A pulmonary nodule is a discrete, well-marginated, round opacity whose maximum diameter is equal to or less than 3 cm. Lesions with a diameter greater than 3 cm are generally defined as masses [1].
With the increasing number of CT scans performed in daily practice, pulmonary nodules currently represent a common incidental finding, with highly variable percentages among the different studies (from 8% up to 51% of CT examinations); when identified, the vast majority of these lesions measure less than 5 mm in maximum diameter and are associated with a relatively low malignancy rate (1-12% according to several studies) [2,3].
In order to guarantee the most accurate detection and characterization of pulmonary nodules, every chest CT scan needs to be reconstructed and visualized with contiguous thin slices (usually 1.0 mm, at most 1.5 mm), in the axial, coronal and sagittal planes [2].
The application of specific reconstruction algorithms such as maximum intensity projection (MIP) has shown a statistically significant improvement in the detection of small pulmonary nodules (<5 mm), compared with standard axial images [4].
RISK ASSESSMENT OF MALIGNANCY
In the case of incidental detection of an undetermined pulmonary nodule, it is important to consider the individual patient’s risk factors and the specific features of the lesion identified at imaging.
Nodules with benign features should be ignored: due to the lack of clinical relevance, further follow-up would imply only an inappropriate radiation exposure and an unnecessary expense, with no significant benefit for the patient.
On the other hand, nodules with non-univocal features should be further investigated through CT follow-up after a certain time interval.
Finally, nodules with more suspicious characteristics need further evaluation by using other non-invasive or invasive techniques, such as contrast-enhanced CT, positron emission tomography-computed tomography (PET-CT), biopsy, open surgery or video-assisted thoracoscopic surgery (VATS).
INDIVIDUAL RISK FACTORS
The personal history of every patient examined should be carefully investigated in order to identify potential risk factors for the development of lung cancer. The main categories of risk include:
Age and Sex
Lung cancer has a very low incidence in younger individuals, while it becomes progressively more frequent with aging, with a peak incidence around the sixth decade [2].
According to some studies, females have a slightly higher risk of lung cancer compared to males [2].
Genetics
The incidence of lung cancer is significantly higher in some specific populations; particularly, black and native Hawaiian individuals have shown to be more frequently affected, compared to white subjects [2].
A personal and family history of pulmonary and non-pulmonary malignancy is another potential indicator of genetic predisposition. Several studies estimated that a family history of lung cancer is associated with a 1.5-1.8 times increased relative risk, regardless of smoking habit or other environmental factors [2].
Environment
Obviously, cigarette smoking is the most consolidated and well-known risk factor for pulmonary malignancy; a personal smoking history equal to or greater than 30 pack-years is associated with a noticeable increase in incidence, compared to non-smokers (between 10 and 35 times according to the literature) [2]. Importantly, smoking represents a major determinant for specific histological types (small cell or squamous cell carcinomas), while its association with adenocarcinoma is not clearly demonstrated [2].
Abstinence from smoking for at least 15 years has shown to completely resolve the induced risk [2].
It should be stressed that passive smoking has been repeatedly identified as an important risk factor as well, although with less relevance compared to primary smoking [2].
Apart from tobacco smoke, the exposure to many other inhaled agents may represent an important risk for malignancy; the most common carcinogens include asbestos, uranium or radon [2].
Chronic pulmonary diseases
Among this wide spectrum of diseases, pulmonary emphysema is the most common to have shown a clear relationship with lung cancer development; specifically, the increasing severity of centrilobular emphysema correlates with an increasing risk for lung malignancy. Another important condition is the idiopathic pulmonary fibrosis (IPF); importantly, the combination of IPF and emphysema increases the risk of developing lung cancer in comparison with emphysema alone.
After a comprehensive assessment of potential risk factors for malignancy, an individual profile is obtained for each subject, discerning between low-risk patients and high-risk patients. A typical example of a low-risk patient might be a young individual with no personal history of smoking or chronic pulmonary disease and no family history of malignancy; conversely, an older patient with a long-time smoking habit, affected by pulmonary emphysema and with a family history of lung malignancy should definitely be classified as high-risk.
