Clinical Review & Education

JAMA | Review

Evaluating the Patient With a Pulmonary Nodule

A Review
Peter J. Mazzone, MD, MPH; Louis Lam, MD

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IMPORTANCE Pulmonary nodules are identified in approximately 1.6 million patients per year CME Quiz at
in the US and are detected on approximately 30% of computed tomographic (CT) images of jamacmelookup.com
the chest. Optimal treatment of an individual with a pulmonary nodule can lead to early
detection of cancer while minimizing testing for a benign nodule.

OBSERVATIONS At least 95% of all pulmonary nodules identified are benign, most often
granulomas or intrapulmonary lymph nodes. Smaller nodules are more likely to be
benign. Pulmonary nodules are categorized as small solid (<8 mm), larger solid (ⱖ8 mm),
and subsolid. Subsolid nodules are divided into ground-glass nodules (no solid component)
and part-solid (both ground-glass and solid components). The probability of malignancy is
less than 1% for all nodules smaller than 6 mm and 1% to 2% for nodules 6 mm to 8 mm.
Nodules that are 6 mm to 8 mm can be followed with a repeat chest CT in 6 to 12 months,
depending on the presence of patient risk factors and imaging characteristics associated
with lung malignancy, clinical judgment about the probability of malignancy, and patient
preferences. The treatment of an individual with a solid pulmonary nodule 8 mm or
larger is based on the estimated probability of malignancy; the presence of patient
comorbidities, such as chronic obstructive pulmonary disease and coronary artery disease;
and patient preferences. Management options include surveillance imaging, defined as
monitoring for nodule growth with chest CT imaging, positron emission tomography–CT
imaging, nonsurgical biopsy with bronchoscopy or transthoracic needle biopsy, and surgical
resection. Part-solid pulmonary nodules are managed according to the size of the solid
component. Larger solid components are associated with a higher risk of malignancy.
Ground-glass pulmonary nodules have a probability of malignancy of 10% to 50% when
they persist beyond 3 months and are larger than 10 mm in diameter. A malignant nodule
that is entirely ground glass in appearance is typically slow growing. Current bronchoscopy
and transthoracic needle biopsy methods yield a sensitivity of 70% to 90% for a diagnosis
of lung cancer.
Author Affiliations: Respiratory
CONCLUSIONS AND RELEVANCE Pulmonary nodules are identified in approximately 1.6 million Institute, Cleveland Clinic,
people per year in the US and approximately 30% of chest CT images. The treatment of Cleveland, Ohio.
an individual with a pulmonary nodule should be guided by the probability that the nodule Corresponding Author: Peter J.
is malignant, safety of testing, the likelihood that additional testing will be informative, Mazzone, MD, MPH, Respiratory
Institute, Cleveland Clinic,
and patient preferences.
9500 Euclid Ave, A90, Cleveland,
OH 44195 ([email protected]).
JAMA. 2022;327(3):264-273. doi:10.1001/jama.2021.24287 Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.

A
pulmonary nodule is a small (<3 cm), focal, distinct known malignancy, patients with multiple pulmonary nodules
radiographic density completely surrounded by lung tis- without a dominant pulmonary nodule, or patients with a pulmo-
sue. Pulmonary nodules are identified in approximately nary mass, defined as a lung opacity with a diameter greater than
1.6 million people per year in the US and are detected on approxi- 3 cm. The management approach to these individuals differs from
mately 30% of computed tomographic (CT) images of the chest.1 that of an individual with a dominant pulmonary nodule, and pul-
More than 50% of patients with a pulmonary nodule have more monary masses have a high probability of malignancy. This review
than 1 nodule.2 Ideal evaluation of an individual with a pulmonary describes current evidence regarding the optimal methods to
nodule would expedite therapy for a malignant nodule and mini- establish the diagnosis of a dominant pulmonary nodule that
mize testing for those with a benign nodule. may be due to primary lung malignancy, metastatic disease, a
This review focuses on evaluation of individuals with a single noninfectious inflammatory process, infection, or scar residual
dominant pulmonary nodule. The term dominant refers to the from a prior infection.
largest or the most suspicious-appearing nodule. This review does This review describes the epidemiology of pulmonary nod-
not discuss management of pulmonary nodules in patients with ules and current evidence-based approaches to treatment of an

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 Evaluating the Patient With a Pulmonary Nodule Review Clinical Review & Education

