National guidelines for diagnosis and treatment of lung cancer 2022 in China (English version)

National Health Commission of the People’s Republic of China

Contents

1.Overview

2.Screening and diagnosis

2.1 Risk factors for lung cancer

2.1.1 Smoking and involuntary smoking

2.1.2 History of chronic obstructive pulmonary disease (COPD)

2.1.3 Occupational exposures

2.1.4 Family history of lung cancer and genetic susceptibility

2.1.5 Other factors

2.2 Screening for high-risk population

2.3 Clinical manifestations

2.3.1 Symptoms arising from local growth of primary tumor itself

2.3.2 Symptoms of primary tumor invading adjacent organs and structures

2.3.3 Symptoms caused by distant metastasis of tumors

2.3.4 Extrapulmonary manifestations of lung cancer

2.4 Physical examination

2.5 Accessory examination

2.5.1 Laboratory examination

2.5.2 Imaging examination

2.5.3 Endoscopy and other examinations

2.6 Histopathological examination

2.6.1 Diagnostic criteria

2.6.2 Specifications for diagnosis

2.6.3 Pathological diagnosis report

3.Pathological type and stage of lung cancer

3.1 WHO’s 2021 standard

3.1.1 Squamous cell carcinoma

3.1.2 Adenocarcinoma

3.1.3 Neuroendocrine carcinoma

3.1.4 Other types of lung cancer

3.1.5 Immunohistochemistry and special staining

3.2 Stage of lung cancer

4.Lung cancer treatment

4.1 Surgery

4.1.1 Surgical anatomy of bronchi and lung system

4.1.2 Indications for lung cancer surgery

4.1.3 Contraindications of lung cancer surgery

4.1.4 Complete resection of lung cancer

4.1.5 Lymph node dissection for lung cancer

4.1.6 Surgical procedures for lung cancer

4.1.7 Surgical complications of lung cancer

4.1.8 A dvances in surgical treatment of lung cancer

4.2 Radiotherapy

4.2.1 Principles of radiotherapy

4.2.2 Indications for NSCLC radiotherapy

4.2.3 Indications for SCLC radiotherapy

4.2.4 Prophylactic cranial irradiation (PCI)

4.2.5 Patients with oligometastasesat stage IV

4.2.6 Palliative radiotherapy for patients with advanced lung cancer

4.2.7 Treatment effect evaluation

4.2.8 Radiation protection

4.3 Medication

4.3.1 Medication for advanced NSCLC

4.3.2 Systemic therapy for unresectable NSCLC

4.3.3 Perioperative chemotherapy for NSCLC

4.3.4 Systemic therapy for SCLC

4.3.5 Principles of lung cancer chemotherapy

4.4 Endobronchoscopic interventional therapy

4.5 Staged treatment mode of NSCLC

4.5.1 Comprehensive treatment for patients with stage I NSCLC

4.5.2 Comprehensive treatment for patients with stage II NSCLC

4.5.3 Comprehensive treatment for patients with stage III NSCLC

4.5.4 Comprehensive treatment for patients with stage IV NSCLC

4.6 Staged treatment mode of SCLC

4.6.1 T1?2N0 limited stage SCLC

4.6.2 Limited stage (more than T1?2,N0) SCLC

4.6.3 Extensive stage SCLC

4.7 Palliative treatment

5.Prognosis

6.Follow-up

1.Overview

Primary lung cancer (PLC) is the most common malignant tumor in China.PLC is generally divided into two major groups based on pathology and treatment:small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).NSCLC including histological subtypes such as adenocarcinoma,squamous cell carcinoma,accounts for 80%?85% and the rest is SCLC.Because of the unique biological characteristics of SCLC,the combination of chemotherapy and radiotherapy is mainly used,in addition to a few early cases.If not specified,lung cancer is always regarded as NSCLC.

Lung cancer is the fastest growing malignant tumor in China in recent 30 years.According to the data of the first death causes retrospective survey conducted in the mid-1970s,the mortality of lung cancer in China was 5.47/100,000,ranking fifth in cancer death,following gastric cancer,esophageal cancer,liver cancer and cervical cancer,accounting for 7.43% of all cancer deaths.The results of the second sampling survey of causes of death in China showed that in the 1990s,lung cancer was the third leading cause of death for cancer,only second to gastric cancer and esophageal cancer.The third retrospective survey of death causes conducted in this century shows that lung cancer has become the leading cause of cancer death.

According to data released by National Cancer Registry,there were about 787,000 new cases of lung cancer in China (520,000 males and 267,000 females) in 2015,accounting for 20.0% of new cases in malignant tumors.The crude incidence rate of lung cancer in China was 57.3/100,000,of which 73.9/100,000 and 39.8/100,000 for males and females,respectively.The incidence rate of lung cancer in urban areas was 59.7/100,000 and 54.2/100,000 in rural areas,both ranking first in malignant tumors.There were about 630,000 deaths of lung cancer in China(433,000 males and 197,000 females) in 2015,accounting for 27.0% of new deaths in malignant tumors.The mortality of lung cancer in China was 45.9/100,000,which was higher among males (61.5/100,000) than females(29.4/100,000).

In terms of regional distribution,mortality of lung cancer was higher in urban areas (47.5/100,000) than in rural areas (43.9/100,000).From the perspective of three major economic regions including eastern,central and western China,the eastern China had the highest mortality of lung cancer (49.6/100,000),followed by the central China (47.0/100,000) and the western China(40.0/100,000).The mortality of lung cancer in China is low at the age group of less than 44 years,but increases rapidly at the age group of more than 45 years,reaching a peak at the group of 80?84 years (416.0/100,000) and declining thereafter.The mortality for lung cancer in urban and rural areas was similar in all age groups.

2.Screening and diagnosis

2.1 Risk factors for lung cancer

National Cancer Center publishedChina Guideline for the Screening and Early Detection of Lung Cancer (2021,Beijing)in 2021.The main risk factors for lung cancer in China in it are summarized as follows.

2.1.1 Smoking and involuntary smoking

Smoking is currently recognized as the most important risk factor for lung cancer.During the ignition process,cigarettes will produce more than 60 kinds of carcinogens.Nitrosamine,polycyclic aromatic hydrocarbons and benzopyrene in tobacco are the most carcinogenic substance to the respiratory system.In 1985,World Health Organization (WHO) International Cancer Research Institute (IARC) identified smoking as the cause of lung cancer.The relationship between smoking and the risk of lung cancer is related to the type of tobacco,the age at which one starts to smoke,the duration of smoking and the amount of smoking.A meta-analysis according to the literature on the Chinese smoking population and lung cancer,published in China and abroad,showed that smokers had a 2.77 times higher risk of lung cancer than non-smokers [odds ratio (OR):2.77,95% confidence interval (95% CI):2.26?3.40)].

Involuntary smoking is also a risk factor for lung cancer,mainly in females.The association between involuntary smoking and lung cancer was first reported in the early 80s of last century.In 2003,Stayneret al.conducted a metaanalysis on a study of 22 workplaces on tobacco exposure and lung cancer risk in 2003,and it indicated that nonsmoking workers increased their risk of lung cancer by 24% [relative risk (RR)=1.24,95% CI:1.18?1.29] due to involuntary smoking in working environment,and the risk of lung cancer among workers highly exposed to environmental tobacco smoke is as high as 2.01 (95% CI:1.33?2.60),moreover the exposure time of environmental tobacco smoke is strongly correlated with lung cancer.

2.1.2 History of chronic obstructive pulmonary disease(COPD)

COPD is an airway disease caused by the chronic inflammation.It can lead to alveolar destruction,bronchial narrowing and even irreversible pulmonary dysfunction at the terminal stage.In a meta-analysis after a systematic search of published studies exploring the correlation strength between COPD and lung cancer in China and abroad since 1995,the results showed that the risk of lung cancer in patients with COPD was 1.43 times (RR=1.43,95% CI:1.14?1.81) and 1.57 times (RR=1.57,95% CI:1.20?2.05) higher than that in patients without COPD in case-control and cohort studies,respectively.