CT FEATURES
Once a pulmonary nodule is identified at chest CT, its specific characteristics need to be analyzed in order to assess its potential malignant nature. Key features that should always be identified are:
Dimensions and Growth Rate
The nodule size represents a dominant factor in the evaluation of each lesion; in fact, the most recent guidelines for patient management consider the maximum diameter as one of the fundamental features to consider for a final decision [5-7]. Previous studies conducted on large population samples have widely demonstrated the relationship between nodule dimensions and the chance of malignancy. The results indicate that the probability of malignant evolution is negligible for very small nodules, with <1% risk for lesions with diameter <4 mm. The probability progressively rises with the increase in nodule size (up to >25% for lesions with a diameter >8 mm) [2].
The increase in nodule size over time represents one of the strongest indicators of malignant disease. The rates at which the nodules grow vary widely according to lesion histology and density pattern [2]. The most important parameter for assessing the evolution of a nodule over time is its volume doubling time (VDT): this is about 150 days (100-400 days) for solid nodules and usually longer for sub-solid nodules, with pure ground-glass lesions showing a VDT of over 800 days and heterogeneous partly solid nodules an intermediate value (more than 450 days) [2].
It should be also considered that malignant nodules generally show a more rapid growth rate in smokers compared to non-smokers [2].
In consideration of these highly variable intervals of time, the follow-up periods must be carefully planned bearing in mind the need to minimize unnecessary CT scans and inappropriate radiation exposure, while making sure that any abnormal growth is detected by follow-up and no progression of tumor stage is missed before the actual diagnosis [2].
Margins
Lesion margins are another fundamental indicator of potential malignant disease. Nodules with smooth and regular margins are more likely to be benign (unless they are early metastatic lesions); lobulated/scalloped margins correspond to an intermediate risk profile; spiculated margins (“corona radiata sign”) represent a suspicious feature that is strongly associated with malignancy [2].
Shape
Polygonal, ovoid or flat morphology is an indicator of benignity, while an irregular and asymmetrical shape may indicate a malignant lesion [2].
Position
A subpleural location has been associated with benignity, while nodules in the upper lobes showed a greater chance of malignancy, in particular if located in the right lung. The peculiar location of a lesion might also be an indicator for a specific histologic type, since squamous cell and small-cell cancers are generally located in hilar or peri-hilar regions, while adenocarcinomas and metastases tend to have a more peripheral distribution [2].
Density
Solid pulmonary nodules have a relatively low prevalence of malignancy (overall only about 7%), whereas pure ground-glass nodules are associated with a higher risk (about 18% prevalence). This percentage shows a considerable further increase in the case of partly solid nodules: heterogeneous lesions with a solid component within the ground-glass opacity are associated with a prevalence of malignancy over 60% [2].
This increasing risk may be explained by the fact that the presence of a partial or complete ground-glass component opens up to a wide range of differential diagnoses, including bronchioloalveolar carcinoma, adenocarcinoma, atypical adenomatous hyperplasia, infection, or focal area of fibrosis [2].
Calcifications
The presence of calcifications within a pulmonary lesion is generally considered an indicator for benignity, since it is a common feature of hamartomas, chronic inflammatory fibrous nodules or granulomas. Several patterns of calcification have been described, including diffuse, central, popcorn and laminated [8]. However, certain types of primary malignancies may cause pulmonary metastasis with calcifications: the most common are osteosarcoma, chondrosarcoma, some intestinal tumors, and thyroid tumors; moreover, in patients with prior chemotherapy, nodules with malignant features may present with calcifications [2,8].
GUIDELINES IN THE MANAGEMENT OF PATIENTS WITH PULMONARY NODULES
SINGLE PULMONARY NODULES
Because of the considerable rise in pulmonary nodule detection as a consequence of the extensive use of chest CT in clinical routine practice, previous guidelines recommended a close follow-up of all incidental lesions, irrespective of individual risk factors and imaging features. The most common protocol consisted of repeating the CT examination at 3, 6, 12, 18 and 24 months. Clearly, this initial approach implied a considerable exposure to unnecessary radiation and an increase in overall clinical costs [2].
Subsequent studies highlighted the need for more appropriate protocols for patient management, and the main current guidelines have been formulated taking into account both the patient’s individual risk factors and the main imaging features of each nodule (in particular density and dimensions) [2].
