Gould MK, Slatore CG, et al. Resource use and guideline concordance in evaluation of



pulmonary nodules for cancer: too much and too little care. JAMA Intern Med 2014; 174:871.

94. Mountain CF. A new international staging system for lung cancer. Chest 1986; 89:225S.

95. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on thenew international staging system. J Thorac Cardiovasc Surg 1988; 96:440.

96. Gail MH, Eagan RT, Feld R, et al. Prognostic factors in patients with resected stage I non-small cell lungcancer. A report from the Lung Cancer Study Group. Cancer 1984; 54:1802.

97. Cummings SR, Lillington GA, Richard RJ. Managing solitary pulmonary nodules. The choice of strategy is a"close call". Am Rev Respir Dis 1986; 134:453.

98. Wiener RS, Gould MK, Woloshin S, et al. What do you mean, a spot?: A qualitative analysis of patients'reactions to discussions with their physicians about pulmonary nodules. Chest 2013; 143:672.

99. Kaplan SH, Gandek B, Greenfield S, et al. Patient and visit characteristics related to physicians' participatorydecision-making style. Results from the Medical Outcomes Study. Med Care 1995; 33:1176.

100. Berghmans T, Dusart M, Paesmans M, et al. Primary tumor standardized uptake value (SUVmax) measuredon fluorodeoxyglucose positron emission tomography (FDG-PET) is of prognostic value for survival in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis (MA) by the European Lung CancerWorking Party for the IASLC Lung Cancer Staging Project. J Thorac Oncol 2008; 3:6.

101. Cheran SK, Nielsen ND, Patz EF Jr. False-negative findings for primary lung tumors on FDG positronemission tomography: staging and prognostic implications. AJR Am J Roentgenol 2004; 182:1129.

102. Marom EM, Sarvis S, Herndon JE 2nd, Patz EF Jr. T1 lung cancers: sensitivity of diagnosis withfluorodeoxyglucose PET. Radiology 2002; 223:453.

103. Zhao YR, Heuvelmans MA, Dorrius MD, et al. Features of resolving and nonresolving indeterminate pulmonarynodules at follow-up CT: the NELSON study. Radiology 2014; 270:872.

104. Swensen SJ. CT screening for lung cancer. AJR Am J Roentgenol 2002; 179:833.

105. Kunitoh H, Eguchi K, Yamada K, et al. Intrapulmonary sublesions detected before surgery in patients withlung cancer. Cancer 1992; 70:1876.

106. Keogan MT, Tung KT, Kaplan DK, et al. The significance of pulmonary nodules detected on CT staging forlung cancer. Clin Radiol 1993; 48:94.

107. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design andfindings from baseline screening. Lancet 1999; 354:99.

108. Henschke CI, Naidich DP, Yankelevitz DF, et al. Early lung cancer action project: initial findings on repeatscreenings. Cancer 2001; 92:153.

109. Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience.Radiology 2005; 235:259.

110. Herth F, Becker HD, Ernst A. Conventional vs endobronchial ultrasound-guided transbronchial needleaspiration: a randomized trial. Chest 2004; 125:322.

111. Paone G, Nicastri E, Lucantoni G, et al. Endobronchial ultrasound-driven biopsy in the diagnosis of peripherallung lesions. Chest 2005; 128:3551.

112. Steinfort DP, Khor YH, Manser RL, Irving LB. Radial probe endobronchial ultrasound for the diagnosis ofperipheral lung cancer: systematic review and meta-analysis. Eur Respir J 2011; 37:902.

113. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management oflung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest 2013; 143:e142S.

114. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/americanthoracic society/european respiratory society international multidisciplinary classification of lungadenocarcinoma. J Thorac Oncol 2011; 6:244.

115. Nakajima T, Yasufuku K, Takahashi R, et al. Comparison of 21-gauge and 22-gauge aspiration needle duringendobronchial ultrasound-guided transbronchial needle aspiration. Respirology 2011; 16:90.

116. Loukeris K, Vazquez MF, Sica G, et al. Cytological cell blocks: Predictors of squamous cell carcinoma and



adenocarcinoma subtypes. Diagn Cytopathol 2012; 40:380.

117. Ost DE, Ernst A, Lei X, et al. Diagnostic yield of endobronchial ultrasound-guided transbronchial needleaspiration: results of the AQuIRE Bronchoscopy Registry. Chest 2011; 140:1557.

118. Oki M, Saka H, Kitagawa C, et al. Randomized Study of 21-gauge Versus 22-gauge EndobronchialUltrasound-guided Transbronchial Needle Aspiration Needles for Sampling Histology Specimens. JBronchology Interv Pulmonol 2011; 18:306.

119. Yarmus LB, Akulian J, Lechtzin N, et al. Comparison of 21-gauge and 22-gauge aspiration needle inendobronchial ultrasound-guided transbronchial needle aspiration: results of the American College of ChestPhysicians Quality Improvement Registry, Education, and Evaluation Registry. Chest 2013; 143:1036.

120. Rivera MP, Mehta AC, American College of Chest Physicians. Initial diagnosis of lung cancer: ACCPevidence-based clinical practice guidelines (2nd edition). Chest 2007; 132:131S.