individual with a pulmonary nodule that is identified incidentally lism in an emergency department, 99 (9.9%) had nodules that
on chest x-ray, chest CT, or during low-dose CT screening (LDCT) required follow-up.10
for lung cancer. The incidence of a pulmonary nodule increases with age,
from 0.4 per 1000 person-years in people aged 18 to 24 years to
20.3 per 1000 person-years in those aged 85 to 89 years. In part,
this increase is explained by the increase in chest CT imaging that
Methods
occurs with age. The incidence of a pulmonary nodule is slightly
PubMed and Cochrane databases were searched for English- higher in women (5.8 per 1000 person-years) than in men (5.2
language articles related to the epidemiology and treatment of per 1000 person-years) overall; however, for those older than 70
adults with pulmonary nodules that were published from January years, the incidence is higher in men.1 In lung cancer screening
1, 2011, through September 28, 2021. Search terms included lung trials, the rate of identifying a pulmonary nodule on baseline
nodule(s), pulmonary nodule(s), and any combination, modified LDCT was similar in men (27.0%) and women (27.8%).9 In chest
by solitary, multiple, screening, screen-detected, and incidental. x-rays, the rate of identifying a pulmonary nodule was slightly
Results were further categorized by the following terms: guide- higher in men than women (9.6%-9.8% vs 8.2%-8.3%).8,9 Rates
lines, risk, risk assessment, calculator, model, algorithm, diagnosis, of nodule identification on LDCT also increase with age. For
diagnostic techniques, procedures, biopsy, bronchoscopy, surgery, example, in a study of 26 309 people aged 55 to 74 years who
resection, (disease) management, treatment, therapy, tumor received an LDCT, the prevalence of pulmonary nodules was
board, and clinic. A total of 286 articles were retrieved. Results 24.3% in those aged 55 to 59 years and 34.0% in those aged 70
were supplemented with relevant articles from the references of to 74 years.9 In this study, the prevalence of pulmonary nodules
selected articles and the authors’ files. A total of 51 articles were was 23.2% in individuals with 30 to 35 pack-year smoking histo-
selected for inclusion, including 9 clinical practice guidelines, 11 ries and 30.3% in those with more than 50 pack-years’ smoking
clinical trials (6 randomized, 5 nonrandomized), 5 prospective histories.8,9 Although the rate of identification of pulmonary nod-
cohort studies, 14 retrospective cohort studies, 5 risk calculator ules on chest x-ray is much lower than on chest CT scan, similar
development or validation studies, 3 systematic reviews with trends in the prevalence of pulmonary nodules were observed in
meta-analyses, 3 biomarker accuracy studies, and 1 questionnaire those screened with chest x-ray (8.0% in those who never
study. Articles were selected with the intent of identifying those smoked, 9.5% in those who previously smoked, 11.0% in those
with the highest-quality study design for each section of the who currently smoke).8,9
review and relevance to a general medical readership. The frequency of identifying pulmonary nodules is particu-
larly high in individuals undergoing imaging for evaluation of a
known extrapulmonary malignancy, reaching 75% (233 of 308) of
patients in 1 study.11 Other factors associated with a higher risk
Discussion
of a pulmonary nodule in a cohort of 26 004 individuals undergo-
Epidemiology ing a baseline LDCT included a history of hard-rock mining (35.0%
Approximately 95% of all pulmonary nodules identified on CT vs 27.3%; odds ratio [OR], 1.40 [95% CI, 1.04-1.89]), White race
scans are benign.1 The prevalence of pulmonary nodules in high- (28.0% vs 20.6%; OR, 1.39 [95% CI, 1.25-1.55]), residence in
risk populations, such as those who are eligible for LDCT screen- an area endemic for Histoplasma such as the Ohio River Valley
ing (ie, those aged 50-80 years with ⱖ20 pack-years’ smoking (OR, 1.30 [95% CI, 1.21-1.40]; calculated absolute rates: 32.5% vs
history who have smoked within the past 15 years),3 those with a 26.4%), farm work (OR, 1.13 [95% CI, 1.03-1.23]; calculated abso-
cancer history, family history of lung cancer, or another significant lute rates: 30.2% vs 27.1%), and a history of chronic obstructive
risk factor (ie, asbestos exposure), has varied, in part based on the pulmonary disease (OR, 1.08 [95% CI, 1.01-1.17], calculated abso-
size threshold used to define a nodule. In a Veterans Health lute rates: 30.1% vs 26.8%).12
Administration lung cancer screening implementation study that
included any size pulmonary nodule in the definition of a positive Pulmonary Nodule Evaluation
finding, 1257 of 2106 screened individuals (59.7%) had a pulmo- A focused history may identify recent exposure to an endemic
nary nodule.4 In the National Lung Screening Trial, nodules 4 mm infection such as histoplasmosis or coccidioidomycosis, symptoms
or larger were identified in 27.3% (7191 of 26 309) of baseline related to infection, systemic inflammatory disease or malignancy,
LDCT scans.5 Among 24 604 patients undergoing a second LDCT and personal histories of malignancy or comorbid conditions that
screening test (12 months after the baseline CT), 644 (2.6%) can manifest as a pulmonary nodule.
were identified as having a new nodule since the prior screening When evaluating a newly diagnosed pulmonary nodule, it is
CT scan. 6 In the NELSON trial of 6309 patients undergoing important to review prior imaging, if available, to determine
screening for lung cancer, 147 patients (2.3%) had a nodule identi- whether the size and other characteristics of the pulmonary nodule
fied during baseline screening that grew at a concerning pace have changed. This may include abdominal imaging if the nodule is
measured 3 months later, defined as a volume doubling time of at the base of the lungs, head and neck imaging if the nodule is in
less than 400 days.7 In 2 studies of screening chest x-rays involv- the upper lung zones, or cardiac imaging. It is not necessary to per-
ing 103 500 participants, a pulmonary nodule was identified in form a diagnostic CT of the entire chest if a low-risk pulmonary
7.8% to 8.9% of the chest x-rays.8,9 Imaging of the neck, abdo- nodule is first noted on a different type of CT scan. Moreover, a
men, and heart can also identify pulmonary nodules. Of 1000 CT solid nodule that has remained unchanged in size on a chest CT
angiograms performed as a diagnostic test for pulmonary embo- over a period of 2 years or longer is considered benign.

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 Clinical Review & Education Review Evaluating the Patient With a Pulmonary Nodule

Figure. Pulmonary Nodule Examples on Computed Tomography

A Calcified nodule B Perifissural nodule C Peripheral nodule D Hamartoma with intrinsic

with satellite nodules fat attenuation

E Arteriovenous malformation F Ground-glass nodule

Panel A shows a calcified pulmonary nodule (blue arrowhead) consistent Panel D shows a pulmonary hamartoma (blue arrowhead) with areas of
with benign calcified granulomas. Panel B shows a typical perifissural nodule intrinsic fat attenuation that appear as black spots on a soft tissue window
(blue arrowhead) abutting the fissure (pink arrowhead). Panel C shows (pink arrowheads). Panel E shows a feeding and draining vessel of an
a peripheral pulmonary nodule (blue arrowhead) with adjacent satellite arteriovenous malformation (blue arrowhead). Panel F shows a ground-glass
nodules (pink arrowheads) consistent with granulomatous process. nodule without a definable solid component (blue arrowhead).

