Incidental Pulmonary Nodules

Differential diagnosis and clinical management

Background: According to data from the USA, the incidence of incidentally discovered pulmonary nodules is 5.8 per 100 000 person-years for women and 5.2 per 100 000 person-years for men. Their management as recommended in the pertinent guidelines can substantially improve clinical outcomes. More than 95% of all pulmonary nodules revealed by computerized tomography (CT) are benign, but many cases are not managed in conformity with the guidelines. In this article, we summarize the appropriate clinical approach and provide an overview of the pertinent diagnostic studies and when they should be performed.

Methods: This review is based on relevant publications retrieved by a selective search in PubMed. The authors examined English-language recommendations issued since 2010 for the management of pulmonary nodules, supplemented by comments from the German lung cancer guideline.

Results: In general, the risk that an incidentally discovered pulmonary nodule is malignant is low but rises markedly with increasing size and the presence of risk factors. When such a nodule is detected, the further recommendation, depending on size, is either for follow-up examinations with chest CT or else for an extended evaluation with positron emission tomography-CT and biopsy for histology. The diagnostic evaluation should include consideration of any earlier imaging studies that may be available as an indication of possible growth over time. Single nodules measuring less than 6 mm, in patients with few or no risk factors, do not require any follow-up. Lung cancer is diagnosed in just under 10% of patients with a nodule measuring more than 8 mm.

Conclusion: The recommendations of the guidelines for the management of incidentally discovered pulmonary nodules are intended to prevent both over- and undertreatment. If a tumor is suspected, further care should be provided by an interdisciplinary team.

More than 1.5 million computerized tomographic (CT) scans of the chest and approximately 13 million chest X-rays are obtained in Germany each year, and incidental pulmonary nodules are commonly found (1).

The number of chest CTs can be expected to increase now that lung cancer screening is in process of being introduced in Germany (2). The proper management of pulmonary nodules, such as those detected by screening, can lower lung cancer mortality by 20% and enable a larger percentage of tumors to be detected in earlier stages while still amenable to curative treatment (3, 4). A retrospective analysis of routine health insurance data revealed that 18% of patients with pulmonary nodules underwent an excessive diagnostic evaluation (e.g., too many follow-up CT scans or multiple biopsies), while 27% had a less extensive evaluation than recommended in the guidelines. This might delay a diagnosis of cancer (5).

A pulmonary nodule is defined as a more or less round, well-demarcated lesion measuring up to 3 cm in diameter (6). There have been major changes in the diagnosis and treatment of pulmonary nodules since the publication of the last review in Deutsches Ärzteblatt International in 2000 (7). The present review concerns pulmonary nodules that have been detected incidentally on any type of imaging study; the data under discussion do not reflect any clinical experience with pulmonary nodules that were diagnosed in the context of the German lung cancer screening program, which is expected to begin soon.

Methods

Guidelines published from 2010 to 2020 that concern the management of pulmonary nodules were were retrieved by a search in PubMed. The pertinent recommendations issued by multiple specialty societies (eTable) contain detailed instructions for a rational, evidence-based diagnostic evaluation (6, 8−10). All guidelines are based on an assessment of the risk of cancer and provide recommendations for further action based on this risk. The Canadian publication by Lam et al. mentioned in the eTable (11) and the publication by the American College of Radiology (9) explicitly concern nodules that have been detected by screening. The Asian publication by Bai et al. (12) is of limited relevance to European populations because of ethnic differences in tumor biology and is not considered further here. Of the remaining guidelines, that of the Fleischner Society (6) is the most recent, and it is therefore summarized here in Tables 1 and 2.

eTable

Overview of international guidelines

There is no German guideline dedicated to the topic of pulmonary nodules. Instead, there is a chapter on pulmonary nodules in the German S3 guideline on the prevention, diagnosis, treatment, and follow-up of lung cancer. The recommendations there are based on those of the British Thoracic Society and the Fleischner Society.

Learning objectives

This article is intended to enable readers to know

• the important definitions and guidelines concerning pulmonary nodules,
• the procedure for a rapid initial assessment of pulmonary nodules, and
• the further diagnostic steps that should be taken.

