Published: May 2014
Pulmonary nodules are small, focal, radiographic opacities that may be solitary or multiple. A classic solitary pulmonary nodule (SPN) is a single, spherical, well-circumscribed, radiographic opacity measuring less than or equal to 30 mm in diameter and is surrounded completely by aerated lung.1 The SPN is a coined term that in the past described solitary nodules detected incidentally by chest radiography (CXR).2 Today, most nodules are detected by computed tomography (CT). The detailed CT images frequently identify more than one nodule, or enlarged lymph nodes. The term "solitary" should not be used in these circumstances. The term "coin lesion" should also be discouraged because nodules are spherical and not coin shaped.1 Indeterminate nodules are those that do not possess features clearly associated with a benign etiology, such as a benign pattern of calcification or stability on imaging for >2 years.1
Pulmonary lesions greater than 30 mm in diameter should be called masses rather than nodules. Masses have a high probability of being malignant.3 Subcentimeter nodules are less than 10 mm in diameter and are much less likely to be malignant.4 Subsolid nodules include pure ground-glass nodules (GGNs) and part-solid nodules.5 GGNs are defined as focal nodular areas of increased lung attenuation through which normal parenchyma structures such as airways, vessels, and interlobular septa can be visualized.5 Since first reported in 1996, it has become increasingly recognized that GGNs frequently represent adenocarcinomas or their precursors.
The widespread use of chest imaging has led to the detection of many pulmonary lesions. The American College of Chest Physicians (ACCP) does not recommend distinguishing between nodules detected by CXR versus CT. The goal in managing patients with pulmonary nodules is to distinguish between benign and malignant nodules, expediting diagnosis for malignant nodules while minimizing testing of those that are benign.
The prevalence of pulmonary nodules varies significantly across studies. This variation stems from the inconsistency among studies in method, enrolled population, and reporting results.6 Most lung nodules are detected incidentally on CXR or CT scans obtained for other purposes. It is estimated that 0.09% to 0.2% of all CXR scans will incidentally detect pulmonary nodules.7 In CT angiograms obtained to diagnose pulmonary embolism, a study reports 13% of cases to have incidental findings of pulmonary nodules.8 In another cohort study, 31% of patients undergoing cardiac CT scans for coronary calcium scoring have incidental findings of pulmonary nodules.9
In lung cancer screening trials, 7% of CXR scans obtained from previously healthy individuals contain pulmonary nodules.6 CT scans to screen for lung cancer detect nodules in 8% to 51% of individuals screened.6 Given the findings from the National Lung Screening Trial, the use of low-dose CT scanning as a screening tool for lung cancer is expected to increase, leading to the discovery of many pulmonary nodules.10
The primary concern when evaluating someone with a pulmonary nodule is that it could represent bronchogenic carcinoma. The differential diagnosis of lung nodules includes many benign diseases. Benign etiologies of pulmonary nodules include healed or nonspecific granulomas and active granulomatous infections, which account for 25% and 15% of all benign causes, respectively.1 Active granulomatous infections include tuberculosis, coccidioidomycosis, histoplasmosis, cryptococcus, and aspergillosis. Hamartomas comprise an additional 15% of benign lesions.1 Other benign causes include nonspecific inflammation and fibrosis, lung abscesses, round atelectasis, bronchogenic cysts, healed pulmonary infarcts, focal hemorrhage, hemangiomas, and arteriovenous malformations.1
The prevalence of malignancy in patients with pulmonary nodules ranges from 1.1% to 12%.6 This rate depends on the nodule characteristics and the population at risk. Most malignant pulmonary nodules are adenocarcinoma (47%), squamous cell carcinoma (22%), solitary metastasis (8%), and small cell lung cancer (4%).1 Other less common causes of malignant lung nodules include: large cell carcinoma, carcinoid tumors, lymphomas, adenosquamous carcinoma, adenoid cystic carcinoma, and malignant teratomas (Table 1).1
|Nonspecific granuloma (15%-25%)||Adenocarcinoma (47%)|
|Harmatoma (15%)||Squamous cell carcinoma (22%)|
|Infectious granuloma (15%)
Small cell lung carcinoma (4%)
|Others: lung abscess, round pneumonia, bronchogenic cysts, focal hemorrhage, hemangiomas, AVMs||Others: large cell carcinoma, carcinoid tumors, lymphomas, malignant teratomas|
Traditionally, established historical and radiographic criteria are used to estimate the probability that a pulmonary nodule is malignant. If this probability is quite low, observation is chosen as the course to follow. If this probability is quite high, immediate surgical resection is indicated. Most pulmonary nodules lie somewhere between these extremes and are said to be indeterminate, requiring further evaluation. Traditional nodule evaluation is most relevant for solid nodules 1 cm or larger in size. The evaluation of subcentimeter and semi-solid nodules has evolved more recently. In considering these issues, this chapter will review the established clinical and radiographic criteria used to estimate the probability of malignancy in solid pulmonary nodules, current invasive and noninvasive methods of evaluating them, their respective test characteristics, and how test results influence the probability of malignancy. Separately, we will discuss some of the unique considerations in the evaluation of subcentimeter and semi-solid nodules. Finally, management guidelines for pulmonary nodules will be summarized.
