Primary Lung Cancer Treatment Guidelines

(2022 Edition)

I. Overview

Primary lung cancer is the most common malignant tumor in China. From the perspective of pathology and treatment, lung cancer can be broadly divided into two categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which non-small cell lung cancer accounts for about 80~85 , including histologic subtypes such as adenocarcinoma and squamous carcinoma, with the remainder being small cell lung cancer. Due to the unique biological characteristics of small cell lung cancer, treatment is mainly a combination of chemotherapy (chemotherapy) and radiation therapy (radiotherapy), except for a few early cases. If not specifically stated, lung cancer refers to non-small cell lung cancer.

Lung cancer is the fastest growing malignancy in China over the past 30 years, and the first retrospective survey of causes of death in China conducted in the mid-1970s showed that the mortality rate of lung cancer in China was 5.47 per 100,000 at that time, ranking ahead of gastric cancer, esophageal cancer, radiotherapy, and lung cancer among the causes of cancer death. The first retrospective survey of causes of death in China in the mid-1970s showed that the mortality rate of lung cancer was 5.47/100,000, ranking 5th among the causes of cancer deaths, after stomach cancer, esophageal cancer, liver cancer and cervical cancer, and accounting for all cancer deaths.

7.43% of all cancer deaths. The results of our second cause-of-death sample survey show that in the 1990s

Lung cancer mortality was the 3rd leading cause of cancer death in the 1990s, after stomach cancer and esophageal cancer.

The third cause-of-death retrospective survey in the 21st century showed that lung cancer was the leading cause of cancer death.

Data from the China Tumor Registry show that in 2015, new lung cancer cases in China

Million cases, including 520,000 men and 267,000 women, accounting for 20.0. The national lung cancer incidence rate (crude rate) was 57.3 per 10

million, of which 73.9/100,000 and 39.8/100,000 were men and women, respectively. The incidence of lung cancer was 59.7/100,000 in urban areas and 54.2/100,000 in rural areas; the incidence of lung cancer ranked first among malignancies in both urban and rural areas. 630,000 lung cancer deaths were reported in China in 2015, including 433,000 in men.

197,000 cases in women, accounting for 27.0 percent of all malignancy deaths. The national lung cancer mortality rate was 45.9 per 100,000, with a higher rate for men (61.5 per 100,000) than for women (29.4 per 100,000).

Regionally, lung cancer mortality was higher in urban areas (47.5/100,000) than in rural areas.

(43.9/100,000). Looking at the three major economic regions, east, central, and west, the eastern region had the highest lung cancer mortality rate (49.6/100,000), followed by the central region (47.0/100,000), and the western region had the lowest (40.0/100,000). Lung cancer mortality in China is low until the age of 44, rises rapidly after the age of 45, peaks at the age of 80 to 84 (416.0/100,000), and declines thereafter. Trends in lung cancer mortality were similar across age groups in urban and rural areas.

II. Screening and diagnosis

(A) Risk factors for lung cancer.

The National Cancer Center published the “Guidelines for Lung Cancer Screening and Early Diagnosis and Treatment in China (2021, Beijing)” in 2021. In it, the main risk factors for lung cancer in China are summarized as follows.

Smoking and passive smoking

Smoking is now recognized as the most important risk factor for lung cancer. Cigarettes form more than 60 carcinogens during the lighting process. The nitrosamines, polycyclic aromatic hydrocarbons, and benzo(a)pyrene in tobacco are highly carcinogenic to the respiratory system.

In 1985, the World Health Organization’s International Agency for Research on Cancer identified smoking as the cause of lung cancer. The relationship between smoking and lung cancer risk was related to the type of tobacco, age at initiation, number of years of smoking, and amount of smoking. In a Meta-analysis of published domestic and international research literature on the Chinese smoking population and lung cancer, smokers had a 2.77-fold higher risk of lung cancer than nonsmokers (ratio: 2.77, and

95
Confidence interval: 2.26 to 3.40)

Passive smoking is also a risk factor for lung cancer development, mainly seen in women. The association between passive smoking and lung cancer was first reported in the early 1980s.Stayner

A 2003 Meta-analysis of 22 workplace studies of tobacco exposure and lung cancer risk showed that nonsmoking workers had a 24% increased risk of lung cancer from passive smoking in the work environment (relative risk ratio=1.24, 95
confidence interval: 1.18 to 1.29), while the risk of lung cancer in workers highly exposed to environmental tobacco smoke was 2.01 (95
confidence interval: 1.33-2.60), and there was a very strong association between duration of exposure to environmental tobacco smoke and lung cancer.

History of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an airway pathology caused by chronic inflammation that can lead to alveolar destruction, narrowing of the bronchial lumen, and irreversible pulmonary dysfunction at the end stage. In a systematic search and Meta-analysis of published domestic and international studies exploring the strength of the association between COPD and lung cancer since 1995, the risk of lung cancer in patients with COPD was 1.43 times higher than that in those without COPD in case-control and cohort studies, respectively (relative risk ratio: 1.43, 95confidence interval: 1.14 to 1.81) and 1.57 times (relative risk rate: 1.57, 95
confidence interval: 1.20 to 2.05).

Occupational exposure

A variety of specific occupational exposures can increase the risk of lung cancer, including asbestos, radon, beryllium, chromium, cadmium, nickel, silicon, soot, and coal soot.

A Meta-analysis of 19 articles on asbestos and lung cancer published between 1950 and 2009 by Lenters et al. showed that each 100 f/ml increase in asbestos exposure was associated with a 66.0 increase in lung cancer risk (relative risk ratio: 1.66, 95confidence interval: 1.53 to 1.79).

Radon is a colorless, odorless and tasteless inert gas with radioactivity. When people inhale it, the radioactive particles produced by radon decay can cause respiratory system to people radiation damage and cause lung cancer. The radon content around uranium-containing mining areas is high, and building materials are the most important source of indoor radon. Such as granite, brick sand, cement and gypsum, especially natural stone containing radioactive elements. The results of three summary analyses in Europe, North America and China show that for every 100Bq/m3 increase in radon concentration, the risk of lung cancer increases by 8(95
Confidence interval: 3 to 16 ), 11 (95
Confidence interval: 0 to 8 ) and 13 (95
Confidence interval: 1 to 36 ).

Beryllium is a basic rare metal used in aerospace, communications, electronics, and nuclear industries. Beryllium and beryllium compounds have been classified as known human carcinogens by the National Toxicology Office.

Nickel is a naturally occurring metallic element in the earth’s crust. Nickel metal and its compounds are widely used in industrial processes, such as nickel refining and electroplating. The International Agency for Research on Cancer (IARC) recognized nickel as a Group I carcinogen in 1987. In vitro studies in China have confirmed that nickel compounds such as nickel chloride activate the TLR4 signaling pathway in human lung cancer cells, and that TLR4/MyD88 signaling promotes nickel-induced invasion of human lung cancer cells.

Indoor soot exposure is a risk factor for lung cancer. (ratio: 2.42, 95confidence interval: 1.62 to 3.63) and increased the risk of lung cancer in women by 1.42 times. 3.63) and 1.52-fold increased risk of lung cancer in women (ratio: 2.52, 95
Confidence interval: 1.94 to 3.28).

Family history and genetic susceptibility to lung cancer

Family aggregation exists among lung cancer patients. These findings suggest that genetic factors may play an important role in populations and/or individuals susceptible to environmental carcinogens. a systematic evaluation by Matakidou et al. showed that a family history of lung cancer was associated with a relative risk ratio of 1.84 for lung cancer (95confidence interval: 1.64-2.05); Lin Huan et al. reported an adjusted ratio of 2.11 for 1 lung cancer patient and 4.49 for more than 2 lung cancer patients in a family lineage of 633 cases. In non-smokers, it was 1.51 (95confidence interval: 1.11 to 2.06). It is now believed that genetic polymorphisms involved in carcinogen metabolism, genomic instability, DNA repair, and regulation of cell proliferation and apoptosis may be genetic susceptibility factors for lung cancer, with metabolic enzyme genes and DNA damage repair gene polymorphisms being two of the more studied aspects.

Other

Other factors associated with lung cancer development include nutrition and diet, physical activity, immune status, estrogen levels, infections (human immunodeficiency virus, human papillomavirus), chronic inflammation of the lung, and economic literacy, but their association with lung cancer is controversial and needs to be further evaluated. The association with lung cancer is controversial and needs to be evaluated in further studies.

(ii) Screening of high-risk groups.

Screening for lung cancer in high-risk groups is beneficial in detecting early lung cancer and improving survival rates. Low-dose spiral CT is 4-10 times more sensitive than conventional chest X-ray in detecting early lung cancer and can detect peripheral lung cancer at an early stage. Data from the International Early Lung Cancer Action Plan show that annual screening with low-dose spiral CT can detect

85 85 Stage I peripheral lung cancer with a 10-year postoperative survival expectancy of 92.

The US National Lung Cancer Screening Trial demonstrated that low-dose spiral CT screening reduces the risk of lung cancer in high-risk individuals by 20of lung cancer mortality, making it the most effective lung cancer screening tool available. New study from the European Lung Cancer Screening Trial shows a 24 and a 33 reduction in lung cancer mortality in women. Low-dose spiral CT is recommended for lung cancer screening in high-risk groups in the pilot technical guidelines for cancer screening and early diagnosis and treatment currently being conducted in a few regions in China.

The most recent guidelines published by the National Comprehensive Cancer Network (NCCN) in 2021 for assessing risk factors for lung cancer screening include History of smoking (current and past), radon gas exposure, occupational exposure (silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel exhaust, nickel, soot, and soot), history of malignancy, family history of lung cancer in first-degree relatives, history of chronic obstructive pulmonary gas or pulmonary fibrosis, and history of passive smoking.

There were 2 groups according to risk status as follows.1. High risk group

Age ≥50 years, history of smoking ≥20 pack years. 2. Low-risk group

Age <50 years and/or history of smoking <20 pack years.

NCCN guidelines recommend lung cancer screening for the high-risk group and not for the low-risk group

Screening.

The Chinese Lung Cancer Screening Standards, published by the National Cancer Center in 2020

and the newly released China Lung Cancer Screening and Early Detection and Treatment Guidelines in 2021

(2021, Beijing), lung cancer screening is recommended for people at high risk for lung cancer. It is recommended that people at high risk for lung cancer should meet one of the following criteria.

Smoking: pack-years of smoking ≥ 30 pack-years, including ever smoking ≥ 30 pack-years but quit less than 15 years.
- Passive smoking: living or working in the same room with a smoker for ≥20 years.
- With COPD.
History of occupational exposure (asbestos, radon, beryllium, chromium, cadmium, nickel, silicon, soot and soot dust) for at least 1 year.
- Have a first-degree relative with a confirmed diagnosis of lung cancer.
Note 1: Number of pack-years smoked = number of packs smoked per day (20 packs per day) x number of years smoked Note 2: First-degree relatives refer to parents, children, and siblings

(C) Clinical presentation.

The clinical manifestations of lung cancer are diverse but not specific, which often leads to delays in the diagnosis of lung cancer. Peripheral lung cancer is usually asymptomatic and is often detected during a health check or during chest imaging for other diseases. The clinical manifestations of lung cancer can be summarized as symptoms caused by local growth of the primary tumor itself, symptoms caused by invasion of adjacent organs and structures by the primary tumor, symptoms caused by distant metastases, and extra-pulmonary manifestations of lung cancer (e.g., paraneoplastic syndrome).
- Symptoms caused by local growth of the primary tumor itself
Signs and symptoms in this category include: (1) cough, which is the most common symptom of lung cancer patients who visit

The most common symptom at the time of presentation, 50 More than half of lung cancer patients have cough symptoms at diagnosis.

(2) Hemoptysis, about 25 in patients with lung cancerto 40 Hemoptysis can occur, usually as blood in the sputum, and macrohemoptysis is rare. Hemoptysis is the most suggestive symptom of lung cancer. (3) Dyspnea, the mechanism of dyspnea may include the following: reduction of alveolar area due to primary tumor expansion, obstruction of central lung cancer or metastatic lymph nodes compressing the airway, pulmonary atelectasis and obstructive pneumonia, intrapulmonary lymphatic dissemination, pleural and pericardial effusion, pneumonia, etc. (4) Fever, fever can be caused by necrosis of tumor tissue, and fever can also be caused by secondary pneumonia caused by tumor. (5) Wheezing. If the tumor is located in the large airways, especially in the main bronchi, it can often cause restrictive wheezing.

Symptoms caused by primary tumor invading adjacent organs and structures

The primary tumor directly invades adjacent structures such as the chest wall, diaphragm, pericardium, phrenic nerve, recurrent laryngeal nerve, superior vena cava, esophagus, or metastatic enlarged lymph nodes mechanically compressing the above structures, and specific signs and symptoms may appear. These include: pleural effusion, hoarseness, phrenic nerve palsy, dysphagia, superior vena cava obstruction syndrome, pericardial effusion, and Pancoast syndrome.

Symptoms caused by distant metastasis of tumor

The most common symptoms are headache, nausea, and vomiting due to central nervous system metastases. Bone metastases usually present with more intense and progressive pain, etc.

Extrapulmonary manifestations of lung cancer

In addition to symptoms caused by local progression of the tumor and symptoms caused by extrathoracic metastases, patients with lung cancer may also present with paraneoplastic syndromes. The paraneoplastic syndrome associated with lung cancer

Syndromes can be seen in about 10to 20 of patients with lung cancer, more commonly small cell lung cancer. Clinically, ectopic endocrine and osteoarticular metabolic abnormalities are common, and some can have neuromuscular conduction disorders. The occurrence of paraneoplastic syndrome does not necessarily correlate positively with the extent of tumor disease and may sometimes precede the clinical diagnosis of lung cancer. In lung cancer with a combined paraneoplastic syndrome that is surgically resectable, recurrence of symptoms is an important indicator of tumor recurrence.

(iv) Physical examination.

Most patients with early-stage lung cancer have no obvious associated positive physical signs.
Patients present with extrapulmonary signs of unknown cause and persistence, such as pestle and mortar

(toe), non-wandering joint pain, gynecomastia, dark skin or dermatomyositis, ataxia, and phlebitis.

Patients with clinical manifestations highly suspicious of lung cancer and physical examination findings of vocal cord paralysis, superior vena cava obstruction syndrome, Horner syndrome, and Pancoast syndrome, etc. suggest the possibility of local invasion and metastasis.
Patients with clinical manifestations highly suspicious of lung cancer and physical examination findings of hepatomegaly with nodules, subcutaneous nodules, and enlarged lymph nodes in the supraclavicular fossa. The lymph nodes in the supraclavicular fossa are enlarged, suggesting the possibility of distant metastasis.

(E) Adjuvant tests.
- Laboratory tests
General laboratory tests: Before treatment, patients need routine laboratory tests to The patient’s general condition and suitability for appropriate therapeutic measures.
- Blood workup.

Liver function, kidney function and other necessary biochemical immunizations, etc. tests.
Coagulation tests.

Serological tumor marker testing: currently recommended by the American Society for Clinical Biochemistry and the European Expert Group on Tumor Markers. The commonly used markers for primary lung cancer recommended by the American Clinical Biochemistry Committee and the European Panel of Tumor Markers are carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratinfragment (CYFRA21), and gastrin-releasing hormone (GRH). -1) and pro-gastrin-releasing peptide (ProGRP), as well as squamous cell carcinoma antigen (SCCAg). The combination of the above tumor markers can improve their sensitivity and specificity in clinical applications.
Adjunctive diagnosis: Tumor markers related to lung cancer can be detected as needed in clinical diagnosis for adjuvant and differential diagnosis. The clinical diagnosis can be based on the detection of lung cancer-related tumor markers as needed to perform auxiliary diagnosis and differential diagnosis, and to understand the possible pathological types of lung cancer.