Additional relevant comments from the German lung cancer guideline are mentioned separately in the text. This article does not apply to patients with an existing diagnosis of cancer, immunocompromised or immunosuppressed patients, those who underwent CT scanning as part of screening for lung cancer, or those with a pulmonary mass measuring more than 3 cm in diameter.

Epidemiology

95% of all pulmonary nodules detected by CT are benign (13). According to data from the USA, women have a slightly higher incidence of pulmonary nodules than men (5.8 versus 5.2 per 1000 person-years), and the incidence in both sexes increases with age (14). One or more pulmonary nodules are detected incidentally in up to 75% of all CT scans; more than 50% of all patients have two or more nodules (13). Primary CT diagnostic evaluation sometimes permits the diagnosis of a benign entity on morphological grounds: granulomas, for example, typically have central, laminar, and diffuse calcification patterns, while popcorn calcifications are pathognomonic for hamartoma (15). Sharply demarcated perifissural nodules are usually lymph nodes with a very low risk of malignancy (eFigure). Morphologically clearly benign findings are a special subgroup of pulmonary nodules that, in some situations, may not require any further diagnostic evaluation (13, 16, 17).

Figure

Further procedure after the detection of a pulmonary nodule

eFigure

Examples of pulmonary nodules of benign appearance on CT

Diagnostic work-up

An important part of the evaluation of newly detected nodules is to review the patient’s prior imaging studies, if any, to assess the temporal course of the lesion (18).

Pulmonary sections in CT images of the neck, heart, or abdomen may be useful in some cases. It is stated in the Fleischner guideline that, in selected patients with no more than a few risk factors (Table 3), nodules that have not changed in size in two years do not require any further follow-up. Pulmonary nodules that have been newly detected by x-ray should be followed up with a chest CT. If the nodule is the only indication for the CT, it should be performed without contrast (expert opinion) (6). CT images should be acquired in thin sections (< 1.5 mm) and reconstructed in coronal and sagittal views for precise characterization and measurement of the nodule(s) (18). Recommendations for the further evaluation of nodules whose nature remains unclear after CT depend on an assessment of the risk of malignancy (Figure, Box).

Box

A case from everyday clinical practice

Table 3

Risk assessment for patients with pulmonary nodules

Solid pulmonary nodules of diameter less than 8 mm

In the US National Lung Screening Trial, 26,309 people were examined with CT, and then with further diagnostic tests, depending on the CT findings. The positive predictive value (PPV) for cancer of nodules measuring less than 4 mm in diameter was 0% (19). (The PPV is the likelihood that a person with the positive finding in question will actually have the condition that is to be diagnosed.) The PPV rises with increasing nodule size (4–6 mm, 0.5%; 7–10 mm, 1.7%; 11–20 mm, 11.9%) (19). FDG-PET is of little use for the evaluation of nodules less than 8 mm in diameter, as this size is less than the spatial metabolic resolution of PET-CT scanners currently in use, although newer generations of scanners have a much finer resolution. According to the Fleischner guideline mentioned above, no further studies are needed for nodules that have not changed in size in two years in a patient with no more than a few risk factors. The patient should, however, be thoroughly informed of the risks and benefits of undergoing or not undergoing further evaluation (e.g., unnecessary radiation exposure through excessive follow-up scanning, interventional risk, worse outcomes due to delayed diagnosis of cancer) (6). In high-risk patients with a nodule smaller than 6 mm, a follow-up study in 12 months is recommended (Table 1) (6). If multiple nodules have been detected, the further procedure is based on the size of the largest one. Any nodule measuring 6 to 8 mm in diameter should be followed up with a further CT scan, with the interval between scans to be determined depending on the risk of malignancy. If a nodule is found to have increased in size, presentation to a specialized interdisciplinary team (e.g., a lung cancer center) should be considered.