Clinical features which are independent predictors of malignancy include age, tobacco smoking status, and the history of a prior malignancy (Table 2).11 The probability of malignancy in a pulmonary nodule is directly related to the individual's age. The calculated likelihood ratio (LR) for malignancy in a lung nodule in individuals under age 30 is 0.05 and is 4.16 to 5.7 for those over age 70.12,13 Cigarette smoking has long been recognized as a risk factor for lung cancer. In a never smoker, the LR for malignancy in a lung nodule is 0.15 to 0.19.12,13 This LR increases as the number of cigarettes smoked increases and decreases with an increased duration of smoking abstinence. Cigar smoking is also an independent risk factor for lung cancer.14 A history of a prior malignancy (>5 years ago) in an individual with a pulmonary nodule is a predictor of malignancy, with LRs for malignancy ranging from 3.82 to 4.95.11
|Age <30 years old in a lifelong nonsmoker
Benign pattern of calcification on radiographic study
Absence of an increase in nodule size for a period of 2 years
|Diameter of nodule >3 cm|
The presence of moderate or severe obstructive lung disease and exposure to fine particulates or sulfur oxide-related pollution are also risk factors for lung cancer.15,16 These risk factors are less well established as independent predictors of malignancy in a lung nodule.
|Clinical/Radiographic Features||Likelihood Ratio*|
|History of other malignancy||3.82-4.95|
|Benign pattern||Near 0|
|Growth <7 days||Near 0|
|No growth >465 days||Near 0|
|Cavity wall thickness|
* The positive likelihood ratio is the ratio of the true positive fraction to the false positive fraction (sensitivity/(1 – specificity) ). It expresses the relative likelihood that a given characteristic (e.g., smoking) or test result would be in a patient with, as opposed to one without, the disorder (e.g., lung cancer). A very high LR rules in a disease, and a very low LR rules out a disease. An LR of 1 means that the posttest probability is identical to the pretest probability.60
Calcification in a pulmonary nodule typically indicates benign disease. Benign nodules often contain dense, central, laminated, popcorn, and punctate patterns of calcification. Malignant pulmonary nodules can also have a calcified appearance. However, these are typically small and contain central niduses with speckled patterns, or eccentric punctate foci (Figure 1 (A - D)59. Since the patterns of calcification typically do not overlap, a benign pattern is one of the few radiographic features that justify a decision that no further evaluation of the lung nodule is warranted. The calculated LR for malignancy in a pulmonary nodule with a benign pattern of calcification approaches 0.12 While benign patterns of calcification can be highly specific for the absence of malignancy, CXR is not a perfect tool for detecting calcification, with a sensitivity of 50% and a specificity of 87%.17 CT has a higher sensitivity for calcification compared with CXR.
The size of a pulmonary nodule influences the probability of malignancy. Benign lesions are smaller overall than malignant ones. As the lesion increases in size, its probability of being malignant increases. The prevalence of malignancy is 0% to 1% for nodules <5 mm, 6% to 28% for nodules 5 to 10 mm, and 64% to 82% for nodules >20 mm in diameter.6 For nodules more than 3 cm in diameter, 93% to 97% are malignant.18,19 Given the high likelihood of malignancy in lesions >3 cm (masses), they are considered malignant unless proven otherwise. The LRs for lesions less than 1 cm and more than 3 cm are 0.5 and 5.2, respectively.12
The growth rate of a pulmonary nodule also has predictive value for benignity and malignancy. A very rapidly growing or very slowly growing pulmonary nodule suggests a benign etiology. The calculated LR for malignancy in a pulmonary nodule approaches 0 if growth is noted in fewer than 7 days, or if no growth is noted for 465 days.12 Thus, a very rapid growth rate or stability over a 2-year time period are accepted indicators of benignity.