121. Loubeyre P, Copercini M, Dietrich PY. Percutaneous CT-guided multisampling core needle biopsy of thoraciclesions. AJR Am J Roentgenol 2005; 185:1294.

122. Choi SH, Chae EJ, Kim JE, et al. Percutaneous CT-guided aspiration and core biopsy of pulmonary nodulessmaller than 1 cm: analysis of outcomes of 305 procedures from a tertiary referral center. AJR Am JRoentgenol 2013; 201:964.

123. Lee SM, Park CM, Lee KH, et al. C-arm cone-beam CT-guided percutaneous transthoracic needle biopsy oflung nodules: clinical experience in 1108 patients. Radiology 2014; 271:291.

124. Takeshita J, Masago K, Kato R, et al. CT-guided fine-needle aspiration and core needle biopsies ofpulmonary lesions: a single-center experience with 750 biopsies in Japan. AJR Am J Roentgenol 2015;204:29.

125. Larscheid RC, Thorpe PE, Scott WJ. Percutaneous transthoracic needle aspiration biopsy: a comprehensivereview of its current role in the diagnosis and treatment of lung tumors. Chest 1998; 114:704.

126. Kothary N, Lock L, Sze DY, Hofmann LV. Computed tomography-guided percutaneous needle biopsy ofpulmonary nodules: impact of nodule size on diagnostic accuracy. Clin Lung Cancer 2009; 10:360.

127. Ng YL, Patsios D, Roberts H, et al. CT-guided percutaneous fine-needle aspiration biopsy of pulmonarynodules measuring 10 mm or less. Clin Radiol 2008; 63:272.

128. Schreiber G, McCrory DC. Performance characteristics of different modalities for diagnosis of suspected lungcancer: summary of published evidence. Chest 2003; 123:115S.

129. Santambrogio L, Nosotti M, Bellaviti N, et al. CT-guided fine-needle aspiration cytology of solitary pulmonarynodules: a prospective, randomized study of immediate cytologic evaluation. Chest 1997; 112:423.

130. Wiener RS, Schwartz LM, Woloshin S, Welch HG. Population-based risk for complications aftertransthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med2011; 155:137.

131. Song YS, Park CM, Park KW, et al. Does antiplatelet therapy increase the risk of hemoptysis duringpercutaneous transthoracic needle biopsy of a pulmonary lesion? AJR Am J Roentgenol 2013; 200:1014.

132. Zwischenberger JB, Savage C, Alpard SK, et al. Mediastinal transthoracic needle and core lymph nodebiopsy: should it replace mediastinoscopy? Chest 2002; 121:1165.

133. Allen MS, Deschamps C, Lee RE, et al. Video-assisted thoracoscopic stapled wedge excision forindeterminate pulmonary nodules. J Thorac Cardiovasc Surg 1993; 106:1048.

134. Bernard A. Resection of pulmonary nodules using video-assisted thoracic surgery. The Thorax Group. AnnThorac Surg 1996; 61:202.

135. Shennib H. Intraoperative localization techniques for pulmonary nodules. Ann Thorac Surg 1993; 56:745.

136. Zaman M, Bilal H, Woo CY, Tang A. In patients undergoing video-assisted thoracoscopic surgery excision,what is the best way to locate a subcentimetre solitary pulmonary nodule in order to achieve successfulexcision? Interact Cardiovasc Thorac Surg 2012; 15:266.

137. Marchevsky AM, Changsri C, Gupta I, et al. Frozen section diagnoses of small pulmonary nodules: accuracyand clinical implications. Ann Thorac Surg 2004; 78:1755.

138. Jennings SG, Winer-Muram HT, Tann M, et al. Distribution of stage I lung cancer growth rates determined



with serial volumetric CT measurements. Radiology 2006; 241:554.

139. Revel MP, Bissery A, Bienvenu M, et al. Are two-dimensional CT measurements of small noncalcifiedpulmonary nodules reliable? Radiology 2004; 231:453.

140. Winer-Muram HT, Jennings SG, Meyer CA, et al. Effect of varying CT section width on volumetricmeasurement of lung tumors and application of compensatory equations. Radiology 2003; 229:184.

141. Mayo JR, Aldrich J, Muller NL, Fleischner Society. Radiation exposure at chest CT: a statement of theFleischner Society. Radiology 2003; 228:15.

142. Rusinek H, Naidich DP, McGuinness G, et al. Pulmonary nodule detection: low-dose versus conventional CT.Radiology 1998; 209:243.

143. Diederich S, Lenzen H. Radiation exposure associated with imaging of the chest: comparison of differentradiographic and computed tomography techniques. Cancer 2000; 89:2457.

144. Revel MP, Merlin A, Peyrard S, et al. Software volumetric evaluation of doubling times for differentiatingbenign versus malignant pulmonary nodules. AJR Am J Roentgenol 2006; 187:135.

145. de Hoop B, Gietema H, van de Vorst S, et al. Pulmonary ground-glass nodules: increase in mass as an earlyindicator of growth. Radiology 2010; 255:199.

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Diagnostic Evaluation and Management of the Solitary Pulmonary Nodule