Table 1

Recommendations concerning solid pulmonary nodules from the Fleischner guideline (modified from [6])

Solid pulmonary nodules measuring 8 to 30 mm

In a retrospective cohort study of over 23 000 persons with pulmonary nodules that were larger than 8 mm in diameter, nearly 10% were found to have lung cancer (20). The probability of a lung cancer diagnosis was affected by risk factors including nicotine abuse, age, and family history, as well as by morphological features of the nodule, such as its location, demarcation, and calcification (6). Further diagnostic evaluation is recommended, including FDG-PET-CT and the obtaining of a specimen for histopathological diagnosis by bronchoscopic or CT-guided puncture biopsy. Primary care physicians should refer patients with nodules of size 8 mm or more to a specialized interdisciplinary team, such as a lung cancer center, to ensure optimal management.

Subsolid pulmonary nodules

Subsolid nodules are defined as opacities in which the CT shows an increased density of low-density lung parenchyma, which, however, is not as high as the density of soft tissue, with vessels and bronchial walls visible within the opacity (21).

Subsolid nodules measuring less than 6 mm do not require routine follow-up. In cases with risk factors or suspicious morphology, the patient may be offered a follow-up CT scan in two years, although the risk of malignancy is less than 1% (22). Subsolid nodules larger than 6 mm in diameter should be followed up by CT in 3–12 months, depending on their morphology (Table 2). The higher the solid tissue content of a subsolid nodule, the greater the risk of malignancy (23, 24). Multiple subsolid nodules of diameter less than 6 mm are often of inflammatory origin; in such cases, imaging follow-up is recommended (6, 25). The management of multiple subsolid nodules is based on that of the largest and most prominent nodule.

Table 2

Recommendations concerning subsolid pulmonary nodules from the Fleischner guideline (modified from [6])

Risk assessment

Multiple models are available for assessing the risk associated with pulmonary nodules, including the Herder model, the Veterans Affairs (VA) model, the Brock University model, the Cleveland Clinic model, and the Mayo Clinic model. Alternatively, a clinical expert can be consulted (18). All of these models incorporate age and nicotine abuse as risk factors (Table 3); only a few of them also consider sex, nodule size, location in the upper lobe, and prior history of cancer. Many offer online risk-calculating algorithms. For a simple risk assessment, the Fleischner Society refers to the risk recommendations of the American College of Chest Physicians (6). The categorization is summarized in Table 2. Further risk factors such as a positive family history, genetic polymorphisms, exposure to ionizing radiation, mining work, and passive smoking are not incorporated in the models but may nevertheless be clinically relevant (26). In the authors’ everyday practice, the risk of cancer is generally assessed by the specialists of an interdisciplinary team (pulmonology, radiology, thoracic surgery) on the basis of their clinical experience. This approach is supported by scientific studies showing that clinical experts and radiologists perform comparably to a validated risk model (27, 28).

Further specialized interdisciplinary approach

Suspect findings are worked up by an interdisciplinary team (radiology, pulmonology, thoracic surgery) on the basis of the cancer risk, comorbidities, available diagnostic studies, and patient preference. Beyond the follow-up CT, the patient can be offered further clarification with FDG-PET-CT and a biopsy to obtain tissue for histopathological analysis. Central pulmonary nodules are biopsied via bronchoscopy, peripheral ones via navigated bronchoscopy or CT-guided fine-needle aspiration. In addition to the risk of cancer, the FDG-PET also displays any involvement of the thoracic lymph nodes and any distant metastases that may be present. The decision between bronchoscopy and CT-guided percutaneous fine-needle aspiration depends both on patient-specific factors—the site of the nodule and the patient’s comorbidities—and on the available clinical expertise. In a meta-analysis, transthoracic CT-guided percutaneous fine-needle aspiration had a higher diagnostic yield (93% [90–96%]) than bronchoscopy (75% [69–80%]), but also an increased risk of pneumothorax (26%) and bleeding (16%) (29). One advantage of bronchoscopy is that it enables not only a biopsy of the nodule itself, but also an endobronchial ultrasound-guided examination of the hilar and mediastinal lymph nodes (30). It is recommended in the guideline that staging for bronchial carcinoma should be completed with a contrast-enhanced magnetic resonance imaging (MRI) scan of the brain (31). If an interventional biopsy is not feasible or fails to yield a definitive diagnosis, the nodule can be resected in a minimally invasive surgical procedure once the staging is otherwise complete and as long as no prohibitive comorbidities are present. If a diagnosis of carcinoma is established, a lobectomy or a limited resection with systematic lymph node dissection is performed, depending on the size of the tumor. Surgery in a designated center is advantageous, as it is associated with lower postoperative mortality and better complication management (32).