2.1.3 Occupational exposures

Multiple kinds of specific occupational exposures can increase the risk of lung cancer,including asbestos,radon,beryllium,chromium,cadmium,nickel,silicon,smoke,soot,etc.

Lenterset al.examined 19 studies on asbestos and lung cancer published from 1950 to 2009 in a meta-analysis.The results showed that each 100 f/mL increase in asbestos exposure increased the risk of lung cancer by 66.0%(RR=1.66,95% CI:1.53?1.79).

Radon is a colorless,odorless,inert gas with radioactivity.When inhaled,radon-decaying radioactive particles can cause radiation damage to the respiratory system and cause lung cancer.Radon content is high in uranium mining areas,and building materials is the main source of indoor radon,such as granite,brick sand,cement and gypsum,especially natural stones containing radioactive elements.The results of three pooled analyses in Europe,North America and China show that the risk of lung cancer increases relatively by 8% (95% CI:3%?16%),11% (95% CI:0?8%) and 13% (95% CI:1%?36%) per 100 Bq/m3increase in radon concentration.

Beryllium is an alkaline rare metal,which is widely used in aerospace,communication,electric and nuclear industries.Beryllium and beryllium compounds have been classified as known human carcinogens by the U.S.National Toxicology Program.

Nickel is a metallic element that occurs naturally in the earth’s crust.Metallic nickel 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.Some scholars in China have shown that nickel compounds (e.g.,nickel chloride) can activate the TLR4 signaling pathway in human lung cancer cellsin vitro.Moreover,the TLR4/MyD88 signal transduction promotes the nickel-induced invasive ability in human lung cancer cells.

Indoor soot exposure is a risk factor for lung cancer.In a meta-analysis on Chinese population studied by Zhaoet al.,indoor soot exposure increased the risk of lung cancer by 1.42 times (OR=2.42,95% CI:1.62?3.63) and 1.52 times(OR=2.52,95% CI:1.94?3.28) the risk of lung cancer in males and females,respectively.

2.1.4 Family history of lung cancer and genetic susceptibility

Phenomenon of familial aggregation exists in patients with lung cancer.These findings suggest that genetic factors may play an important role in populations and/or individuals susceptible to environmental carcinogens.Systematic review of Matakidouet al.showed that the RR of lung cancer and family history was 1.84 (95% CI:1.64?2.05).After investigating 633 cases of lung cancer family,Lin Huanet al.reported that the adjusted OR was 2.11 for one lung cancer patient in the family and 4.49 for two or more lung cancer patients.And that was 1.51 (95%CI:1.11?2.06) in non-smokers.At present,it is believed that genetic polymorphisms involving carcinogen metabolism,genomic instability,DNA repair,cell proliferation and apoptosis regulation may be the genetic susceptibility factors of lung cancer.Metabolic enzyme gene and DNA damage repair gene polymorphisms are two aspects which are mostly studied.

2.1.5 Other factors

Other factors related to lung cancer include nutrition and diet,physical exercise,immune status,estrogen levels,infections [human immunodeficiency virus (HIV) and human papillomavirus (HPV)],chronic inflammation of the lungs,economic and cultural levels,etc.However,the relationship between lung cancer and other factors is still controversial and needs further study and evaluation.

2.2 Screening for high-risk population

Screening for lung cancer among high-risk population is beneficial for detection of early-stage lung cancer and improving the survival rate.Low-dose computed tomography (LDCT) is 4?10 times more sensitive than conventional chest radiography in detecting early peripheral lung cancer.According to the International Early Lung Cancer Action Plan (I-ELCAP),85% of stage I peripheral lung cancer can be detected by annual LDCT screening,and the postoperative expected 10-year survival rate is 92%.

The National Lung Cancer Screening Test in the United States has proved that LDCT screening can reduce lung cancer mortality by 20% in high-risk population and is the most effective lung cancer screening tool at present.The latest study from the European lung cancer screening test shows that screening with LDCT reduces lung cancer mortality by 24% in males and 33% in females.LDCT is recommended for lung cancer screening in high-risk population in the pilot technical guidelines for cancer screening and early diagnosis and treatment in a few areas in China.

The risk factors for lung cancer screening proposed in the latest National Comprehensive Cancer Network(NCCN) guidelines published in 2021 include smoking(present and past),radon exposure,occupational exposures(silicon,cadmium,asbestos,arsenic,beryllium,chromium,diesel exhaust,nickel,smoke and soot),history of malignancy,family history of lung cancer in first-degree relatives,history of chronic obstructive emphysema or pulmonary fibrosis,and history of involuntary smoking.

Two groups are divided according to the risk states:

(1) High-risk group:age ≥50 years old,smoking history ≥20 package years.

(2) Low-risk group:age ＜50 years or/and smoking history＜20 package years.

The NCCN guidelines recommend that lung cancer screening be performed in high-risk groups,while screening in low-risk group is not recommended.

Lung cancer screening guideline of Chinapublished in 2020 by National Cancer Center andChina Guideline for the Screening and Early Detection of Lung Cancer (2021,Beijing)recommend that lung cancer screening be performed in high-risk groups.People at high risk for lung cancer should meet one of the following conditions.

(1) Smoking:smoking history ≥30 packages years,including former smokers with package years ≥30 and cessation ＜15 years.

(2) Involuntary smoking:living or working in the same room with a smoker ≥20 years.

(3) History of COPD.

(4) History of occupational exposures (asbestos,radon,beryllium,chromium,nickel,silicon,smoke and soot) ≥1 year.

(5) First-degree relative diagnosed with lung cancer.

Note 1:package years=packages smoked per day × years of smoking

Note 2:first-degree relative refers to parents,children and siblings.

2.3 Clinical manifestations

Clinical manifestations of lung cancer are diverse but lack specificity,which often lead to delay in diagnosis of lung cancer.Peripheral lung cancer usually does not present any symptoms and is often found on a health check-up or chest imaging for other diseases.Clinical manifestations of lung cancer can be summarized as:symptoms arising from local growth of the primary tumor itself;symptoms of primary tumor invading the adjacent organs and structures;symptoms of distant metastasis and extrapulmonary manifestations of lung cancer (paraneoplastic syndrome),etc.

2.3.1 Symptoms arising from local growth of primary tumor itself

These symptoms and signs include:1) Cough.Cough is the most common symptom of lung cancer patients,more than 50% of lung cancer patients present cough at the time of diagnosis;2) Hemoptysis.Hemoptysis is found in about 25%?40% of lung cancer patients,usually presenting as blood filaments in sputum,while massive hemoptysis is rarely seen.Hemoptysis is the most suggestive symptom of lung cancer;3) Dyspnea.Mechanisms of dyspnea may include reduction of alveolar area caused by primary tumor expansion,obstruction of central lung cancer or compression of airway by metastatic lymph nodes,atelectasis and obstructive pneumonia,intrapulmonary lymphatic dissemination,pleural effusion,pericardial effusion,pneumonia,etc.;4) Fever.Necrosis of tumor tissues can cause fever,and secondary pneumonia caused by tumor can also cause fever;and 5) Wheeze.If the tumor is located in the large airway,especially in the main bronchus,it can often cause localized wheezing symptoms.

2.3.2 Symptoms of primary tumor invading adjacent organs and structures

Primary tumors directly invade adjacent structures,such as the chest wall,diaphragm,pericardium,phrenic nerve,recurrent laryngeal nerve,superior vena cava or esophagus.Mechanical compression of the above structures by metastatic lymph nodes may lead to specific symptoms and signs,which include pleural effusion,hoarseness,phrenic paralysis,dysphagia,superior vena cava compression syndrome,pericardial effusion,Pancoast syndrome,etc.

