ABSTRACT
Pulmonary nodules are often encountered in primary care during radiographic evaluation of respiratory symptoms, incidental imaging, and lung cancer screening. While most nodules are low risk, accurately identifying nodules that require surveillance, determining appropriate follow-up intervals, and deciding when specialist evaluation and intervention is indicated are challenging.
Pulmonary nodules detected through incidental imaging or lung cancer screening cause psychological distress in patients and impose a substantial cognitive and management burden on primary care physicians.
Lung cancer is the leading cause of cancer-related death for men and women in the United States, yet adherence to recommended screening for eligible patients remains low.
Early detection of lung nodules allows lung cancer to be identified at an earlier stage, which significantly improves treatment options and can reduce the risk of death.
Effective pulmonary nodule management requires guideline-concordant care as well as familiarity with local referral pathways, including multidisciplinary nodule clinics, particularly for higher-risk nodules or when management uncertainty exists.
Pulmonary nodules are focal radiographic opacities 3 cm or less in diameter—larger lesions are classified as pulmonary masses. Nodules are primarily organized by imaging characteristics—specifically size and tissue attenuation. By size, they are classified as either small (< 8 mm) or large (≥ 8 mm). By attenuation they are further categorized as solid or subsolid, with the latter encompassing part-solid and ground-glass nodules—an opacity of the lung architecture without any identifiable solid component.
This review outlines the epidemiology of pulmonary nodules and offers practical guidance for their evaluation, risk assessment, and follow-up.
See related editorial, page 485
VERY COMMON, BUT 95% ARE BENIGN
Pulmonary nodules are commonly identified in radiographic imaging, often unexpectedly. They are discovered on approximately 25% of all computed tomography (CT) scans of the chest, and in the United States, an estimated 1.6 million pulmonary nodules are discovered annually.1 Fortunately, the vast majority are benign, with only about 5% representing malignancy.1
UPDATE: SCREEN THOSE AGE 50 TO 80 WITH 20-PACK-YEAR SMOKING HISTORY
In 2013, low-dose CT replaced plain film chest radiography as the standard of care for lung cancer screening. This change was based on recommendations from the US Preventive Services Task Force (USPSTF), which advised screening in adults at high risk, ie, those who are age 55 to 80 with a 30-pack-year smoking history. This recommendation was driven by findings from the National Lung Screening Trial in the United States,2 which demonstrated a 20% reduction in lung cancer mortality when screening by low-dose CT rather than plain chest radiography, with approximately 320 low-dose CT screenings needed to prevent 1 lung cancer death over a median follow-up of 6.5 years.
In 2021, the USPSTF broadened the defined high-risk population to include persons age 50 to 80 with a 20-pack-year smoking history.3 This expansion followed the contributions of the European-based Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial,4 which showed similar benefits in a younger cohort with a lower pack-year history.
Today, fewer people smoke, cancer treatment has improved, and more people are being screened—which together contributed to a 34% decline in the overall lung cancer death rate from 1991 through 2022. Still, lung cancer remains the leading cause of cancer-related death in both men and women in the United States, killing more people than colorectal, breast, and prostate cancers combined.5
MANY POSSIBLE CAUSES, INCLUDING CANCER
Pulmonary nodules can be caused by a diverse set of disease processes6:
Infectious causes include mycobacterial disease, histoplasmosis, coccidioidomycosis, aspergillosis, organizing pneumonias, Echinococcus granulosis infections, and septic emboli
Vascular abnormalities such as arteriovenous malformations, infarction, and pulmonary venous varices may also present as a nodule
Benign structural causes include bronchogenic cysts, hamartomas, rounded atelectasis, amyloidosis, and intrapulmonary lymph nodes
Autoimmune etiologies include nodular sarcoidosis, granulomatosis with polyangiitis, and rheumatoid nodules
Environmental exposures (silica, coal dust, asbestos fibers, beryllium) can cause pneumonoconiosis and manifest as pulmonary nodules
Malignant neoplasms such as primary lung cancer and metastatic disease that has spread to the lung also present as nodules.