1) SCLC: NSE and ProGRP are ideal indicators to aid in the diagnosis of SCLC.

② NSCLC: Elevated levels of CEA, SCC, and CYFRA21-1 in patients’ serum contribute to the diagnosis of NSLCL. It is generally believed that SCC and CYFRA21-1 have a high specificity for squamous lung cancer. If NSE, CYFRA21-1, ProGRP, CEA and SCCAg are combined, the accuracy of identifying SCLC and NSCLC can be improved.
- Caution
1) The results of tumor marker assays are closely related to the assay used, and direct comparison of the results obtained by different assays is not appropriate. During treatment observation, the

If the assay is changed, it must be measured simultaneously and in parallel using the original assay to avoid incorrect medical interpretation.

②Laboratories should study the assay used and establish an appropriate reference interval.

③Inadequate specimens such as hemolysis, coagulation, and insufficient blood volume can affect the results of tests for coagulation, tumor markers such as NSE, and even liver and kidney markers.

4) Specimens should be sent for testing as soon as possible after collection, and prolonged storage may affect the results of tumor markers such as ProGRP and other laboratory markers.

Imaging

The imaging methods for lung cancer include X-ray chest X-ray, CT, MRI, ultrasound, nuclear imaging, PET and other methods. They are mainly used for lung cancer diagnosis and differential diagnosis, staging and restaging, assessment of surgical resectability, efficacy monitoring and prognostic assessment. Imaging is the best method for non-invasive detection and evaluation of tumors, and imaging information enables clinicians to be more certain about the prognosis of tumors and to make treatment decisions. In the diagnosis and treatment of lung cancer, one or more imaging methods should be selected reasonably and effectively according to different examination purposes.

Chest X-ray: In China, frontal and lateral X-ray is often the basic imaging method to detect lung lesions in primary hospitals. The diagnostic value for early lung cancer is limited. Once lung cancer is suspected by X-ray chest radiography, CT chest examination should be performed promptly.
Chest CT: Chest CT is currently the most important and commonly used method for diagnosis, staging, efficacy evaluation and post-treatment follow-up of lung cancer. CT is able to display image information that is difficult to detect on X-ray chest films and can effectively detect lung cancer.

Detect early lung cancer and further verify the location and extent of lesion involvement. For patients with initial diagnosis of lung cancer, the chest CT scan should include both adrenal glands. For lesions in the chest that are difficult to diagnose qualitatively, CT-guided percutaneous lung aspiration biopsy can be used to obtain a cytologic or histologic diagnosis.

Traditional imaging staging of lung cancer is divided into central, peripheral, and site-specific based on the location of the lung cancer. The central type of lung cancer occurs in the main bronchus and lobar and segmental bronchus and often causes secondary obstructive changes. Peripheral lung cancer occurs in the distal part of the segmental bronchus. Site-specific lung cancers such as supraglottic sulcus tumors.

Central lung cancer: Most central lung cancers are squamous or small cell carcinomas, but in recent years, the number of adenocarcinomas presenting as central lung cancer has increased. The early stage of central lung cancer is characterized by limited thickening of the bronchial wall, irregularity of the inner wall, narrowing of the lumen, and intrabronchial striations or dotted (axial view) hyperintensities in the pulmonary arteries, usually without obstructive changes. The imaging manifestation can sometimes be mainly obstructive pneumonia, and the inflammation dissipates after anti-inflammatory treatment, but it is still necessary to pay attention to whether the proximal bronchial wall is thickened. In the middle and late stage of central lung cancer, central mass and obstructive changes are the main manifestations. The obstructive changes first become obstructive emphysema, and then further develop into obstructive pneumonia and pulmonary atelectasis. The proximal end of the obstructed lung often protrudes due to the tumor, forming a transverse “S” sign. Bronchial inflations may be seen on CT in cases of incomplete bronchial obstruction. Enhanced CT often reveals dilated, mucus-filled bronchi. CT thin-section (1-1.25 mm reconstruction layer thickness) and multiplanar reformation (MPR) are valuable in the preoperative evaluation of central lung cancer and should be routinely used. If there is no contraindication, enhanced scanning should be performed. Central lung cancer with lung

In the case of atelectasis, MRI is useful to differentiate tumor from atelectasis, with higher signal in atelectasis than tumor in T2WI and higher enhancement in atelectasis than tumor in T1WI.

Peripheral lung cancer: usually confined lesions ≤1 cm in diameter in the lung are referred to as small nodules, confined lesions 1 cm <3 cm in diameter are referred to as nodules, and confined lesions ≤3 cm in diameter are referred to as nodules. The lesions with a diameter of 1 cm or less than 3 cm are called nodules, and those with a diameter of >3 cm are called masses. The size, morphology, density, internal structure, tumor-lung interface, and volume doubling time of the nodule or mass are the most important diagnostic indications when analyzing the imaging presentation. When observing the characteristics of nodules/masses, thin layer CT (layer thickness 1-1.25 mm) should be routinely applied and MPR can be used to observe the morphology of nodules in all directions, which helps in qualitative diagnosis. For solid nodules, the differential diagnosis can be made by selecting enhancement scans, dual-phase enhancement scans and dynamic enhancement scans, depending on the situation. For subsolid nodules in the lung, especially pure ground glass nodules, only thin plain scan is recommended.
Size and morphology: typical peripheral lung cancer is mostly round, oval, or irregular in shape and is mostly fractionated. lobular. With the gradual popularization of physical examination, there are more and more early lung cancers with imaging manifestations of small lung nodules and pulmonary nodules. At this time, the diagnosis is relatively easy based on the contour and marginal features of the mass.
- Density
CT plain scan: The nodules can be classified as solid nodules, partially solid nodules, and pure ground glass nodules (the latter two are collectively referred to as ground glass nodules or subsolid nodules), depending on whether they obscure the lung parenchyma. Pure ground glass nodules are purely ground glass-like densities, which are tumors growing along the alveolar architecture without obscuring the lung parenchyma, with peripheral pulmonary vascular penetration visible within the lesion; solid nodules completely obscure the lung parenchyma without ground glass-like density components; and partially solid nodules have both components. Persistent ground glass nodules, depending on size and density, are most often associated with atypical adenomatous hyperplasia, adenocarcinoma in situ, microinfiltrative

adenocarcinoma and infiltrative adenocarcinoma. Lung cancers presenting as ground glass nodules have a tendency to be multiple, and preoperative thin-section CT of the whole lung should be carefully observed to facilitate treatment planning.

Enhanced scans: Enhanced CT scans with a 15-20 HU increase compared with plain scans are used as a threshold to differentiate benign from malignant lesions, and dual-phase enhanced scans and dynamic enhanced scans can be chosen to further aid in the diagnosis when peripheral nodules are difficult to diagnose.

Internal structure

Bronchial inflation sign and vacuoles: seen in lung cancer, inflammatory lung lesions, or lymphoma, but more commonly in lung cancer. Thin-layer CT is better and often coexists with the vacuolation sign. Image post-processing techniques such as MPR can help show oblique bronchial inflation signs. The vacuoles are generally small cavities of about 1 mm in size and are commonly found in adenocarcinoma, accounting for about 20% to 25% of cases, often multiple, some of which may be axial phases of inflated bronchioles, or residual air-containing alveoli that have not been filled with tumor.

Calcifications: Thin-layer CT is much more likely to detect calcifications in nodules than conventional CT, and calcifications can be found in approximately 6% to 10% of lung cancers. Diffuse dense calcifications, stratified or popcorn-like calcifications are almost always benign. The high spatial resolution algorithm produces edge enhancement artifacts that tend to outline high density at the nodal margins and can be mistaken for calcification.

Cavities and cavities: Cavities are generally considered to be formed after bronchial drainage of necrotic material and can be 1 to 10 cm in size, either centrally or eccentrically. The cavity wall is mostly 0.5-3 cm, and the thick-walled cavity and the uneven inner wall support the diagnosis of lung cancer. The cavity is usually thought to be partly a cancer occurring in the wall of a pulmonary macula or cyst, and partly

The lesion can grow on one side of the cystic cavity or around it, and the cavity wall is mostly heterogeneous, and the tumor can be predominantly solid or ground glass in composition. The tumor can be predominantly solid or ground glass.

Solid lung lesions: tumors that grow and infiltrate along the alveolar wall without completely disrupting the alveolar septa, but thicken the alveolar wall or have secretions in the adjacent alveoli, with some alveoli still containing air, resulting in solid lung lesions, also known as pneumonic changes. On enhancement scan, enhanced blood vessels can be seen in the solid lung tissue, which is called angiographic sign on CT image. It can be seen in mucinous adenocarcinoma of the lung, as well as in obstructive and infectious pneumonia, lymphoma, pulmonary infarction, and pulmonary edema.

Tumor-pulmonary interface: A linear shadow extending around the nodal edge, with slightly thicker burr-like changes near the nodal end, most often seen in lung cancer. Usually, the thickness is <2mm, and the thickness is >2mm, which is called fine burr. The pathologic basis for burr formation is tumor invasion of adjacent lobular septa, peri-tumor parenchymal fibrosis, and/or inflammatory cell infiltration.
- Adjacent structures
Pleural changes: pleural depression sign is a thin linear or striated hyperdense shadow from the nodule or mass to the pleura, sometimes with a flared periphery, and localized pleural depression is seen in the gross lesion. It is mainly caused by the contraction of the scar caused by the fibroblastic reaction within the mass that pulls the local pleura, which may be filled with fluid or extra pleural fat, most commonly in pulmonary adenocarcinoma. The above linear changes are thick or irregular and should be considered as a possible tumor infiltration along the pleura.

Satellite lesions: These are usually adenocarcinoma of the lung and can be nodular or small.

stage. Benign lesions, especially tuberculosis, are also seen as satellite lesions.

Tumor volume doubling time: Tumor volume doubling time is defined as a 1-fold increase in tumor volume (diameter increase of approximately 26), which is one of the important indicators to determine the benignity and malignancy. The growth rate of different pathological types of lung cancer varies significantly, and the doubling time is highly variable, generally >30 days, <400 days, squamous carcinoma < adenocarcinoma < microinvasive adenocarcinoma or adenocarcinoma in situ < atypical adenomatous hyperplasia, and the volume doubling time of purely ground glass nodules is often >800 days. Three-dimensional volumetric measurements make it easier to accurately compare changes in nodule volume and determine the time to multiplication.
Supraspinal sulcus tumor: CT can show apical lung lesions, differentiate masses from pleural thickening, show bone destruction, chest wall It can show the extent of bone destruction, chest wall invasion, and whether the tumor invades into the cervical root. The use of enhanced CT-MPR and maximum density projection is important, with the latter being used primarily to show whether large vessels, such as the subclavian artery, are invaded. MRI has good soft tissue resolution and can show anatomic detail of the superior thoracic orifice and brachial plexus, and is better than CT for determining the extent of tumor invasion and the presence or absence of bone marrow invasion.
- Differential Diagnosis of Lung Cancer Imaging
Differential diagnosis of bronchial obstructive lesions: The causes of bronchial obstructive lesions can be divided into the following categories.

Neoplastic: including central lung cancer, benign tumors in the bronchial lumen such as malignancies and papillomas, inflammatory myofibroblastic tumors, and in rare cases metastases and lymphomas can cause bronchial obstructive changes.

Infectious: tuberculosis, nodular disease, right middle lung syndrome, etc. Other: foreign body, bronchiectasis, pulmonary amyloidosis, etc.

a1 Central lung cancer: as previously described.

a2 Nodules: the lung presents with more involvement of one or more segments than of the whole lobe. Sometimes disseminated lesions are seen in different lobes or contralaterally. If the entire lobe is caseous, the lobe may be enlarged and the interlobular fissures may be dilated and cavities may be present. The obstructive changes caused by lung cancer are usually obstruction of the entire distal segment or lobe or atelectasis (or inflammation).

Tuberculous bronchial lesions can result in distorted bronchial stenosis or irregular bronchial dilatation and inflation without proximal masses, an important differentiator from lung cancer. The diagnosis of tuberculosis is sometimes supported by calcifications in the bronchial wall.

Massive lymph nodes in the hilum or mediastinum due to tuberculosis do not correlate significantly with the lymphatic drainage area and may have calcification or circumferential enhancement with blurred, fused margins in a polycyclic pattern, which is typical of tuberculosis. The metastatic lymph nodes of lung cancer are related to the distribution of the drainage area, and circumferential enhancement of lymph node margins is occasionally seen in metastases of squamous carcinoma, but rarely in adenocarcinoma and small cell carcinoma.

a3 Endobronchial tumors: Benign endobronchial tumors are rare, and pulmonary malignancies, papillomas, and neurogenic tumors can cause obstructive changes to varying degrees. When soft tissue density masses or nodules in the bronchial cavity are associated with pulmonary atelectasis without mediastinal or hilar lymph node enlargement, it is difficult to distinguish benign and malignant tumors by imaging, but benign tumors are very rare and are mostly diagnosed as central lung cancer before surgery. The identification of intraluminal bronchial misshapen tumors is relatively easy as thin-layer CT can mostly detect fatty density and calcified foci.

In addition, inflammatory myofibroblastic tumors located in the bronchial lumen may be associated with obstruction

inflammatory pneumonia and pulmonary atelectasis, which are low-grade malignant mesenchymal tumors.

a4 Endobronchial foreign body: A history of foreign body aspiration and recurrent fixed site infections support the diagnosis of foreign body with obstructive changes.

The diagnosis of foreign body with obstructive changes is supported by CT.

Differential diagnosis of isolated pulmonary nodules/masses: The causes of isolated pulmonary nodules/masses are as follows.

Neoplastic: malignant tumors include peripheral lung cancer, solitary pulmonary metastases, malignant lymphoma, and malignant mesenchymal lung tumor; benign tumors include mismatched tumors, sclerosing pneumocytoma, etc.

Infectious inflammatory lesions: tuberculosis globules, spherical pneumonia, lung abscess, mechanized pneumonia, fungal infections.