2.3.3 Symptoms caused by distant metastasis of tumors

The most common symptoms are headache,nausea and vomiting caused by central nervous system metastasis.Bone metastases are usually accompanied by severe and progressive pain.

2.3.4 Extrapulmonary manifestations of lung cancer

Apart from symptoms of local tumor progression and extrathoracic metastasis,paraneoplastic syndrome can also occur in lung cancer patients.Lung cancer associated paraneoplastic syndrome can be seen in about 10%?20% of lung cancer patients,mostly in SCLC.Ectopic endocrine disorders,abnormal bone and joint metabolism and neuromuscular conduction disorders are common clinical manifestations.Paraneoplastic syndrome does not always positively correlate with the degree of tumorigenesis,and may sometimes precede the clinical diagnosis of lung cancer.For operable lung cancer with paraneoplastic syndrome,recurrence of symptoms has important implications for tumor recurrence.

2.4 Physical examination

(1) Most early lung cancer patients have no obvious related positive signs.

(2) Patients present extrapulmonary signs such as clubbing fingers (toes),non-wandering joint pain,male breast hyperplasia,skin darkness or dermatomyositis,ataxia and phlebitis.

(3) In patients with highly suspected lung cancer,vocal cord paralysis,superior vena cava obstruction syndrome,Horner’s syndrome and Pancoast syndrome may be found by physical examination,suggesting the possibility of local invasion and metastasis.

(4) In patients with highly suspected lung cancer,hepatomegaly with nodules,subcutaneous nodules,supraclavicular fossa lymph node enlargement and other indicators reveled by physical examination suggest the possibility of distant metastasis.

2.5 Accessory examination

2.5.1 Laboratory examination

2.5.1.1 General laboratory testing

Before treatment,routine laboratory tests are needed to know the general condition of the patient and whether he or she is suitable for corresponding treatment.

(1) Routine blood test;

(2) Liver and kidney function and other necessary biochemical and immunological tests;

(3) Coagulation function test.

2.5.1.2 Serologic testing of tumor markers

The primary lung cancer markers currently recommended by the American Clinical Biochemical Commission and the European Group of Tumor Markers Experts are carcinoembryonic antigen (CEA),neuron-specific enolase (NSE),cytokeratinfragment 21-1 (CYFRA21-1),progastrinreleasing peptide (ProGRP),and squamous cell carcinoma antigen (SCCAg).Combined use of tumor markers above can improve their sensitivity and specificity in clinical application.

(1) Auxiliary diagnosis

Lung cancer-related tumor markers can be detected according to the needs in clinical diagnosis,to be used as auxiliary diagnosis and differential diagnosis,and to predict the possible pathological types of lung cancer.

1) SCLC:NSE and ProGRP are ideal markers for auxiliary diagnosis of SCLC.

2) NSCLC:Elevated serum levels of CEA,SCCAg and CYFRA21-1 contribute to the diagnosis of NSLCL.SCCAg and CYFRA21-1 are generally considered to be highly specific for lung squamous cell carcinoma.Combined detecting of NSE,CYFRA21-1,ProGRP,CEA and SCCAg could improve the accuracy of differentiating SCLC and NSCLC.

(2) Notes

1) The detection results of tumor markers are closely related to the detection methods used,and the results obtained by different detection methods should not be directly compared.In the process of treatment observation,if the detection method is changed,the original detection method must be used simultaneously for parallel detection,so as to avoid wrong medical interpretation.

2) Each laboratory should study the detection methods to establish appropriate reference intervals.

3) Unqualified specimens such as hemolysis,coagulation and insufficient blood volume can affect the detection results of coagulation function,NSE and other tumor markers and even liver and kidney indicators.

4) Specimens should be sent to the laboratory as soon as possible after collection,and the test results of tumor markers such as pro-gastrin-releasing peptide (Pro-GRP)and other laboratory indicators can be affected after being placed for too long.

2.5.2 Imaging examination

Imaging examination methods of lung cancer mainly include chest X-ray,computed tomography (CT),magnetic resonance imaging (MRI),ultrasound,radionuclide imaging,positron emission tomography-CT (PET-CT)and other methods.It is mainly used for diagnosis and differential diagnosis of lung cancer,staging and re-staging,evaluation of resectability,therapeutic effect monitoring,pre-evaluation,etc.Imaging examination is the best method for non-invasive detection and evaluation of tumors.The imaging information makes clinicians more confident in the judgment of tumor prognosis and the formulation of treatment decisions.In the diagnosis and treatment of lung cancer,one or more imaging examination methods should be selected reasonably and effectively according to different examination purposes.

2.5.2.1 Chest X-ray

In China,positive and lateral chest radiography is often the basic image examination method for the discovery of lung diseases in primary hospitals,which has limited value in the diagnosis of early lung cancer.Once lung cancer was suspected in the chest radiography,CT scan should be timely executed.

2.5.2.2 Chest CT scanning

Chest CT is the most important and commonly used imaging method in the diagnosis,staging,therapeutic evaluation and follow-up after treatment of lung cancer.CT scan can display the image information which cannot be clearly identified on chest X-ray,which can effectively detect early-stage lung cancer,and further verify the location and extent of involvement of lesions.The chest CT scan should cover both adrenal glands in patients with primary lung cancer.For chest lesions that are difficult to be diagnosed qualitatively,the cytological or histological diagnosis can be obtained by means of CT-guided percutaneous lung puncture biopsy.

The traditional imaging type of lung cancer is divided into central,peripheral and specific sites according to the location of lung cancer.Central lung cancer occurs in the main bronchus,lobes and segments,often causing secondary obstructive changes.Peripheral lung cancer occurs in distal segment of bronchus.The specific sites of lung cancer include superior pulmonary sulcus tumor(Pancoast tumor),etc.(1) Central lung cancer Central lung cancer is mostly squamous cell carcinoma and small cell carcinoma,and adenocarcinoma of the central lung cancer has increased in recent years.Early central lung cancer is characterized by localized thickening of the bronchial wall,irregular internal wall,stenosis of the lumen,and increased density in the bronchi with pulmonic artery (axial view),usually without obstructive changes.The imaging findings can sometimes be dominated by obstructive pneumonia,and the inflammation may dissipate after receiving anti-inflammatory treatment,but it is still necessary to consider whether the proximal bronchial wall is thickened.The main manifestations of middle and late central lung cancer were central tumors and obstructive changes,and the earliest obstructive changes were obstructive emphysema,which further developed into obstructive pneumonia and atelectasis.Due to the convex tumor,obstruction of the proximal lung usually forms the opposite“S”sign.Thebronchial ventilation signcan be seen in CT if there was incomplete bronchial obstruction existing.Enhanced CT can often see dilated and mucusfilled bronchi.A few cases of central lung cancer may show branching changes along segment and sub-segment bronchus.CT thin slice (reconstruction thickness of 1?1.25 mm) enhanced scanning and multi-planar reformation(MPR) are of great value in preoperative evaluation of central lung cancer and should be routinely applied.If there is no contraindication,an enhanced scan should be performed.When central lung cancer is accompanied by atelectasis,MRI can help to distinguish the difference between tumor and atelectasis,the signal of atelectasis on T2WI is higher than that of tumor,and the intensity of atelectasis on T1WI enhanced scan is higher than that of tumor.

(2) Peripheral lung cancer

In general,the limited lesions within the lung no more than 1 cm are called small nodules,those no more than 3 cm are called nodules,and those with ＞3 cm are called masses.The size,morphology,density,internal structure,tumor-lung interface,and volume-doubling time of the node or mass are the most important diagnostic indications in the process of analyzing the image presentation.When observing the characteristics of nodules/masses,thin CT (layer thickness of 1.00?1.25 mm) should be routinely applied.MPR can observe the morphology of nodules in all directions,which is helpful for qualitative diagnosis.As for solid nodules,enhanced,biphasic and dynamic enhanced scans can be selected for differential diagnosis.Intrapulmonary sub-solid nodules,especially pure ground glass nodules,are recommended to be used only in a thin layer.

