Q1: What are the differential diagnoses to be considered when SPNs are found?
A1: The differential diagnosis for solid SPNs is malignancy (primary lung cancer such as non-small cell carcinoma, small cell carcinoma, carcinoid tumors and lymphoma, isolated metastases), benign lesions (such as malformations and arteriovenous malformations), infectious lesions (granulomas, spherical pneumonia, abscesses and purulent emboli) and non-infectious lesions (amyloid tumors, subpleural lymph nodes, rheumatic nodules, Wegener’s granulomatosis, focal scarring and pulmonary infarction), among others.
The differential diagnosis of non-solid SPNs are malignant tumors such as lung adenocarcinoma (pre-invasive lesions, atypical adenomatous hyperplasia, and adenocarcinoma in situ), melanoma/renal cell carcinoma/pancreas, breast, and gastrointestinal adenocarcinoma with pulmonary metastases and lymphoproliferative lesions; benign tumors such as mechanized pneumonia, focal interstitial fibrosis and endometriosis.
Q2: What is the role of X-ray chest radiographs in detecting SPN?
A2: Although microscopic nodules are often detected on CT, there are still SPNs that come on X-ray chest radiographs. If a nodule is diffusely calcified, it is definitely a benign nodule, and nodules that are stable for more than 2 years are currently followed up using CT. Although the nodule can be seen to be unchanged on the follow-up chest radiograph, the psychological stress when a patient first discovers an SPN in the lung is very high, and both the physician and the patient’s family should be aware of this.
In addition, the size of non-calcified nodules is stable over several years, and although malignancy is rare, regular follow-up should be noted. Technical innovations in X-ray chest radiography are helpful in improving the sensitivity of SPNs detection, for example, X-ray dual-energy silhouette radiography is a computer software program that reduces or even completely removes the effect of overlapping clavicles and ribs, thus significantly improving the detection of SPNs. detection of SPNs. Unfortunately, this technique is no longer available in domestic clinical work due to the low cost of MDCT.
Q3: Is a small nodule of 5 mm or less found on CT physical examination a lung cancer?
A3: According to Ginsberg et al. 115 out of 275 patients (about 42%) with nodules of 5 mm or smaller were lung cancer. The likelihood of lung cancer is positively correlated with the diameter of the SPN, meaning that the larger the diameter of a small nodule, the more likely it is to be lung cancer, but tiny nodules cannot be ruled out as lung cancer. If a small nodule is found on chest X-ray or CT, a consultation with a specialist in chest imaging should be sought, and if necessary, a routine MDCT or high-resolution CT should be redone on the lesion, and the lesion should be carefully analyzed after target reconstruction, and a regular follow-up of 3 months is needed for difficult small nodules.
[Of course, the follow-up time for small nodules is controversial among guidelines and experts, but the purpose is to serve the interests of patients].
The chance that a small nodule <4 mm in diameter is a primary lung cancer is <1%, while the chance that a small nodule 8 mm in diameter is a primary lung cancer rises to 10%-20%. With the widespread use of MDCT and the popularity of lung cancer screening, the detection rate of 1-5 mm microscopic lung nodules has increased significantly. A retrospective analysis of eight lung cancer CT screening studies found that the incidence of SPNs ranged from 8% to 51%, whereas the incidence of lung cancer ranged from 1% to 12%, and this difference was strongly related to the screening conditions, exclusion conditions, and population differences set by each study.
Q4: Is SPN with smooth margins benign, while SPN with lobes and burrs is lung cancer?
A4: In fact, the margins and morphology of SPN overlap between benign and malignant lesions, which is what we radiologists often say: “the same disease can have different manifestations, and the same manifestation can be a different disease” (i.e., same disease, different symptoms, different diseases). Therefore, if you encounter SPN, you should seek a consultation with an experienced chest imaging specialist.
Generally speaking, benign nodules show smooth edges and smooth surfaces, whereas lung cancer is lobulated or irregular with burrs on the edges. The formation of burrs is due to the growth of cancer cells along the interstitial space around the nodule, while the lobulation of nodules is due to the different growth rates of cancer cells within the nodule. Helioid or radial burrs are highly predictive of lung cancer in nodules, with studies showing a 90% positive predictive value for burr signs. However, lipid pneumonia due to infection or inflammation, localized pulmonary atelectasis, tuberculosis bullae, and progressive massive fibrosis can also present with the burr sign. In addition, SPN with smooth margins does not exclude malignancy, as many pulmonary metastases and approximately 20% of primary lung cancers have smooth margins.
Q5: Is an SPN with calcification a benign tumor?