Developmental abnormalities: bronchial/pulmonary cysts, pulmonary isolation, arteriovenous fistula. Other: spherical pulmonary atelectasis.

b1 Peripheral lung cancer: as previously described.

b2 Tuberculosis spheres: Tuberculosis spheres are often located in the posterior segment of the upper or dorsal segment of the lower lobe, but not infrequently occur in atypical sites. The image presentation is usually round or round-like in shape, either regular or irregular, and the contours are often flat and angular. Due to its inflammatory nature, the margins may have long haptic or cord-like shadows, and the adjacent pleura is often thickened and adherent, which is different from the burr and pleural invagination of lung cancer due to fibrogenic reaction or infiltration of cancer cells along the lobular septa, but sometimes it is also extremely difficult to distinguish. Calcifications and cavities are not uncommon, and the walls of tuberculous cavities are mostly thin and smooth, which is different from the nodular thickening of cavities caused by necrosis in lung cancer, and the fluid surface is rarely seen inside the cavity. The cavity can also be

behave in a crescentic or circling grotesque shape. The nodule (mass) is often surrounded by patches of satellite lesions. In some cases, draining bronchi may be seen. Enhancement scans are more characteristic and may be non-enhancing or circumferential, with the thickness of circumferential enhancement depending on the amount of granulation tissue surrounding the nodule bulb.

b3 Pulmonary malformation tumor: smooth or peripheral nodules with superficial lobulation, which may be calcified and typically popcorn-shaped. Thin-section CT is useful to detect the fatty component of the tumor. Enhancement scans do not show significant enhancement. Chondromatous malformations can be lobulated without calcification or fatty components and sometimes need to be differentiated from peripheral lung cancer.

b4 Sclerosing pneumocytoma: A well-defined mass or nodule with round or oval borders, as outlined with a pen, is seen on X-ray chest radiographs, and has uniform density on CT plain scan, sometimes with small hypointense areas and coarse punctate calcifications, and occasionally cystic changes. For round, ovoid and well-defined masses or nodules with early enhancement, a time-lapse scan should be performed. The lesion may sometimes have mild obstructive changes distal to the lesion. The involvement of hilar and mediastinal lymph nodes is rare and does not affect the prognosis.

b5 Spherical pneumonia, lung abscess, and mechanized pneumonia: Mostly in the dorsal and basal segments of the lower lobes of both lungs, located in the periphery of the lung, near the pleura, and may be square, flattened, or triangular in shape, with multiplanar reconstruction showing irregular lesions, whereas lung cancer is more uniformly spherical in all directions. In acute inflammatory disease, the central density is more uniform. In acute inflammation, the central area is high density, the surrounding area is low density, and the edges are blurred; in the case of abscess formation, a more regular low-density necrotic area may appear in the center of the lesion; in the case of small cavity formation, the cavity wall is more regular. The adjacent pleura is reactive thickened and more extensive. After effective anti-infective therapy, the lesion usually shrinks significantly.

b6 Fungal infection: typical presentation is a well-defined nodular foci with well-defined margins within a thick- or thin-walled cavity with an air crescent sign, which is mobile on changing body scans. Vascular invasive Aspergillosis presents early as focal pulmonary solid lesions with blurred margins or ground glass density, and late can present as cavernous nodules with air crescent sign, i.e., Aspergillus globules. Chronic necrotizing aspergillosis may present as solid, large cavernous lesions with an irregular lining. It may be associated with hilar and mediastinal lymph node enlargement, pleural effusion, and pleural thickening.

b7 Pulmonary isolation disease: imaging is very important in the diagnosis of pulmonary isolation disease and can confirm the diagnosis in most cases. It is mostly located in the posterior or inner basal segments of the lower lobes, more on the left than on the right. The intralobular type mainly presents as a uniform density mass, round, ovoid, a few may be triangular or polygonal, with clear borders, and CT values similar to muscle in those with uniform density; those with bronchial communication show inhomogeneous density and cystic changes within, with intracapsular density close to water and clear border rules, and gas is sometimes seen within the capsule, and if there is concomitant infection, a fluid level may be seen, which may change in the short term. The lung lobes appear as hyperdense shadows adjacent to the posterior mediastinum or diaphragm, with clear margins and uniform density, rarely with cystic changes. The abnormal arteries and internal structures are better visualized with computed tomographic angiography, which allows multiple views of the abnormal blood supply arteries from the thoracic, abdominal, or other rare arteries and draining veins.

b8 Bronchial/pulmonary cysts: those located in the middle mediastinum near the paratracheal or hilar areas are more typical and not difficult to diagnose. Those located in the periphery of the lung mostly present as round or round-like, well-defined, smooth, and rarely lobulated. It is typical to have a watery density, and it is not uncommon to have higher densities, and in a few cases, those containing calcium lactate may be higher than the soft tissue density.

But there is no enhancement on enhancement scans. There may be calcification in the cyst wall. Cysts arising in the fine bronchi may be lobulated, with poorly defined margins and even small vacuoles within them, making them difficult to differentiate from lung cancer.

b9 Pulmonary arteriovenous fistula: Pulmonary arteriovenous fistula is a congenital vascular developmental anomaly that is more common in young women. The patient’s blood supply is usually thickened and draining.

b10 Spherical atelectasis: Spherical atelectasis is a specific type of atelectasis commonly caused by localized pleural adhesions that limit lung expansion after resolution of pleuritis and effusion. CT scans can reveal vascular and bronchial shadowing in the form of arcs and distortions toward the center of the mass, like a snail or comet tail, with thickening of the adjacent pleura, reduction in lung volume in the lesion, and compensatory emphysema in the surrounding lung tissue.

b11 Solitary pulmonary metastases: most images appear as round or slightly lobulated nodules with clear margins and uniform or heterogeneous density, but a few may show irregular burr margins. The clear, well-defined margins need to be differentiated from benign pulmonary lesions such as sarcoidosis and malignant tumors, and those with irregular margins need to be differentiated from second primary lung cancer.

MRI examination: MRI examination can be used selectively in the chest to determine whether the chest wall or mediastinum is invaded; to show MRI is particularly useful in determining the presence or absence of brain and spinal cord tumors.

metastasis, and brain-enhanced MRI should be used as a routine preoperative staging test for lung cancer. The sensitivity and specificity of MRI for metastases in the bone marrow cavity are high and can be used according to clinical needs.

PET examination

PET is the best method for lung cancer diagnosis, staging and restaging, outcome evaluation, and prognosis assessment. The use of PET is recommended for the diagnosis and differential diagnosis of isolated pulmonary nodules (solid nodules ≥8 mm, partially persistent solid nodules with internal solid components ≥

6mm); (ii) pre-treatment staging of lung cancer, where PET has better diagnostic efficacy for lymph node metastases and extrathoracic metastases (except brain metastases); (iii) localization of lung cancer radiotherapy and outlining of target areas; and (iv) aids in identifying postoperative scarring and tumor recurrence that cannot be determined by conventional CT, such as PET. (4) to help identify postoperative scarring and tumor recurrence that cannot be determined by conventional CT, such as increased PET uptake, which requires biopsy confirmation; (5) to help identify post-radiotherapy fibrosis and tumor remnants/recurrence that cannot be determined by conventional CT, such as PET uptake, which requires biopsy confirmation; (6) to help evaluate lung cancer efficacy (especially molecularly targeted therapy), it is recommended to apply PET criteria for evaluating the efficacy of solid tumors (Table 1).

Table 1 Evaluation criteria for PET efficacy in solid tumors (2009)

Measurable lesion 18F-FDG uptake completely disappears to low

complete metabolic remission

Partial metabolic remission

in liver-averaged radioactivity and not distinguishable from the surrounding blood pool background

Target lesions 18F-FDG uptake is reduced by ≥30 with an absolute reduction of ≥0.8

Disease metabolic stabilization Incomplete metabolic remission, partial metabolic remission, disease generation

Progress in Disease Metabolism

Progress in Xie

Target lesion 18 F-FDG uptake increased ≥30 and absolute value increase ≥0.8; or the appearance of new lesions

Note: Lean weight-corrected standard uptake values are recommended to reduce the impact of patient weight changes on parameters during treatment

Ultrasound: Ultrasound usually does not show intrapulmonary lesions due to gas in the lungs and obscuration of the ribs and sternum. Ultrasound should be used to observe metastases and to provide information for tumor staging. Ultrasound can also be used for examination of pleural and pericardial effusion and localization before fluid extraction. Ultrasound-guided aspiration can be used to obtain specimens for histological examination of subpleural lung tumors, supraclavicular lymph nodes, and metastases from parenchymal organs. The diagnosis of lung cancer is based on clinical manifestations and various ancillary tests. The diagnosis of lung cancer, especially peripheral lung cancer, is difficult to distinguish on imaging from some pulmonary nodular lesions and some chronic inflammatory lesions, so the diagnosis of lung cancer requires various biopsies or punctures to obtain pathologic or cytologic evidence.
Bone nuclide scan: a routine test used to determine bone metastases from lung cancer. When bone scan suggests suspicious bone metastasis, MRI, CT or PET is performed to verify the suspicious area; preoperative PET can replace bone scan.
- Endoscopy and other examinations
Bronchoscopy and ultrasound bronchial aspiration biopsy: Bronchoscopy is important for localization of tumors and obtaining histological diagnosis.

value. For central lung cancer, bronchoscopy can directly visualize the lesion, and 95 or more can be detected by A definitive pathologic diagnosis can be obtained by cytologic brushings and histologic biopsies. Ultrasound bronchoscopy also allows for puncture biopsy of hilar and mediastinal lymph nodes adjacent to the bronchi for qualitative diagnosis of lung cancer and staging of mediastinal lymph nodes. A variety of navigational techniques are available to perform puncture biopsies for peripheral lung cancer.

Mediastinoscopy: Standard and expanded mediastinoscopy can be performed to obtain 2R, 2L, 4R, 4L, 5, 6, 7, and 10 zone lymph nodes for the qualitative diagnosis of lung cancer and regional lymph node staging. In the past, it was used as the gold standard for evaluating mediastinal lymph node metastasis. The use of mediastinoscopy in the diagnosis and staging of lung cancer has tended to decrease because of the need for general anesthesia for mediastinoscopy and the maturation of trans-ultrasound bronchoscopic and esophagoscopic puncture biopsy techniques.
Thoracoscopic or open lung biopsy: For imaging-detected pulmonary lesions, although sputum cytology, bronchoscopy, and various methods of puncture and biopsy are used, the use of mediastinoscopy is decreasing. For those who cannot obtain a definitive histological and cytological diagnosis despite sputum cytology, bronchoscopy, and various methods of puncture and biopsy, and for those who have a high clinical suspicion of lung cancer or cannot exclude the possibility of lung cancer after short-term observation, thoracoscopy or even open lung biopsy is one of the methods for qualitative diagnosis of lung cancer.
Sputum exfoliative cytology: Sputum exfoliative cytology is simple, noninvasive, and easily accepted by patients, and is one of the simple and effective methods for qualitative diagnosis of lung cancer. It can also be used as a screening tool for high-risk groups. The positive rate of sputum exfoliation cytology depends on the method of sputum specimen collection, the method of cytology smear preparation, the diagnostic level of the cytologist, and the location and pathological type of the tumor.

(vi) Pathologic histology.

Diagnostic criteria

Pathological diagnosis of lung cancer from biopsy tissue specimens mainly clarifies the presence or absence of tumor and tumor type. For patients with advanced inoperable disease, the pathological diagnosis should be subtyped as much as possible, and for cases with atypical morphology, immunohistochemical staining should be combined. The diagnosis of “non-specific type” should be avoided as much as possible. Biopsies from patients with advanced NSCLC should also be examined for molecular pathology, especially in patients with adenocarcinoma. The histologic type of lung cancer in large surgically resected specimens should be based on the most recent version of the WHO lung cancer classification. The pathologic diagnosis of adenocarcinoma in situ, microinvasive adenocarcinoma, and large cell carcinoma cannot be completed in small biopsy specimens, intraoperative frozen specimens, and requires surgical resection of the specimen tumor in its entirety or adequate sampling for a definitive diagnosis.

Diagnostic Guidelines

The diagnostic guidelines for lung cancer pathology consist of specimen handling, specimen sampling, pathological examination and pathological report.

Specimen Handling Essentials: Recommended 10Neutral buffered formaldehyde fixative, avoid using fixative containing heavy metals, fixative volume should be ≥10 times the volume of the specimen being fixed, and fixation at room temperature. Specimens should not be fixed for more than 60 minutes from isolation. Biopsy specimens should be placed directly into the fixative, and lobar or whole lung resection specimens can be fixed by injecting a sufficient amount of fixative from the bronchus, or by inserting a probe along the bronchial wall and tumor incision lung tissue. Duration of fixation: 6 to 24 hours for small biopsy specimens; 12 to 48 hours for surgical resection specimens.

Fixation of cytologic smears (sputum, pleural effusion) should be performed using 95ethanol fixation

Fixation time should not be less than 15 minutes, or non-gynecologic liquid-based cytology fixative (fixation time and method can be done according to the instructions); when it is necessary to make a desquamative solution.

When wax blocks of fallen cells are to be made, the cell masses are centrifuged with the same tissue fixation procedure, using

10 The samples were fixed in neutral buffered formaldehyde fixative for ≥2 hours.

Broad description of the specimen and requirements for sampling

The biopsy specimen will be checked for accuracy and then all the tissue will be sent for sampling.
Partial pneumonectomy specimen

①Remove surgical sutures or metal staples.

②Record the size of the specimen and the condition of the pleural surface.

③Slice the lung parenchyma perpendicular to the incisional margin and describe the size of the mass, the condition of the incision (with or without hemorrhage, necrosis, or cavity formation) and its relationship to the pleura and lung parenchyma, and the distance between the margin of the mass and the incisional margin.

4. Depending on the location and size of the lesion, the tumor, tumor and pleura, and tumor and lung parenchyma margins should be excised in their entirety when the tumor is <3 cm.

5) Excision of non-tumor lung tissue. 3) Lobectomy specimens

1) Examine the five basic structures of the lung: airways, lung parenchyma, pleura, blood vessels, and lymph nodes. Measure the size and orient the specimen with the lung hilum.

②Take the bronchial margins, vascular margins, and tumors closest to the pleura, or the adhesions to other lung lobes.

③Look for hilar lymph nodes.

4. Depending on the location and status of the tumor, there are 2 options: one is to cut the specimen along the bronchial wall and the tumor through the lung tissue (with the aid of a probe inserted into the trachea), opening the bronchi and their branches to best expose the lesion in relation to all levels of bronchi and surrounding lung tissue. The structural relationship between the lesion and the bronchi and surrounding lung tissue is best exposed. The second is the injection of formaldehyde into the main bronchus

specimens with formaldehyde injected into the main bronchus are incised at 0.5- to 1.0-cm intervals, with the section being coronal and perpendicular to the pulmonary hilum.

5 Describe tumor size, cut surface (with or without hemorrhage, necrosis, or cavity formation), location within lobes and segments of the lung and relationship to bronchi, extent of lesion (focal or metastatic), and distal or local secondary changes. The number of blocks to be obtained depends on the size of the specific lesion (all tumors <3 cm should be obtained), the specific location, and the presence of concomitant lesions (related to clinical staging), and should include the tumor and the pleura, the tumor and the lobe or segmental bronchus (varies by specimen), the tumor and the surrounding lung or secondary lesions, and the tumor and the lung section or bronchial section; the cross-lobe specimen should also include the part of the tumor in relation to the cross-lobe. All lymph nodes in N2 or other areas should be counted for clinical examination. The recommended volume of the tissue block is no larger than 2.5×1.5

×0.3 cm.

Key points of pathological description: the general description includes specimen type, tumor size, relationship with bronchi (different types of specimens) or pleura, other concomitant lesions or multiple lesions. The relationship with the bronchus (different types of specimens) or pleura, other concomitant lesions or multiple lesions, and cut margins.