1) Size and shape

The typical peripheral lung cancer is mostly round,oval or irregular,and mostly lobulated.With the gradual popularity of physical examinations,the imaging manifestations of lung nodules and lung nodules in the early stage of lung cancer are increasing.At this point,the diagnosis was relatively easy according to the contour and marginal features of the tumor.

2) Density

CT plain scan:the nodules can be divided into solid nodules,part-solid nodules and pure ground-glass nodules according to whether the nodules cover the lung parenchyma (the latter two are collectively referred to as ground glass nodules with nodes or sub-solid nodules).The pure ground-glass nodules show simple ground-grass density,which means the tumor is creeping along the alveolar framework without covering the lung parenchyma.Peripheral pulmonary vessels can be seen in the lesions.Solid nodules completely cover the lung parenchyma without ground-glass density.Part-solid nodules have both components.Persistent ground-glass nodules,depending on their size and density,are mostly associated with atypical adenomatoid hyperplasia,adenocarcinomain situ,minimally invasive adenocarcinoma,and invasive adenocarcinoma.The manifestations of lung cancer with ground-glass nodules tend to be multiple.Preoperative careful observation of the thin CT layer of the whole lung is beneficial to the determination of treatment program.

Enhanced scanning:compared with plain scanning,enhanced CT scan was used to increase 15?20 HU as the threshold to identify benign and malignant lesions.When peripheral nodules are difficult to diagnose,double-phase enhanced scanning and dynamic enhanced scanning can be selected for further diagnosis.

3) Internal construction

Bronchial ventilation sign and vacuoles:These can be seen in lung cancer,pneumonia or lymphoma,but lung cancer is more common.The sign is showed better by thin-slice CT,and it usually coexisted with vacuolar sign.Image reprocessing techniques such as MPR are helpful in showing the oblique bronchial ventilation sign.Vacuoles refer to small cavities of about 1 mm generally,which are common in adenocarcinoma,accounting for about 20%?25%.They are often multiple,and some of them maybe axial phases of the air bronchus,but they are also residual air alveoli that are not filled by tumors.

Calcification:The incidence of intra-nodule calcification was much higher than that of conventional CT,and calcification was found in about 6%?10% of lung cancer.The calcification in the center of nodules/tumors was mostly malignant,and the diffuse small“pepper”shape and indefinite shape were mostly malignant,while the diffuse dense calcification,stratified or popcorn calcification was almost all benign.High spatial resolution algorithm(HRCT) produces edge enhanced artifacts,which are easy to sketch the“high density”of the nodules edge,and easy to mistake for calcification.Standard algorithm or soft tissue reconstruction algorithm can avoid such artifacts.

Vacuole and vesicle:The vacuole is generally believed to be formed by removal of necrotic material through bronchi,which can reach 1?10 cm,and can be central or eccentric.The vacuole wall is mostly 0.5?3 cm,and the thick-walled vacuole and lumpy inner wall support the diagnosis of lung cancer.The cyst vacuole is generally considered to be a part of lung bullae or lung cyst wall cancer,and some are caused by the active valve effect formed inside the tumor.The lesions can be located on one side of the cyst vacuole or can grow around the cyst vacuole.The cyst wall is often uneven,and the main components of the tumor can be solid or ground glass.

Lung consolidation:The growth and infiltration of the tumor along the alveolar wall have not completely destroyed the inter-alveolar septum,but make the alveolar wall thickened or have secretions in the adjacent alveoli,and some alveoli still contain gas,forming pulmonary consolidation,also known as pneumonia type change.Enhanced vessels in the parenchyma of solid lung tissues are seen on enhancement scans,which are called angiogram sign on CT images.This can be seen in lung mucinous adenocarcinoma,as well as in obstructive and infectious pneumonia,lymphoma,pulmonary infarction and pulmonary edema.

4) Tumor-lung interface

Linear shadows extending from the margin of the nodules to the periphery and slightly coarser burr like changes in the proximal nodules are more common in lung cancer.Usually,the thickness ＜2 mm is called fine burr,while the thickness ＞2 mm is called rough burr.The pathological basis for the formation of burrs is the invasion of adjacent interlobular septa,peritoneal pulmonary parenchymal fibrosis or/and accompanied by inflammatory cell infiltration.

5) Nearby structures

Pleural changes:Pleural indentation sign is the fine line or strip density between the nodule or mass and the pleura,sometimes with a bell mouth-like circumference.Localized pleural indentation can be seen in the gross lesion.It is mainly caused by the pulling on localized pleura by scar contraction formed by the fibro-genic reaction in the mass.Liquid or fat outside the pleura can be filled within.The sign is most common in lung adenocarcinoma.The possibility of tumor infiltration along the pleura should be considered in those with thick or irregular linear changes.

Satellite lesions:It is common in lung adenocarcinoma.The shape may be performed as nodules or small flaps.The satellite tumors and the main lesions are located in the same lobes in T3 stage and in the same side of the lung in T4 stage.Benign lesions,especially tuberculosis,can also be seen as satellite lesions.

6) Tumor volume doubling time

Tumor volume doubling time refers to the time required for the doubling of tumor volume (about 26% in diameter),which is an important indicator for judging benign and malignant tumors.The growth rate of lung cancer of different disease types is significantly different,and the doubling time changes greatly:generally the time lasts more than 30 d,less than 400 d;squamous cell carcinoma ＜adenocarcinoma ＜ minimally invasive adenocarcinoma or adenocarcinomain situ＜ atypical adenomatoid hyperplasia;the volume doubling time of ground-glass nodules in the lung often exceeds 800 d.Three-dimensional volume measurements are easier to accurately compare the changes in nodal volume and determine the doubling time.

(3) Pancoast tumor

CT can show the lesion of apex pulmonis,distinguish the tumor or pleural thickening,and show the extent of bone destruction,chest wall invasion and whether the tumor is invading to the root of the neck.The application of enhanced CT-MPR and maximum density projection is very important,and the latter is mainly used to show whether large vessels,such as subclavian artery,are invaded.MRI has a good soft tissue resolution,showing the anatomical details of the thoracic entrance and brachial plexus,and is superior to CT in determining the extent of tumor invasion and bone marrow invasion.CT is superior to MRI in determining the invasion of cortical bone.

(4) Differential diagnosis of lung cancer in imaging examination

a.Differential diagnosis of bronchial obstructive lesions

Reasons of bronchial obstructive lesions:

Oncogenicity:including central lung cancer,endobronchial benign tumors such as hamartoma,papilloma,etc.Inflammatory myofibroblastoma,metastatic tumors and lymphoma in a few cases can also cause bronchial obstructive changes.

Infection:tuberculosis,sarcoidosis,right lobe syndrome,etc.

Others:foreign body,broncholithiasis,pulmonaryamyloidosis,etc.

a1.Central lung cancer:As mentioned above.

a2.Tuberculosis:Lung involvement is more in one or more segments than in the whole lobe.Sometimes diffuse lesions can be seen in different lobes or opposite sides.If the whole lobes are cheesy,the lobes can be enlarged in volume,interlobular fissure dilated,and there can be cavities within.Most obstructive changes caused by lung cancer are obstruction of distal whole or leaf or atelectasis(or inflammation).

Tuberculous bronchial lesions may cause bronchial distortion and stenosis,or may be the expansion of the irregular bronchi,and there is no tumor in the proximal end of the lesion,which is an important differentiator from lung cancer.Sometimes,calcification can be seen in the bronchial wall,which supports the diagnosis of tuberculosis.It is difficult to differentiate lung cancer from bronchial stenosis.