The radiographic edge characteristics of a pulmonary nodule influence the probability of malignancy. Nodule edges can be smooth, lobulated, irregular, and spiculated based on CT appearance. Typically, benign nodules have well-defined borders while malignant nodules are irregular or elongated. However, one cannot use edge characteristics alone as an endpoint as there is much overlap. The LR for a smooth edge is 0.3, for a lobulated edge 0.74, and for an irregular or spiculated edge 5.54.12 A spiculated edge is an independent predictor of malignancy in a lung nodule.11
There are other characteristics which are less studied which also influence the probability of malignancy. The thickness of the wall of a cavitary pulmonary nodule is useful in predicting the likelihood of malignancy, with LRs of 0.07 for malignancy in those with cavity wall thickness ≤4 mm and 37.97 for those with wall thickness ≥16 mm. The location of the pulmonary nodule may affect the probability of malignancy. Upper or middle lobe pulmonary nodules have a LR for malignancy of 1.2 to 1.6.12 The upper lobe location has been shown to be an independent predictor of malignancy.11 Nodules meeting criteria for hamartomas (those with diameters of 2.5 cm or less, smooth edges, and focal collections of fat or fat alternating with areas of calcification) are also likely to be benign.
Once all established clinical and radiographic criteria are considered, a probability of malignancy can be estimated. For pulmonary nodules with a clinical and radiographic probability of malignancy between thresholds justifying follow-up with surveillance imaging and immediate resection, further evaluation is indicated. Noninvasive evaluation involves imaging, typically with positron emission tomography (PET). Invasive evaluation commonly includes flexible bronchoscopy (FB) and transthoracic needle aspiration (TTNA). Knowledge of the characteristics of these tests allows for their appropriate utilization.
Malignant cells have a relatively increased metabolism, leading to increased cellular uptake of both glucose and a glucose analog, 18-fluorodeoxyglucose (FDG), which can be imaged. FDG-PET as a diagnostic tool for malignancy has a sensitivity of 80% to 100% and specificity of 40% to 100%.6 The LR for malignancy given a positive test is 4.36 and for a negative test is 0.04.20 False positive test results are reported in benign nodules that are metabolically active such as active infectious or inflammatory lesions. False negative results occur in tumors with relatively low metabolic activity (e.g., adenocarcinoma in situ [AIS], carcinoids), and small tumors.
FB is commonly used in evaluating lung nodules. Factors that influence the diagnostic yield of FB include location (central vs. peripheral), lesion size, and the presence of a "bronchus sign" on CT. The "bronchus sign" on CT is present when a bronchus can be seen within or leading directly to the nodule, predicting a higher diagnostic yield from FB. Endoscopically visible nodules are also more likely to be diagnosed by FB. Other factors that influence the diagnostic yield of FB include nodule size (lower yield with smaller nodules), and nodule location (lower yield with nodules in the periphery or difficult to reach anatomic sites).