A benign pattern of calcification (eg, dense central [ie, a nodule

Box 1. Commonly Asked Questions with a large calcification in the middle vs a small one at the edge],
Are there any situations in which a pulmonary nodule does not laminated, stippled, or popcorn patterns of calcification; Figure, A)
require subsequent imaging or further evaluation? can obviate the need for follow-up imaging. In addition, a perifis-
If a pulmonary nodule has a very low probability of being sural nodule, consisting of a smooth, well-circumscribed nodule
malignant, further follow-up with imaging is not warranted. adjacent to a lung fissure, most likely represents a lymph node
Examples include patients with prior imaging showing that the and does not require subsequent monitoring with CT scans
nodule has been stable for 2 years or longer; a nodule that has
(Figure, B).13 Satellite nodules, defined as small solid nodules sur-
imaging features confirming a benign diagnosis (eg, dense
rounding a larger nodule, with nearby adenopathy may suggest a
central calcification, fat density within the nodule); or a solid or
a pure ground-glass nodule <6 mm in diameter in an individual granulomatous infection (Figure, C). Fat density within the nodule
without any lung cancer risk factors. is suggestive of a hamartoma (Figure, D), and vessels leading into
Are there scenarios where practice guidelines do not apply? (feeding) and exiting from (draining) the nodule can be seen with
Practice guidelines may not apply to patients for whom the an arteriovenous malformation (Figure, E).
risk of malignancy differs from the general population. Evaluation of an individual with a pulmonary nodule requires
For example, patients with a known malignancy or recent knowledge about the factors associated with the probability that the
history of malignancy; patients with organ transplant or other nodule is malignant, the performance characteristics of additional
immunocompromised state; or patients aged <35 years.
testing, and the advantages and disadvantages of less intensive or
For these individuals, referral to a pulmonologist or to
a multidisciplinary pulmonary nodule specialty clinic may
more intensive follow-up (Box 1). Recognizing that the probability
be warranted. of malignancy and the yield of available diagnostic tests vary with
When should a primary care physician consider referring
the size and character of the nodule, nodules are often considered
a patient with a pulmonary nodule to a specialist? and managed by categorizing them into 1 of 3 groups: small solid nod-
Primary care physicians should refer a patient for specialty ules, larger solid nodules, and subsolid nodules.
evaluation when they are uncomfortable with or uncertain
about the most optimal evaluation plan. In addition, primary Small Solid Pulmonary Nodules (<8 mm)
care physicians should consider referring patients with When incidentally discovered on imaging in individuals without a
a large solid pulmonary nodule (ⱖ8-30 mm) or a subsolid
known history of malignancy, or when detected during LDCT
pulmonary nodule due to their higher risk of malignancy.
screening, the probability of malignancy is very low. In the National
Lung Screening Trial of 26 309 people at high risk for having lung
Imaging features should be carefully reviewed. CT images cancer who received an LDCT, pulmonary nodules 4 to 6 mm in
should be reconstructed in axial, coronal, and sagittal planes to diameter accounted for 52.3% (3668 of 7019) of all nodules 4 mm
provide the most detailed characterization of nodule features. or larger and had a 0.5% probability of malignancy, while nodules

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 Evaluating the Patient With a Pulmonary Nodule Review Clinical Review & Education

Table 1. Society Guidelines for the Management of Pulmonary Nodules

American College
Nodule diameter of Chest Physicians15a Fleischner Society14a Lung-RADS16b
3
≤4 mm: <6 mm/<100 mm : <6 mm at baseline (or new Abbreviations: CT, computed
Low-risk: patient discussion, Low-risk: No follow-up nodule <4 mm on follow-up): tomography; LDCT, low-dose CT; PET,
optional follow-up return to annual screening
High-risk: Optional (category 2) positron emission tomography.
High-risk: follow-up CT scan follow-up CT in 12 mo a
The American College of Chest
at 12 mo (if stable no further
follow-up) Physicians criteria for low risk
Up to 6 mm include individuals of younger age,
>4 to 6 mm:
little or no smoking history, smaller
Low-risk: follow-up CT scan nodule size, regular margins, and
at 12 mo (if stable, no
further follow-up) location other than upper lobe.
Criteria for high risk include
High-risk: follow-up CT scan
at 6-12 mo (if stable, individuals of older age, heavy
follow-up at 18-24 mo) smoking history, larger nodule size,
>6 to <8 mm: 6 mm to 8 mm/100 mm3 to ≥6 mm to <8 mm at baseline irregular or spiculated margins, and
250 mm3: (or new nodule 4 mm to <6 mm upper lobe locations.
Low-risk: follow-up CT scan
at 6-12 mo (if stable, Low-risk: follow-up CT in on follow-up): LDCT in 6 mo Intermediate-risk individuals have a
follow-up at 18-24 mo) 6-12 mo, then consider (category 3) combination of high- and low-risk
6 to 8 mm criteria. The Fleischner Society uses
High-risk: follow-up CT scan follow-up scan at 18-24 mo
3-6 mo (if stable, then 9-12 High-risk: follow-up CT in the same risk stratification as the
mo and 24 mo) 6-12 mo, then repeat scan American College of Chest
in 18-24 mo Physicians.
≥8 mm: Assess surgical risk and 8 mm/>250 mm3: ≥8 mm to <15 mm at baseline b
Guideline is used for management
determine pretest probability Low-risk: consider follow-up (or growing <8 mm or new
of screen-detected pulmonary
of malignancy: CT at 3 mo, PET/CT, or tissue nodule 6 mm to <8 mm on
follow-up): 3-mo LDCT or nodules as part of lung cancer
Pretest probability <5%: sampling
PET/CT (category 4A) screening program. The Lung-RADS
surveillance CT in 3 mo High-risk: consider ≥15 mm (new or growing ≥8 guideline categorizes nodules based
Pretest probability 5%-65%: follow-up CT at 3 mo, mm): CT, PET/CT, and/or tissue on their risk of malignancy: category
8 mm or greater PET/CT scan to determine PET/CT, or tissue sampling sampling depending on
continued surveillance, 1 is a CT without any nodules;
probability of malignancy and
nonsurgical biopsy, or comorbidities (category 4B) category 2 nodules have an average
surgical biopsy/resection probability of malignancy <1%;
Pretest probability >65%: category 3 nodules have an average
referral for surgical biopsy or probability of malignancy of 1%-2%;
resection after appropriate category 4A nodules, 5-15%; and
staging workup
category 4B >15%.