There is no significant correlation between the location of the lymph node and the lymphatic drainage area in the tuberculosis,and there is calcification or edge ring-like enhancement.Metastatic lymph nodes of lung cancer are related to the distribution of drainage area.Peripheral ringlike enhancement of lymph nodes can be seen in the metastasis of squamous cell carcinoma,but rarely in adenocarcinoma and small cell carcinoma.

a3.Intraluminal neoplasms:Endobronchial benign neoplasms are rare,and hamartoma,papilloma,and neurogenic neoplasms can all lead to different degrees of obstructive alteration.It is difficult to differentiate benign and malignant tumors by imaging when there is no mediastinal or hilar lymph node enlargement in patients within traluminal soft tissue density masses or nodules with atelectasis in the bronchial cavity.However,benign tumor is very rare so the preoperative diagnosis is usually central lung cancer.When the clinical history is long and there is no evidence of malignancy on multiple bronchial examinations,the possibility of the benign tumor should be considered.The thin layer CT of hamartoma in the bronchial cavity can detect the fat density and calcification,and the differentiation is relatively easy.

In addition,inflammatory myofibroblastoma located in the bronchial cavity may be associated with obstructive pneumonia and atelectasis.It belongs to low-grade mesenchymal tumors.

a4.Intrabronchial foreign body:A history of foreign body inhalation and repeated immobilization of infection at the site support the diagnosis of foreign body with obstructive changes.CT examination can easily diagnose when fatdensity lesions (lipid inhalation) or high-density lesions(bone inhalation) are found in the bronchial cavity.

b.Differential diagnosis of isolated pulmonary nodules/tumors

Etiology of isolated pulmonary nodules/tumors:

Neoplastic:malignant tumors include peripheral lung cancer,single metastatic tumor,malignant lymphoma,lung malignant mesenchymal tissue tumor;benign tumors include hamartoma,sclerosing hemangioma,etc.

Infectious inflammatory diseases:tuberculoma,spherical pneumonia,pulmonary abscess,mechanical pneumonia and fungal infection.

Dysplasia:bronchial/pulmonary cyst,pulmonary sequestration and arteriovenous fistula.

Others:spherical atelectasis.

b1.Peripheral lung cancer:As mentioned above.

b2.Tuberculoma:Tuberculoma is usually located in the posterior segment of the upper lobe or the dorsal segment of the lower lobe,and it sometimes occurs in atypical sites.The image is usually in a circular,quasi-circular shape,regular or irregular,and the contour is often straight into angle.Based on the characteristics of inflammation,the edge may have long antenna shape or cable shape shadow,and there is often pleural thickening and adhesion in the vicinity,which is different from the burr and pleural indentation caused by fibro-genic reaction or infiltration of tumor cells along the interlobular septa.Calcification and cavities are quite common,and the nodular thickening of the wall of the tuberculous cavity caused by the necrosis of lung cancer is thinner and lighter,and liquid level is rare in the cavity.The nodule hole can also be crescent shaped or a“ring”of oddities.Patchy satellite lesions are often seen around tubercular nodules (masses).In some cases,drainage bronchi can be seen.Enhanced scanning is characterized by no enhancement or circular enhancement,and the thickness of circular enhancement depends on the amount of granulation tissue surrounding the nodule.

b3.Pulmonary hamartoma:Peripheral nodules smooth or with shallow lobes,calcified,typically“popcorn”.Thinlayer CT examination of the fat content in the tumor is helpful for diagnosis.There was no obvious enhancement in enhanced scanning.Chondromatous hamartoma may be lobulated,not calcified or fatty,and may sometimes be differentiated from peripheral lung cancer.

b4.Sclerosing alveolar cell tumor:On chest radiograph,a mass or nodule with a circular,ovoid border,as outlined with a pen.CT scanning has uniform density,sometimes with small and low-density areas and massive punctate calcification,with cystic changing occasionally.Moderate to significant enhancement manifest after CT enhancement.Delayed scanning should be performed for tumors or nodules with a circular,ovoid border with obvious uneven enhancement at the early stage of enhancement.Slight obstructive changes may sometimes occur in the distal portion of the lesion.Pulmonary hilar and mediastinal lymph nodes were rarely involved,and the prognosis was not affected.

b5.Spherical pneumonia,pulmonary abscess and organizing pneumonia:Most of them occur in the dorsal and basal segments of the lower lobe of both lungs,which are located at the periphery of the lung near the pleura,and can be square,flat or triangular.The MPR shows that the lesion is irregular,while the lung cancer is mostly spherical in all directions.In acute inflammation,the central density is high,the surrounding density is low and the margins are blurred.When an abscess is formed,the center of the lesion may have a regular area of low-density necrosis.The wall of the cavity is relatively regular when a small cavity is formed.Adjacent to the pleural reactivity thickened,the range is wider.After effective anti-infective treatment,the lesions are usually significantly reduced.

b6.Fungal infection:Typically,there is a thick or thin wall cavity where the nodules with clear edge can be seen inside,with air crescent sign.After changing body position to scan,the aspergilloma can move.Angio-invasive aspergillosis presents as blurred margins or focal lung consolidation with ground glass density in the early stage.In the late stages it may present as vacuolar nodules with air crescent signs,so called as aspergilloma.Chronic necrotic aspergillosis can be manifested as consolidation,large cavities,and irregular internal walls.It can be accompanied by lymph node enlargement in pulmonary hilum,mediastinal,pleural effusion and pleural thickening.

b7.Pulmonary sequestration:Imaging examination is very important in the diagnosis of pulmonary sequestration,and the diagnosis can be confirmed in most cases.Most of them are in posterior inferior lobe or inner basal segment,more on the left side than on the right side.Intralobar pulmonary sequestration mainly manifests as uniform density lump,which is circular,ovoid,few can be triangular or polygonal,and the boundary is clear,some with uniform density have similar CT value to muscles,and those connecting the bronchus is characterized by uneven density,cystic change,within the cyst density close to the water,clear boundary,gas sometimes can be seen in the cyst.If any infection accompanies,the liquid level is visible,which can change in the short term.The appearance of the extra-lobar pulmonary sequestration is characterized by an increasing density shadow near the posterior mediastinum or on the diaphragm,with clear margins and uniform density and few cystic changes.CT angiography has greater advantages in displaying abnormal arteries and internal structures,and can be used to observe the source of abnormal blood supply arteries from thoracic aorta,abdominal aorta or other rare arteries and drainage veins from multiple perspectives.

b8.Bronchial/pulmonary cysts:It is not difficult to be diagnosed when located near the trachea of mediastinum or the hilum of lung.In peripheral lung,most of them are round or nearly round,with clear contour,smooth and few lobes.Water density is typical,and high density is not uncommon.A few people with calcium in milk have higher density than that of soft tissues,but no enhancement was found in enhanced scanning.The cyst wall may be calcified.Cysts occurred in bronchioles can be lobulated,with not only rounded edges,but also even small vacuoles which can be seen inside.It is difficult to distinguish from lung cancer,and no changes in density before and after enhancement may help in diagnosis.

b9.Pulmonary arteriovenous fistula:Pulmonary arteriovenous fistula is congenital vascular dysplasia,which is common in young females.CT images are presented as one or more round or oval nodules,with circular or arcuate calcification.Enhanced scans usually show thickened blood supply arteries and draining veins.

b10.Spherical atelectasis:Spherical atelectasis is commonly seen after pleurisy and effusion absorption due to local pleural adhesion limiting the expansion of the lung.It is a special type of atelectasis.Most of them are located at the bottom of the lung or the back of the lung,showing round or nearly circular margin clear masses.The CT scan can show that the vascular and bronchial shadow is curved and twisted in the center of the tumor,like a snail or comet tail,adjacent to thickened pleura.The lung volume of the diseased part shrinks,and compensatory emphysema occurs in the surrounding lung tissue.

b11.Single lung metastatic tumor:Most images show circular or slightly lobed nodules with distinct edges,uniform or uneven density,but a few may show irregular edges with burrs.The tumor with clear and smooth edge needs to be identified with granuloma,hamartoma and other lung benign diseases,while the tumor with irregular edge needs to be identified with the second primary lung cancer.