Diagnosis includes tumor site, histologic subtype, extent of involvement (bronchial, pleural, vascular, neurologic, type of concomitant lesions, intrapulmonary foci, lymph node metastases, etc.), margins, and special staining, immunohistochemistry, or molecular pathology as needed. The information included should meet the needs of clinical staging and give pTNM staging. For multiple lung cancers the nature of the lesion should be clarified as much as possible based on the morphologic features of the individual lesions, i.e., intrapulmonary metastatic cancer or multiple primary cancers.
Immunohistochemistry, special staining, and molecular pathology: immunohistochemical markers for differentiating adenocarcinoma from squamous carcinoma should be TTF-1 Napsin-A, p63, p40

and CK5/6, or just TTF-1 and p40 if there is insufficient tissue. The neuroendocrine tumor markers should be CD56, Syn, CgA, Ki-67 and TTF-1, and at least one neuroendocrine marker should be clearly positive on the basis of neuroendocrine morphological features, and the number of positive cells should be >10 Tumor cell volume is required for diagnosis of neuroendocrine tumors; identification of intracellular mucus material is indicated by mucus Carmine staining, AB-PAS special staining; special staining of elastic fibers should be performed to confirm suspected involvement of pleura.

Recommended for patients with stage II-IIIA NSCLC, N1/N2 positive non-squamous carcinoma, and small specimen squamous carcinoma, the tumor tissue epidermal growth factor receptor

(epidermal growth factor receptor, EGFR) mutations. For patients with advanced NSCLC, EGFR gene mutations, anaplastic lymphoma kinase (ALK), ROS1 and RET fusion genes, and CMET exon 14 jump mutations in tumor tissue should be routinely performed at the same time of diagnosis. For those who are eligible, tests for mutations in KRAS, BRAF, HER2, NTRK1/2/3 and NRG1/2 fusion genes are available. PD-L1 immunohistochemical testing for those who intend to opt for immunotherapy. Detection of EGFR mutations can be performed by amplification blocked mutation system method or high-throughput sequencing (HTSHTS); ALKfusion gene detection by Ventana immunohistochemistry, FISH, RT-PCR or HTS; ROS1 fusion gene detection by RT-PCR, FISH or HTS; RET gene fusion and CMET exon 14 The RET gene fusion and CMET exon 14 jump mutation are preferred to be detected together with other driver gene assays, either by RT-PCR or HTS. In patients with advanced NSCLC where tissue is not available, blood can be used as a complement to tissue for EGFR testing by

There is a choice of highly sensitive amplification-arrested mutation systems, HTS or digital PCR; for ALK, ROS1, RET fusion genes and CMET exon 14 jump mutation detection. Liquid biopsy specimens are not recommended as a first step. The EGFRT790M test is recommended for patients with EGFR TKIs resistance. Histology is the gold standard, and blood ctDNA EGFR T790M testing can be a useful supplement when tissue is not available.

Pathology Diagnostic Report
- Tumor

①Tissue typing (including morphological subtypes)

② Extent of involvement

③Whether the pleura is invaded

④Vascular infiltration

⑤Nerve invasion

Cut margins

①Bronchial cutting edge

②Vascular margins

③Lung margins (local lung margin specimens)

Other pathological findings (e.g., obstructive pneumonia, treatment-related changes, etc.)

Regional lymph nodes (including peribronchial, hilar, and isolated lymph nodes)

①Total

②Number of involved
- Distant metastases

Other tissues/organs
- pTNM Staging

Difficult cases are referred to a higher level hospital for consultation (provide Original pathology report to verify the information of the sent sections to reduce errors, provide adequate lesion sections or wax blocks, and intraoperative observations, etc.)

III.

(a) World Health Organization 2021 Histologic staging criteria for lung cancer.

Histologic typing and subtyping Histologic typing and subtyping

Epithelial tumors Large cell carcinoma

Papillary tumors Adenosquamous carcinoma

Bronchial papilloma Adenosquamous carcinoma Sarcomatoid carcinoma

Sclerosing pneumocytoma pleomorphic carcinoma

Alveolar adenoma Pneumoblastoma

Papillary adenoma Carcinosarcoma

Fine bronchial adenoma/ciliated mucinous nodular papillary tumor

Other epithelial tumors

Mucinous cystadenoma NUT carcinoma of the lung

Mucinous cystadenoma Chest SMARCA4-deficient undifferentiated tumor gland precursor lesion Salivary gland type tumor

Atypical adenomatous hyperplasia Polypoid adenoma

Adenocarcinoma in situ Adenoid cystic carcinoma

Adenocarcinoma epithelial-myxopapillary

Microinvasive adenocarcinoma Mucinous epidermoid carcinoma

Infiltrative non-mucinous adenocarcinoma Clear cell carcinoma with vitelliform transformation

invasive mucinous adenocarcinoma myoepithelial and myoepithelial carcinoma glioid adenocarcinoma pulmonary neuroendocrine tumor

Fetal-type adenocarcinoma Precursor lesion

Intestinal-type adenocarcinoma Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia squamous cell precursor lesion Neuroendocrine tumor

Squamous cell atypical proliferation and carcinoma in situ Carcinoid/neuroendocrine tumor squamous carcinoma Neuroendocrine carcinoma

Squamous carcinoma Small cell lung cancer

Lymphoepithelioid carcinoma Large-cell neuroendocrine carcinoma

The major tissue types of lung cancer are adenocarcinoma and squamous carcinoma, which account for approximately 80 percent of all primary lung cancersAbout 80% of all primary lung cancers are adenocarcinoma and squamous carcinoma. The next most common type of primary lung cancer is small cell carcinoma, which accounts for about 15. Other rare types of primary lung cancer include adenosquamous carcinoma, large cell carcinoma, and carcinomas of salivary gland origin (adenoid cystic carcinoma, mucinous epidermoid carcinoma, etc.). Undifferentiated tumors with SMARCA4 deficiency in the chest have been added to the latest classification. Fine bronchial adenomas have been added to epithelial benign tumors.

Squamous carcinoma

The incidence of squamous lung cancer has been on the decline in recent years, accounting for about 30 percent of lung cancers～

40 The carcinoma may be centrally located, with 2/3 of it being central and 1/3 peripheral, and may be associated with cavity formation or may protrude into the bronchial lumen in a polyp-like fashion. This type of cancer is generally recognized as

Squamous bronchial epithelial metaplasia originating from smoking stimulation is classified as highly, moderately, or poorly differentiated according to the degree of differentiation of the keratinized cells in the nest. Squamous carcinomas are more likely to have lymphatic and hematogenous metastases, and may also directly invade mediastinal lymph nodes and parabronchial and mediastinal soft tissues. Local recurrence is more common after surgery than in other types of lung cancer. There are extensive, multifocal molecular pathological abnormalities in the bronchial and pulmonary respiratory epithelium of smokers and lung cancer patients, and regional oncogenic effects can result in multicentric tumors in the lung due to smoking.

Adenocarcinoma

Adenocarcinoma accounts for 40 to 55 of lung cancers img src=”https://www.kiraspecialist.com/wp-content/uploads/2022/06/062222_1314_202267.png” alt=””/>, and has surpassed squamous carcinoma as the most common type of lung cancer in many countries. Adenocarcinoma is clinically more common as a peripheral type, and cavity formation is rare. The most significant changes in the pathology of lung adenocarcinoma in recent years have been the introduction of the concept of adenocarcinoma in situ, the recommendation to discontinue the term bronchoalveolar carcinoma, and the recommendation to discontinue the use of mixed adenocarcinoma as a type of infiltrative adenocarcinoma with the predominant component and the proportion of other components. (1) Atypical adenomatous hyperplasia (AAH), which is at least a precancerous lesion of lung adenocarcinoma, is usually less than 0.5 cm in size and is often characterized by glassy changes on CT scan. The microscopic histology shows intact alveolar structure, consistent alveolar epithelial hyperplasia in a rectangular or short columnar shape, mild atypia, and lack of or blurred nuclei. (2) Adenocarcinoma in situ (AIS), a new concept introduced in 2011, is defined as a solitary adenocarcinoma ≤3 cm, consisting of type II alveolar epithelium and/or clara cells confined to normal alveolar structures (epithelial growth). The disease-free survival rate for surgical resection of AIS is 100. (3) Micro-invasive adenocarcinoma (MIA).

MIA is defined as a solitary adenocarcinoma ≤3 cm, well-defined, with predominantly epithelial growth and an infiltrative form other than epithelial, with a maximum diameter of infiltrating interstitium ≤5 mm, excluding risk factors such as vascular invasion, pleural invasion, and intra-airway dissemination of tumor cells. Adenocarcinoma with multifocal occurrence in the lung may also be suitable for the diagnosis of MIA, provided that the possibility of intrapulmonary dissemination is excluded. The overall 5-year survival rate for MIA with complete resection is 100. (4) Invasive adenocarcinoma. Adenocarcinoma may be solitary, multiple, or present diffusely. The main types of invasive adenocarcinoma are epithelial, alveolar, papillary, micropapillary, and solid. The micropapillary and solid types are poorly differentiated subtypes and should be labeled with percent content.

Neuroendocrine carcinoma

Pulmonary neuroendocrine tumors are classified into carcinoid/neuroendocrine tumors (typical carcinoid, atypical carcinoid) and small cell lung cancer and some large cell neuroendocrine cancers. Small-cell lung cancer accounts for 15 of all lung cancers and is a poorly differentiated neuroendocrine carcinoma with common necrosis and a high high nuclear fission index. Small cell lung cancer has neuroendocrine granules on electron microscopy in at least 2/3 of cases. Complex small cell carcinoma refers to small cell carcinoma combined with other non-small cell lung cancer types and is seen in less than 10 cases of small cell carcinoma. Based on clinical behavior and pathologic features, carcinoid/neuroendocrine tumors are divided into typical carcinoid tumors, which are less malignant, and atypical carcinoid tumors, which are slightly more malignant. The distinction between the two is made by the presence or absence of small focal necrosis, which is also distinguished by the presence or absence of 2 nuclear images in the microscopic field of 2 mm2. Atypical carcinoid tumors are more often peripheral than typical carcinoid tumors and have an increased metastasis rate and a relatively poor prognosis. Large cell neuroendocrine carcinoma is a large cell carcinoma with immunohistochemical and morphologic features of neuroendocrine differentiation. It is usually a peripheral nodule with necrosis and has a prognosis similar to that of small cell carcinoma

Similarly, compound large cell carcinoma is a combination of other well-differentiated non-small cell cancer components, most of which are adenocarcinomas.

Other types of lung cancer

(1) Adenosquamous carcinoma: only 0.6 of all lung cancers~2.3 . According to the new WHO classification, tumors must contain at least 10 of adenocarcinoma or squamous carcinoma to be diagnosed as adenocarcinoma Squamous carcinoma, often located peripherally and associated with central scar formation. Metastatic features and molecular biology do not differ from other non-small cell carcinomas. (2) Sarcomatoid carcinoma: A poorly differentiated type of non-small cell carcinoma with sarcoma or sarcomatoid component [spindle and/or giant cell-like]. (3) Carcinoma of salivary gland origin: including adenoid cystic carcinoma, mucinous epidermoid carcinoma, and epithelial-myoepithelial carcinoma. The key to differentiation is that the latter is a poorly differentiated adenocarcinoma with obvious heterogeneity. (4) Large-cell carcinoma is a poorly differentiated adenocarcinoma without the differentiation features of adenocarcinoma, squamous carcinoma, or small-cell carcinoma, and is a diagnosis of exclusion.

(5) In addition to NUT carcinoma, the new classification adds undifferentiated tumors with SMARCA4 deficiency in the thorax, a highly malignant undifferentiated tumor with a unique immunohistochemical phenotype and biological behavior, accompanied by SMARCA4 gene mutations and deletion of protein expression.

Immunohistochemistry and specific staining

Rational and appropriate selection of immunohistochemistry programs can effectively preserve sufficient tissue specimens for molecular diagnosis. When tumors are poorly differentiated and lack clear morphologic features of adenocarcinoma or squamous carcinoma, the use of immunohistochemistry or mucin staining is necessary for definitive diagnosis. Immunohistochemical markers for differentiation of adenocarcinoma from squamous carcinoma are appropriate for TTF-1, Napsin-A, and

p63, p40, and CK5/6, with p40 and TTF-1 addressing the majority of adenocarcinoma and squamous carcinoma differential diagnoses. For patients with further disease progression, in order to preserve tissue for molecular pathology as much as possible, the use of restrictive immunohistochemical index tests for histologic classification is recommended, for example, detection of the protein p63/p40, which is expressed singly on squamous carcinoma cells, and TTF-A/Napsin-1, which is expressed singly on adenocarcinoma cells, will classify most non-small cell lung cancers. The identification of solid-type adenocarcinoma with intracellular mucus material should be confirmed by mucus carmine staining and AB-PAS special staining; special staining of elastic fibers should be performed when pleura is suspected to be involved. The diagnosis of neuroendocrine tumors can be made by using CD56, Syn, CgA, Ki-67, and TTF-1. At least one neuroendocrine marker is clearly positive on the basis of neuroendocrine morphologic features, and the number of positive cells should be >10% of the tumor cell volume; the diagnosis of neuroendocrine tumors should be closely combined with pathologic morphology if only CD56 is positive for endocrine markers.

(ii) Staging of lung cancer.

TNM staging (pTNM staging UICC 8th edition) is based on the following criteria.T staging (primary tumor)

pTX: No primary tumor found, or cancer cells found by sputum cytology or bronchial lavage but not detected by imaging and bronchoscopy.

pT0: no evidence of primary tumor. pTis: carcinoma in situ

pT1: tumor ≤3 cm in maximum diameter, surrounded by lung tissue and dirty pleura, and bronchoscopically seen to invade the lobar bronchi but not the main bronchi.

pT1mi: microinvasive adenocarcinoma.

pT1a: tumor ≤ 1 cm in maximum diameter. pT1b: tumor 1 cm< maximum diameter ≤ 2 cm. pT1c: tumor 2 cm< maximum diameter ≤ 3 cm.

pT2: Tumor 3cm<maximal diameter ≤5cm; or tumor invades main bronchus

(Uncommon superficially spreading tumors, regardless of size, are T1 when invasion is limited to the bronchial wall, although they may invade the main bronchus) but do not invade the bullae; invade the dirty pleura; have obstructive pneumonia or partial or total atelectasis. Any 1 of these conditions is classified as T2.

pT2a: tumor 3cm< maximal diameter ≤4cm. pT2b: tumor 4cm< maximal diameter ≤5cm

pT3: tumor 5cm<maximal diameter ≤7cm. or any size tumor directly invading any 1 of the following, including: chest wall (including supraglottic sulcus tumor), phrenic nerve, and

pericardium; isolated cancer nodules in the same lung lobe. If any 1 of these conditions is met, the patient is classified as T3.

pT4: Tumor >7 cm in maximum diameter; invades any 1 of the following sites regardless of size, including: mediastinum, heart, great vessels, ramus, recurrent laryngeal nerve, main trachea, esophagus, vertebral body, diaphragm; isolated cancer nodules in different lung lobes on the same side.

N-Regional lymph nodes

pNX: regional lymph nodes could not be assessed. pN0: no regional lymph node metastasis.

pN1: Metastases to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary lymph nodes, including those involved by direct invasion.

pN2: Metastases in the ipsilateral mediastinum and/or subserosal lymph nodes.

pN3: Contralateral mediastinal, contralateral hilar, ipsilateral or contralateral anterior oblique muscle, and supraclavicular lymph node metastases.

M-Distant metastases.