The sensitivity of standard bronchoscopy in diagnosing central bronchogenic carcinomas is excellent, at 88% based on pooled data from 1971 to 2004.21 For peripheral lung lesions, the sensitivity is lower, at 63% for those with diameters >2 cm and 34% for those with diameters <2 cm.21 Technologic advances have enhanced the performance of bronchoscopy for the evaluation of peripheral, smaller lung lesions difficult to sample via standard bronchoscopy. These advances include electromagnetic navigation bronchoscopy (ENB) and peripheral ultrasound, both tools capable of guiding biopsy instruments towards and localizing lung nodules.22 Peripheral radial probe endobronchial ultrasound (RP-EBUS) guided bronchoscopy has an overall sensitivity of 73% for identifying malignant lung lesions based on pooled data.23,24 ENB has an overall diagnostic yield of 67% for peripheral lung lesions.25 With the concomitant use of RP-EBUS to confirm lesion location, the yield has been reported to be as high as 88%.26 Finally, real-time virtual bronchoscopy using an ultrathin bronchoscope is used to improve yield for sampling small nodules, and has an overall yield of 72% based on pooled data.25 A meta-analysis of all guidance systems for sampling of peripheral lung nodules shows diagnostic yields of 60.9% and 82.5% for lesions ≤2 cm and >2 cm, respectively.25
TTNA is useful in determining the nature of the indeterminate pulmonary nodule. Imaging with CT or fluoroscopy is used to guide an aspiration or cutting needle into pulmonary nodules. The overall diagnostic yield for TTNA is 90% based on pooled data.6 Smaller nodule sizes and central locations lead to lower diagnostic rates. The use of TTNA has been shown to be cost effective, improve physician agreement, and reduce the number of unnecessary surgeries.27
Compared with FB, TTNA carries a higher rate of pneumothorax based on pooled data (1.5% versus 15%). The rate of pneumothorax requiring chest tube placement for FB is 0.6%, while that for TTNA is significantly higher at 6.6%.25,28 If an invasive test is deemed necessary, a choice between FB and TTNA must be made. In making this choice, one must consider the size and location of the nodule, the presence of a "bronchus sign," the known complications of the procedure, patient factors, and the presence of local experience with these procedures.29
Surgical evaluation of pulmonary nodules includes traditional thoracotomy and video-assisted thoracoscopic surgery (VATS) with lung resection. Traditional thoracotomy is usually limited to lesions with high likelihood of malignancy when lobectomy and nodal dissection are necessary for definitive lung cancer staging and treatment. VATS, typically performed by thoracic surgeons, can be both diagnostic and therapeutic. VATS is becoming more widely available. It is associated with decreased perioperative morbidity. Given the highly invasive nature of the procedure, leading to potential morbidity and mortality, surgical evaluation of pulmonary nodules is only warranted when the probability of cancer is very high, or moderately high and not accessible by other means.2
The goal of decision making for patients with pulmonary nodules is to expedite therapy of a potentially curable cancer while minimizing the number of benign nodules that are surgically removed. Decision analytic approaches make the decision process more scientific, typically determining a probability of malignancy through a Bayesian analysis of relevant clinical and radiographic variables. No single prediction model has been shown to be superior to an experienced clinicians' judgment or advanced imaging.30,31
When considering performing further noninvasive and/or invasive testing in assessing indeterminate pulmonary nodules, one must keep in mind the goal of testing. The probability of malignancy thresholds used to determine if observation alone or immediate resection is warranted depends on physician comfort, patient wishes, and patient co-morbidities. For the purposes of this discussion, we will use a pretest probability of malignancy of <10% as indicating observation, and one of >90% as indicating immediate surgery. Once the pre-test probability and management goals are clear, one can apply the test characteristics of an adjuvant test to calculate the post-test probability for malignancy, and tailor management strategies according to test results. For example, using the above listed test characteristics for FDG-PET imaging (LR+ = 4.36, LR- = 0.04), a positive test will lead to a post-test probability of malignancy of >90% only if the pre-test probability was >67%. Thus if the pre-test probability of malignancy is 50%, a positive FDG-PET scan will not prompt immediate surgical resection and further evaluation with FB or TTNA may be indicated. Similarly, a negative FDG-PET test will lead to a post-test probability of malignancy of <10% only if the pre-test probability was <73%. Thus, if the pre-test probability of malignancy was 80%, a negative FDG-PET scan would not permit observation and further evaluation with FB or TTNA may be indicated. Similar principles apply to pre-surgical invasive testing.
The ACCP evidence-based clinical practice guidelines outline a management algorithm for pulmonary nodules (Figures 2 and 3).1,2 Management strategies are based on the size of the nodules, categorized as subcentimeter or indeterminate nodules.
In every patient with a pulmonary nodule, it is recommended that clinicians review previous imaging for comparison. If there is no growth detected over a period of 2 years or more, no additional evaluation is needed. Nodules with benign patterns of calcification do not need additional evaluation. In patients with indeterminate nodules, it is recommended that clinicians estimate the pretest probability of malignancy either qualitatively by using clinical judgment or quantitatively by using a validated model. Those with a pre-test probability of malignancy of ≤5% are considered to be low risk, while those with ≥60% pre-test probability are considered high risk. Those in between these two spectrums (5%-60%) are considered intermediate risk.