2.5.2.3 MRI testing

MRI can be used selectively in the chest to determine whether the chest wall or mediastinum is invaded;to show the relationship between the Pancoast tumor and the brachial plexus and blood vessels;to identify the boundary between pulmonary mass and atelectasis and obstructive pneumonia.For patients who are contraindicated in injection of iodine-forming agent.MRI is the first choice for observation of mediastinal,pulmonary large vessels invasion and lymph node enlargement.It is also valuable for differentiating fibrosis and the recurrence of tumors after radiotherapy.MRI is especially suitable to confirm whether there is brain or spinal cords metastasis,and brain enhanced MRI should be used as the preoperative routine examination for staging of lung cancer.MRI’s high sensitivity and specificity in metastasis of bone marrow can be selected according to clinical requirements.

2.5.2.4 PET-CT testing

PET-CT is now the best test for the diagnosis,staging and re-staging,evaluation of the effects and assessment of prognosis of lung cancer.According to the clinical practice manual of NCCN and The American College of Chest Physicians (ACCP) and the consensus of Chinese experts,PET-CT is recommended in such conditions:1) diagnosis and differential diagnosis of the isolated nodule in lung(solid nodules diameter ≥8 mm,persistent part-solid nodules containing solid components diameter ≥6 mm);2)preoperative stage of lung cancer,PET-CT has great efficiency in diagnosis of lymph nodes and extra-chest(except brain metastasis) metastasis;3) localization of radiotherapy for lung cancer and delineation of target area;

4) adjuvant testing method for identification of postoperative scarring of tumor or the recurrence of tumors that CT cannot help,if lesions uptake in PET-CT,biopsy is needed for the further diagnosis;5) adjuvant testing method for diagnosis for the fibrosis of tumor after radiotherapy or postoperative tumor recurrence,if PETCT uptake,biopsy is needed to confirm;and 6) adjuvant testing method to evaluate the therapy efficiency of the lung cancer (especially the molecular targeting therapy),PET Response Criteria in Solid Tumors (PERCIST) is recommended (Table 1).

2.5.2.5 Ultrasound testing

Due to the shelter of the air in lung and ribs and sternum,ultrasound usually cannot show the lesion in the lung.Ultrasound is always used in the supraclavicular lymph nodules,liver,adrenal glands,kidneys and other viscera where tumors metastasize to support the information of the stage of the tumors.Ultrasound can help to detect the pleural and pericardial effusion and locate the fluid before pumping.Ultrasound-guided puncture can be used to perform biopsy for metastatic tumor of sub-pleural lung tumor,supraclavicular lymph nodes and parenchymal viscera.The diagnosis of lung cancer is mainly based on the clinical manifestations and the various auxiliary examinations.Lung cancer,especially peripheral lung cancer,is difficult to differentiate in images from some tuberculosis lesions,as well as some chronic inflammatory lesions.Therefore,the diagnosis of lung cancer requires various biopsies or puncture techniques to obtain pathological or cytological evidence.

2.5.2.6 Bone scintigraphy

Bone scintigraphy is the routine examination of bone metastasis of lung cancer.When the bone scintigraphy reveals suspicious bone metastasis,MRI,CT and PET examination should be performed to verify the suspicious site.Preoperative PET examination can replace bone scintigraphy.

2.5.3 Endoscopy and other examinations

2.5.3.1 Bronchoscopy and ultrasound trans-bronchial needle aspiration biopsy

Bronchoscopy is of great value in localization and histologic diagnosis of tumors.For central lung carcinoma,bronchoscopy can directly observe the lesion,and more than 95% of the lesions can be confirmed by cytological brush and histological biopsy.Biopsy can also be performed in lung hilum and mediastinal lymph nodes adjacent to the bronchus by ultrasound bronchoscopy for the qualitative diagnosis of lung cancer and diagnosis for the stage of mediastinal drenching.A variety of navigation techniques have been used to perform biopsy for peripheral lung cancer.

2.5.3.2 Mediastinoscopy

By standard and expanded mediastinoscopy,2R,2L,4R,4L,5,6,7,and 10 lymph nodes can be obtained for qualitative diagnosis of lung cancer and regional lymph node staging.Previously,it was used as the gold standard for the assessment of mediastinal lymph node metastasis.Due to the need of general anesthesia for mediastinoscopy and the maturity of ultrasound bronchoscopy and esophagoscopic biopsy,mediastinoscopy has a decreasing trend in the diagnosis and staging of lung cancer.

2.5.3.3 Thoracoscopy or open lung biopsy

For those with lung lesions found in the imaging examination but failing to obtain histological and cytological evidence by sputum cytology examination,bronchoscopy and puncture for biopsy examination in the diagnosis of lung cancer,or failing to exclude the possibility of lung cancer after clinically short-term observation,thoracoscope or even open-surgery lung biopsy can be one of the methods of qualitative diagnosis of lung cancer.

2.5.3.4 Sputum exfoliation cytology examination

Sputum exfoliation cytology is simple,non-invasive and can be accepted by patients easily.It is one of the simple and effective methods for qualitative diagnosis of lung cancer and can also be used as a screening method for high-risk groups of lung cancer.The positive rate of sputum exfoliation cytology was related to the collection of sputum specimens,the preparation of cytology smear,the diagnostic level of cytologists,the location of tumors and the pathological type.

2.6 Histopathological examination

2.6.1 Diagnostic criteria

The pathological diagnosis of lung cancer in biopsy specimens mainly detects the presence and type of tumor.The pathological diagnosis should be classified into subtypes as far as possible for patients with advanced inoperability,and immunohistochemical staining is necessary for morphologically atypical cases.The diagnosis of non-small cell carcinoma-not otherwise specified(NSCC-NOS) should be avoided.Biopsy specimens from patients with advanced NSCLC,especially adenocarcinoma,should be combined with molecular pathology tests.Histologic type of large lung cancer specimens resected by surgery should be based on the latest WHO classification standard version of lung cancer.The pathological diagnosis of adenocarcinomain situ,minimally invasive adenocarcinoma and large cell carcinoma cannot be completed in small biopsy specimens and intraoperative freezing,and the diagnosis can only be made after surgical removal of all specimens or sampling.

2.6.2 Specifications for diagnosis

The pathological diagnosis of lung cancer is composed of specimen processing,specimen collection,pathological examination and pathological report.

2.6.2.1 Specimen processing essentials

It is recommended that 10% neutral buffer formalin fixative solution should be used to avoid the use of fixed liquid containing heavy metals.Fixed liquid should be at more than 10 times the amount of the volume of the fixed specimen at constant temperature.Specimens should not be leftin vitrofor more than 60 min.Biopsy specimens can be inserted directly into the fixative fluid,and lung lobes or total pneumonectomy specimens can be injected with sufficient fixative fluid from the bronchi,or probes can be inserted along the bronchial wall and cut into lung tissues for fixation.Fixed time:the small biopsy specimen should be 6?24 h;surgical specimens resected should be stored for 12?48 h.

Cytological smear (sputum,pleural fluid) should be fixed with 95% alcohol solution,which should not be less than 15 min,or non-gynecological liquid-based cytological fixative solution (fixation time and method can be operated according to instructions).When the exfoliated cell wax block is needed,the cell mass after centrifugation is the same as the tissue fixation procedure and is fixed with 10%neutral buffer formalin fixative solution for a duration of more than 2 h.

2.6.2.2 General description and requirements for sampling

(1) All biopsy specimens will be taken after check.

(2) Specimens for local pneumonectomy.

1) Remove surgical sutures or metal pins.

2) Record the size of the specimen and the appearance of the pleural surface.