RISK FACTORS FOR LUNG CANCER
Risk factors for primary lung cancer include the following6–8:
Cigarette smoking
Exposure to ionizing radiation such as from environmental radon (for which home radon testing can be advised to reduce modifiable risk)
Exposure to occupational carcinogens such as arsenic, chromium, nickel, silica, asbestos, tar, and soot
Exposure to air pollution
Comorbid lung conditions such as idiopathic pulmonary fibrosis, chronic obstructive lung disease, and tuberculosis
Asian ethnicity, particularly among women and including never-smokers
Older age
Family history of cancer
History of previous lung cancer.
INITIAL EVALUATION
As we said above, although about 95% of pulmonary nodules are benign, lung cancer remains the leading cause of cancer-related death in the United States.1 The goal of evaluation and monitoring is to catch malignancy at an intervenable stage, ideally with curative intent, while also minimizing unnecessary risk from interventions to patients who harbor benign lesions. Given the stark contrast in outcomes, with 5-year survival rates of approximately 65% for early-stage lung cancer vs only 10% for late-stage disease, early detection is critical.9
The initial evaluation of a pulmonary nodule should focus on assessing pretest probability for malignancy by addressing 2 questions:
What are the patient-specific risk factors?
What are the nodule-specific risk factors?
Patient-specific risk factors to consider include age, ethnicity, tobacco history, family history of lung cancer, personal cancer history, comorbid pulmonary diseases, symptoms, and context in which the nodule was identified, eg, incidental vs health maintenance screening.
Nodule-specific risk factors include nodule type (solid, part-solid, ground-glass), size, location, shape of border, pattern of calcification, and growth rate. The latter can be established with careful review of previous imaging, if available. CT evaluation of the chest is essential and superior to plain radiography or magnetic resonance imaging for nodule characterization. However, thin axial sections (≤ 1.5 mm) are essential for accurate characterization.10,11
Radiographic features
Table 1 summarizes radiographic features that suggest a low risk (Figure 1) vs a high risk (Figure 2) of malignancy in pulmonary nodules.
Low-risk and high-risk radiographic features of pulmonary nodules
Pulmonary nodules: low-risk radiographic signs. (A) Smooth margins. (B) Benign calcification patterns (left to right: diffuse, central, popcorn, lamellated). (C) Macroscopic fat. (D) Small solitary nodule.
Pulmonary nodules: high-risk radiographic signs. (A) Rapid growth (≥ 1.5 mm growth of solid nodule on 3-month interval surveillance imaging). (B) Spiculated margins. (C) Lobulated margins. (D) Part-solid. (E) Ground-glass (lung window). (F) Increased metabolic activity on positron emission tomography.