After the initial guidelines published in 2005 [5], the Fleischner Society released updated recommendations in 2017, optimizing the management of patients with pulmonary nodules in consideration of more recent epidemiologic data [6]. Two major changes have been applied in this new version [6]:
- A reduced number of CT examinations are recommended during the follow-up period;
- The minimum diameter indicated for starting follow-up of a nodule has been raised from 4 mm to 6 mm.
The American College of Chest Physicians (ACCP) also published its own recommendations for the management of patients with pulmonary nodules (updated in 2013). These guidelines mainly consider the pretest probability of malignancy and nodule size [2,7].
However, it should always be remembered that both guidelines are meant to help clinicians in the management of an average patient with incidental and undetermined pulmonary nodules and therefore their approach is not rigid but open to being adapted to the individual case. For example, patients with known or suspected primary cancer with a potential for lung metastasis should be followed up according to the protocol in place for their primary malignancy. Similarly, patients with fever of unknown origin could benefit from short-time follow-up or other options, since a pulmonary nodule might be the result of an active infection. Another case concerns younger patients: due to the relatively low incidence of lung cancer among <35-year-old subjects and the higher impact of radiation exposure, the usual protocols requiring multiple CT follow-up scans should be omitted unless a known primary malignancy is present. Instead, a single low-dose CT follow-up scan 6-12 months after the first examination should be preferred [2].
SOLID PULMONARY NODULES
The absence of any changes in nodule dimension for a period of 2 years is an indicator of benign disease and thus no further follow-up is recommended beyond this period of time [9,10].
On the contrary, lesions with an evident growth during this period should be addressed by biopsy, if not specifically contraindicated, in order to obtain a histological diagnosis [2].
PET-CT is a less invasive alternative that may reduce the need for biopsy in the case of non-enhancing solid nodules [2]. This technique proved to be reliable for solid nodules between 1 cm and 3 cm in diameter, with high sensitivity and specificity rates [2]. Causes of false-positive results at PET-CT include foci of active inflammation due to the relatively high glucose metabolism, while false-negative findings tend to be malignancies with low glucose metabolism, such as low-grade adenocarcinoma or carcinoid [2].
Fleischner Society Guidelines
The classical setting of the Fleischner Society guidelines requires a first discrimination between low-risk and high-risk patients, taking into account individual risk factors. The two categories follow different pathways for clinical management, with high-risk patients having more intensive and prolonged imaging surveillance over time.
Overall, nodules with a diameter shorter than 6 mm do not need any further diagnostic assessment, unless risk factors are present in the personal history or at imaging; nodules ranging between 6 and 8 mm usually require one or more CT scans at predetermined intervals. Nodules greater than 8 mm are generally managed with CT, PET/CT or biopsy.
The specific recommendations can be consulted in the original 2017 guidelines (https://pubs.rsna.org/doi/10.1148/radiol.2017161659) [6].
American College of Chest Physicians Guidelines
The recommendations of the American College of Chest Physicians start from an initial differentiation based on nodule size (≤8 mm or >8 mm). Management then depends on the pretest likelihood of malignancy, as assessed qualitatively based on clinical judgment and/or quantitatively using a validated model. The specific recommendations are summarized in Table 1 [2,7].
Table 1. American College of Chest Physician Guidelines (2013) for the follow-up of patients with a solid solitary pulmonary nodule [2,7]
| SOLID NODULES ≤8 mm | |
| Nodule dimension | Management |
| <4 mm | No follow-up required |
| 4-6 mm | CT follow-up at 12 months; no additional follow-up if unchanged |
| 6-8 mm | CT follow-up at 6-12 months, then CT at 18-24 months |
| SOLID NODULES >8 mm | |
| Pretest probability | Management |
| Low probability (<5%) | CT follow-up at 3-6 months, 9-12 months and 18-24 months |
| Intermediate probability (5-65%) | Functional imaging (preferably with PET scan) for characterization |
| High probability (>65%) | Pre-surgery biopsy (open or VATS); no additional examinations are needed |
CT: computed tomography; PET: positron emission tomography; VATS: video-assisted thoracoscopic surgery
SUBSOLID PULMONARY NODULES
Subsolid nodules usually have a longer VDT compared with solid lesions. For this reason, the current guidelines recommend a longer follow-up period, which has been extended to 5 years.