3) The lung parenchyma was excised from the vertical incisal margin to describe the size of the mass,the cut surface (with no bleeding,necrosis,cavitation) and its relationship with the pleura and lung parenchyma,as well as the distance between the edge of the mass and the incisal margin.

4) Tumor,tumor and pleura,tumor and lung parenchyma were cut according to the lesion location and size,and the tumor body should be collected when the tumor ＜3 cm.

5) Excise lung tissues from non-tumor sites.

(3) Lobectomy specimen.

1) Five basic structures of the lung:airways,lung parenchyma,pleura,blood vessels,and lymph nodes.Measurements were taken to locate the specimen in the hilum of the lung.

2) The bronchial incisal edge,the vascular incisal edge,and the proximal part of the tumor to the pleura,or the adhesion to other pulmonary lobes were taken.

3) Looking for lymph nodes of lung hilum.

4) According to the location and stage of the tumors,there are two choices:First,the specimens of lung tissues (by means of a probe inserted into the trachea) can be incised along the bronchial wall and tumor,by which the bronchi and their branches can be exposed greatly,and so is the relationship of the lesion and the surrounding lung tissues.Second,for those samples with main bronchus filled with formaldehyde should be cut every 0.5?1.0 cm,and the section should be in the coronal plane,perpendicular to the hilum of the lung.

5) Describing the tumor size,cross section (with no bleeding,necrosis,cavitation),position in lobes and lung segments and relationship with bronchi,range of lesions(focal or metastasis),and distal and local secondary changes.The number of the samples relies on the size of the lesion (tumors should be taken if diameter ＜3 cm),the site,accompanying symptoms (related to clinical stage),and it should contain tumor and pleura,tumor and lobe or segment bronchus (different from specimens),tumor and peripheral lung tissues or secondary lesions,tumor and pulmonary or bronchial broken residuals.Cross-lobe specimens should also include the part of the tumor and the crossed lobes.All lymph nodes should be collected from N2 or other sites.It is recommended that the volume of tissue blocks obtained should not be greater than 2.5 cm ×1.5 cm × 0.3 cm.

2.6.2.3 Key pathological features

General descriptions contain type of specimen,size of tumor,relationship with bronchial (different specimens) or with the pleural,other accompanying lesions and multiple lesions,and incisal margins.

Diagnosis contents contain tumor location,histological subtypes,range of involvement (bronchi,pleural,vascular,nerves,types of accompanying lesions,intrapulmonary spread and metastasis of lymph nodes),incisal margin and necessary special dyeing,immunohistochemical results or molecular pathological results.And the included information should satisfy the need of clinical stage,offering the pTNM stage.Multiple lung cancers should be identified as clearly as possible according to the morphological features of each lesion,namely intrapulmonary metastasis or multiple primary cancers.

2.6.2.4 Immunohistochemical,special dyeing and molecular pathological examination

Immunohistochemical biomarkers (TTF-1,Napsin-A,p63,p40,and CK5/6) should be chosen to differentiate adenocarcinoma and squamous cell cancer.TTF-1 and p40 can be firstly chose if the tissue was not enough.CD56,Syn,CgA,Ki-67 and TTF-1 should be selected as the markers of neuroendocrine tumors.Based on the morphological features of neuroendocrine,at least one neuroendocrine marker is definitely positive,and the number of positive cells should be more than 10% of the tumor cells before the diagnosis of neuroendocrine tumor.The identification of intracellular mucous substances should be carried out by special staining of mucicarmine staining and AB-PAS.Special staining of elastic fibers should be performed for suspected involvement of pleura.

It is recommended that epidermal growth factor receptor(EGFR) mutation should be examined for II?IIIa nonsquamous cell lung cancer with positive N1/N2 and small specimen squamous-cell lung cancer patients.For patients with advanced NSCLC,EGFR,anaplastic lymphoma kinase(ALK),ROS1,RETrearrangement andCMETex14 skipping mutation detection should be routinely performed at the time of diagnosis.If condition permitted,KRAS,BRAF,HER-2mutation,NTRK1/2/3andNRG1/2gene fusion can be performed.For patients who intend to choose immunotherapy,PD-L1 immunohistochemical testing should be performed.The detection ofEGFRmutation can adopt amplification-refractory mutation system (ARMS)method or high-throughput sequencing (HTS).The detection ofALKgene fusion can be performed by Ventana immunohistochemistry,fluorescencein situhybridization(FISH),real-time polymerase chain reaction (RT-PCR) or HTS method.The detection ofROS1gene fusion can be done by RT-PCR,FISH or HTS method.RETgene fusion andCMETex14 skipping mutation are recommended to be tested together with other driver genes by RT-PCR or HTS method.For some patients with advanced NSCLC,the tissues cannot be offered,blood can replace tissues for EGFR examination and detection methods can be selected by technologies such as highly sensitive ARMS,HTS or digital PCR.Liquid biopsy is not recommended inALK,ROS1,RETrearrangement andCMETex14 skipping mutation detection.Detection ofEGFR T790Mis recommended in patients with EGFR TKIs resistance.Histological examination is the gold standard.If tissues cannot be offered,detection of ctDNAEGFR T790Mof blood can be the effective supplement.

2.6.3 Pathological diagnosis report

2.6.3.1 Tumor

(1) Histological type (including histological subtypes)

(2) Range of involvement

(3) Pleural invasion

(4) Vascular invasion

(5) Neural invasion

2.6.3.2 Incisal margin

(1) Bronchi incisal margin

(2) Vascular incisal margin

(3) Pulmonary incisal margin (regional lung incisal margin)

2.6.3.3 Other pathological stuff (such as obstructive pneumonia,changes related to the treatment)

2.6.3.4 Regional lymph nodes (including peripheral bronchi,hilar and isolate lymph nodes)

(1) Total number

(2) Number of involvements

2.6.3.5 Metastasis

2.6.3.6 Other tissues/organs

2.6.3.7 pTNM staging

2.6.3.8 For cases with difficulty,submit to a superior hospital for consultation (provide original pathology report to check the submitted biopsy information to reduce errors,provide adequate pathological sections or wax blocks,intraoperative condition,etc.)

3.Pathological type and stage of lung cancer

3.1 WHO’s 2021 standard

Table 2shows the histological type of lung cancer (WHO 2021).The main tissue types of lung cancer are adenocarcinomas and squamous carcinomas,which account for about 80% of all primary lung cancers.This is followed by SCLC,which accounts for about 15%.Other rare types include:adeno-squamous carcinomas,large cell carcinomas,salivary gland-type tumors (e.g.,adenoid cystic carcinoma,mucoepidermoid carcinoma),etc.Thoracic SMARCA4-deficient undifferentiated tumors were added to the latest classification.Bronchiolar adenoma was added to epithelial benign tumors.

Table 2 Histological type of lung cancer (WHO 2021)

3.1.1 Squamous cell carcinoma

The incidence of lung squamous cell carcinoma has declined in recent years,accounting for 30%?40% of lung cancer,of which 2/3 is central type,1/3 is peripheral type,and can be formed with cavities.Polyps can be located at the center.The spurs protrude toward the bronchial lumen.This type of cancer is generally thought originating from squamous metaplasia of bronchial epithelium after smoking stimulation,and is classified into high,medium,and poor differentiated according to the degree of differentiation of cancerous keratinocytes.Squamous cell carcinoma is frequently metastasized by lymphoid and blood vessels,and may directly invade mediastinal lymph nodes,bronchus and mediastinal soft tissues.Postoperative local recurrence was more common than other types of lung cancer.Extensive,multifocal molecular pathological abnormalities exist in bronchial and respiratory epithelium of smokers and lung cancer patients.Regional carcinogenic effects can result in multi-center lung tumors caused by smoking.