For patients with low risk for cancer, observation with serial imaging is recommended. Observation is also recommended if the clinical probability is intermediate and FDG-PET is negative for hypermetabolic activity, or if needle biopsy is nondiagnostic and the lesion is not hypermetabolic by FDG-PET. The recommended intervals for serial imaging are at 3, 6, 12, and 24 months.
In patients with intermediate risk of malignancy (5%-60%), it is recommended that FDG-PET imaging be performed to further characterize the nodule. FDG-PET is discouraged in patients with high pre-test probability of malignancy (>60%) or in those with subcentimeter nodules that measures <10 mm. TTNA or FB is appropriate when the clinical pre-test probability and findings on imaging tests are discordant (i.e., when the pre-test probability is high and the lesion is not hypermetabolic by FDG-PET).
Surgical diagnosis is recommended when the pre-test probability is moderate to high (>60%) or when the nodule is hypermetabolic by FDG-PET. Thoracoscopy with wedge resection is recommended for indeterminate pulmonary nodules in the peripheral third of the lung. If there is evidence of malignancy by frozen section, systematic mediastinal lymph node sampling or dissection should be performed under the same anesthesia. In those judged to be marginal candidates for lobectomy, wedge resection/segmentectomy is recommended. External-beam radiation or clinical trial enrollment in experimental treatments such as stereotactic radiosurgery or radiofrequency ablation is recommended for those who have a malignant pulmonary nodule who are not surgical candidates based on co-morbidities.
Advances in chest imaging and the increased use of CT as a diagnostic modality have lead to incidental identification of many small pulmonary nodules. The vast majority of nodules detected on CT are subcentimeter based on early lung screening trials (61%-89%). The overwhelming majority of these are benign.32,33 The actual risk for malignancy in subcentimeter nodules is lower than the predicted risk based on clinical and radiographic criteria for pulmonary nodules. The Mayo Clinic CT Screening Trial reports 0% of nodules measuring <4 mm and 0.8% measuring between 4 and 7 mm in diameter are malignant.32 Another study reports 0% of nodules measuring <5 mm in diameter are malignant, while the rate is 5.9% of those measuring 5 to 9 mm in diameter.33
Subcentimeter nodules pose unique challenges in management because of their small size. Reports show that inter- and intra-observer agreement is poor not only in identification of the nodules, but also assessment of their sizes and growth rates.34,35 It is also more difficult to predict the probability of malignancy using nodule edge characteristics and shape. In addition, FDG-PET is less sensitive for identifying malignancy in subcentimeter nodules due to weak metabolic signals from small tumors. While no report has studied bronchoscopic diagnostic yield for subcentimeter nodules, TTNA is known to have lower diagnostic yield for subcentimeter nodules, with reported sensitivity of 50% for nodules measuring between 5 and 7 mm in diameter.36 Lastly, surgical evaluation is difficult. One study reports that 63% of subcentimeter nodules positioned more than 5 mm from the pleura are not found by VATS; this rate is 100% for those more than 10 mm from the pleura.37 Advances in imaging and biopsy technologies, as well as biomarker development, are being used to improve the evaluation of these nodules.
The ACCP and Fleischner Society offer management guidelines for patients with subcentimeter nodules.1,38 For patients with subcentimeter nodules, the presence of clinical risk factors for lung cancer, and the size of the nodule, helps to determine the frequency and duration of follow-up imaging. For those with no clinical risk factors for lung cancer with nodules ≤4 mm, no follow-up is needed. For those >4 to 6 mm, repeat imaging is recommended at 12 months and if no growth is detected, no addition follow-up is needed. For nodules >6 to 8 mm, follow-up between 6 and 12 months is recommended, and then again between 18 and 24 months if unchanged. For those with clinical risk factors for cancer (smoking history or other risks) the recommendations in each size category were the same as the low-risk group in the next size category up. For those with unequivocal evidence of growth during follow-up, tissue diagnosis with surgical resection, TTNA, or bronchoscopy is recommended. For those with multiple nodules, each nodule should be evaluated individually.
