Common Knowledge About Pulmonary Nodules (Part 3)

In Common Knowledge About Pulmonary Nodules (1), I introduced some general facts about pulmonary nodules; in Common Knowledge About Pulmonary Nodules (2), I described some features of benign and malignant pulmonary nodules. In today's article, Common Knowledge About Pulmonary Nodules (3), I will introduce the routine examination methods for pulmonary nodules. This section follows the previous two, so much of what was covered there will not be repeated; for basic questions about pulmonary nodules, please refer to the earlier two articles.

What are the routine examination methods related to pulmonary nodules? In broad terms, they fall into two major categories: imaging examinations and biological laboratory tests. The imaging examinations include chest CT, contrast-enhanced CT, chest magnetic resonance imaging (MRI), PET-CT, bronchoscopy, and endobronchial ultrasound; chest CT is further divided into high-dose CT and low-dose CT. The biological tests include pathological examination, tumor marker testing, and genetic testing.

I will introduce the role and characteristics of each of these tests one by one.

Chest CT is a method of examining the chest using X-ray computed tomography. Chest CT has many slices, and each slice shows different structures; the more slices, the more accurate the result. CT equipment has also become increasingly advanced with the progress of science and technology.

Nowadays, the CT equipment in many large hospitals is thin-slice CT with more slices, but primary hospitals in some less developed areas still use thick-slice CT, which is gradually being phased out. Tiny nodules that can be diagnosed by thin-slice CT may be missed by thick-slice CT. Before CT became widespread, chest examination mainly relied on X-ray, a traditional method with even poorer accuracy and greater radiation that is harmful to the body; it has now basically been abandoned.

All X-ray examinations produce ionizing radiation and are harmful to the body, which is why we see warning signs reading “Radiation is hazardous to health” outside X-ray rooms. When undergoing CT, there are usually two dose options: low-dose and high-dose, where “dose” refers to the radiation dose. High-dose radiation is 4–5 times that of low-dose and is more harmful to the body, but it allows more precise visualization of nodular features and helps in judging benign versus malignant nodules. Generally, if a low-dose spiral CT suspects a malignant nodule, a high-dose spiral CT can be used further to characterize it. In routine follow-up, low-dose spiral CT is usually chosen.

Contrast-enhanced CT, also called contrast-enhanced scanning, is one of the CT scanning techniques that uses an intravascular contrast agent. Before scanning, an iodine-containing organic compound (usually 60% meglumine diatrizoate) is injected intravenously; after injection, the iodine level in the blood is maintained at a certain level. This enhances the images of organs and lesions during scanning, making them appear more clearly.

Usually, for pulmonary nodules highly suspected to be malignant, we recommend contrast-enhanced CT to examine the nodule's characteristics and internal blood flow more clearly. Contrast-enhanced CT can also detect lesions that ordinary CT cannot. But neither ordinary CT nor contrast-enhanced CT can rule out malignancy 100%. Patients with iodine allergy cannot undergo contrast-enhanced CT.

Chest MRI (magnetic resonance imaging) is also a common imaging examination. The magnetic resonance used in medicine exploits its resonance spectroscopy. Nuclear magnetic resonance is a physical process in which atomic nuclei with non-zero magnetic moment undergo Zeeman splitting of their spin energy levels under an external magnetic field and resonantly absorb radio-frequency radiation of a certain frequency. NMR spectroscopy is a branch of spectroscopy whose resonance frequencies lie in the radio-frequency band, with the corresponding transitions being those of nuclear spin between nuclear Zeeman energy levels.

Compared with CT, MRI has no adverse effects on human health, and chest MRI also visualizes blood vessels and larger masses well, allowing distinction of mass characteristics such as cystic, solid, cystic-solid, fatty, or vascular. However, the spatial resolution of chest MRI is inferior to CT, its observation of fine lung structures is worse, and its sensitivity for nodules below 10 mm in diameter is lower than CT. Therefore, tiny pulmonary nodules are generally not examined by MRI; MRI is only useful for pulmonary nodules larger than 1 cm.

PET-CT is a new imaging technique using the positron-emitting radionuclide fluorine-18 labeled glucose analogue (18F-FDG) for imaging. Before the examination, a radioactive substance is also injected into the bloodstream. These radioactive substances travel with the blood circulation to all parts of the body; if there is a tumor, they accumulate at the tumor site, forming a relatively high concentration that is revealed by imaging.

Usually, the PET-CT report reports the FDG uptake value. Malignant tumors have higher FDG uptake than benign tumors and normal tissues; lesions with FDG uptake above 2.5 have a greater probability of being malignant tumors.

Like ordinary CT, PET-CT involves radiation harmful to the body and is expensive. PET/CT has limited diagnostic value for small pulmonary nodules and can hardly show nodules below 10 mm in diameter. However, for pulmonary nodules above 10 mm, its sensitivity and specificity can reach 96.8% and 77.8% respectively. Moreover, PET-CT can also detect whether there are metastatic lesions throughout the body. Therefore, PET-CT is not suitable for small pulmonary nodules below 10 mm. For solid pulmonary nodules above 10 mm or mixed pulmonary ground-glass nodules, PET-CT can be considered to determine the nature of the nodule.