Size. In the United States, nodule measurements are reported as mean nodule diameter. Nodule size correlates with malignancy risk, although nonlinearly, and therefore guides surveillance intensity and consideration of procedural intervention.12,13
As a rule of thumb, nodules measuring 8 mm or larger generally warrant consideration for workup beyond surveillance. However, nodule size should be considered in the context of its attenuation type—solid, part-solid, or ground-glass—as they pose different risks of malignancy.12
Growth rate. Malignant solid-type nodules grow quickly, with an average volume doubling time of 400 days or fewer, corresponding to an approximately 25% increase in mean diameter.14 Subsolid nodules, even when malignant, grow more slowly. Meta-analyses report average volume doubling times for malignant part-solid nodules as 536 days and ground-glass nodules as 669 days.15
Review of all previous imaging is critical, as growth trends may already be present. Growth rates are a principal feature used to assess stability and infer benignity without invasive procedures. For example, solid nodules that are stable for 18 to 24 months are likely benign and may prompt discontinuation of nonroutine surveillance.1 Growth of 1.5 mm or more on serial imaging is significant, accounting for measurement variability inherent to manual CT measurements, and thus warrants further diagnostic consideration (Figure 2A).16
Location is also useful for risk-stratifying: upper lobe nodules are approximately twice as likely to be malignant.17 Ventilation-perfusion differences are likely the primary driver of this effect, as inhaled carcinogens are preferentially delivered to the upper lobes. The right lung also has a higher cancer incidence, attributed to greater airflow through the more vertically orientated right mainstem bronchus.18
When an air-filled bronchus is located within or adjacent to a nodule (the bronchus sign), malignancy is 30% less likely.17 Bronchial dilatation as it enters the nodule, however, suggests vascular or lymphatic invasion, making cancer more likely.17 Perifissural nodules are often benign intrapulmonary lymph nodes, but a well-circumscribed border would be expected.1
Nodule margins provide additional diagnostic information. Spiculation, defined as small needle-like projections extending from the nodule, is especially concerning, as it often represents vascular and lymphatic invasion, conferring a more than 5 times greater relative risk of cancer (Figure 2B).17 Conversely, smooth margins decrease risk fivefold (Figure 1A). Lobulation is associated with a modest 10% increase in malignancy likelihood (Figure 2C).
Calcification can suggest either a higher or lower risk of malignancy, depending on the pattern.19 Diffuse, central, lamellated, and popcorn-style calcifications favor benignity (Figure 1B).13 Eccentric, stippled (punctate), and amorphous patterns of calcification raise concern for malignancy.20
Macroscopic fat on CT imaging is a reliable and specific finding for a pulmonary hamartoma, which account for about 75% of all benign pulmonary nodules (Figure 1C).21
Small solid nodules (< 8 mm)
Small solid pulmonary nodules, defined as solid nodules less than 8 mm in diameter, carry a low probability of malignancy, estimated to be less than 2% for all-comers (Figure 1D).1 Radiographic surveillance is not universally required and should instead be individualized based on patient-specific risk factors and nodule-specific characteristics. These nodules are most appropriately followed in the primary care setting.
Patients with a solitary small solid nodule measuring 6 to 8 mm should undergo a repeat chest CT at 6 to 12 months, whereas nodules smaller than 6 mm are imaged at 12 months only if patient-specific risk factors (eg, smoking history, family history of lung cancer) or radiographic risk factors (eg, spiculation, lobulation, nodule location in an upper lobe) are present.22 If the first interval chest CT remains stable, a second follow-up scan at 18 to 24 months should be performed to assess continued stability for both 6-to-8-mm nodules and higher-risk nodules smaller than 6 mm.
Although no surveillance is necessary for low-risk nodules, characterized as smaller than 6 mm with no known patient risk factors or high-risk radiographic features (Table 1), it is reasonable to use shared decision-making and obtain a 12-month interval scan.
If there are multiple nodules 6 to 8 mm in size, the Fleischner Society guidelines22 recommend follow-up CT imaging at 3 to 6 months, regardless of perceived risk factors, and repeat imaging at 18 to 24 months to evaluate stability. However, these guidelines exclude patients with a history of malignancy, age younger than 35 years, or with known immunosuppression. These patients should be considered for specialty clinic referral due to their complexity.
Large solid nodules (8–30 mm)
The probability of malignancy in a large solid pulmonary nodule is highly variable, and therefore risk-stratification models are useful to balance both patient-specific and nodule-specific risk factors. Regardless, a referral to a multidisciplinary pulmonary nodule clinic should be initiated without delay, as risk stratification is more complex and often involves advanced imaging or procedural intervention. If specialist evaluation is anticipated to be delayed beyond 3 months from the original image, a 3-month interval CT scan should be completed to expedite the workup.
Part-solid nodules
Clinically, part-solid nodules carry a substantially higher risk of malignancy than do solid nodules and pure ground-glass nodules.23 These nodules represent a key radiologic manifestation along the lung adenocarcinoma spectrum and are defined by the coexistence of ground-glass and solid components (Figure 2D).