A5: The type of calcification is very helpful for the benignity of SPN. 10% of lung cancers have calcifications detectable on CT, and their indeterminate types include punctate, eccentric and indeterminate calcifications. For the display of calcifications, CT is much more sensitive than X-ray plethysmography. Therefore, plain CT often uses a thin layer of 1 to 3 mm and a low-frequency, soft-tissue or smooth reconstruction algorithm for the display of nodules. Recent studies have shown that dual-energy CT can distinguish calcifications from iodine-containing contrast agents, but a multicenter clinical trial showed that 3 mm thin-layer dual-energy CT was not reliable for identifying benign and malignant nodules by changes in attenuation values of material at two voltages, 140 and 80 kV.
Common types of benign calcifications are diffuse, central (bull’s eye sign), lamellar, and popcorn-like calcifications. Granulomatous infections show more typical diffuse, central (bull’s-eye sign), and laminar calcifications. Cartilaginous calcifications in malignant tumors show characteristic popcorn-like calcifications. It is worth noting, however, that pulmonary metastases from chondrosarcomas and osteosarcomas can also present with the benign types of calcification described above and be mistaken for benign lesions.
Q6: Is the presence of a cavity in SPN a benign lesion or a malignant tumor?
A6: Studies have shown that 95% of SPN with cavities and wall thickness >15 mm are malignant, while 92% of SPN with cavities <5 mm in wall thickness are benign. For SPNs with a cavity wall thickness between 5 and 15 mm, it is clear that this is one of the difficulties in identifying cavernous SPNs, and it is important to seek the help of an experienced chest imaging specialist at this time.
Cavernous SPNs can occur in both infectious or inflammatory lesions such as lung abscesses, infectious granulomas, vasculitis, and pulmonary infarction, as well as in primary lung cancer and metastases, especially tumors with features of squamous cell carcinoma. The vacuolar sign in SPNs can be seen in lesions such as adenocarcinoma, lymphoma, nodular disease, and mechanized pneumonia. The air bronchial sign is a sign of airless parenchymal background formed by the evacuation of gas from the alveoli through resorption (atelectasis), substitution (e.g., pneumonia), or a combination of both, while the bronchi within the lesion are filled with gas, suggesting a patent airway proximal to the lesion. The air bronchial sign is seen in adenocarcinoma, lymphoma, and infection, but is more common in lung cancer (29%) than in benign SPN (6%). My MDCT study at the master’s level also showed that adenocarcinoma is most commonly associated with a bifurcated bronchial sign (i.e. type III bronchial sign) within the tumor, while the more malignant the tumor, the more likely it is that the bronchus associated with SPN is truncated at the edge of the SPN or becomes thin and pointed within the SPN with conical changes (i.e. type I and II bronchial signs).
Q7: Is non-solid SPN in the lung malignant?
A7: Non-solid SPN can present as pure GGO (pGGO) nodules or as partially solid GGO (mGGO) nodules, which, as the name implies, are soft tissue densities with scattered GGO. studies have shown that approximately 37.6% of pGGO resorbs or regresses, compared to 48.7% of mGGO. Persistent non-solid SPN tend to be malignant nodules, especially primary lung cancer, but can also be benign nodules (e.g., focal interstitial fibrosis and opportunistic pneumonia). In a study by Kim et al. 75% of persistent pGGO nodules were found to be adenocarcinoma and 6% were Atypical Adenomatous Hyperplasia (AAH).
Non-solid SPNs are nodules that contain a partially ground glass-like (GGO) component that is somewhat denser than normal air-containing lung parenchyma and somewhat less dense than soft tissue (e.g., pulmonary vasculature), as described in the introduction to this article. The formation of non-solid SPNs may be caused by infection, inflammation, hemorrhage, or tumor. Typical inflammatory lesions appear to resorb within a short time on CT. During a 2.7-year follow-up observation period in a group of patients with resected lung cancer, 174 pGGO nodules were identified, 63% of which regressed spontaneously.
For solid nodes, morphologic features of SPN are helpful in identifying benign and malignant lesions, but evaluating non-solid SPN containing GGO is very challenging because clinical experience of CT morphologic features studied in previous decades are suddenly not available and need to be supplemented by new research results, thus non-solid SPN is a hot research topic in the last decade and many results have been achieved.
Adenocarcinoma accounts for approximately half of the pathological types of lung cancer and is more likely to present as non-solid SPN than other pathological types of non-small cell lung cancer (NSCLC).The most recent classification of lung cancer pathology uses a clearer term to describe the extent of growth along the alveolar wall (i.e., Lepidic Growth), and it uses an invasive component to define pre-invasive and invasive lesions.