7 mm to 10 mm in diameter accounted for 30.1% (2115 of 7019) of between 6 mm and 8 mm should be monitored with a chest CT in
all nodules 4 mm or larger and had a 1.7% probability of 6 months. Flexibility in these time intervals (eg, 3-6 months, 6-12
malignancy.9 However, these probabilities represented means months) is included in the guidelines to accommodate nodule fea-
among all individuals who present with a nodule in these size tures other than size, as well as clinician and patient preferences.
ranges. The probability of malignancy in an individual with lung Low radiation dose techniques are suggested for CT imaging.
cancer risk factors who has a 7-mm pulmonary nodule with con- Details of the guideline recommendations for management of
cerning imaging features (ie, irregular or spiculated edges, upper small solid pulmonary nodules can be found in Table 1.14-16
lobe location) may approach 10%.
18
F-fludeoxyglucose–positron emission tomography (FDG- Larger Solid Pulmonary Nodules (≥8 to 30 mm)
PET) imaging, bronchoscopy, and transthoracic needle biopsy The evaluation of larger solid nodules, 8 mm to 30 mm in diameter,
are unlikely to help identify malignancy in individuals with small involves consideration of patient and nodule characteristics, as well
solid pulmonary nodules. Nodules smaller than 8 mm in diameter as an understanding of the diagnostic accuracy and safety of addi-
are below the spatial resolution of FDG-PET imaging and are tional testing. The probability of malignancy in solid nodules of 8
difficult to locate during bronchoscopic or transthoracic needle mm to 30 mm ranges from very low (<1%) to high (>70%), depend-
biopsy. For these reasons, individuals with pulmonary nodules ing on patient lung cancer risk factors and imaging features such as
smaller than 8 mm in diameter are usually monitored with serial nodule size, location, edge features (eg, smooth, irregular, lobu-
chest CT imaging. The time interval between CT scans, performed lated, or spiculated edges), and the presence of calcification. Avail-
to monitor changes in the nodule that could indicate malignancy, is able tests, such as FDG-PET/CT imaging, bronchoscopy, and trans-
based on the nodule size and the presence of risk factors for lung thoracic needle biopsy, have a higher diagnostic yield for nodules 8
cancer. More recently published guidelines recommend longer mm to 30 mm in diameter than for small solid pulmonary nodules.
intervals, such as 6 or 12 months, rather than 3 months, between Primary care clinicians should consider referring individuals with a
monitoring scans.14 pulmonary nodule of 8 mm to 30 mm in size to a multidisciplinary
In summary, available guidelines suggest that a nodule smaller pulmonary nodule program if available (Box 1).
than 6 mm should be monitored with a chest CT in 12 months in
individuals with lung cancer risk factors such as a history of smok- Risk Prediction | The evaluation of a larger solid pulmonary nodule
ing or a family history of lung cancer. No additional CT imaging is (ie, 8-30 mm) should begin with an estimate of the probability that
required in those without lung cancer risk factors (Box 1). A nodule the nodule is malignant. This estimate can be based on an expert

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 Clinical Review & Education Review Evaluating the Patient With a Pulmonary Nodule

Table 2. Validated Risk Prediction Models for Evaluation of Pulmonary Nodules

Risk prediction Mayo Clinic Herder Brock University Cleveland Clinic
model model17 model18 VA model19 model2 model20
Nodule detection Incidental nodule Incidental nodule Incidental nodule Nodules detected Incidental nodules
on chest on chest seen on chest on LDCT as part of referred to biopsy
radiograph radiograph and radiographic lung cancer or resection
PET scan was confirmed screening
performed for on CT imaging program
further evaluation +/− PET scan
% Of nodules that 23 57 54 5.5 66.5
were malignant
in the cohort
used to develop
the model
Model variables Age Mayo Clinic model Age Age Age
Smoking history + FDG-PET uptake Smoking history Sex Smoking history
History of Time since Family history of Upper lobe location
extrathoracic quitting smoking lung cancer Solid and
malignancy ≥5 y Nodule diameter Emphysema irregular/spiculated
ago Nodule Size nodule edges
Nodule diameter Nodule type Emphysema
Spiculation Location FDG-PET avidity Abbreviations: CT, computed
Upper lobe Nodule count History of cancer tomography; FDG, 18F-fludeoxyglucose;
location other than lung
LDCT, low-dose CT; PET, positron
Area under 0.83 0.88 0.79 ≥0.94 0.75-0.81 emission tomography; VA, Veterans
the curve (C-index)
Affairs.