The 2023 American Association for Thoracic Surgery (AATS) consensus statement24 divides part-solid nodules into 2 subtypes: real part-solid nodules and heterogenous ground-glass nodules. A real part-solid nodule has a solid component visible on the mediastinal window, whereas in a heterogenous ground-glass nodule the solid component is visible only on the lung window. This distinction is clinically important, with real part-solid nodules having the highest risk of malignancy, heterogenous ground-glass nodules carrying an intermediate risk and being more likely than nonsolid nodules (pure ground-glass nodules) to progress to real part-solid nodules, and nonsolid nodules having the lowest risk.24
Management is dictated by the size of the largest solid component when risk-stratifying; the ground-glass portion is thus not included in size measurement. For example, a part-solid nodule with a 5-mm solid component within a 17-mm total nodule would be managed according to the less-than-6-mm solid component pathway. Based on the Fleischner Society guidelines,22 if the solid component is larger than 6 mm, a 3-to-6-month follow-up CT scan should be performed. It would also be reasonable to refer the patient to a multidisciplinary pulmonary nodule clinic at this juncture.
Ground-glass nodules
Ground-glass nodules, more precisely termed nonsolid nodules in the 2023 AATS consensus statement,24 are defined as areas of increased attenuation visible on a CT lung window but not visible on a standard CT mediastinal window and without any solid component (Figure 2E). Nodules that are a byproduct of an underlying benign inflammatory process often disappear in as little as 3 months on follow-up imaging.20,25
Just like part-solid nodules, persistent ground-glass nodules fall on the adenocarcinoma spectrum. The development of a solid component should be considered an invasive adenocarcinoma until proven otherwise. For solitary ground-glass nodules measuring 6 mm or larger, CT surveillance should be performed at 6 to 12 months and then every 24 months up to 5 years per the 2017 Fleischner Society recommendations.22
However, the 2023 AATS consensus statement adopts a slightly more accelerated approach, recommending the first follow-up CT scan at 6 months. We support this strategy, as persistent ground-glass nodules beyond 6 months should prompt consideration for a multidisciplinary nodule clinic referral.24 When multiple ground-glass nodules are present, even if all nodules are less than 6 mm in size, CT surveillance should be performed in 3 months, and a multidisciplinary nodule clinic referral is recommended.22
Benign-appearing nodules
While most nodules are benign, establishing this without CT surveillance or tissue sampling is challenging. However, nodules with a clearly benign pattern of calcification or the appearance of macroscopic fat on CT imaging do not need to be monitored out of concern for malignant potential (Figure 1).10 Solid perifissural nodules are also presumed benign when the mean diameter is less than 10 mm, with smooth margins and an oval, lentiform, or triangular shape. These do not require surveillance.1,26
RISK STRATIFICATION FRAMEWORK
Risk stratification for pulmonary nodules is fundamental in guiding patient care. Stratification allows clinicians to select the most appropriate surveillance interval and diagnostic tool. Several validated risk stratification models are used in clinical practice; we briefly highlight 4 commonly used models.