MX: Distant metastasis cannot be determined.

pM1a: focal intrathoracic, contralateral intrapulmonary cancer nodule; pleural or pericardial nodule; or malignant pleural (pericardial) exudate.

pM1b: distant single-organ unifocal metastasis (including a single non-regional lymph node metastasis) beyond the thoracic cavity.

pM1c: distant single-organ multifocal metastasis/multi-organ metastasis beyond the thoracic cavity. Clinical staging

Cryptogenic carcinoma: TisN0M0

Stage IA1: T1a(mis)N0M0, T1aN0M0 Stage IA2: T1bN0M0

IA3 phase: T1cN0M0 IB phase: T2aN0M0

Phase IIA: T2bN0M0

Phase IIB: T1a~cN1M0, T2aN1M0, T2bN1M0, T3N0M0

Phase IIIA: T1a~cN2M0, T2a~bN2M0, T3N1M0, T4N0M0, T4N1M0

Phase IIIB: T1a~cN3M0, T2a~bN3M0, T3N2M0, T4N2M0 Phase IIIC: T3N3M0, T4N3M0

Phase IVA: any T, any N, M1a, any T, any N, M1b Phase IVB: any T, any N, M1c

IV.

The treatment of lung cancer should be based on a combination of multidisciplinary team (MDT) and individualized treatment, i.e., according to the patient’s body condition, tumor’s The MDT model is based on the patient’s physical condition, the pathological histological type and molecular typing of the tumor, the extent of invasion and the trend of development, and the planned and rational application of surgery, radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy, with the aim of maximizing the patient’s survival time, increasing the survival rate, controlling tumor progression and improving the patient’s quality of life.

(i) Surgical treatment.

Anatomic pneumonectomy is the primary treatment for early to mid-stage lung cancer and is currently the key clinical cure for lung cancer. Lung cancer surgery is divided into complete resection, incomplete resection and indeterminate resection. We should strive for complete resection to achieve complete removal of the tumor, reduce metastasis and recurrence, and perform accurate pathological TNM staging and strive to clarify molecular pathological staging to guide comprehensive postoperative treatment.

Surgical Anatomy of the Bronchial and Pulmonary Systems

The trachea is the airway that connects the pharynx to the bronchopulmonary system. The length of the trachea is approximately 10-13 cm, starting from the lower edge of the cricoid cartilage (approximately the lower edge of the flat 6th cervical vertebra) to the ramus (approximately the level of the 4th thoracic vertebra), usually with 18-22 cartilage rings. The blood supply to the trachea is segmental, with the upper part coming mainly from branches of the inferior thyroid artery and the lower part from branches of the bronchial artery. Therefore, the trachea should not be freed too much, as this may affect the blood supply and healing of the preserved trachea.

The trachea divides into the left and right main bronchus at the level of the bulge. The angle of the main bronchus to the trachea is flatter on the right than on the left, and tracheal foreign body aspiration is more likely to enter the right main bronchus

The right main bronchus is further divided into the right main bronchus and the right main bronchus. The right main bronchus is further divided into the right upper lobe bronchus and the middle segment bronchus. The middle segment bronchus is further divided into middle and lower lobe bronchus. The right upper lobe bronchus is further divided into three segments: the apical, posterior, and anterior bronchi. The middle lobe bronchus is divided into medial and external

Lateral 2 segmental bronchi. The lower lobe bronchi emit dorsal segmental bronchi and a total of 4 basal segmental bronchi, medial, anterior, lateral, and posterior. The length of the left main bronchus is about 4.5-5 cm, and it is divided into upper and lower lobe bronchi downward. The left upper lobe bronchus is subdivided into the intrinsic upper lobe bronchus and the lingual lobe bronchus. The former is usually divided into anterior and post-apical bronchi, while the latter is divided into supralingual and inferior lingual bronchi. The lower lobe bronchi give off dorsal segments and anterior internal, external, and posterior basal segment bronchi. The right lung consists of the horizontal and oblique fissures, which are divided into 3 lobes and 10 segments, accounting for 55 respiratory functions. The left lung is divided by the oblique fissure

2 lobes and 8 segments, accounting for 45respiratory function.

Blood flow to the lungs includes the pulmonary circulatory system of the pulmonary arteries and the body circulatory system of the bronchial vessels. The bronchial arteries mainly emanate from the descending aorta or intercostal arteries and travel with the bronchi, eventually forming a network of capillaries supplying the bronchi in the bronchial epithelium and submucosa. The venous blood mainly flows into the pulmonary veins, and to a lesser extent into the bronchial veins, and then into the odd and semi-odd veins. The common pulmonary artery trunk originates from the right ventricle and travels upward to the left, dividing into the left and right pulmonary artery trunks under the aortic arch. The right pulmonary artery trunk is longer than the left pulmonary artery trunk, but it begins to branch earlier than the left. The pulmonary artery is usually accompanied by the corresponding bronchus. Both the right and left pulmonary veins include the upper and lower pulmonary veins, which converge into the left atrium, respectively. The right middle pulmonary vein usually co-trunks with the right upper pulmonary vein to form the upper pulmonary vein.

Indications for lung cancer surgery

The absolute indications for lung cancer surgery from the perspective of lung cancer alone are also known as the indications for lung cancer surgery.

The more consistent indications for lung cancer surgery are lesions in the T1-3N0-1M0 stage; the relative indications for lung cancer surgery, which are currently accepted by most people, are lesions in the partial T4N0-1M0 stage; the more controversial indications for lung cancer surgery are lesions in the T1-3N0-1M0 stage; and the more controversial indications for lung cancer surgery are lesions in the T4N0-1M0 stage. The more controversial indications for lung cancer are lesions in stages T1 to 3N2M0; exploratory indications for lung cancer include some isolated metastatic lesions in stages T1 to 3N0 to 1M1.

Contraindications to lung cancer surgery

Recognized contraindications to surgery for lung cancer include: (1) lung cancer beyond the indication for surgery; (2) poor systemic status with a Canovske score of less than 60: it is recommended that the score be considered in conjunction with the ECOG score in line with international practice; (3) acute myocardial infarction within 6 weeks; (4) severe ventricular arrhythmias or uncontrolled heart failure; (5) cardiopulmonary failure for the intended procedure; (6) 75 years of age or older and carotid stenosis greater than 50, under 75 years of age with carotid stenosis greater than 70 or more (7) those over 80 years of age with lesions requiring total pneumonectomy; (8) severe, uncontrollable concomitant disease that persistently impairs the patient’s physical and psychological function; and (9) patients who refuse surgery.

The concept of complete resection for lung cancer

Currently, complete surgical resection of lung cancer should include anatomic lobectomy (including composite lobectomy) and partial lobectomy (for some early-stage lung cancers), total pneumonectomy or bronchial or (and) pulmonary angioplasty lobectomy (including The NCCN guidelines specifically define complete resection for lung cancer as (1) negative for all margins including bronchi, arteries, veins, peribronchial tissue, and tissue adjacent to the tumor; (2) systemic or lobar systemic

Lymph node dissection, which must include 6 groups of lymph nodes, 3 from intrapulmonary (lobar, interlobular, or segmental) and hilar lymph nodes and 3 from mediastinal lymph nodes, including subserosal lymph nodes; (3) separate (3) the mediastinal lymph nodes or marginal lymph nodes of the resected lobe must not have extra-nodal invasion; and (4) the highest lymph node must be resected and microscopically negative. Only if all 4 conditions are met can the lung be classified as a complete resection; otherwise, it is an incomplete or inconclusive resection.

Lymph node dissection for lung cancer

Mediastinal/portal/segmental lymph node dissection is an integral part of complete lung cancer resection, and lobectomy or total pneumonectomy with systematic mediastinal lymph node dissection is considered to be the standard procedure for lung cancer surgery. However, recent high-level evidence-based medical evidence suggests that partial lobectomy with lung lobe specific lymph node dissection has a long-term survival rate that is not inferior to the standard procedure and may also be an option for some early stage lung cancers.

The currently common international atlas of draining lymph nodes in lung cancer is the 2009 Lymph Node Atlas of the International Consortium for the Study of Lung Cancer. The mediastinal lymph nodes include 9 groups of lymph nodes from station 1 to 9, and the hilar lymph nodes include all groups of lymph nodes up to station 10. The standard mediastinal lymph node dissection requires complete resection of the mediastinal lymph nodes and their surrounding adipose tissue, also known as complete mediastinal lymph node dissection.

Overview of lung cancer surgery

Lung cancer surgery can be divided into: complete resection (radical resection) and incomplete resection (palliative resection), as well as biopsy surgery mainly for diagnostic purposes, depending on how much lung tissue is removed; wedge resection (partial resection), segmental resection, lobectomy, and compound lobectomy, depending on how much lung tissue is removed (removal of more than 1 lobe containing the tumor), total lung

resection, pneumonectomy with tracheal, bronchial, and/or pulmonary angioplasty, and extended lung cancer resection with combined resection of tumor-invaded organ tissue. The size of the incision and trauma can be divided into: conventional open-heart surgery, small-incision open-heart surgery and minimally invasive thoracoscopic surgery. The term lung cancer resection is generally used to refer to complete resection.

The standard method of anesthesia for lung cancer resection is double-lumen tracheal intubation, with the lung on the operated side being unventilated. The patient is placed in the healthy-side position. The surgical incision is usually made through a posterior lateral incision into the chest cavity via the 5th or 6th intercostal space; for a thoracoscopic incision, the incision is made according to the patient and the surgeon’s

Variations in thoracoscopic incisions vary according to the patient’s and surgeon’s preferences, usually with single-port thoracoscopy through 4 or 5 intercostal spaces, and more variable with two/three port thoracoscopy. The surgical keys to lobectomy are ligation and dissection of the arterial branches and pulmonary veins of the lobe, dissection and closure of the lobe bronchi, and dissection of the interlobular lung fissures. For lobectomy, surgery starting with dissection of the lung fissures is the usual choice. Sleeve lobectomy is usually considered when the central lung cancer tumor encroaches on the lobar bronchial opening, when there is tumor remaining at the bronchial margin of the lobectomy or when it is too close to the tumor. If the bronchial margins of the sleeve lobectomy are still inadequate, then total pneumonectomy needs to be considered. The most common reason for total pneumonectomy is not a positive bronchial margin, but rather invasion of the pulmonary artery. Clinically, total pneumonectomy is usually performed on the left side. Right-sided total pneumonectomy is rarely performed because of the high level of pulmonary impairment, the low quality of life of the patient and the poor tolerance of postoperative adjuvant therapy. Complex lobectomies are mainly middle and lower lobectomies and upper and middle lobectomies of the right lung. Middle and lower lobectomy of the right lung is commonly performed because the middle lobe of the right lung invades the middle lobe bronchial opening and the dorsal segment of the lower lobe of the right lung invades the segmental bronchial opening, and middle and lower lobectomy is usually required to ensure negative bronchial margins. Since the pulmonary veins of the middle lobe of the right lung usually converge

into the upper lobe pulmonary veins that make up the right upper pulmonary vein, either upper or middle lobe carcinoma of the right lung may require upper or middle lobectomy if it invades the confluence of the upper and middle lobar veins of the right upper pulmonary vein. The anatomic partial lobectomy, which includes segmental, combined segmental, and combined subsegmental resections, is more delicate and complex, and 3D reconstruction software can help the surgeon complete the procedure more accurately and smoothly.

Surgical Complications of Lung Cancer

The complication rate after lung cancer surgery is about 8to 35 . Complications of surgical procedures can occur, most commonly respiratory and cardiovascular complications, while the more unique complications of pneumonectomy include postoperative air leak in the lung section and bronchopleural fistula.

Respiratory complications: Most commonly seen in patients with preoperative chronic bronchitis. The common complication is poor pulmonary reopening on the surgical side, including atelectasis and obstructive emphysema. The main cause is the blockage of bronchi by sputum. In some patients, due to early anesthetic intubation, intraoperative rub injury, and repeated pulmonary atrophy and reopening, there is an increase in secretion from the affected lung, as well as an inability to cough up sputum due to pain, vagal nerve bronchial branch injury, and inadequate ventilation. The clinical manifestations are decreased breath sounds in the affected lung, shortness of breath, decreased oxygen saturation, and fever and other symptoms of infection. In severe cases, bronchoscopic aspiration is required, and in rare patients, tracheotomy is required.
Lung cross-sectional air leak: most often seen in patients with preoperative emphysema, pulmonary aspergillosis, and in some patients with partial lobectomy due to trauma. It also occurs in some patients with partial lobectomy due to large lung trauma, mainly due to air leakage from the lung fissure during dissection. The clinical manifestation is a chest drainage tube

Prolonged and persistent air bubble escape. The diagnosis should exclude bronchopleural fistulas, and the key to treatment is adequate drainage to ensure good reopening of the remaining lung and prevention of infection. The majority of patients have a gradual decrease in air leakage from the section with postoperative tissue adhesions.

Bronchopleural fistula: A bronchopleural fistula is a series of clinical signs and symptoms caused by a poorly healed bronchial dissection where the bronchial stump communicates with the pleural space. Vest et al. 1991 summarized 2243 cases of pulmonary surgery in which bronchopleural fistulas

The incidence of bronchopleural fistula was 1.6, with a large group of domestic cases reporting an incidence of about 1, mostly seen in

at about 1 week postoperatively. Clinical manifestations include cough and sputum, shortness of breath, and fever. The signs and chest radiographs mainly showed encapsulated liquid pneumothorax, pus thorax changes, and some patients had aspiration pneumonia changes. The cough and sputum are suggestive. Initially, the sputum is significantly increased, thinner and light red pleural effusion-like, further it can appear as pus sputum, especially when there is obvious pus chest. However, the most direct diagnostic modality is tracheoscopy. Treatment is based on chest drainage, with drains placed around the fistula as much as possible. For early postoperative occurrences, surgical repair may be attempted; otherwise, surgical repair is very difficult and most can only be drained. Placement of a tracheal stent to temporarily close the fistula has been reported. Closure of the fistula with medical bioprotein gel has been reported in cases after the inflammation has been limited.
- Advances in the surgical treatment of lung cancer
The role of televised thoracoscopic surgery in the surgical management of lung cancer: Televised thoracoscopic surgery is one of the greatest advances and developments in thoracic surgery technology in the last 20 years. The role of TV thoracoscopic surgery in lung cancer surgical treatment is gaining more and more attention and is one of the future directions of lung cancer surgical treatment. There are many different opinions about the indications for the procedure, which depend on how early or late the procedure is performed by medical units and the surgeon.

preferences and proficiency of the surgeon. However, as noted in the NCCN guidelines, the premise of thoracoscopic surgery as the procedure of choice in lung cancer surgery is consistent with the principle of lung cancer surgery, which is to ensure the safety of the procedure without compromising the completeness of surgical resection.

Surgical options for early-stage peripheral lung cancer: lobectomy has long been considered by most thoracic surgeons to be the standard procedure for surgical resection of stage I non-small cell lung cancer, and recent clinical evidence supports that for However, recent clinical evidence supports that for peripheral stage I non-small cell lung cancer up to 2 cm in diameter, especially purely ground glass nodules, lung segmental resection or wedge resection may be a better surgical resection option. With the increasing number of retrospective reports, the use of partial lobectomy (segmental or wedge resection) for peripheral early-stage lung cancer with a predominantly ground-glass component is becoming the consensus in thoracic surgery. The recent results of the large randomized controlled trial JCOG0802 showed that in patients with a solid component greater than 50 and peripheral non-small cell lung cancer with a tumor diameter ≤2 cm, 5-year survival is better with segmental resection than with lobectomy and better preservation of lung function. As more studies like this are disclosed, partial lobectomy may become the standard procedure for this type of lung cancer.

(ii) Radiation therapy.