clinician’s assessment or may be calculated using a validated pul- section via a video or robotic-assisted approach. If a new nodule is
monary nodule risk prediction calculator (Table 2). Variables in pul- first identified on a chest x-ray, a chest CT should be performed to
monary nodule risk calculators include lung cancer risk factors (age, better characterize the nodule and assess for lymphadenopathy.
smoking history, personal history of other cancers, family history of Serial CT imaging is appropriate if a pulmonary nodule has a low
lung cancer, presence of chronic obstructive pulmonary disease) probability of malignancy (eg, <10%), if other management op-
and nodule features known to be associated with an increased tions (FDG-PET imaging, bronchoscopic or transthoracic needle bi-
probability of malignancy (larger size, upper lobe location, part- opsy) are considered unlikely to be informative or are high-risk pro-
solid density, irregular or spiculated edges, fewer total pulmonary cedures, or if an informed patient prefers a less aggressive approach.
nodules, increased FDG uptake on PET imaging, or a concerning For solid pulmonary nodules 8 mm to 30 mm in size, when surveil-
growth rate such as nodule volume doubling or diameter increasing lance chest CT is the preferred approach, the first surveillance chest
by >25% in 30-400 days). CT should be performed 3 months after the initial CT. A meaningful
Several risk calculators have been developed and their accura- change in nodule size is defined as an increase of 2 mm or more in
cies have been externally validated (Table 2).2,17-20 Individual risk cal- mean diameter, rounded to the nearest millimeter.23 If the nodule
culators are more accurate in populations similar to those in which decreases in size, additional monitoring is not required. If the nod-
they were developed. For example, a risk calculator developed in a ule remains stable in size, a chest CT should be performed 6 months
cohort of people with a pulmonary nodule presenting to a surgical later. If the nodule is unchanged on this subsequent imaging, a fol-
clinic would not be as accurate when used to assess individuals with low-up chest CT 12 months later would be appropriate. If the nod-
a pulmonary nodule identified during lung cancer screening. Thus, ule is growing at a pace consistent with malignancy (eg, volume dou-
it is important to use a model that was derived from a population bling time >30 days and <400 days), it should be further evaluated
similar to the patient whose nodule is undergoing evaluation. A cal- without delay (see options below). If the nodule grows at a very slow
culator developed in a screening population can be used to esti- pace (eg, volume doubling time >400 days), an indolent malig-
mate the probability of malignancy in small solid pulmonary nod- nancy remains possible and a discussion with the patient about the
ules as well. Many risk calculators have online tools to assist with their management strategy should occur.
use. The clinical utility of pulmonary nodule risk calculators has been FDG-PET imaging can assist with characterization of an
more difficult to confirm than their accuracy. Some studies have intermediate-risk large solid pulmonary nodule (eg, 10%-70%
shown that the assessments of clinical experts and radiologists are probability of malignancy). FDG-PET imaging provides information
comparable with that of the validated risk calculator scores (ie, area about the metabolic activity of the nodule. A pulmonary nodule
under the curve, 0.70-0.85 compared with 0.72-0.77, respectively, with high metabolic activity is more likely to be malignant, although
for identifying the presence of lung cancer).21,22 there is significant overlap in FDG uptake between malignant and
benign (ie, infectious/inflammatory) nodules. An indolent malig-
Management Options | In addition to the probability of malignancy, nancy can have a false-negative result given its lower metabolic
the evaluation of an individual with a larger solid pulmonary nodule activity. A meta-analysis evaluating the discriminative accuracy of
is based on the yield of available diagnostic testing, patient comor- FDG-PET imaging for pulmonary nodule evaluation reported a
bidities, and patient preferences. Management options for CT- pooled sensitivity of 89% (95% CI, 86%-91%) and specificity of
detected pulmonary nodules include follow-up monitoring with se- 75% (95% CI, 71%-79%).24 There was significant heterogeneity of
rial CT imaging, further evaluation with FDG-PET imaging, nonsurgical the specificity, with lower specificity values identified in higher-
biopsy (bronchoscopy, transthoracic needle biopsy), or surgical re- quality studies and a 16% lower specificity in areas with endemic

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 Evaluating the Patient With a Pulmonary Nodule Review Clinical Review & Education

fungal infections such as the Ohio River Valley (histoplasmosis) and

Southwestern US (coccidioidomycosis).24 FDG-PET imaging may Box 2. Individualized Pulmonary Nodule Management Based on
also identify regional and distant spread of lung cancer. Probability of Malignancy14-16,31-33a
When imaging findings suggest an intermediate probability of <1% No additional testing or monitoring needed.
malignancy (eg, 10%-70%), a nonsurgical biopsy, such as a 1%-5% Monitoring with chest computed tomography (CT) per
CT-guided transthoracic needle biopsy or guided bronchoscopy, guideline recommendations, based on nodule size.
may be offered. The choice between a CT-guided transthoracic 5%-30% Monitor with chest CT in 3 months or pursue additional
needle biopsy and a guided bronchoscopy procedure is based on testing with positron emission tomography (PET)/CT imaging
several factors, including location of the nodule, available clinical and/or a nonsurgical biopsy. Factors that favor monitoring include
expertise, and patient comorbidities and values. A pulmonary nod- severe comorbidities, limited life expectancy, difficult nodule loca-
ule located in the periphery of the lung field is more likely to be tion, patient favors conservative management, slow growth rate,
accessible by transthoracic needle biopsy, while a pulmonary nod- and low metabolic activity.