Challenges and open questions

Routine clinical care that is not based on the recommendations found in published guidelines may lead to worse outcomes. In an American study of 197 patients with pulmonary nodules, 88 (44.7%) received a recommendation that did not conform to the guidelines, e.g., performance of the next imaging at an interval shorter or longer than recommended, interventional biopsy instead of CT follow-up, no radiological follow-up, or incorrect radiological follow-up; 17.8% of recommendations were excessive, and 26.9% were insufficient (5). Other studies confirm that the work-up of pulmonary nodules is often suboptimal in Europe as well (33, 34).

Some sites in the USA now offer nodule evaluation programs in which the patients’ radiological findings are searched electronically and evaluated by specialized personnel. The patients or their physicians are then contacted by trained staff members and advised about further management in conformity with the guidelines (35). One such program detected more cases of early lung cancer than a lung cancer screening program that was carried out simultaneously (35).

The guidelines of the Fleischner Society, the American College of Chest Physicians, and the British Thoracic Society are generally similar, with some notable differences. For instance, the Fleischner Society recommends axial measurement of the nodule in two planes, while the British Thoracic Society recommends either a two-dimensional measurement technique or volumetry (6, 10). The British Thoracic Society recommends a 2D measurement of the greatest diameter of the nodule, while the Fleischner Society recommends the mean of its short and long axes (6, 10). It is stated in the German lung cancer guideline that volumetry is now preferred. The minimum size constituting an indication for follow-up also varies across guidelines: 4 mm according to the American College of Chest Physicians, 5 mm according to the British Thoracic Society, and 6 mm according to the Fleischner Society (6, 8, 10). In contrast, in the German lung cancer guideline, follow-up is recommended for nodules of diameter >5 mm. The recommended follow-up intervals and the total duration of follow-up vary as well: e.g., for a subsolid nodule, three years of follow-up are recommended by the American College of Chest Physicians, four years by the British Thoracic Society, and five years by the Fleischner society (6, 8, 10). The subclassification of subsolid nodules also varies widely across guidelines, but this is a specifically radiological challenge of no direct relevance to this review (36). The differences mentioned indicated that a number of questions about the management of pulmonary nodules remain unanswered.

Future perspectives

Coming advances in artificial intelligence, particularly in neural networks, may markedly improve the identification and classification of pulmonary nodules. A neural network that has been trained on a dataset comprising more than 15 000 images from the National Lung Screening Trial has demonstrated the capacity of this deep learning algorithm to more intelligently classify patients into low- and high-risk groups, in comparison to conventional risk models.

It might, therefore, help prevent unnecessary invasive procedures and delays in diagnosis (37). Other experimental approaches are aimed at improving the management of patients with pulmonary nodules through the methods of personalized medicine (plasma protein analysis or RNA sequencing of genomic risk factors) (38, 39).

Conflict of interest statement
HW received consulting fees from BMS, Astra Zeneca, Intuitive, Medtronic and Roche. He has received support for continuing medical education presentations from BMS, Astra Zeneca, Intuitive, Medtronic, and Roche and reimbursement of travel expenses from Astra Zeneca, Intuitive, Medtronic, and Roche.

The remaining authors state that they have no conflict of interest.

Manuscript dates

Submitted on 15. February 2024 and accepted after revision on 21 August 2024.

Translated from the original German by Ethan Taub, MD.

Corresponding author
Dr. med. Philip Baum

Thoraxklinik-Heidelberg gGmbH
Universitätsklinikum Heidelberg
Röntgenstr. 1, D-69126 Heidelberg, Germany

Cite this as:
Baum P, Schlamp K, Klotz LV, Eichhorn ME, Herth F, Winter H: Incidental pulmonary nodules: Differential diagnosis and clinical management. Dtsch Arztebl Int 2024; 121: 853–60.
DOI: 10.3238/arztebl.m2024.0177

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