Radiotherapy for lung cancer includes radical radiotherapy, palliative radiotherapy, adjuvant radiotherapy, and prophylactic radiotherapy.
- Principles of radiotherapy
Radical radiotherapy: for patients with Canovskite score ≥70, including early-stage NSCLC inoperable due to medical or (and) personal factors

(stereotactic radiotherapy), unresectable locally advanced NSCLC, and limited-stage SCLC.
- Palliative radiotherapy: for both primary and metastatic foci of advanced lung cancer

Decompensative therapy. For patients with surgically resected single brain metastases from NSCLC, observation or local radiotherapy in the operative area, for patients with single metastases or oligometastases from NSCLC, stereotactic radiotherapy can be considered, and for patients with extensive stage SCLC, thoracic radiotherapy is feasible.

Adjuvant radiotherapy: for preoperative radiotherapy, postoperative radiotherapy with positive cut margins

(R1 and R2); patients with inadequate surgical exploration or close surgical margins; for patients with positive postoperative pN2, participation in clinical studies of postoperative radiotherapy is encouraged, and postoperative radiotherapy is recommended in the NCCN guidelines (2021.v4) based on the results of nonrandomized studies.

Design of postoperative radiotherapy: the patient’s surgical pathology report and surgical records should be consulted.
Prophylactic whole-brain radiotherapy after complete remission with a combination of chemotherapy and radical radiotherapy in the limited phase of SCLC. Patients with effective chemotherapy in the extensive phase can be followed closely with either prophylactic whole-brain radiotherapy or brain MRI.
Synchronous radiotherapy is recommended for patients with inoperable locally advanced NSCLC. If the patient cannot tolerate it, sequential radiotherapy can be administered. The recommended regimen for synchronous chemotherapy is EP (pegylated glycosides + cisplatin) or TC (paclitaxel + carboplatin), and pemetrexed in combination with cisplatin or carboplatin can also be one of the preferred regimens for synchronous or sequential administration in nonsquamous cell NSCLC.
Immune checkpoint inhibitor dulvalizumab (PD-L1 monoclonal antibody) for locally advanced Consolidation therapy after concurrent radiotherapy for NSCLC has been shown to significantly prolong overall survival and progression-free survival (PACIFIC study, Class 1 evidence), and PD-L1 expression is not mandatory, but there may be no significant benefit in overall survival for those with negative PD-L1 expression. And grade 3 to 4 serious adverse reactions (including grade 3

and above pneumonia) were not statistically significant compared with controls.

Patients receiving radiotherapy/chemotherapy are at increased risk for potential adverse effects and should be informed prior to treatment. The lungs, heart, esophagus, and spinal cord should be protected when designing and administering radiation therapy. Unplanned interruptions of radiotherapy due to inadequate management of adverse reactions should be avoided whenever possible during treatment.
Advanced radiotherapy techniques such as 3D conformal radiotherapy, intensity-modulated radiotherapy techniques, or image-guided radiotherapy are used. Stereotactic body radiation therapy (SBRT) is recommended with excellent radiophysical technology.
Enhanced CT localization or PET localization is recommended when outlining the target area for radiotherapy. The tumor target can be outlined in the enhanced CT localization image by referring to the tumor bio-image from PET.
Patients receiving radiotherapy or radiochemotherapy should be adequately monitored and supported during treatment breaks.
- Indications for radiotherapy in NSCLC
Radiotherapy can be used for radical treatment of early-stage NSCLC patients who are medically inoperable or refuse surgery, preoperative and postoperative adjuvant therapy for operable patients, local treatment for patients with unresectable locally advanced lesions, and palliative treatment for patients with advanced incurable disease. treatment.

Major fractionated radiation therapy is an effective radical treatment for patients with stage I NSCLC who are medically unfit for surgery or who refuse surgery, and SBRT is recommended. Biological effectors are usually given

A dose of ≥100 Gy should be fully considered and carefully evaluated when planning SBRT. The tolerated dose of radiation therapy to the spinal cord, esophagus, trachea, heart, chest wall, and brachial plexus nerve should be fully considered and carefully evaluated when planning SBRT.

For patients with surgically treated NSCLC with negative postoperative surgical margins and positive mediastinal lymph nodes (stage pN2), postoperative radiotherapy may be added to the usual postoperative adjuvant chemotherapy, and a chemotherapy followed by sequential radiotherapy sequence is recommended. The sequence of chemotherapy followed by sequential radiotherapy is recommended. For those with significant residual (R2 resection), simultaneous postoperative radiotherapy is recommended, if physically possible.

For patients with stage II-III NSCLC who cannot undergo surgery for medical reasons, conformal radiotherapy or intensity-modulated radiotherapy should be given in combination with concurrent chemotherapy, if physically possible. For patients with clinical hope of cure, a more conformal radiotherapy plan and more aggressive supportive therapy should be used to minimize interruption of treatment time or reduction of treatment dose when receiving radiotherapy or concurrent radiotherapy. For patients with stage IV NSCLC with extensive metastases, some patients may receive radiation therapy to both primary and metastatic sites for palliative reduction. When the benefit of systemic therapy is evident in patients with oligometastases, SBRT techniques may be considered to treat residual primary and/or oligometastases for potential radical results.

Indications for radiotherapy in SCLC

The combination of radiotherapy and chemotherapy is the standard of care for limited-stage SCLC. Patients with limited-stage SCLC are recommended to have synchronized chemoradiotherapy with initial treatment or 2 cycles of induction chemotherapy followed by synchronized chemoradiotherapy. If the patient cannot tolerate it, sequential chemoradiotherapy is also available. Radiation therapy for limited-stage SCLC should be started as early as possible, if possible, and can be considered in conjunction with the first or second cycle of chemotherapy. If the lesion is large, radiation

If the risk of lung injury from radiation therapy is too high, consider also synchronizing radiation therapy with the 3rd cycle of chemotherapy.

For patients with extensive SCLC, the addition of thoracic radiotherapy after control of distant metastases with chemotherapy may also improve tumor control and prolong survival; there is no prospective evidence to further improve the efficacy of thoracic radiotherapy in patients treated with chemotherapy in combination with immunotherapy. evidence from randomized controlled clinical trials; participation in clinical studies is encouraged.

Preventive Brain Irradiation

Patients with limited-stage SCLC are recommended to undergo prophylactic brain irradiation after complete remission of intrathoracic lesions with treatment, as well as in patients who achieve partial remission. Prophylactic brain irradiation may also reduce the risk of brain metastases in SCLC when chemotherapy is effective in extensive SCLC. The recommended time for prophylactic brain irradiation is approximately 3 weeks after all chemoradiotherapy, preceded by brain-enhanced MRI to rule out brain metastases, with a recommended whole-brain radiation dose of 25 Gy in 10 fractions over 2 weeks.

The decision for whole-brain prophylactic irradiation in extensive SCLC should be fully discussed between the physician and patient, weighing the pros and cons on a case-by-case basis.

Patients with oligometastatic stage IV: The definition is not uniform, with no more than 3 metastatic organs, no more than 5 metastatic lesions, and the feasibility of radical therapy considered important factors in defining oligometastatic status. If systemic therapy is effective (chemotherapy, targeted therapy, etc.), aggressive local therapy (SBRT, surgery, etc.) targeting the residual primary site and/or oligometastases may prolong disease control and patient survival for a potentially curative outcome. Because of the lack of high-level evidence, consolidation of local therapy after oligometastatic stage IV patients should be decided through MDT discussions that

Recommended participation in clinical studies.

Palliative radiotherapy for patients with advanced lung cancer

The primary goal of palliative radiotherapy for patients with advanced lung cancer is to address local compression symptoms due to primary or metastatic lesions, pain due to bone metastases, and neurological symptoms due to brain metastases. The use of large fractionated irradiation techniques can be considered for such patients, allowing for easier access to treatment and more rapid symptom relief.

Treatment results

The evaluation of the recent efficacy of radiation therapy was performed according to WHO criteria for evaluating the efficacy of solid tumors.

Protection

Advanced radiotherapy techniques are used whenever possible, with attention to lung, heart, esophagus and spinal cord protection to avoid serious radiation injury. The study was conducted by the International Consortium for Radiation Therapy in Oncology (ICRTO), and was based on the International Classification of Radiation Injuries in Oncology (ICRAO).

(iii) Drug therapy.

Pharmacologic therapy for lung cancer includes chemotherapy, molecular targeted therapy, and immunotherapy. Chemotherapy is divided into neoadjuvant, adjuvant, and palliative chemotherapy, which should be administered under the guidance of a medical oncologist with strict clinical indications. Chemotherapy should be administered under the guidance of medical oncologists, taking into account the patient’s disease stage, physical condition, adverse effects, quality of life and patient’s wishes, and avoiding over- or under-treatment. The efficacy of chemotherapy should be evaluated in a timely manner, adverse effects should be closely monitored and prevented, and drugs and/or doses should be adjusted as appropriate. Molecularly targeted therapy requires the identification of gene mutation status and guidance of targeted therapy based on molecular typing. In recent years, immune checkpoint inhibitors (e.g., PD-1 monoclonal antibody or PD-L1) have been used to treat the patient.

monoclonal antibodies, etc.) have been shown to improve survival in lung cancer patients. Multiple PD-1 monoclonal antibodies and/or PD-L1 monoclonal antibodies are currently approved and marketed for the treatment of advanced and locally advanced NSCLC and SCLC, and additional clinical indications are still being explored.

Pharmacological treatment of advanced NSCLC

First-line drug therapy: For patients with driver-negative disease, a platinum-containing two-drug regimen is the standard first-line chemotherapy regimen, and for non-squamous cancer patients can be combined with anti-vascular therapy such as bevacizumab or vascular endothelial inhibitory protein on top of chemotherapy. A platinum-containing two-drug chemotherapy based on karilizumab, pablizumab, tirelizumab, sindilizumab or atelelizumab in combination with pemetrexed is recommended. For squamous carcinoma, two-drug chemotherapy with pablizumab, tirelizumab in combination with paclitaxel or sindilizumab in combination with gemcitabine is recommended. If the patient is PD-L1 positive (TPS ≥1), pabolizumab monotherapy is feasible. The benefit of immunotherapy was more pronounced in patients with high PD-L1 expression (TPS ≥50 ). Patients with high PD-L1 expression (TC ≥ 50 or IC ≥ 10 ), may also receive atelelizumab monotherapy. For patients with driver gene positivity, such as EGFR mutation

(including exon 19 deletions, exons 21 L858R and L861Q, exon 18 G719X, and exon 20 S768I) positive patients can choose epidermal growth factor receptor tyrosine kinase inhibitors ( epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), including gefitinib, erlotinib, erlotinib, erlotinib, daclotinib, afatinib, or oseltinib. The first-line treatment with gefitinib or erlotinib may also be considered in combination with chemotherapy, and erlotinib may be combined with bevacizumab.

Patients with positive ALK fusion gene can be treated with alectinib, ceritinib, or crizotinib. Patients with positive ROS1 fusion gene may be treated with crizotinib. For patients with C-met14 jump mutation who are intolerant to chemotherapy, cervolitinib is an option. The current treatment options are detailed in Tables 2 and 3.

Table 2 Common first-line chemotherapy and chemotherapy-combined immunotherapy regimens for non-small cell lung cancer

chemotherapy regimen	Dose	dosing time	Time and period
NP Program Changchun Ruibin	25 mg/m 2	Day 1, 8	21 days for 1 cycle,
Cisplatin	75 mg/m2	Day 1	4 to 6 cycles
TP program Paclitaxel	135 to 175 mg/m2	Day 1
Cisplatin or carboplatin Cisplatin	75 mg/m 2	Day 1	< span style="font-family:Arial; font-size:12pt"> Day 1	< span style="font-family:Arial; font-size:12pt">21 days for 1 cycle. 4 to 6 cycles
Carboplatin	AUC=5 to 6	Day 1
GP Program Gemcitabine	1000 to 1250 mg/m2	Day 1, 8
Cisplatin or carboplatin Cisplatin	75 mg/m 2	Separate Day 1 and 2	21 days for 1 cycle. 4 to 6 cycles
Carboplatin	AUC=5 to 6	Day 1
DP Program Docetaxel	60 to 75 mg/m2	Day 1
Cisplatin or carboplatin				< span style="font-family:Arial; font-size:12pt">21 days is 1 cycle,

Cisplatin Carbide

Nedaplatin (squamous carcinoma only)

75 mg/m2 AUC=5 to 6

100 mg/m2

Day 1

4 to 6 cycles

PP program

Pemetrexed

(Non-squamous carcinoma)

500 mg/m2

Day 1

< td>

Carboplatin

4 to 6 cycles

< /tr>

Cisplatin or carboplatin

Cisplatin

75 mg/m 2

Day 1

21 days for 1 cycle

AUC=5-6

Day 1

4 to 6 cycles

LP Program

Paclitaxel Lipid

135 to 175mg/m2

Day 1

21 days for 1 cycle

Body

Pabrolizumab in combination with a platinum-containing doublet (squamous carcinoma)

Cisplatin or carboplatin				4-6 cycles
Cisplatin	75mg/m2	Day 1
Cappella	AUC=5~6	Day 1
Gicitabine in combination with docetaxel
Gicitabine	1000 to 1250 mg/m2	Day 1, 8	21 days for 1 cycle
Doxorubicin	60 to 75 mg/m2	Day 1	4 to 6 cycles
Gicitabine in combination with Vincristine
Gicitabine	1000 to 1250 mg/m2	Day 1, 8	21 days for 1 cycle
Changchun Ruibin	25 mg/m2	Day 1, 8 span>	4 to 6 cycles

td>

day

Pabolizumab 200mg Anti Paclitaxel/albumin-bound paclitaxel 200mg/m< span style="font-size:6pt">2	Day 1 Day 1	21 days for 1 cycle 4 cycles
< p style="margin-left: 26pt">Abumin binding 100mg/m2	th 1, 8, 15	<
Type 2 paclitaxel
Card Platinum AUC=6	Day 1

Pabrolizumab in combination with a platinum-containing doublet (non-squamous carcinoma)

Pabrolizumab 200mg day 1 21 days for one cycle of anti
Pemetrexed
500mg/m2
Day 1
4 cycles carboplatin AUC=5 day 1
Tirelizumab in combination with carboplatin and paclitaxel (squamous carcinoma)
Tirelizumab 200mg Day 1 21 days for one cycle
Anti
Carboplatin AUC=5 Day 1 4-6 cycles paclitaxel or albumin-bound paclitaxel
Paclitaxel 175mg/m2 Day 1
Albumin-bound paclitaxel
100mg/m2 Day 1, 8, 15
Carrilizumab in combination with pemetrexed and carboplatin (non-squamous carcinoma)
Carrilizumab 200mg Day 1 21 days for one cycle
Anti
Pemetrexed 500mg/m2 Day 1 4 cycles carboplatin AUC=5 Day 1
Sindilizumab in combination with pemetrexed and platinum (non-squamous)
Sindilizumab
Pemetrexed Carboplatin or cisplatin 200mg
500mg/m2 Day 1
Day 1 21 days for one cycle
4 cycles carboplatin AUC=5 day 1 cisplatin 75mg/m2 day 1
Atelelizumab in combination with pemetrexed and platinum (non-squamous carcinoma) Atelelizumab 1200mg day 1 21 days for one cycle Anti-pemetrexed 500mg/m2 day 1 4 weeks Carboplatin or cisplatin Carboplatin AUC=5 day 1 Cisplatin 75mg/m2 day 1 Note: Specific drug doses should be adjusted as appropriate for the patient’s clinical condition
Table 3 Commonly used anti-vascular therapy, immunotherapy and
Targeted therapies
Drug dose Dosing schedule Anti-angiogenic drugs Vascular endothelial inhibitory protein
7.5mg/m2
Days 1-14, 1 for 21
cycle
Bevacizumab 7.5 to 15 mg/kg day 1, 21 days for 1 cycle immunotherapy drug Sindilizumab 200 mg day 1, 21 days for 1 cycle tirelizumab 200 mg day 1, 21 days for 1 cycle carrilizumab (PD-1) 200 mg day 1, 21 days for 1 cycle nabritumomab (PD-1) 3 mg/kg day 1 14 days for one cycle of pablizumab (PD-1) 200mg day 1, 21 days for one cycle of atelelizumab 1200mg day 1, 21 days for one cycle of
(PD-L1)
Dulvalizumab
(PD-L1)
10mg/kg day 1, 1 cycle of 14 days
Targeted therapy drugs Gefitinib 250mg 1 time/day Erlotinib 150mg 1 time/day Exotinib 125mg 3 times/day Daclotinib 45mg 1 time/day Afatinib 40mg 1 time/day Ocetinib 80mg 1 time/day Crizotinib 250mg 2 times/day Alectinib 600mg 2 times/day Ceritinib 450mg 1 time/day

Maintenance therapy is an option for patients who achieve disease control (complete remission, partial remission, or stable) after first-line therapy. Current agents with evidence-based evidence for same-drug maintenance therapy include pemetrexed (non-squamous), bevacizumab (non-squamous), and gemcitabine, with a recommended 2-year cycle for immune checkpoint inhibitors in the absence of disease progression and intolerable adverse events; agents with evidence-based evidence for switch maintenance therapy include pemetrexed (non-squamous), and for EGFR gene-sensitive mutations Patients can choose EGFR-TKI for maintenance therapy.
Second-line drug therapy: chemotherapy options include docetaxel, pemetrexed, etc.; molecularly targeted drugs for patients with EGFR mutations, ALK fusions, or ROS1 fusion positivity; and immunotherapy options include nabumetinumab.