ule located along the path of an airway may be more easily 30%-65% Additional testing with PET/CT imaging and/or a non-
approached by bronchoscopy. In a meta-analysis, transthoracic surgical biopsy. Factors that favor guided bronchoscopy vs trans-
thoracic needle biopsy include airway leading to the nodule, se-
needle biopsy had a higher pooled diagnostic yield (93% [95% CI,
vere emphysema, available local expertise, and need to invasively
90%-96%]) than bronchoscopy (75% [95% CI, 69%-80%]), but stage the mediastinum.
was associated with an increased risk for pneumothorax (26%) and
65%-90% Additional testing with PET/CT imaging and/or a non-
hemorrhage (16%).25 Advances in technologies that augment the surgical biopsy or proceed directly to thoracoscopic surgical resec-
ability to guide the bronchoscope to a peripheral nodule, confirm tion. Factors that favor surgical resection include low-yield nonsur-
the location of the nodule, and provide representative samples of gical biopsy location, excellent cardiopulmonary fitness, and
the nodule, including electromagnetic navigation,26 radial endo- patient favors aggressive management.
bronchial ultrasound, ultrathin bronchoscopes,27 and robotic- >90% Thoracoscopic surgical resection or stereotactic radio-
assisted bronchoscopy,28 have substantially improved diagnostic therapy based on patient comorbidities and values.
yields of guided bronchoscopy while maintaining low complication a
Probability of malignancy is estimated based on clinical experience or a
rates. In a meta-analysis, the pooled sensitivity for malignancy of validated risk prediction calculator.
electromagnetic navigation bronchoscopy was 77% (95% CI, 72%-
82%) with a 2.0% risk of pneumothorax (95% CI, 1.0%-3.0%) and
0.8% risk of major bleeding (95% CI, 0.5%-1.1%).29 An added value probability of malignancy may be managed differently. Factors that
of performing bronchoscopy is the ability to perform endobron- influence clinical decisions include the anticipated diagnostic yield
chial ultrasound-guided biopsy of the hila and mediastinum if indi- of a nonsurgical biopsy, patient comorbidities that influence the
cated for staging. safety of a procedure, the likelihood of benefit from establishing a
When the probability of malignancy is high (eg, >70%), pro- diagnosis (life expectancy, nodule growth rate, metabolic activity),
ceeding to surgical resection via a video or robotic-assisted ap- and patient values (Box 2). It is important to note that after
proach is recommended in individuals without life-limiting comor- completion of all nonsurgical testing (ie, FDG/PET imaging, nonsur-
bidities, such as severe emphysema or severe heart failure, and who gical biopsy), in some patients the probability of malignancy may
meet criteria of cardiopulmonary fitness, such as predicted post- be higher than accepted thresholds for monitoring with imaging
operative forced expiratory volume in 1 second and diffusing capac- and lower than accepted thresholds for surgical resection. In this
ity greater than 60% predicted, suggesting a low risk associated with situation, the managing clinician and patient should discuss the
surgical resection.30 Ideally, a surgical wedge resection to confirm tradeoffs of monitoring vs surgical resection to determine the most
the presence of cancer, obtained during an intraoperative frozen sec- appropriate next step for that individual. It is also important to rec-
tion, can be followed by definitive treatment (eg, lobectomy or seg- ognize that some cancers may grow slowly on serial imaging, pro-
mentectomy) during the same operation. For individuals with life- viding the opportunity for the clinician and patient to discuss the
limiting comorbidities and for those at high risk for complications preferred timing of treatment.
from surgical resection, other potential nonsurgical options may in-
clude nonsurgical biopsy (transthoracic needle biopsy and bron- Subsolid Pulmonary Nodules
choscopy), stereotactic radiotherapy, or other ablative therapies. Fea- Subsolid pulmonary nodules consist of pure ground-glass (Figure, F)
sibility of the biopsy, patient fitness, and patient preferences help and part-solid pulmonary nodules. Ground glass refers to a density
inform this decision-making process. in which the lung architecture (such as blood vessels) is not ob-
scured by the nodule. Part-solid refers to a nodule that has both
Individualizing Care | In general, nodules can be classified into 1 of 3 ground-glass and solid components. Malignant subsolid pulmo-
categories of risk of malignancy and managed accordingly: those nary nodules grow at a slower pace than malignant solid nodules and
with a low risk (eg, <10%) can be monitored with imaging; those are typically adenocarcinomas (adenocarcinoma in situ or mini-
with an intermediate risk (eg, 10%-70% risk) should typically mally invasive adenocarcinoma in the ground-glass portion and in-
undergo additional diagnostic testing, and those with a high risk vasive adenocarcinoma in the solid portion). In 1 series of 439 pure
(eg, >70% risk) should proceed directly to surgery. These thresh- ground-glass nodules that were smaller than 6 mm in diameter and
olds refer to the management of the population of patients with a followed up for at least 5 years (median imaging follow-up, 6.0 years),
pulmonary nodule and need to be considered in the context of 45 (10.3%) grew and 4 (0.9%) developed into adenocarcinomas.34
other factors for individual patients. Two nodules with an identical In another series of 226 patients with subsolid pulmonary nodules,

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 Clinical Review & Education Review Evaluating the Patient With a Pulmonary Nodule