The Lung Imaging Reporting and Data System (Lung-RADS)
The Lung-RADS imaging classification system was introduced in 2014 and most recently updated in 2022 by the American College of Radiology to standardize the reporting and recommended management of pulmonary nodules identified on lung cancer screening with low-dose CT for qualifying patients.26 As such, the risk of malignancy is extrapolated purely from nodule-specific characteristics such as size, nodule type, growth rate, location, margins, and calcification pattern. Through standardization, Lung-RADS has successfully reduced both false-positive screens and unnecessary follow-up.26
Nodules are classified within alphanumerical categories—0, 1, 2, 3, 4A, 4B, 4X—with a standardized set of recommendations for each.26 Category 0 indicates an incomplete evaluation due to poor image quality or a confounding variable such as active pneumonia limiting interpretation. Nodules assigned Lung-RADS categories 1 and 2 have an estimated malignancy risk of less than 1%, while category 3 carries a 1% to 2% risk. Category 4A nodules are associated with a 5% to 15% estimated risk of malignancy, and categories 4B or 4X with a greater than 15% likelihood of malignancy.27
The Mayo Clinic model
The Mayo Clinic model uses a logistical regression model based on 6 independent predictors of lung malignancy (age, nodule diameter, smoking history, previous extrathoracic cancer diagnosis ≥ 5 years ago, upper lobe location, and presence of spiculation). It categorizes patients as being at low (< 5%), intermediate (5% to 65%), or high risk (> 65%) of malignancy.17,28
The model was first established by Swensen et al29 for solitary pulmonary nodules, and was based on a retrospective cohort study of 419 patients of Mayo Clinic with solitary pulmonary nodules measuring from 4 to 30 mm incidentally discovered by chest radiography between 1984 and 1986. Despite adequate validation, a meta-analysis by Papalampidou et al28 found that the model may be less accurate in Asian populations, likely due to higher tuberculosis prevalence, which limits diagnostic accuracy.
The Brock University model
The Brock University model also uses a logistic regression model to estimate the pretest probability that a nodule is malignant. Developed and validated in lung cancer screening–eligible populations through the Pan-Canadian Early Detection of Lung Cancer Study and the National Lung Screening Trial, respectively, it has been adopted by the British Thoracic Society in clinical practice.13,30
The most distinctive predictor in the Brock model is nodule size (diameter); other factors are age, sex, family history of lung cancer, emphysema, nodule size, upper lobe nodule location, nodule type, nodule count, and spiculation.
Overall, the Brock model is best suited for smaller (≤ 15 mm) subsolid nodules and performs less well with solid tumors and in Asian populations, who have a higher prevalence of tuberculosis and in whom this model’s emphasis on upper lobe location confers falsely higher risk.31,32
The Herder model
The Herder model is effectively the Mayo model with the added input of fluorodeoxyglucose uptake on positron emission tomography (PET)-CT. Risk of malignancy is categorized as less than 10%, 10% to 70%, and more than 70%. In a study comparing the Mayo, Brock, and Herder models, the Herder model was more reliable than the others for predicting malignancy in patients with solid pulmonary nodules.32
DIAGNOSTIC APPROACH AND MANAGEMENT STRATEGIES
Serial imaging
Low-dose CT overtook plain radiography in 2013 for lung cancer screening, following the landmark National Lung Screening Trial2 findings that showed a 20% relative reduction in lung cancer–related mortality. The USPSTF currently issues a grade B recommendation for annual screening via low-dose CT for patients age 50 to 80 with a 20-pack-year history or greater who are current smokers or who have quit within the past 15 years.3 Beyond initial screening, low-dose CT with thin sections (≤ 1.5 mm) is also the standard modality for surveilling nodules, as this helps to reduce cumulative radiation exposure by nearly 60% to 80% of the total dose of regular CT.12
PET-CT uses fluorodeoxyglucose, an analogue of glucose that is absorbed preferentially into tissue with high glucose metabolism (Figure 2F). Absorption is expressed numerically as a standardized uptake value (SUV), with emphasis on the region of highest metabolic activity within a nodule, known as SUVmax. The likelihood of malignancy increases with higher SUVmax values, but there is insufficient evidence to standardize numerical risk.33
PET imaging is limited by its susceptibility to both false-positive and false-negative results. Factors associated with false-negative results include small nodule size (< 8 mm), carcinoid tumors, and subsolid nodules. False positives are common for infectious or inflammatory lesions, rheumatoid nodules, and sarcoidosis.10
Tissue sampling
The 2 main strategies to sample pulmonary nodules are navigational bronchoscopy and transthoracic needle biopsy. Navigational bronchoscopies are performed under general anesthesia, while transthoracic biopsies are performed with local anesthetics. In cases in which the diagnostic probability of cancer is near 100%, surgical resection by wedge biopsy or segmentectomy is also an option for patients at higher risk in order to avoid unnecessary diagnostic delays and the risk of false-negative biopsies.24
Historically, transthoracic needle biopsy was preferred for peripherally located nodules because of higher diagnostic yield, whereas navigational bronchoscopy was reserved for more centrally located lesions. More recently, the VERITAS (Navigation Endoscopy to Reach Indeterminate Lung Nodules Versus Trans-Thoracic Needle Aspiration) trial34 showed navigational bronchoscopy was noninferior to transthoracic biopsy in diagnostic accuracy for peripheral nodules as small as 10 mm, with a more favorable safety profile.