In patients with positive driver mutations, molecular targeting agents should be prioritized in second-line therapy if the appropriate molecular targeting agent is not used in first-line and maintenance therapy; patients who are resistant to first-line EGFR-TKIs and have EGFR T790M mutation-positive patients who are resistant to first-line EGFR-TKIs and who are EGFR mutation-positive should be treated with third-generation EGFR-TKIs, such as oseltinib, ametinib or vomitinib, as a priority in second-line therapy. For ALK fusion-positive patients who develop resistance after first-line treatment with crizotinib, ceritinib or aletinib may be chosen for second-line treatment. In case of oligogenic or CNS progression after resistance to first-line molecular targeted therapy, the combination of targeted therapy with local therapy, such as radiotherapy or surgery, may be continued. For patients with resistance to first-line EGFR-TKI or ALK inhibitors, second-line therapy may also be based on the patient’s Eastern Cooperative Oncology Group behavioral status score (ECOG).

performance status, ECOG PS) to choose a platinum-containing two-drug or single-agent chemotherapy regimen, or in the case of non-squamous cancer, to In the case of non-squamous cancer, an anti-vascular agent such as bevacizumab can be combined with this.

Patients with negative driver genes should be prioritized for chemotherapy, and for patients without driver genes and with a squamous histologic type, afatinib is an option

(Table 3).

Immune checkpoint inhibitor therapy is an option for patients with NSCLC after failure of platinum-containing two-drug combination chemotherapy/targeted therapy.

Third-line drug therapy: optional participation in clinical trials, third-line therapy is also an option for VEGF receptor tyrosine kinase VEGF receptor tyrosine kinase inhibitor as a single oral agent, or if no immune checkpoint inhibitor is used in the first or second line, nabolutumab may be considered. The current drugs with evidence-based support for third-line treatment with VEGF receptor tyrosine kinase inhibitors are anlotinib.
Locally advanced or metastatic NSCLC with MET exon 14 jump mutations that have progressed after chemotherapy or are intolerant to standard platinum-containing chemotherapy can be treated with sevolitinib; for Locally advanced or metastatic NSCLC with a positive RET gene fusion that has received prior platinum-containing chemotherapy may be treated with pratinib. For other driver mutations, such as BRAF V600E mutations, NTRK fusions, and other mutations, there are new targeted drugs that have shown good efficacy in clinical trials, so patients with rare mutations are encouraged to participate in the appropriate clinical trials and may be considered for treatment in appropriate clinical situations.

Table 4 Common second-line treatment options for non-small cell lung cancer

Treatment regimen Dose Dosing time Duration and period

Docetaxel 75mg/m2 Day 1 21 days for 1 cycle pemetrexed (non-squamous) 500mg/m2 Day 1 21 days for 1 cycle alfatetaxel (non-squamous) Days for 1 cycle Afatinib (squamous carcinoma) 40mg 1 time/day 1 time/day

Oxitinib (T790M) 80mg 1 time/day 1 time/day

Pharmacologic Treatment of NSCLC that cannot be Surgically Resected

The combination of radiotherapy and chemotherapy is recommended, with synchronous or sequential radiotherapy depending on the circumstances. The recommended chemotherapeutic agents for synchronous treatment are etoposide in combination with cisplatin (EP) or carboplatin (EC), pemetrexed in combination with cisplatin or carboplatin, paclitaxel or docetaxel in combination with platinum. Sequential therapy chemotherapeutic agents were cisplatin + etoposide, cisplatin + paclitaxel, cisplatin + docetaxel, cisplatin or carboplatin + pemetrexed (non-squamous non-small cell lung cancer). Multidisciplinary team discussion to evaluate the possibility of surgery in patients with descending stage after induction therapy and consider surgery if complete resection can be achieved. Patients with stage III NSCLC who do not experience disease progression after synchronous radiotherapy and are not amenable to radical resection may be considered for sequential dulcolizumab therapy for 1 year.

Perioperative Drug Therapy for NSCLC

Postoperative adjuvant chemotherapy: 4 cycles of postoperative adjuvant chemotherapy with a platinum-containing two-drug regimen is recommended for completely resected stage II-III NSCLC. Adjuvant chemotherapy begins when the patient’s postoperative physical status has largely returned to normal and is generally started 4 to 6 weeks after surgery, with a recommendation of no later than 3 months after surgery.

Neoadjuvant chemotherapy: 2 to 3 cycles of preoperative neoadjuvant chemotherapy with a platinum-containing double agent is indicated for resectable stage III NSCLC. Efficacy should be evaluated in a timely manner, and adverse effects should be monitored and managed to avoid additional surgical complications. Surgery is usually performed 2 to 4 weeks after the completion of chemotherapy. Postoperative adjuvant chemotherapy should be continued or adjusted as appropriate according to the patient’s tolerability if it is effective, or adjusted if it is ineffective, based on preoperative staging and neoadjuvant chemotherapy efficacy. A total of 4 cycles of chemotherapy in the perioperative period is recommended.

Perioperative immunotherapy: Evidence-based evidence shows that platinum-containing chemotherapy combined with neoadjuvant PD-1 monoclonal antibody or postoperative adjuvant PD-L1 monoclonal antibody improves pathologic complete remission rates or prolongs relapse-free survival, so patients are encouraged to participate in perioperative immunotherapy. patients to participate in clinical trials of perioperative immunotherapy.

Drug therapy for SCLC

First-line treatment options: T1 to 2N0 lobectomy is recommended for limited stage small cell lung cancer + hilar and mediastinal lymph node dissection with postoperative adjuvant chemotherapy. Beyond T1-2N0, a combination of radiotherapy and chemotherapy is recommended for small cell lung cancer in the restricted stage. The chemotherapy regimen recommended is etoposide combined with cisplatin (EP) or etoposide combined with carboplatin

(EC) regimen. Chemotherapy or combination of chemotherapy (EP or EC regimen) with immunotherapy, such as PD-L1 monoclonal antibody, is recommended for extensive small cell lung cancer, and combination of chemotherapy with radiotherapy or other local therapies is recommended for those with local symptoms or brain metastases. The chemotherapy regimens recommended are EP, EC, irinotecan combined with cisplatin (IP), irinotecan combined with carboplatin (IC), or etoposide combined with loplatin

(EL) regimens.
- Second-line regimens: relapse or progression within 6 months after first-line chemotherapy

Topotecan, irinotecan, gemcitabine, vincristine, temozolomide, or paclitaxel for relapse or progression after 6 months; initial regimen for relapse or progression after 6 months. The initial treatment regimen was selected. Patients are encouraged to participate in clinical trials of new drugs.

Third-line regimens: choose anlotinib or participate in clinical trials. 5. Principles of chemotherapy for lung cancer

(1) Chemotherapy is contraindicated in lung cancer patients with KPS<60 or ECOG>2, and may be relaxed for SCLC patients.

(2) Leukocytes <3.0×109/L and neutrophils <1.5×109/L, platelets <100×109/L, erythrocytes <2×1012/L, and hemoglobin <80g/L. In principle, patients should not be treated with chemotherapy.

Patients with severe abnormal liver and kidney function, and/or severe abnormal laboratory parameters, or severe complications and tendency to infection, fever, or bleeding should not be treated with chemotherapy in principle.
Discontinuation or change of regimen should be considered if the following occurs during chemotherapy: progression of disease after 2 weeks of treatment, or reoccurrence during the rest period of the chemotherapy cycle. If the lesion progresses after 2 weeks of treatment or deteriorates again during the rest period of the chemotherapy cycle, the original regimen should be discontinued and an alternative regimen should be used as appropriate; if the adverse effects of chemotherapy reach grade 3 to 4 and pose a significant threat to the patient’s life, the drug should be discontinued and the regimen should be adjusted at the next treatment; if serious complications occur, the drug should be discontinued and the regimen should be adjusted at the next treatment.
Standardization and individualization of treatment regimens must be emphasized. The basic requirements of chemotherapy must be mastered. In addition to the routine application of antiemetic drugs, platinum drugs other than carboplatin require hydration and diuresis. Close monitoring of routine blood and biochemical parameters after chemotherapy.
- Efficacy evaluation of chemotherapy Refer to RECIST efficacy evaluation criteria.
(iv) Bronchoscopic intervention.

With the increasing popularity of bronchoscopy in clinical applications, the following local therapies are available as treatment options for patients who cannot undergo surgery and radiotherapy, various bronchoscopy-mediated laser, high-frequency electric knife, radiofrequency ablation, argon plasma coagulation

(argon plasma coagulation, APC), microwave, photodynamic therapy, cryopreservation, airway stenting, balloon dilation, submucosal or intratumoral drug injections, etc. The indications for endobronchial interventions must be strictly defined, the goals of treatment must be clarified, and the ability of the proposed treatment to achieve the desired outcome must be objectively assessed. The purpose of endobronchial interventions must be clearly defined, the objective of the treatment must be objectively assessed, and the treatment must be carried out in hospitals where it is available.

For intraluminal polyp-like tumors, direct laparoscopic resection or carbon dioxide cryosurgery is possible, and APC is performed on the root of the tumor.
For canal wall infiltrates, photodynamic therapy is usually performed after resection of the intraluminal tumor, and then Radioactive particle therapy can be considered in cases where external irradiation is contraindicated_.
For patients with central airway stenosis who are inoperable or refuse surgery, endoscopic endoluminal Interventional treatment. This includes techniques such as thermal ablation (high-frequency electric knife, radiofrequency ablation, APC, microwave, laser, etc.), photodynamic therapy, cryopreservation, airway stenting, and submucosal or intratumoral drug injection.
For airway stenosis and airway fistula that cannot be relieved by conventional treatment, the treatment should be based on endoprosthesis placement, which can be divided into 2 types: metal stents and nonmetal stents. The metallic stents can be divided into permeable stents and non-permeable stents (bare stents) according to the presence or absence of a permeable membrane. Non-metallic stents can be divided into silicone stents, plastic stents, etc.

If there is loss of lung function distal to the lesion or if the lesion also obstructs a small airway, endoscopic interventions should be carefully chosen.

The choice of individualized bronchoscopic endoluminal interventions is important and needs to be discussed in the MDT, taking into account the performance of the equipment and personnel of the proposed technique. The ideal treatment is a combination of multiple modalities, such as thermocoagulation or cryotomy to remove large intraluminal lesions and freeze-thawing to remove basal lesions.

(v) Staging treatment modalities for non-small cell lung cancer.
- Comprehensive treatment for patients with stage I NSCLC
Surgical treatment is preferred, including lobectomy plus systemic hilar and mediastinal The preferred surgical treatment includes lobectomy with systemic hilar and mediastinal lymph node dissection and partial lobectomy with selective lymph node dissection, either minimally invasive or open thoracotomy such as TV thoracoscopy, robotic surgery.
Anatomic pulmonary segmental or wedge resection with systematic lymph node dissection can be considered for some stage IA NSCLC patients with advanced age or low lung function. segmental or wedge resection plus systemic hilar and mediastinal lymph node dissection or sampling.
Patients with completely resected stage IA and IB NSCLC are not recommended for routine postoperative adjuvant chemotherapy, radiation therapy, and targeted drug therapy. The patients with stage IA and IB NSCLC are not recommended for routine application of postoperative adjuvant chemotherapy, radiation therapy and targeted drug therapy.
Re-operation is recommended for stage I lung cancer with positive margins, and post-operative combination radiotherapy is recommended for patients who cannot undergo re-operation for any reason.
Stereotactic radiation therapy is recommended for patients with severe medical comorbidities, advanced age, and refusal of surgery.
- Comprehensive treatment for patients with stage II NSCLC

Preferred surgical treatment is lobectomy plus systemic hilar and mediastinal lymph node dissection or sampling.
Anatomic lung segmental or wedge resection plus systematic hilar and mediastinal lymph node dissection or sampling may be considered in patients with advanced age or low lung function.
Postoperative platinum-containing two-drug adjuvant chemotherapy is recommended for patients with complete resected stage II NSCLC.
When the tumor invades the mural pleura or chest wall, a complete chest wall resection should be performed. The extent of resection should be at least 2 cm from the upper and lower margins of the nearest rib, and the length of resection of the invaded rib should be at least 5 cm from the tumor.
Reoperation is recommended for stage II lung cancer with positive margins, and for patients who are unable to undergo reoperation for any reason, postoperative simultaneous radiotherapy is recommended if the patient is physically able. If the patient is physically able, postoperative concurrent radiotherapy is recommended, and radiotherapy should be started as early as possible.
- Comprehensive treatment for patients with stage III NSCLC
Locally advanced NSCLC is defined as patients with TNM staging of stage III. Multidisciplinary combination therapy is the best option for stage III NSCLC. Locally advanced NSCLC is divided into 2 major categories: resectable and unresectable.
- Resectable locally advanced NSCLC includes

①For patients with T3-4N1 or T4N0, surgery + adjuvant chemotherapy or radical radiotherapy or chemotherapy is recommended, and neoadjuvant therapy may be considered.