The lesions may, however, have a different evolution, with a variable profile of aggressiveness [11-13]. In particular, pure ground-glass nodules tend to be the result of an inflammatory process and thus spontaneously resolve over time; conversely, heterogeneous partly solid nodules are more suspicious lesions with a higher malignancy rate. For this reason, both guidelines base their recommendation on the specific composition of each nodule [2].
Fleischner Society Guidelines
As previously mentioned, the Fleischner Society guidelines start from the actual composition of the subsolid nodule; subsequent recommendations depend on nodule dimensions.
Overall, both pure ground-glass or partly solid nodules with a diameter shorter than 6 mm do not need any further diagnostic assessment, unless risk factors are present in the personal history or at imaging. Nodules greater than 6 mm usually require additional CT follow-up scans at predetermined intervals, which should be closer in the case of partly solid nodules.
The specific recommendations can be consulted in the original 2017 guidelines (https://pubs.rsna.org/doi/10.1148/radiol.2017161659) [6].
American College of Chest Physicians Guidelines
Similarly, the American College of Chest Physicians guidelines start from the composition of subsolid nodules, and then structure their recommendations according to nodule dimensions (Table 2).
Table 2. American College of Chest Physician Guidelines (2013) for the follow-up of patients with a subsolid solitary pulmonary nodule [2,7]
| PURE GROUND-GLASS | |
| Nodule dimension | Management |
| <5 mm | No follow-up required |
| >5 mm | CT follow-up every 12 months for at least 3 years |
| >10 mm | Early CT follow-up at 3 months may be useful; then, CT follow-up every 12 months for at least 3 years |
| PARTLY SOLID | |
| Nodule dimension | Management |
| <8 mm | CT at 3, 12 and 24 months, followed by annual surveillance for additional 1-3 years |
| >8 mm | CT at 3 months, followed by PET, nonsurgical biopsy, and/or surgical resection in case of nodule persistence |
CT: computed tomography; PET: positron emission tomography
MULTIPLE PULMONARY NODULES
Multiple pulmonary nodules can be the manifestation of a wide range of different diseases, including lung malignancy [14].
As seen for single nodules, the Fleischner Society guidelines base their recommendations for multiple nodules on the evaluation of individual risk factors and imaging features (mainly density and dimensions). However, in this case, the clinical decision should be guided by the nodule with more suspicious characteristics [2,6].
Overall, multiple solid nodules with a diameter shorter than 6 mm do not need any further diagnostic assessment, even though an optional CT follow-up examination could be considered in high-risk patients. Nodules greater than 6 mm usually require additional CT follow-up scans at predetermined intervals. In the case of multiple subsolid nodules, more CT follow-up examinations are always recommended. Nodules greater than 6 mm could require further investigation.
The specific recommendations can be consulted in the original 2017 guidelines (https://pubs.rsna.org/doi/10.1148/radiol.2017161659) [6].
CT examination is particularly helpful in the evaluation of patients with multiple nodules since it allows the detection of several diagnostic characteristics. One of the most important aspects in this setting is the anatomical distribution of the lesions, which may guide the clinician through a wide range of differential diagnoses [15]. Classically, taking into account the anatomical architecture of the secondary pulmonary lobule, three main patterns of distribution have been described [2]:
- Perilymphatic: pulmonary nodules are localized on the peri-broncho-vascular interstitium, the interlobular septa and subpleural regions. This pattern is the result of the involvement of pulmonary lymphatics within interstitial structures; it may be associated with different conditions such as sarcoidosis, silicosis, pneumoconiosis, lymphangitic spread of tumors or lymphoproliferative disorders.
- Centrilobular: pulmonary nodules are localized roughly at the center of the secondary lobule, sparing the pleural surface, fissures and interlobular septa. Centrilobular nodules may be the expression of either interstitial or airspace disorders: they are typically seen in hypersensitivity pneumonitis, respiratory bronchiolitis, infectious airway diseases (endobronchial spread of tuberculosis or non-tuberculous mycobacteria, bronchopneumonia). Though uncommonly, they may be found in bronchioloalveolar carcinoma, pulmonary edema and vasculitis.
- Random: pulmonary nodules are scattered across the whole secondary lobule irrespective of its components; for this reason, they simultaneously involve the interstitial structures and the centrilobular areas. Lung involvement is usually bilateral and symmetrical. Random distribution is common in patients with miliary tuberculosis, miliary fungal infections and hematogenous metastasis.
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