1.Introduction
An isolated pulmonary nodule (SPN) is defined as a round/round-like opaque shadow ≤75 px in diameter surrounded by lung parenchyma. Lesions larger than 3 cm are called masses and are usually malignant. on CT, nodules can be solid, semi-solid (mixed attenuation) or ground glass. Patients with SPN detected on radiographs today are likely to undergo CT scans. Most thin-section CT scans of smokers reveal small intrapulmonary nodules, most of which are less than 7 mm in diameter. however, the vast majority of these small nodules are benign, and their clinical importance is fundamentally different from that of the larger nodules found on chest radiographs.
This point has been highlighted in several recently published papers on CT screening for lung cancer. In the past, if such nodules were found incidentally, a 2+ year follow-up using multiple examinations was usually recommended; this included CT follow-up at 3, 6, 12, 18, and 24 months. However, this protocol also results in increased radiation exposure to the follow-up population. This article will describe the current evidence-based medical imaging management of isolated pulmonary nodules.
2. Morphologic evaluation of isolated pulmonary nodules
The most common intrapulmonary malignant lesions are metastatic carcinoma and primary bronchopulmonary carcinoma. All histologic types of tumors can produce pulmonary nodules, but adenocarcinoma is the most common. Nodule characteristics, such as shape, margin features, cavity, and location fail to accurately identify benign and malignant nodules. The basis for benign nodules include stable nodules for more than two years, well-defined borders, and specific forms of calcification (central, diffuse, laminar, or popcorn-like).
Although primary lung cancer can also present as a main nodule adjacent to multiple small satellite nodules, the tendency for multiple nodules to cluster in a single location within the lung is diagnosed as an infectious process. Laminar or central calcifications are typical of sarcoidosis, while “popcorn”-like calcifications are most commonly seen in malignant tumors. High-resolution CT can clearly show fat and cartilage images in approximately half of the malformations. The fatty component suggests a malformation or occasionally a lipoid granuloma or lipoma.
Speckled or eccentric calcifications are associated with cancer. Another type of benign solidity is rounded pulmonary atelectasis. A diagnosis of round pulmonary atelectasis is made when the lesion has the following specific morphologic features: subpleural location, curved vascular projection into an opaque shadow, and evidence of pleural disease. No further examination is required when the nodule is clearly benign. Irregular, burr-like, or lobulated margins of nodules are usually characteristic of malignancy. Although most SPNs have smooth, well-demarcated margins, these are not diagnostic features of benign nodules. Approximately 21% of malignant nodes are well delineated.
3. Management of isolated pulmonary nodules of undetermined nature
When the SPN on the first examination cannot be characterized, the patient’s risk factors should be evaluated. The relative risk of lung cancer formation in male smokers is about 10 times higher than that in non-smokers. The relative risk for heavy smokers is 15 to 35 times higher. Low-risk individuals were defined as those <50 years of age and a history of smoking <20 years. The moderate risk group was defined as age >50 years and history of smoking or secondhand smoke >20 years without other risk factors (history of random exposure, occupational exposure, history of cancer, family history, or history of lung cancer).
A positive correlation between nodule size and the probability of malignancy has been clearly demonstrated. The commonly used standard size value is the average of the maximum and minimum cross-sectional diameters of the most representative areas of the nodule. Meta-analysis based on eight large census trials showed that the probability of malignancy depended on nodule size: 0% to 1% when nodules were 5 mm or smaller, 6% to 28% when nodules were 5 to 10 mm in size, and 64% to 82% when nodules were 20 mm or larger.
Even among smokers, the percentage of all nodules smaller than 4 mm that ultimately prove fatal is very low (<1%), while the percentage of nodules in the 8 mm range is approximately 10% to 20%. The Fleischner Society 2005 guidelines (Table 1) state that at least 99% of all nodules 4 mm or smaller are benign. Such small shadows are common on thin CT scans and thus CT follow-up is not recommended for every case; a single follow-up scan within 12 months should be considered for cases with suspicious nodule morphology or high risk.
The increased use of CT screening for lung cancer has led to increased identification of early lesions, such as adenocarcinoma in situ (AIS, pathological size ≤30 mm, non-invasive volvulus-like growth, usually non-solid on CT; Figure 3) and minimallyinvasive adenocarcinoma MIA ( The pathology is ≤30 mm in size, with predominantly infiltrative vascular growth of 5 mm or less, and is largely non-solid on CT, but may contain a central solid component of nearly 5 mm.
These lesions should not be considered as common invasive adenocarcinoma and can be followed up for observation rather than surgical resection. When nodules are 5 to 9 mm in diameter, they are found to be enlarged in approximately 6% of cases on follow-up scans at 4- to 8-month intervals. The best strategy to adopt for such nodules is surveillance. The timing of these surveillance examinations. Timing varies depending on nodule size (4 to 6 or 6 to 8 mm) and patient type, especially in the presence of low-risk/high-risk factors associated with malignancy.
Non-calcified nodules larger than 8 mm in diameter are highly suggestive of malignancy and should be considered for additional testing such as contrast-enhanced CT, positron emission tomography (PET), percutaneous lung aspiration biopsy, thoracoscopic resection, or television-assisted thoracoscopic resection. Previous CT scans, chest X-rays and other relevant imaging data should be collected for nodal comparison whenever possible, as they can be used to show whether the suspected nodule is stable or growing. Metastases should be highly suspected in patients with known primary malignancy, regardless of whether the lung nodules are isolated or multiple.