Advances in imaging have lead to the increased recognition of subsolid nodules. Ground-glass and part-solid nodules appear to have a higher risk for malignancy than pure solid nodules, while the malignancies that they represent tend to be more indolent than those that begin as solid nodules. Meta-analysis of subsolid nodules show that pure GGNs have a 59% to 73% risk for malignancy, while the risk is 7% to 9% for all solid pulmonary nodules.6 The differential diagnosis of GGNs includes focal inflammation, hemorrhage, edema, or fibrosis, atypical adenomatous hyperplasia (AAH), AIS, minimally invasive, and invasive adenocarcinoma. AAH and AIS are most likely to appear as pure GGNs. AIS with some alveolar collapse may appear as a part-solid nodule. AIS with active fibroblastic foci may have a ground-glass component in the periphery or appear entirely solid.39
Important predictors of malignancy include larger relative percentage of the solid portion of a part-solid nodule, larger size of both pure GGNs and part-solid nodules, and the presence of a lobulated border.40-42 An increase in size over time, the development of a solid component in a pure GGN, or an increase in the solid component of a part-solid nodule are also signs of malignancy.43 Growth rates can be very slow in malignancies represented by pure GGNs, with doubling times reported as long as 813 days.44 Features of GGNs that are more likely to resolve include younger age of the patient, detection of the GGN during a follow-up study, blood eosinophilia, lesion multiplicity, a large solid portion, ill-defined border, and polygonal shape.45-47
GGNs also impose unique challenges in management. First, the means of obtaining the CT image can influence the appearance of a GGN. Thick section imaging (e.g., 5 mm) may mistake solid nodules for GGNs, while low-dose tube currents hinder the ability to identify GGNs.48,49 Second, even in ideally imaged lungs, GGNs may be overlooked. Approximately 69% of lung cancers missed on CT screening are GGNs.50 Third, there is only a moderate degree of agreement in size measurements within and between reviewers, and even between separate scans performed the same day, leading to difficulties in evaluating growth rates.51,52 Fourth, adjunctive imaging and nonsurgical biopsies have lower yields than for solid nodules.53,54
Guidelines for management of GGNs have been suggested.5 Isolated pure GGNs <5 mm in diameter likely do not require follow-up though it is recognized that many of these are AAH. For pure GGNs 5 to 10 mm in diameter, confirmation of persistence in 3 to 6 months is suggested. It is recommended that persistent GGNs be followed serially rather than resected. Surveillance should persist for >2 years. Thin section CT should be performed for follow-up with any change in size or attenuation leading to resection. FDG-PET imaging should be discouraged. Core needle biopsy rather than aspiration is suggested when biopsy is deemed appropriate. Pure GGNs >10 mm in diameter should be resected if appropriate. FDG-PET and nonsurgical biopsy have limited value. Any part-solid nodule should receive further evaluation which may include FDG-PET, biopsy, and/or resection. Multiple GGNs should be followed with serial imaging unless there is a dominant nodule >10 mm in diameter, or a part-solid nodule. Sub-lobar resection should be considered when appropriate.
A few additional challenges and potential solutions exist. Despite management guidelines being present for several years, their acceptance into practice is varied. For instance, for the management of subcentimeter nodules, a survey of radiologists shows that 77.8% are aware of the guidelines, while 58.8% work in practices that use them.55 Another survey shows that only 27% of the responses to 13 clinical scenarios were appropriate based on Fleischner criteria.56 The detection of pulmonary nodules will likely increase as lung cancer screening programs are developed based on the findings of the National Lung Screening Trial. The effect of detecting pulmonary nodules on a patient's quality of life needs to be considered. In the NELSON lung cancer screening trial, those with an indeterminate result had a clinically relevant worsening of lung cancer specific distress.57 In a separate study, those with malignant nodules had poorer quality of life than those with benign nodules, and both groups had lower quality of life than the general population.58 Issues related to the evaluation of lung nodules may improve with technologic advances in imaging and molecular biomarker development. Computer-assisted detection and/or diagnosis systems are expected to assist in clinical decision making. Volumetric nodule measurements may improve intra- and inter-observer differences. Novel molecular biomarkers are being developed to recognize the presence of malignant nodules based on changes in the genome, transcriptome, proteome, and metabalome of their host. Accurate, validated, noninvasive, and inexpensive testing will help to advance our ability to manage patients with indeterminate lung nodules.