The incidence rate and death rate of lung cancer in China are the highest among malignant tumors, and the 5-year survival rate is only 19.7%. To prevent and treat lung cancer at an earlier stage and to improve the cure rate of lung cancer, primary health care practitioners need to learn and master the strategies of lung cancer screening and early diagnosis and treatment. Expert Consensus (2019 Edition)”. The author interprets the key points of the Consensus as follows for your study and reference.
I. Significance of early lung cancer screening
The most effective way to improve the survival rate of lung cancer is secondary prevention, i.e. early detection, early diagnosis and early treatment. Compared with western countries, China has a high proportion of smokers and passive smokers, air pollution and younger lung cancer incidence. The “Consensus” has made the high-risk group of lung cancer the main target of screening. The Chinese high-risk group for lung cancer is defined as those who are ≥40 years old and have any of the following risk factors: (1) smoking ≥400 years (or 20 pack years), or ever smoked ≥400 years (or 20 pack years) and quit smoking <15 years; (2) having environmental or high-risk occupational carcinogenic factors (such as asbestos, beryllium, uranium, radon, etc.); (3) having combined COPD, diffuse pulmonary fibrosis or previous history of (3) combination of COPD, diffuse pulmonary fibrosis or previous history of tuberculosis; (4) previous malignancy or family history of lung cancer, especially family history of first-degree relatives. For non-smoking women, passive smoking, cooking fumes and air pollution should also be considered.
Imaging tests for lung cancer screening
1.X-ray or chest CT
Imaging examination is a powerful weapon for early detection and diagnosis of lung cancer. The Consensus believes that although ordinary X-ray chest X-ray can improve the detection rate of lung cancer, it is difficult to detect lesions with a diameter of <5-6 mm and is not recommended for lung cancer screening. Low-dose CT (LDCT) can also reduce lung radiation damage, which is more beneficial for screening. If possible, lung cancer screening should be performed with 16 or more layers of multi-layer spiral CT. To reduce potential radiation-induced carcinogenesis, high false-positive rate, overdiagnosis and increased medical costs, chest CT is recommended once a year. After screening, conventional CT or high-resolution CT can be used for differential diagnosis.
2.PET-CT examination
PET-CT is commonly used in cancer diagnosis, and has high sensitivity and specificity in diagnosing lung cancer in terms of disease location, staging and treatment evaluation. For lung nodules found in LDCT screening, it is difficult to distinguish benign and malignant lesions by morphology and CT value, and to know whether there are distant or lymph node metastases, PET-CT examination has certain diagnostic significance. The “Consensus” points out that PET-CT is expensive and not universally available, and that it should be used only for patients with abnormal chest CT results and special requirements, and not as a routine primary screening tool for lung cancer.
The “consensus” gives several recommendations for application.
①For pure hairy glass nodules with chest LDCT suggestive of ≤8mm in diameter, the application is generally not recommended.
② For solid pulmonary nodules >8 mm in diameter, PET-CT scan is feasible to differentiate benign from malignant when pathologic biopsy or puncture is not available for definitive diagnosis.
③For semi-solid pulmonary nodules >8 mm in diameter that cannot be characterized, it is recommended to add an enhancement scan to help improve the positive rate in addition to the conventional scan.
Body fluid and genetic examination
Based on the traditional “4P” (preventive, predictive, individualized, and participatory) disease diagnosis and treatment model, the consensus adds “5P” precision medicine and liquid biopsy. The content of the “5Ps” precision medicine and liquid biopsy was added to the Consensus. The aim is to better reflect the characteristics of individualized lung cancer screening at the genetic and cytological levels. In order to meet the requirements of “5P” medicine, it is necessary to dynamically track the changes of tumor cells in order to monitor their high heterogeneity over the course of disease or treatment, so as to complement screening and develop precise individualized treatment plans.