4. CT follow-up of isolated pulmonary nodules
The volume doubling time of malignant bronchial tumors is rarely less than 1 month or greater than 1 year. The nodule doubling time (DT) can be calculated based on the following formula: DT = (t.ln2) / ln (Vf/Vi) where Vi is the initial volume of the nodule, Vf is the final volume, t is the time interval between two observations, and ln is the logarithm. This formula is based on an exponential model of nodule growth.
Isolated nodules that have been stable in volume for more than 2 years are usually considered benign. Recently, articles have been published on the imaging-pathological correlation of pure ground glass density nodules and mixed density nodules with lung adenocarcinoma. Small, purely ground glass shadows (non-solid) but pathologically characteristic malignant nodules can grow very slowly, with an average volume doubling time of about 2 years. On the other hand, solid carcinomas often grow rapidly, with an average volume doubling time of 6 months. Non-solid (ground glass shadow) and small volume nodules require longer intervals of follow-up.
Even if malignant, a non-solid nodule less than 6 mm may not increase significantly in size within 12 months. The accuracy of measuring subcentimeter nodule growth is questionable. According to the formula V=4/3πr3 (r denotes radius), doubling the volume of the sphere corresponds to only a 26% increase in diameter. Therefore, it is difficult to assess the increase or decrease in the cross-sectional diameter of a nodule between two consecutive CT examinations, and even for small nodules of 5 mm and below no specific diameter change values can be measured. In fact, a doubling of the volume of a 5 mm nodule results in an increase in diameter of only 1.25 mm.
For these reasons, it is possible that less than 20% of the variation is due to the method of measurement. For optimal CT evaluation of subsolid pulmonary nodules, a thin-layer scan is recommended. For subsolid malignant nodules, it is also meaningful to measure the increase in attenuation coefficient in serial CT scans compared to measuring nodule diameter or volume [28]. In the follow-up of ground glass nodules, malignancy is highly suspected if a soft tissue component is present even if the total volume of the nodule remains unchanged or shrinks. When follow-up of pulmonary nodules is the sole purpose of CT examination, a low-dose, thin-level, flat-scan approach with limited longitudinal scan range should be used.
5. Enhanced CT of isolated pulmonary nodules
After rapid intravenous injection (concentration: 300 mg/mL; speed: 2 ml/s) of iodinated contrast agent, nodule enhancement of less than 15 Hu is highly suggestive of benignity, while enhancement of more than 20 Hu reflects tumors containing neovascularization and suggests malignancy. A recent Meta-analysis based on 10 dynamic enhanced CT studies reported that the sensitivity of enhanced CT diagnosis for SPN was 93%, specificity was 76%, positive predictive value (PPV) was 80%, and negative predictive value (NPV) was 95%.
The limitation of contrast-enhanced CT is the misdiagnosis of inflammatory lesions as malignant; errors in measurement of small nodules can also occur. Given the difficulty in measuring the density of nodules with heterogeneous composition and diameters less than 1 cm, in practice only enhanced CT scan information is reliable for homogeneous nodules of 8 mm or more in diameter.
6. Positron emission tomography (PET) and combined PET-CT
The added diagnostic value of PET-CT is the detection of metabolically active lesions and/or lymph nodes outside the pulmonary nodes to support the diagnosis of SPN as a primary or secondary malignancy. The sensitivity and specificity of CT scans for detecting involved lymph nodes in the mediastinum were 55%?88% and 76%?85%, respectively.
The sensitivity and specificity of PET for detecting abnormal lymph nodes identified by CT scan were 94% and 82%, respectively. Some benign lesions such as granulomas (e.g., histoplasmosis or tuberculosis) and inflammation can present similarly to malignant nodes and lead to false-positive results. On the other hand, PET-CT can produce false negative results for the following three main scenarios of SPN: small volume lesions, low tumor metabolic activity and hyperglycemia.
Modern PET scanners have a spatial resolution of about 7 mm, and the detection of small lesions (<1 cm) is difficult to diagnose because of the limited spatial resolution. The low metabolic activity and low proliferation rate of some highly differentiated malignancies can also cause false-negative PET-CT results. Approximately 50% of FDG PET results in patients with fine bronchoalveolar carcinoma are false-negative, and in addition adenocarcinoma in situ results can be false-negative. In addition, metastases from certain primary malignancies (e.g., renal cell carcinoma, testicular or prostate cancer) have little FDG tracer concentration and are not even detectable by PET-CT. False-negative FDG PET-CT results may also occur in patients with hyperglycemia.
7. Transthoracic fine-needle aspiration biopsy
Transthoracic fine-needle aspiration biopsy usually requires a nodule diameter of at least 7 mm. for malignant lesions, transthoracic fine-needle aspiration biopsy has a diagnostic sensitivity of 80% to 95% and a specificity of 50% to 88% [38-39]. Timely puncture biopsy results negate the diagnosis of malignancy, but malignancy cannot be excluded in the absence of a specific benign lesion diagnosis.
Frequently, needle aspiration biopsy does not affect subsequent treatment (positive results confirm high clinical suspicion and subsequent excision of the lesion; negative results do not exclude malignancy and the lesion is surgically excised due to high clinical suspicion), and thus the best option for SPN with high clinical suspicion of malignancy requiring surgery is surgical excision; because the patient’s treatment plan does not remain the same regardless of positive or negative results.
This article focuses on avoiding overexposure of patients due to unnecessary CT follow-up. After the publication of the Fleischner Society guidelines for pulmonary nodules in 2005, many unnecessary CT follow-up examinations were still reported. The guidelines for low-dose, thin-section, and limited-coverage follow-up CT are not well implemented.