Table 3. Society Guidelines for the Management of Subsolid

to perform additional testing or monitoring in selected situations. A
Pulmonary Nodules ground-glass nodule 6 mm or larger can be followed with a chest
CT in 6 to 12 months followed by every 2 years for 5 years if it
American College
of Chest Physicians15 Fleischner Society14 Lung-RADS16a remains stable. The management of a part-solid nodule should be
≤5 mm: no follow-up <6 mm/<100 mm : 3
Ground glass nodule based on the size of the solid component. Surveillance with a chest
<30 mm at baseline
Ground-glass nodule:
(or any size unchanged):
CT should occur in 6 months if the solid component is smaller than
no routine follow-up
return to annual 6 mm or in 3 months if the solid component is 6 mm to 8 mm.
Part-solid: no routine screening (category 2)
follow-up Management of a part-solid nodule in which the solid component is
Part-solid nodule <6 mm
at baseline: return to 8 mm or larger should follow the recommended guidance for large
annual screening solid nodules.16,17 When monitoring a subsolid pulmonary nodule,
(category 2)
the development or growth of a solid component of the nodule is a
Part-solid nodule <6 mm
(new): follow-up CT scan concerning finding that should lead to more frequent surveillance
at 6 mo (category 3) imaging, nonsurgical biopsy, or surgical resection based on the size
>5 mm: ≥6 mm/>100 mm3: Ground glass nodule
≥30 mm at baseline or
of the solid component of the nodule. Growth of the ground-glass
Ground-glass nodule: Ground-glass nodule:
follow-up CT scan at follow-up CT scan new on follow-up: component alone does not suggest a malignancy has become inva-
12 mo then annual 6-12 mo then every follow-up 6-mo CT
(category 3) sive and thus does not require more intensive or invasive manage-
through 3 y 2-5 y
Part-solid nodule: ment. FDG-PET imaging is not useful for evaluating the probability
Part-solid nodule: ≤8 Part-solid nodule:
mm solid component: follow-up CT scan Solid component of malignancy unless a solid component of at least 8 mm is present.
follow-up CT scan at 3-6 mo then annually <6 mm: follow-up CT Minimally invasive sublobar resection may be considered without
3, 12, and 24 mo for 5 y at 6 mo (category 3)
then annual until 5 y Solid component ≥6 to
biopsy when the size of the solid component of a subsolid lung
>8 mm solid <8 mm or new or nodule is growing and is 8 mm or larger (Table 3 and Box 1).14-16
component: growing and <4 mm:
follow-up CT scan at follow-up CT at 3 mo
3 mo, further (category 4A) Guidelines
evaluation with PET, Solid component
nonsurgical biopsy, Several societies have developed guidelines to assist with the
≥8 mm or new or
and/or resection if growing and ≥4 mm: evaluation of an individual with a pulmonary nodule.14-16,31-33 These
persists further evaluation guidelines vary in their scope and focus, and some are specific to
(category 4B)
certain geographic regions and health systems.32,33 Some of these
Abbreviations: CT, computed tomography; PET, positron emission tomography.
guidelines focus on management of a small incidentally detected
a
Guideline is used for management of screen-detected pulmonary nodules as
pulmonary nodule, others focus on management of an LDCT
part of lung cancer screening program.
screen-detected pulmonary nodule, and some focus on both types
of nodules. However, all the guidelines are organized based on an
invasive cancer was identified in 4.1% (3 of 74) of resected pure estimate of the probability that a pulmonary nodule is malignant,
ground-glass malignant nodules (median diameter at time of de- knowledge of the risk of malignancy in nodules of different densi-
tection, 10 mm), 70.0% (14 of 20) with a solid component greater ties, and workup for further assessment of the nodule. Differences
than 25% of the total nodule size, and 45.5% (10 of 22) of those with in guideline recommendations include the use of different thresh-
growth in the solid component.35 A summary of 24 case series that olds for the probability of malignancy to provide management rec-
included 704 patients reported that the 5-year lung cancer– ommendations (eg, <5%, 10%, or 15% probability for monitoring
specific survival rate was 100% for malignant pure ground-glass nod- for nodule growth, 5%-15% to 65%-70% for additional nonsurgical
ules with a mean tumor size of 7.9 mm to 16.6 mm.36 evaluation, and >65% or >70% for surgical resection), the fre-
Malignant subsolid pulmonary nodules are relatively slow quency and duration of image-based monitoring, the preferred risk
growing compared with malignant solid nodules. In the series calculators for identifying likelihood of malignancy, and whether
described above of 226 patients with subsolid pulmonary nod- volumetric imaging with growth rate calculation is recommended.
ules, the solid component of a malignant part-solid nodule grew Guideline recommendations have changed over time, based
in 100% (17 of 17) of nodules within the first 3 years of monitor- on a better understanding of probability of malignancy and growth
ing, and in 86.4% (19 of 22) of malignant pure ground-glass nod- patterns of malignant pulmonary nodules. Changes have included
ules, but none of these cancers spread beyond the nodule during using a higher threshold for probability of malignancy, compared
this follow-up period.35 The metabolic activity of a malignant sub- with past guidelines, for use of imaging to monitor growth of a nod-
solid pulmonary nodule is relatively low (positive FDG-PET scan in ule (eg, <15% probability currently compared with <5% probability
60%)37 and the yield of transthoracic needle biopsies is also rela- in the past), monitoring less frequently and for shorter durations,
tively low (51.2%).37,38 These findings suggest that longer periods and allowing more flexibility in frequency of diagnostic testing, to
of imaging surveillance may be appropriate when following up accommodate consideration of patient risk factors, comorbidities,
patients with pure ground-glass nodules, particularly in people and values. These guidelines refer to an incidentally or screen-
with advanced age or with comorbid conditions whose life expec- detected pulmonary nodule and not a pulmonary nodule in an indi-
tancy is lower than in people who are younger or without comor- vidual with a known malignancy for whom metastatic disease is a
bid conditions. concern (Box 1). Pulmonary nodule guideline recommendations are
In summary, current guidelines suggest a pure ground-glass summarized in Table 1 and Table 3.
nodule smaller than 6 mm in diameter does not require additional Compliance of clinicians with guideline recommendations and
testing or monitoring, but patients and clinicians may decide patients’ actual follow-up in practice may be suboptimal. In 1 study

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 Evaluating the Patient With a Pulmonary Nodule Review Clinical Review & Education