1.Tumor markers
Tumor tissues express and secrete glycoprotein substances, enzymes and hormonal substances, etc., which can be obtained through blood and body fluid examination. Several markers related to lung cancer are mainly as follows
Gastrin-releasing peptide precursor, which can be used as a preferred marker for diagnosis and differential diagnosis of small cell lung cancer; neuron-specific enolase, which is used for diagnosis of small cell lung cancer and monitoring of treatment response; carcinoembryonic antigen, which is mainly used for screening of lung adenocarcinoma and observation of efficacy during lung cancer treatment; cytokeratin 19 fragment, which has reference significance for diagnosis of squamous lung cancer; squamous cell carcinoma antigen, which is of The antigen of squamous cell carcinoma, which is valuable for monitoring the efficacy and prognosis of lung cancer.
Based on the subtypes of lung cancer at the pathological diagnosis level, sometimes there are mixed types of lung cancer, such as adenosquamous carcinoma, or adenocarcinoma combined with neuroendocrine cell components, and the above tumor markers are often combined. In addition, there are still some lung cancer tumor markers that have negative results. When screening for lung cancer, the diagnosis must be given in conjunction with imaging results. If necessary, consult a professional oncologist.
2.New markers
(1) Autoantibodies to tumor-related antigens
The “Consensus” combines the application of modern medicine in immunological technology in order to detect and diagnose lung cancer at an earlier stage. MAGEA1, SOX2, p53, GAGE7, PGP9.5, CAGE, GBU4-5 have high sensitivity (62% and 59%) in stage I and II lung cancer patients, and are the first approved blood adjuvant tests for small lung nodules in China. It has an important informative value for clinical joint imaging assessment of small lung nodules and detection of early lung cancer.
Immune function markers are simple, easy to perform, inexpensive, easy to master, less invasive and high patient involvement, and may play an important role in future precision screening.
(2) Circulating tumor cells (CTC)
CTCs are cells shed from the primary site of malignant tumor and enter the blood circulation through blood vessels or lymphatic system, which can reflect the tumor tissue. It has been confirmed that CTCs are related to lung cancer staging and may predict the efficacy of targeted therapy for patients.
The results of a multicenter large-scale clinical trial in China showed that the sensitivity and specificity of lung cancer detection by CTC detection technology with folic acid receptor-targeted PCR were 80.2% and 88.2%, respectively, with a diagnostic sensitivity of 67.2% for stage I non-small cell lung cancer patients. This technology is the only and the first kit approved by the State Food and Drug Administration for clinical lung cancer CTC detection in China. In addition, CTC test combined with imaging can greatly improve the specificity of lung nodule diagnosis. However, more convincing studies with large samples are still needed.
(3) ctDNA and other blood components
Targeted drug therapy is the earliest treatment used in lung cancer. with the increasing maturity of genetic level testing and research, NCCN guidelines have approved that ctDNA testing for EGFR and other gene mutations can be used to guide clinical drug use in non-small cell lung cancer. advanced lung cancer with EGRFR and other gene mutations can use targeted drugs for first-line treatment. However, more evidence of effectiveness is still needed for widespread dissemination of this technology for early screening of lung cancer.
(4) Epigenetic-based testing
Epigenetics is a subdiscipline of genetics that studies heritable changes in gene expression without changes in the nucleotide sequence of genes, including DNA methylation, histone acetylation and chromatin conformational changes.
With the increasing research in environmental medicine, the important role of epigenetics has been highlighted, and epigenetic alterations can not only explain the pathogenesis of certain diseases, but also serve as markers for early diagnosis and prevention of diseases. Among them, DNA methylation is a very potentially valuable marker. It was found that the methylation levels of many genes in lung cancer tissues and sputum specimens were significantly higher than those in benign lung and healthy control groups. For example, SHOX2 hypermethylation can distinguish lung cancer from other benign lung diseases such as lung abscess, infection and obstructive lung disease, with a sensitivity and specificity of 68% and 95%, respectively, suggesting that SHOX2 hypermethylation can be used as one of the markers to assist in lung cancer diagnosis.