Pre-invasive lesions are atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS), both pathological types that show epithelial growth and are purely along the alveolar wall, but cannot be distinguished from each other at the cellular level. The typical AAH presents as a pGGO nodule less than 1 cm in diameter, although larger ones have been seen. The typical AIS presents as a pGGO nodule less than 3 cm in diameter, which also shows a purely epithelial growth pattern without invasiveness. Of course, it is now increasingly known that the former subtype of adenocarcinoma, Bronchioloalveolar Carcinoma (BAC), is no longer used.
Pathology is like any other medical specialty: knowledge is changing rapidly and staging is advancing, so the pathological staging of various diseases is constantly being improved and updated as knowledge advances.
Minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma are adenomas that are less than 3 cm in diameter, predominantly non-necrotic adnexal tumors without lymphovascular, vascular or pleural invasion, and with no invasive component larger than 5 mm in any part of the lesion. MIA may appear as GGO nodules and mGGO nodules on MDCT. Invasive adenocarcinomas can be further classified according to their histologic features as epithelial growth-dominant, alveolar, papillary, micropapillary, and solid types. For example, there are mucinous and non-mucinous types of adenocarcinoma. Similarly, there are mucinous and non-mucinous types of AIS and MIA. For mucinous lung cancer, invasive mucinous adenocarcinoma has replaced the former mucinous BAC, and its typical MDCT presentation is a solid SPN or mGGO.
Q8: How can I know that the SPN is growing up?
A8: Whether an SPN grows is very important to distinguish the benignity of solid SPNs from non-substantial SPNs. Typical SPN growth can be calculated by the volume multiplication time of the nodule, which is usually spherical and therefore the volume of the nodule can be calculated by the spherical volume formula of 4πr3. According to the formula, a 26% increase in the diameter of the nodule multiplies its volume (i.e., doubles its volume).
Solid SPNs that are malignant have a volume doubling time of less than 100 days (range 20-400 days). Those nodules with a volume doubling time of less than 20 days are often infectious or inflammatory lesions, which is the main reason why radiologists often advise patients to review after short-term treatment when they cannot confirm the diagnosis of SPN as lung cancer by CT in clinical practice. For SPN with volume doubling time greater than 400 days, it is usually benign as well. However, this SPN growth characteristic cannot be applied to non-solid adenocarcinomas (pGGO and mGGO nodules) because one study showed that it takes 1346 days (about 3 years and 8 months) for volume doubling. We found that when the CT presentation of lung adenocarcinoma was pGGO nodules, the volume doubling time was significantly longer than that of mGGO nodules, which in turn was significantly longer than that of solid SPNs.
For solid SPNs, the generally accepted follow-up time is 2 years (which implies a doubling time of >730 days), and if the nodule remains stable for more than 2 years, it is reliably determined to be a benign lesion. However, small nodules are difficult to assess for volume multiplication because of their imperceptible change in diameter; therefore, small nodules that have not grown for more than 2 years are generally considered to be benign lesions. A limitation in the evaluation of non-solid SPN growth is that the nodules are mixed, these nodules are typically small with indistinct margins, and nodule growth is inactive and difficult to identify. The evaluation of solid SPNs is based only on the size of the nodule, whereas the growth of non-solid SPNs takes into account the enlargement of the nodule, the increase in density, the increase in the size of the solid component or the increase in the size of the solid component, and these imaging features of nodule growth suggest an increased chance of lung cancer.The volumetric assessment of SPNs has been studied for many years, but the accuracy of the assessment of the growth rate of solid and non-solid SPNs remains controversial. Therefore, the use of MASS measurements combined with nodal volume and density to assess the growth rate of non-solid SPNs has been proposed in recent years.
In addition, there are two unusual patterns of lung cancer growth that require vigilance. One is the thickening of the wall of an isolated cystic air cavity, which can be solid or GGO, both of which should be highly suspicious for lung cancer. The other is a transient nodal narrowing of the SPN, which may be another fibrotic atrophy during the formation of the fibrous component of the nodule. The latter is very unlikely to occur, and continuous MDCT follow-up is needed to confirm the long-term stability of the nodule or its regression.
Q9: Enhanced CT shows enhancement of SPN, how does it help to determine the benignity or malignancy of the nodule?
A9: For solid SPNs, the degree of nodule enhancement can be quantitatively assessed on CT to identify the benignity or malignancy of the nodule. Enhanced CT can help determine the degree of risk for malignancy in nodules ≥5 mm. The degree of enhancement in SPNs correlates with the degree of vascular supply (size and number of vessels), which is significantly higher in malignant nodules and more pronounced on enhanced CT.