of 197 patients with pulmonary nodules, 88 (44.7%) received care nodule to be at least 30% when the calculated average risk was
inconsistent with guidelines (eg, next surveillance imaging prior to 10%.46 High-quality communication from clinicians has been asso-
or after the interval recommended in the guidelines, a nonsurgical ciated with less patient distress. No distress after a pulmonary nod-
biopsy instead of surveillance imaging).39 Features leading to non- ule diagnosis was reported in 60.3% of patients who received high-
compliance include inappropriate radiologist guidance (65.6% vs quality communication compared with 40.7% in those who received
10.8%; overevaluation relative risk [RR], 4.6 [95% CI, 2.3-9.2]; low-quality communication.47 In 316 clinician encounters regard-
underevaluation RR, 4.3 [95% CI, 2.7-6.8]), receiving care at more ing management of pulmonary nodules in which decision-making
than 1 facility (RR, 2.0 [95% CI, 1.5-2.7]), and nodule detection dur- occurred, patients preferred to have an active role in the manage-
ing an inpatient stay or preoperative visit (RR, 1.6 [95% CI, ment of their pulmonary nodule in 313 (98%) of the encounters.
1.1-2.5]).39 Features associated with compliance with following However, only one-half of clinicians reported engaging in shared de-
guideline management recommendations by clinicians and compli- cision-making with patients diagnosed with a pulmonary nodule.48
ance with care recommendations by patients include patient dis- Clinicians with more years of experience and those who reported
tress (64.4% vs 57.4%),40 point-of-care reference materials pro- feeling more comfortable evaluating a pulmonary nodule used shared
vided in the emergency department (80.2% vs 67.5%),41 clinical decision-making more often.48
decision support tools at workstations (65.2% vs 49.6%),42 guide-
line templates added to radiology reports (45% vs 31%),43 and Future Directions
high-quality communication (OR, 3.7 [95% CI, 1.3-10.6]).40 Large imaging data sets have supported the application of artificial
intelligence to identify pulmonary nodules most likely to be malig-
System of Care nant. A convolutional neural network trained on more than 15 000
In practice, primary care clinicians must counsel patients about the images from the National Lung Screening Trial showed improved
evaluation and diagnostic testing of pulmonary nodules and moni- classification over available risk prediction models when externally
tor timing of follow-up diagnostic testing. validated (area under the curve, 0.84-0.92 vs 0.78-0.82).49 Sev-
Multidisciplinary pulmonary nodule specialty clinics are avail- eral molecular biomarkers have been developed to improve pulmo-
able in some regions to assist in the treatment of patients with pul- nary nodule risk prediction. Some of these biomarkers, present in
monary nodules. These clinics, comprised of a multidisciplinary team the blood, airway epithelium, and breath, evaluate changes in cir-
of nodule management experts (eg, pulmonologists, thoracic sur- culating tumor DNA, mRNA expression, proteins, autoantibodies,
geons, radiologists), identify patients with pulmonary nodules by or metabolites, and are currently undergoing assessment for clini-
flagging radiology reports (either manually or through computa- cal utility.50,51 Multidisciplinary programs of care for individuals
tional linguistics) when a pulmonary nodule is identified on imaging. with a pulmonary nodule, described above, are increasing in num-
Clinicians at these clinics communicate directly with patients to in- ber. Population management tools, which may include decision
form them of the results, use guideline-based pulmonary nodule support tools and may help people adhere to recommended
management algorithms and health management systems to en- follow-up diagnostic testing, are also increasingly available. These
sure adherence to appropriate follow-up testing, and provide auto- programs may improve clinician adherence with guideline recom-
mated patient reminders. In a series of 113 patients, care followed mendations, patient adherence with recommended management,
guideline recommendations in 76 patients (67.2%), with the high- communication, and patient-related outcomes.
est rates (88% concordant) observed in those with malignant
nodules.44 In this setting, among 5057 individuals in which 1863 Limitations
(37%) received less intensive evaluation than recommended in This review has several limitations. First, for some covered topics,
guidelines, fewer procedure-related adverse events (risk differ- high-quality data were not available. Second, some relevant ar-
ence, −5.9%), lower radiation exposure (−9.5 mSv), and lower ex- ticles may have been missed. Third, a formal quality assessment of
penditures (−$10 916) were noted, without affecting the stage of can- included articles was not performed.
cer at diagnosis (risk difference, 4.6%).45 These results may suggest
that individualizing care in a multidisciplinary pulmonary nodule clinic
could yield favorable outcomes.
Conclusions
Shared Decision-making Pulmonary nodules are identified in approximately 1.6 million
In a study of 121 patients with pulmonary nodules, psychological dis- people per year in the US and approximately 30% of chest CT
tress about the presence of a pulmonary nodule was reported by 69 images. The treatment of an individual with a pulmonary nodule
patients (57.0%), with 25% reporting continued distress 2 years af- should be guided by the probability that the nodule is malignant,
ter a pulmonary nodule was diagnosed.46 Fifty-five patients (45.5%) safety of testing, the likelihood that additional testing will be infor-
estimated the risk of malignancy associated with their pulmonary mative, and patient preferences.

ARTICLE INFORMATION Concept and design: Both authors. Administrative, technical, or material support: Both
Accepted for Publication: December 19, 2021. Acquisition, analysis, or interpretation of data: Both authors.
authors. Supervision: Mazzone.
Author Contributions: Dr Mazzone had full access Drafting of the manuscript: Both authors.
to all of the data in the study and takes Conflict of Interest Disclosures: Dr Mazzone
Critical revision of the manuscript for important reported receiving grants from the
responsibility for the integrity of the data and the intellectual content: Both authors.
accuracy of the data analysis. Patient-Centered Outcomes Research Institute,

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 Clinical Review & Education Review Evaluating the Patient With a Pulmonary Nodule

Biodesix, DELFI, Exact Sciences, MagArray, Nucleix, screening: a brief report from the NELSON Study. transthoracic needle biopsy: a systematic review
PrognomiQ, Tencent, and Veracyte paid to his J Thorac Oncol. 2020;15(1):125-129. doi:10.1016/j. and meta-analysis. PLoS One. 2018;13(1):e0191590.
institution outside the submitted work. No other jtho.2019.09.193 doi:10.1371/journal.pone.0191590
disclosures were reported. 14. MacMahon H, Naidich DP, Goo JM, et al. 26. Folch EE, Pritchett MA, Nead MA, et al;
Submissions: We encourage authors to submit Guidelines for management of incidental NAVIGATE Study Investigators. Electromagnetic
papers for consideration as a Review. Please pulmonary nodules detected on CT images: from navigation bronchoscopy for peripheral pulmonary
contact Mary McGrae McDermott, MD, at the Fleischner Society 2017. Radiology. 2017;284(1): lesions: one-year results of the prospective,
[email protected]. 228-243. doi:10.1148/radiol.2017161659 multicenter NAVIGATE Study. J Thorac Oncol. 2019;
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