But the diagnostic accuracy of PET-CT for malignant pulmonary nodules is not 100%, so PET-CT can also produce misdiagnosis and missed diagnosis. 18F-FDG is not a specific tumor-imaging agent either; tuberculosis, granulomatous disease, and histoplasmosis may also show elevated 18F-FDG. Thus, a patient with a positive PET-CT report does not necessarily have a malignant nodule, and a patient with a negative PET-CT report cannot be completely ruled out for lung cancer.

Bronchoscopy is an examination in which a slender bronchoscope is inserted through the mouth or nose into the patient's lower respiratory tract—through the glottis into the trachea, bronchi, and more distal airways—to directly observe tracheobronchial lesions, and bronchoscopic treatment can also be performed according to the lesion.

In a broad sense, bronchoscopy includes transbronchial lesion biopsy, bronchial mucosal biopsy, transbronchial lung biopsy (TBLB), and transbronchial needle aspiration (TBNA). Most pulmonary and airway diseases—such as tumors, interstitial lung disease, granulomatous disease, and certain infectious diseases—require transbronchial biopsy for diagnosis; this is the most commonly used examination.

All undiagnosed pulmonary nodules can be considered for bronchoscopy, but for nodules below 10 mm, the positive rate of bronchoscopy is low. Moreover, most pulmonary nodules below 10 mm are benign and can simply be followed up periodically with low-dose CT, so bronchoscopy is unnecessary.

Endobronchial ultrasound (EBUS) is a method in which an ultrasound probe is placed inside the bronchoscope to obtain ultrasound tomographic images of the structures around the trachea and bronchi. EBUS is divided into convex-probe EBUS (CP-EBUS) and radial-probe EBUS (RP-EBUS).

The former places the ultrasound probe at the tip of the bronchoscope to form an integrated ultrasound-fiber bronchoscope, mainly used for central lesions such as lymph node metastasis staging of lung cancer; it can also be used to diagnose intrapulmonary tumors, unexplained hilar or mediastinal lymphadenopathy, and mediastinal tumors.

The latter places the ultrasound probe inside a special sheath; radial EBUS can perform a 360-degree scan of the bronchial lumen and is mostly used for peripheral pulmonary lesions. Small pulmonary nodules are mainly diagnosed with this radial-probe bronchoscopy. During diagnosis, biopsy forceps and a cytology brush can also be passed through the bronchoscope to obtain specimens for pathological testing to determine whether the nodule is benign or malignant.

The above are the common imaging methods for pulmonary nodules; I will now introduce the routine biological tests closely related to them.

First and most important is pathological examination. Pathology involves taking a portion of tissue from a lesion, observing its shape with the naked eye and its cellular characteristics under a microscope; it is the gold standard for diagnosing cancer. In principle, no lesion can be confirmed as cancer without pathological examination. Although doctors can use experience to judge whether a tumor on an imaging report is malignant or benign, that is ultimately not 100% accurate; truly confirming cancer requires pathological testing. Pathology can also determine the nature and type of canceration, providing an important basis for subsequent treatment.

As I actually mentioned above, when performing radial-probe bronchoscopy, biopsy forceps and a cytology brush can be passed in to obtain specimens for pathological testing. This is one method of pathology, but the more commonly used method is CT-guided percutaneous lung nodule biopsy.

However, biopsy also has contraindications. Patients with poor coagulation function or heart, liver, or kidney failure should best avoid puncture; patients with severe emphysema or pulmonary bullae should also be cautious with puncture. Unconscious patients who cannot fully cooperate—including those with mental illness, those with neurological disorders who cannot control themselves, and those with uncontrollable severe coughing—should best avoid puncture, as serious accidents may occur during biopsy.

Besides the above biopsy methods, there is also surgical biopsy. Generally, surgical biopsy has higher accuracy, essentially reaching 100%. The positive rates of needle biopsy and bronchoscopic biopsy only reach 90%, meaning missed diagnosis is possible.

Tumor marker testing is another biological method, but its sensitivity and specificity are limited. That is, a positive tumor marker does not necessarily mean cancer, and a negative tumor marker does not necessarily mean no cancer. Tumor markers only help judge the likelihood that a pulmonary nodule is malignant and cannot accurately diagnose whether the patient is benign or malignant. Clinically, tumor markers are more often used for dynamic observation of treatment efficacy after lung cancer therapy.

Tumor markers commonly associated with lung cancer include neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag), and cytokeratin 19 fragment (CYFRA-211).

Genetic testing is an emerging method of precision medicine for lung cancer in recent years. Before human tissue becomes cancerous, multiple genetic abnormalities have already occurred, and these abnormalities often precede clinical symptoms. Genetic testing for lung cancer looks for molecular markers of lung cancer. Examining whether mutations exist at related gene loci does indeed help judge the nature of pulmonary nodules in some patients. But current genetic testing technology is not yet mature: about two-thirds of lung adenocarcinoma patients and most squamous cell carcinoma and small-cell lung cancer patients have no known gene mutations. So genetic testing also cannot accurately determine whether a pulmonary nodule is benign or malignant.

So, if we unexpectedly discover a pulmonary nodule during a physical examination or while being examined for another disease, how should we choose among the above tests? How often should these tests be done? This first depends on the nodule's risk classification. The vast majority of intermediate- or low-risk pulmonary nodules only require periodic low-dose CT to observe changes in nodule shape and size. High-risk pulmonary nodules are different. In the next section, I will detail how different pulmonary nodule patients should choose their examination items and frequency.