CT-guided transthoracic needle biopsy costs on average $1,694 less than bronchoscopy.35 However, it is disproportionately affected by complications, with pneumothorax occurring approximately 25% more frequently and nearly 7% of transthoracic needle biopsy–related complications requiring hospitalization within 1 week.34–36 Navigational bronchoscopy also uniquely allows for simultaneous ancillary bronchoscopy-mediated procedures such as staging via endobronchial ultrasonography.
Applying guidelines to management
Guideline-directed pulmonary nodule management begins with screening eligible patients for lung cancer. Nationally, fewer than 1 in 5 eligible patients are up to date with lung cancer screening.37
Once a pulmonary nodule is identified, whether from screening or incidentally, primary care physicians should perform a targeted evaluation of both patient-specific and nodule-specific risk factors. These attributes guide 3 fundamental decisions: whether surveillance is warranted, which imaging modality and timing are most appropriate, and when referral is indicated.
Figure 3 provides a framework for primary care physicians to integrate the collected information and address each fundamental question in accordance with the 2017 Fleischner Society guidelines.22,23 In applying this framework, clinicians should also consider patient preferences, values, and comorbidities when discussing follow-up. Patients of advanced age, with life-limiting comorbid conditions, or who would decline cancer-directed therapy may experience greater potential harm than benefit from frequent surveillance or invasive testing.
Pathway for follow-up vs referral of a pulmonary nodule.22,23 This algorithm is not intended for patients with history of prior malignancy or known immunosuppression or younger than 35 years.
aRisk assessment relies on clinical judgment. High-risk features include older age, significant smoking history, family history of lung cancer, exposure to inhaled environmental carcinogens (eg, asbestos, radon), upper lobe location, and irregular or spiculated nodule borders. Low-risk features include younger age, minimal smoking history, smooth margins, and non–upper lobe location.
bAlthough follow-up imaging is not required, a computed tomography (CT) scan of the chest at 12 months may be considered for patient reassurance due to potential psychological distress.
cGrowth ≥ 1.5 mm on surveillance imaging is considered significant regardless of initial size and warrants referral. Development of a solid component in a ground-glass nodule is also considered significant growth and warrants referral.
dIf specialist evaluation is anticipated to be delayed beyond 3 months from the original image, a 3-month interval CT scan should be completed.
eNodule size is based on the solid component. Ground-glass components are not included for part-solid pulmonary nodules when determining the need for surveillance.
fReferral to a multidisciplinary pulmonary nodule clinic is preferred; however, a pulmonary referral is acceptable if such resources are unavailable.
Management should remain dynamic: changes in nodule size or morphology necessitate reevaluation and adjustment of the care plan. When referral is indicated, a multidisciplinary nodule clinic is preferred if available, though referral to pulmonary medicine may also be appropriate—local resources and expertise may guide diagnostic options. The burden of tissue acquisition decisions should not be placed on the primary physician. While not all patients require biopsy, when it is indicated, navigational biopsy should be considered given its favorable safety profile and diagnostic efficacy.
By following these principles, primary care clinicians can play a pivotal role in early detection and safe, evidence-based management of pulmonary nodules.
DISCLOSURES
The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
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