IV. Bronchoscopy
Liquid biopsy-based detection techniques can diagnose early lung cancer at the cellular and molecular levels when pathological biopsy samples are not available, and have the advantages of being simple, easy to perform, easy to master, non-invasive, and highly predictive, individualized and patient participatory, but still have the problem of high price. Non-invasive techniques such as imaging cannot confirm the diagnosis of central lung cancer. Bronchoscopy is feasible for patients with imaging-negative but recurrent bloody sputum and for early central lung cancer with positive sputum exfoliative cells.
(1) Autofluorescence bronchoscopy (AFB)
AFB examination technique has the advantages of high sensitivity, good specificity, predictability and individualized operation, and has obvious advantages for early central type lung cancer, especially small lesions in the bronchial lumen that are difficult to be shown by CT. This is because conventional white light bronchoscopy (WLB) is difficult to detect some early mucosal and submucosal lesions. AFB is required for patients in whom malignant cells are found in sputum and no lesions are seen on WLB. AFB examination is of great significance for those at high risk of central squamous carcinoma who smoke heavily for a long time, especially for patients with negative imaging but repeated bloody sputum.
(2) Fluorescence confocal microscopy (FCFM)
FCFM is a technique successfully developed in recent years, which can be combined with AFB for early diagnosis of lung cancer. In precancerous lesions where there are changes in the fibrous structure of the basement membrane reticular plate, FCFM combined with bronchoscopy can be used for early detection of tumors in the bronchial wall. It requires the operator to have some experience in the use of bronchoscopy and the financial means to acquire it. For the above reasons, it is not routinely recommended, but can be carried out at the discretion of centers that have the conditions.
V. Sputum cytology
Sputum cytology is a more convenient and economical method for lung cancer diagnosis, and is widely used for lung cancer screening because of the advantages of easy acceptance by patients and higher specificity.
In addition to the traditional direct smear method, new examination methods include liquid-based thin-layer cytology filming technique and sputum sediment agar paraffin double-embedded section. The accuracy of liquid-based thin-layer cytology testing technique for diagnosis and staging of lung cancer is higher than that of the direct smear method. Sputum cytology is a highly specific and less sensitive tool. The use of molecular biomarkers can enhance the sensitivity of lung cancer detection, including carboxyphenylporphyrin-labeled sputum cells and sputum methylation gene detection can be used for early screening and adjuvant detection of lung cancer.
Sputum examination still has certain limitations, and therefore can only play a suggestive role in lung cancer diagnosis, but not as a primary screening tool. It is recommended to use sputum examination in combination with other methods to improve the positive diagnosis rate.
VI. Summary
(1) LDCT
LDCT can be used as a reliable screening tool for lung cancer in high-risk groups. The recommended screening cycle is once a year. PET-CT can be considered under special circumstances, but not as a routine screening tool for lung cancer.
(2) Tumor markers
Commonly used markers such as gastrin-releasing peptide precursor, neuron-specific enolase, carcinoembryonic antigen and cytokeratin 19 fragment have reference value for lung cancer diagnosis, but a negative test cannot exclude lung cancer.
(3) Bronchoscopy
Minimally invasive examination procedure is not used as a routine screening method, but for those with positive sputum exfoliative cells and those with no abnormal imaging and high suspicion of lung cancer, clinicians need to choose bronchoscopic biopsy as an adjuvant screening method according to patient’s request.
(4) Sputum cytology examination
Sputum cytology is a highly specific but less sensitive tool, and is not used as a routine lung cancer screening tool. It can be used as a supplement to routine lung cancer screening.
VII. Flow chart of lung cancer screening management
For initial screening, refer to flowchart 1 for initial screening. For people with high-risk factors, especially asymptomatic people, they should also follow the medical advice strictly for regular reexamination.