②In stage N2 with a single group of mediastinal lymph nodes that are enlarged and <3 cm in diameter, or two groups of mediastinal lymph nodes that are enlarged but not fused and expected to be completely resected, multidisciplinary discussion is recommended, and neoadjuvant chemotherapy±radiotherapy + surgery, or manual therapy is recommended.

surgery+chemotherapy±radiotherapy. For EGFR mutation-positive patients, surgery + adjuvant EGFR-TKI therapy ± postoperative radiotherapy is used. Preoperative mediastinoscopy, ultrasound-guided transbronchial needle aspiration biopsy or ultrasound endoscopy-guided fine-needle aspiration biopsy is recommended, and preoperative neoadjuvant chemotherapy or neoadjuvant radiotherapy or chemotherapy is administered after clarifying the N2 staging, followed by surgery. For patients with multiple N2 lymph node metastases with the expectation of complete resection, radical simultaneous radiotherapy is recommended first because the risk of recurrence is significantly higher than that of single-site N2; a combination of neoadjuvant chemotherapy +/- radiotherapy + surgery ± adjuvant chemotherapy ± postoperative radiotherapy can also be considered. For EGFR mutation-positive patients, surgery + combined adjuvant EGFR-TKI therapy ± postoperative radiotherapy is also recommended.

③ For stage II-IIIA NSCLC, EGFR mutation testing is recommended for patients with stage II-IIIA non-squamous cell NSCLC, N1 to 2, based on data from the ADAURA, EVIDENCE, ADJUVANT, and EVAN studies on the benefit of targeted adjuvant therapy. testing.

Unresectable locally advanced NSCLC including

Some stage IIIA (N2) patients with imaging suggestive of fusion-like enlarged lymph nodes in the mediastinum and positive NSCLC confirmed by mediastinoscopy, ultrasound-guided transbronchial needle aspiration biopsy or ultrasound endoscopy-guided fine-needle aspiration biopsy must be identified by definitively unresectable patients after MDT discussion of thoracic tumors.

② Patients with IIIB/IIIC.

③In unresectable locally advanced NSCLC with a PS score of 0 to 1, the recommended treatment of choice is concurrent chemoradiotherapy, and if there is no disease progression after concurrent radiotherapy, additional doxycycline may be considered. If there is no disease progression after synchronous radiotherapy, maintenance therapy with dovalizumab can be considered.

Comprehensive treatment for patients with stage IV NSCLC

Stage IV NSCLC patients should obtain tumor tissues for gene mutation testing before starting treatment, such as EGFR, ALK and ROS1 etc., and the appropriate treatment strategy will be determined based on these genetic profiles. In stage IV NSCLC, systemic therapy is the mainstay, and the goal is to improve quality of life and prolong survival.

Treatment of stage IV NSCLC patients with isolated brain, adrenal and lung metastases

①Patients with NSCLC with isolated brain metastases and resectable lung lesions can have their brain lesions surgically resected or treated with stereotactic radiation therapy, while primary lesions in the chest are treated according to staging principles.

②In patients with NSCLC with isolated adrenal metastases and resectable pulmonary disease, surgical resection of the adrenal lesion is considered, and the primary thoracic lesion is treated according to the principles of staging.

③ Isolated nodules in the contralateral lung or other lobes of the ipsilateral lung can be treated according to the respective staging of the 2 primary tumors if the primary lung lesion is surgically resectable; if surgery is performed, adjuvant therapy is guided by pathology.
- Systemic therapy for patients with stage IV NSCLC
1) Patients with stage IV NSCLC with EGFR gene-sensitive mutations are recommended for first-line EGFR-TKI therapy, and ALK fusion gene-positive patients are recommended for ALK inhibitors such as crizotil.

First-line treatment with ALK fusion gene positive patients and first-line treatment with ROS1 fusion gene positive patients is recommended for crizotinib.

②Patients with stage IV NSCLC with negative EGFR genes, ALK and ROS1 fusion genes or unknown mutation status who have an ECOG PS score of 0 to 1 should start platinum-containing two-drug chemotherapy as early as possible, possibly in combination with an immune checkpoint inhibitor (e.g., PD-1 monoclonal antibody) or bevacizumab (non-squamous cancer). monoclonal (non-squamous) systemic therapy; if the patient is PD-L1 positive (TPS ≥1), the pablizumab monotherapy is available, where PD-L1 high expression (TPS ≥50) Patients with high PD-L1 expression (TPS ≥ 50) had a more significant benefit from immunotherapy; if patients with high PD-L1 expression (TC ≥ 50 or IC ≥10), they may also receive atelelizumab monotherapy. For patients who are not candidates for platinum-based therapy, a non-platinum-based two-drug combination regimen of chemotherapy may be considered.

③ Patients with advanced NSCLC with an ECOG PS score of 2 should be given single-agent chemotherapy, but cytotoxic chemotherapy should be used with caution in patients with an ECOG PS score >2.

For elderly patients, the evidence does not support age as the sole basis for choosing chemotherapy regimens, but must be evaluated in conjunction with organ function indicators and ECOG PS status. Patients with ECOG PS score 0-1 may still be considered for platinum-containing two-drug regimens and patients with ECOG PS score 2 for single-agent chemotherapy; systemic chemotherapy is not recommended for those with severe organ dysfunction and those with ECOG PS score 2 or higher.

Second-line therapy options include docetaxel, pemetrexed, PD-1 monoclonal antibody, or targeted therapy. For patients with positive driver mutations, if the appropriate molecular targeting agent is not applied at first-line and maintenance therapy, second-line therapy

Patients who are resistant to first-line EGFR-TKIs and have a positive EGFR T790M mutation should be prioritized for second-line therapy. Patients who are resistant to first-line EGFR-TKIs and have positive EGFR T790M mutations should be prioritized for second-line therapy with third-generation EGFR-TKIs, such as oseltinib, ametinib or vomitinib. For ALK fusion-positive patients who have developed resistance after first-line crizotinib treatment, second-line treatment may include ceritinib or alectinib. In case of oligogenic or CNS progression after resistance to first-line molecular targeted therapy, the combination of targeted therapy with local therapy, such as radiotherapy or surgery, may be continued. For patients with resistance to first-line EGFR-TKI or ALK inhibitors, second-line therapy may also include a two-drug platinum-containing regimen or a single-agent chemotherapy regimen based on the patient’s ECOG PS score, or in the case of non-squamous cancer, a combination of anti-vascular agents such as bevacizumab. For patients with driver-negative disease, nabumetinumab therapy may be considered in the second line if PD-1 monoclonal antibody is not applied in the first line.

6 Patients with stage IV NSCLC with an ECOG PS score >2 generally do not benefit from chemotherapy and are recommended for best supportive care. In addition to systemic therapy, appropriate local therapies can be selected for specific local conditions to improve symptoms and quality of life.

(7) High-throughput sequencing (HTS) has been widely used in the clinic for detection of genetic mutations, assessment of tumor mutational load, and as an aid to determine the mechanism of resistance to molecularly targeted drugs and to guide the next step in therapy.

(vi) Staging models for SCLC.

The staging of SCLC has followed the American Legion Lung Cancer Society’s stage II staging approach, based primarily on the importance of radiation therapy in the treatment of small cell lung cancer. The AJCC TNM staging system is used to select patients with T1 to 2N0 stage lung cancer suitable for surgery.

Clinical studies should first use the TNM staging system because it can more accurately assess prognosis and guide treatment.

T1 to 2N0 limited stage SCLC

T1 to 2N0 focal SCLC without mediastinal lymph node metastasis after systemic staging is recommended: surgery + adjuvant chemotherapy (EP regimen or EC regimen, 4-6 cycles). If the presence of mediastinal lymph node metastasis is not clear by systematic staging, mediastinoscopy, ultrasound endoscopy or pathology may be performed to exclude potential mediastinal lymph node metastasis. Prophylactic brain irradiation is recommended postoperatively.

Limited stage SCLC beyond T1 to 2N0

Prophylactic brain irradiation is recommended for those who achieve disease control (complete or partial remission) with the combination of chemotherapy and radiotherapy.

ECOG PS score 0 to 2: Prefer synchronous chemotherapy and radiotherapy; if the patient cannot tolerate synchronous radiotherapy and chemotherapy, sequential chemotherapy and radiotherapy are also viable options.
ECOG PS score 3 to 4 due to SCLC: All factors should be fully integrated and treatment regimens should be carefully selected, and single agent chemotherapy or reduced combination chemotherapy regimens can be considered. If the ECOG PS score can reach below 2 after treatment, sequential radiotherapy can be considered, and if the ECOG PS score still cannot be recovered to below 2, chest radiotherapy can be used on a case-by-case basis.
Non-tumor ECOG PS score of 3-4: in principle, best supportive care.
- Extensive stage SCLC

Patients with ECOG PS 0 to 2 and ECOG PS 3 to 4 due to SCLC should be treated with a combination of chemotherapy-based therapy. First-line therapy is recommended for EC regimens with or without atelelizumab, 4 to 6 cycles of chemotherapy with EP, IP, or IC regimens, and best supportive care for patients with ECOG PS 3 to 4 not due to tumor.

Patients with no local symptoms and no brain metastases: Chest radiotherapy is feasible for patients in complete/partial remission with first-line chemotherapy. Patients with no brain metastases on review after effective initial therapy may be considered for prophylactic brain irradiation.
Patients with local symptoms: Symptomatic conditions should be treated on an elective basis with first-line chemotherapy Local treatment, such as local radiotherapy can be given electively in patients with superior vena cava syndrome or obstructive pulmonary atelectasis or spinal cord compression; patients with bone metastases can be treated with local orthopedic fixation in addition to elective local palliative external irradiation, if necessary, for sites with high risk of fracture. Patients without brain metastases on review after effective initial therapy should also be given prophylactic brain irradiation.
Patients with brain metastases: whole-brain radiotherapy is recommended in addition to first-line systemic chemotherapy. Chest radiotherapy is feasible for patients who achieve complete remission or partial remission with initial treatment. Stereotactic radiotherapy can be selected for patients with small tumor size (<4 cm in diameter), or intracranial oligometastases, or metastases that are recurrent after whole-brain radiotherapy, with deeper tumor location and poor general condition of patients who cannot tolerate conventional radiotherapy or surgery.
Follow-up treatment for patients with relapsed/resistant progressive SCLC: Relapsed or progressive patients can choose topotecan, irinotecan, gemcitabine

Tabine, vincristine, temozolomide, or paclitaxel; those who relapse or progress after 6 months may choose the initial regimen. Third-line regimens: options are

Anlotinib or enrollment in a clinical trial.

(vii) Palliative care.

Palliative care is a special treatment modality that improves the quality of life for patients and families facing death from disease through pain control, symptom relief, and spiritual and social support. In our country, the number of people requiring palliative care has increased dramatically with the progression of an aging population and the expected increase in cancer morbidity and mortality, so it has become increasingly important to provide palliative care that meets WHO and NCCN standards.

Palliative care includes the management of the physical, spiritual, psychological, and social needs of patients with cancer. Palliative care can be initiated once the cancer is diagnosed and in the early stages of cancer, and can be adapted as the patient’s needs evolve. Studies have shown that early introduction of palliative care not only improves the quality of life of patients with advanced cancer, but also increases survival rates and reduces caregiver depression and stress scores. There is strong evidence that combining palliative care with standard anticancer therapy or as a focus of treatment leads to better outcomes for patients and caregivers, so for any patient with metastatic cancer and/or a high symptom burden, combining standard anticancer therapy with palliative care should be considered early in treatment. For patients with lung cancer, palliative care includes the use of palliative surgery, chemotherapy, radiation therapy, endocrine therapy, targeted therapy, immunotherapy, and/or other means of relieving the patient’s symptoms, such as pain and dyspnea. Patient comfort is a priority at all stages of treatment. Hospice care may be considered if the physician and patient agree that treatment is no longer slowing or stopping the progression of the cancer.

The goal of palliative care is to relieve symptoms, alleviate suffering, and improve quality of life. All lung cancer patients should be screened, evaluated, and treated for symptoms throughout the course of palliative medicine. Symptoms screened for include both common physical symptoms such as pain, dyspnea, malaise, anorexia and cachexia, nausea and vomiting, constipation, diarrhea, and other psychological problems such as sleep disturbances, anxiety and depression, and delirium.

Quality of life evaluation should be included in the overall evaluation system of patients with lung cancer and in the evaluation of the efficacy of palliative care. The European Organization for Research and Treatment of Cancer quality of life-C30 (EORTC QLQ-C30) is recommended.

(V3.0) for overall assessment, and the EORTC QLQ-LC13 for screening and assessment of common symptoms in patients with lung cancer.

V. Prognosis

The prognosis of patients with lung cancer (including NSCLC and SCLC) is determined by a combination of clinicopathologic characteristics of the patients. In addition, certain biochemical indicators (e.g., white blood cell count, hypercalcemia, etc.) and blood tumor marker levels (e.g., CEA) have also been shown to be significantly associated with the prognosis of lung cancer patients. Currently, clinicopathological staging, or TNM staging, remains the most important and stable predictor of survival time for lung cancer patients. The prognosis of lung cancer patients depends largely on the TNM stage of the tumor at the time of disease detection. Patients with different clinical stages have significantly different prognosis. According to the results of a meta-analysis of 94,703 patients with NSCLC reported in the AJCC 8th edition tumor staging manual in 2017, the 5-year survival rate for stage IA patients with NSCLC is approximately 80, with stage IA1, IA2, and IA3

The 5-year survival rates of patients were 92, 83 , 77 ; 5-year survival rate for stage IB patients is 68 ; stage II patients have a 5-year survival rate of about 55 ; for stage III patients, the 5-year

survival rate drops to 20; while the 5-year survival rate for stage IV patients was less than 5, with a median SCLC is more malignant than NSCLC and more prone to recurrence and metastasis, so the survival of SCLC patients is significantly shorter than that of NSCLC. 5-year survival rate of stage I SCLC patients is about 50; stage II is about 25; Phase III drops to about 10; and Phase IV is less than 3. Stage IV is less than 3. The data on the prognosis of lung cancer patients with various TNM stages reported in China are similar to those of the AJCC, and a comprehensive analysis of several large-scale statistics from 2000 to 2012 showed that the 5-year survival rate of stage I NSCLC patients in China was about 75 and about 55 in stage II, Phase III about 20, and about 5 for stage IV. For our SCLC patients, the above data are 45, 25, 25 = “https://www.kiraspecialist.com/wp-content/uploads/2022/06/062222_1314_2022117.png” alt=””/>, and

8 , 3 , 3 .

VI. Follow up

After lung cancer treatment, all patients need to be reviewed regularly. The purpose of the review is to monitor the efficacy of the treatment and to detect recurrence and metastasis of the tumor at an early stage. The examination is mainly based on imaging examination. For early and mid-stage lung cancer after comprehensive treatment including surgery, it is generally advocated that 2 years after treatment

every 3 months for 2 years, every 6 months for 2 to 5 years, and every 5 years for 5 years.

After that, the review will be conducted every 1 year.

Attachment

Lung Cancer Guideline (2022 Edition) Development and Validation Expert Group

(in surname stroke order)

Team leader: Herje

Deputy leaders: Yilong Wu, Shugeng Gao, Jie Wang

Members: Wang Zhijie, Wang Jun, Wang Zhehai, Wang Luhua, Tian Hui, Bi Nan, Liu Lunxu, Xu Lin, Li Hecheng, Wu Ning, He Jianxing, Ying Jianming

Song Qibin, Tension, Zhang Lanjun, Lu Shun, Chen Ming, Chen Haiquan, Fan Yun, Zhou Cai Cun, Zhao Lujun, Gao Yusun, Huang Yunchao, Huang Cheng, Ge Hong, Cheng Ying, Fu Xiaolong, Tan Fengwei, Xue Qi