The enhancement value of malignant SPNs is more than 20 HU higher than the CT value on plain CT, generally between 20 and 60 HU (medium to high enhancement), while the difference between the enhancement value of benign SPNs and the CT value on plain CT is <15 HU. SPNs with enhancement <15 HU are almost always benign nodules, and it was found to have a positive predictive value of 96%, sensitivity of 98%, specificity of 58%, and accuracy of 77 percent. It is worth noting that in SPNs ≤2 cm in diameter, caution should be exercised when applying this aforementioned SPNs enhancement pattern to discriminate the benignity of nodules. This is because the smaller the nodule, the more likely it is to be benign and the less likely it is to undergo necrosis. In addition, computer-aided diagnosis (CAD) software regarding SPNs has been in the research stage, and the research data are promising, but there is still a long way to go to apply them to clinical work.
Note: The layer thickness of the evaluated images should be ≤3 mm is preferred, measurements should be performed on the mediastinal window to reduce the effect of partial volume effect, round or oval measurement ROI should be placed in the middle of the nodule, covering more than 70% of the nodule cross-section, and relatively spherical and uniformly dense areas should be selected for measurement, avoiding fat, calcification, cavities and necrotic areas].
Q10: How useful is PET-CT for determining the benignity and malignancy of intrapulmonary nodules (such as SPN) found by CT, as recommended by our doctor?
A10：With the rapid development of China’s economy and the people’s life becoming more and more affluent, the application of 18F FDG PET-CT (18-fluoro-2-fluoro-2-deoxy-D-glucose PET-CT) to examine tumors is more and more widely used, and the application of PET-CT to evaluate solid SPNs is also significantly increasing. PET-CT is used to identify the benignity and malignancy of SPNs by detecting the uptake of FDG, a tracer of glucose metabolism in the human body, and the most common semi-quantitative method is to measure the FDG SUV value of lung nodules. Usually, glucose metabolism is significantly higher in malignant tumors, and we determine SPNs as lung cancer when the SUV value is >2.5. For SPNs ≥1 cm, this SUV threshold has 90% sensitivity and specificity for identifying SPNs as malignant tumors.
The application of FDG PET to the evaluation of solid SPNs also takes into account clinical risk factors (e.g., patient age, smoking history, and history of malignancy) and imaging features that determine clinical management. Let’s say that a patient with a solid SPN assessed by multiple imaging follow-ups has an approximately 20% likelihood of having lung cancer and a negative FDG PET exam, the likelihood that this solid SPN is a lung cancer drops to 1% and is feasible for conservative management. In the same patient, the probability of lung cancer is about 80%, and the FDG PET is also negative, so the probability of solid SPN being lung cancer drops to 14% and requires puncture biopsy or surgical resection. Thus, it is clear that the patient’s history and the follow-up information of his intrapulmonary nodes are extremely important for the interpretation of negative FDG PET-CT results, because a positive PET result (+) increases the likelihood of SPN malignancy and naturally raises the alertness of the patient’s family and physicians, whereas a negative PET result (-) tends to lower the alertness of the patient’s family and physicians.
As attentive readers have noticed, the two paragraphs I mentioned above are for solid SPNs ≥1 cm, and I will share my experience with FDG PET-CT examination of non-solid SPNs below. In contrast to solid SPNs, the malignant pGGO nodes and mGGO nodes in non-solid SPNs have diverse variations in FDG uptake, and current PET techniques are not reliable for identifying benign and malignant nodes. A recent study showed a sensitivity of 10% and specificity of 20% for PET assessment of non-solid SPNs, which is significantly lower than the corresponding 90% and 71% for solid SPNs. In this study, 9 of 10 highly differentiated adenocarcinomas with non-solid SPNs were falsely negative for PET, while 4 of 5 benign non-solid SPNs were falsely positive.
In addition to the limitations of PET in the evaluation of non-solid SPNs, its spatial resolution is very limited, which contributes to the increase of false negatives in SPNs <1 cm in diameter. Currently, PET used clinically to evaluate SPNs of approximately 7 mm in diameter is still feasible. False-negative PET examinations are uncommon but can still occur in lung carcinoid and lung adenocarcinoma.The low positive predictive value of PET assessment of SPNs is associated with false positives formed by inflammation or infection.
PET-CT is performed by acquiring the results of both PET and CT examinations almost simultaneously, while spatially matching the functional and anatomical data of the patient. it is the PET-CT examination that evaluates SPNs after integrating the two data spatially and temporally. In a comparative study of PET-CT and dynamic-enhanced MDCT, PET-CT was more sensitive (96% vs. 81%) and more accurate (93% vs. 85%) in assessing SPNs than dynamic-enhanced CT.