3.1.2 Adenocarcinoma

Adenocarcinoma,which accounts for 40%?55% of lung cancer,has surpassed squamous cell carcinoma as the most common type of lung cancer in many countries.Adenocarcinoma is more common in clinic with peripheral type,and the formation of cavities is rare.In recent years,the most important change in the pathology of lung adenocarcinoma is the concept of“adenocarcinomain situ”.It is suggested that the term“bronchioloalveolar carcinoma”should not be used any more.For invasive adenocarcinoma,it should be named by its preponderant components while indicating the proportion of other components,and the type of“mixed adenocarcinoma”should no longer be used.Briefly as follows:1) Atypical adenomatous hyperplasia (AAH).AAH is the precancerous lesion of at least one type of lung adenocarcinoma.AAH is usually within 0.5 cm,and the“ground glass”is usually the characteristic of CT scanning.Microscopic histology shows that the alveolar structures are intact,alveolar epithelialhyperplasia is uniformly cuboid or short column,with mildly atypical,and nucleoli are absent or vague;2)Adenocarcinomain situ(AIS).AIS is a new concept proposed in 2011.Solitary adenocarcinoma is defined as no more than 3 cm,confined to normal alveolar structures(adherent growth) and consists of type II alveolar epithelium and/or Clara cells.Nuclear atypia of AIS is not marked,and the widening of alveolar septum with fibrosis is common.The disease-free survival rate after surgical resection is 100%;3) Minimally invasive adenocarcinoma(MIA).MIA is defined as a single adenocarcinoma of ≤3 cm,with clear boundaries and adherent growth.The invasive carcinoma should be in a form other than adherence.The maximum diameter of the invasive interstitial is less than 5 mm,except for vascular invasion and pleural invasion,and risk factors such as dissemination of tumor cells in the airway.Multifocal adenocarcinoma in the lung can also be used for the diagnosis of MIA,except for the possibility of dissemination in the lungs.If MIA is completely excised,the overall 5-year survival rate is 100%;and 4) Invasive adenocarcinoma.Adenocarcinoma can be single,multiple,or diffuse.The morphology of invasive adenocarcinoma mainly includes lepidic,acinar,papillary,micropapillary and solid mucus secretion.Among them,the micropapillary and solid adenocarcinoma belong to poorly differentiated subtypes and should be recorded with the percentage of each histologic pattern.

3.1.3 Neuroendocrine carcinoma

Neuroendocrine carcinomas are classified into carcinoid tumor/neuroendocrine tumor (typical carcinoid and atypical carcinoid),SCLC,and some large cell neuroendocrine carcinomas.SCLC accounts for 15% of all lung cancers and is a poorly differentiated neuroendocrine carcinoma with necrosis and a high mitotic index.SCLC has neuroendocrine granules in at least two-thirds of cases under electron microscopy.Combined SCLC refers to SCLC combined with other non-small cell types,found in less than 10% of SCLC cases.According to the clinical behavior and pathological features,carcinoid tumor/neuroendocrine tumor is divided into typical carcinoid and atypical carcinoid,the former is low malignant,and the latter is slightly more malignant.The differential standard for typical and atypical carcinoid tumor is 2 mitotic figures per 2 mm2.In addition,the presence or absence of small necrosis is a kind of differences.Compared with typical carcinoid,atypical carcinoids often occur in the periphery,the metastasis rate increases,and the prognosis is relatively poor.Large cell neuroendocrine carcinoma is a large cell carcinoma with morphological and immunohistochemical differentiation characteristics of neuroendocrine tumors.It usually presents as peripheral nodules with necrosis and has a prognosis similar to that of small cell carcinoma.Combined large cell carcinoma refers to the combination of other differentiated non-small cell carcinoma components,and most of the components are carcinoma.

3.1.4 Other types of lung cancer

(1) Adenosquamous carcinoma.It only accounts for 0.6%?2.3% of all lung cancers.According to the new WHO classification,tumors must contain at least 10%adenocarcinoma or squamous cell carcinoma to diagnose adenosquamous carcinoma,often located in the periphery with central scar formation.Metastatic characteristics and molecular biology are indistinguishable from other NSCLCs.(2) Sarcomatoid cancer.A poorly differentiated non-small cell carcinoma containing sarcoma or sarcomatoid components (fusiform or/and giant cell-like),dividing into 3 subtypes:pleomorphic carcinoma,carcinosarcoma and pulmonary blastoma.(3) Salivary gland-type tumors.It includes adenoid cystic carcinoma,mucoepidermoid carcinoma and epithelial-myoepithelial carcinoma,etc.Sometimes mucoepidermoid carcinoma and solid mucinous adenocarcinoma are difficult to differentiate.The key difference is that the latter belongs to the poorly differentiated adenocarcinoma category,and the atypia is obvious.(4) Large cell carcinoma is a poorly differentiated adenocarcinoma defined mainly on exclusion of the differentiation characteristics of adenocarcinoma,squamous cell carcinoma or small cell carcinoma.(5) In addition to NUT carcinoma,the new classification adds thoracic SMARCA4-deficient undifferentiated tumor,a highly malignant undifferentiated tumor with a unique immunohistochemical phenotype and biological behavior,accompanied bySMARCA4gene mutation and deficient protein expression.

3.1.5 Immunohistochemistry and special staining

Reasonable and appropriate selection of immunohistochemistry projects can effectively retain enough tissue specimens for molecular diagnosis.When tumor differentiation is poor and there is no clear morphological features of adenocarcinoma or squamous cell carcinoma,it is necessary to use immunohistochemistry or mucin staining to confirm the diagnosis.

Immunohistochemical markers for the differentiation of adenocarcinoma and squamous cell carcinoma should be selected from TTF-1,Napsin-A,p63,p40 and CK5/6.Among them,p40 and TTF-1 can solve the problem of differential diagnosis of most adenocarcinoma and squamous cell carcinoma.For patients with further progression of the disease,in order to preserve tissues as much as possible for molecular pathology,it is recommended that restriction immunohistochemistry should be used to detect histological classification.For example,to detect the protein p63/p40 expressed in squamous cell carcinoma,single expression in the protein TTF-A/Napsin-1 on adenocarcinoma cells can classify most NSCLC.The identification of mucous material in solid adenocarcinoma cells should be carried out by mucicarmine staining and AB-PAS special staining;if the pleura is suspected,special staining of elastic fiber should be confirmed.Neuroendocrine tumor markers can be selected from CD56,Syn,CgA,Ki-67 and TTF-1.On the basis of neuroendocrine morphological features,at least one neuroendocrine marker is clearly positive,and the number of positive cells should be ＞10% of tumor cells to diagnose neuroendocrine tumors;endocrine markers only need to be closely combined with pathological morphology when CD56 performs positive.

3.2 Stage of lung cancer

TNM staging (pTNM staging UICC 8th edition) standard

T stage (primary tumor)

TX:primary tumor cannot be assessed,or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.

T0:no evidence of primary tumor.

Tis:carcinomain situincluding squamous cell carcinoma insitu(SCIS);AIS:adenocarcinoma with pure lepidic pattern,≤3 cm in greatest dimension.

T1:tumor ≤3 cm in greatest dimension,surrounded by lung or visceral pleura,without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e.,not in the main bronchus).

T1mi:minimally invasive adenocarcinoma:adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.

T1a:tumor ≤1 cm in greatest dimension.A superficial,spreading tumor of any size whose invasive component is limited to the bronchial wall and may extent proximal to the main bronchus also is classified as T1a,but these tumors are uncommon.

T1b:tumor ＞1 cm but ≤2 cm in greatest dimension.

T1c:tumor ＞2 cm but ≤3 cm in greatest dimension.

T2:tumor ＞3 cm but ≤5 cm or having any of the following features:1) Involves the main bronchus,regardless of distance to the carina,but without involvement of the carina;2) Invades visceral pleura (PL1 or PL2);and 3) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region,involving part or all of the lung.

T2a:tumor ＞3 cm but ≤4 cm in greatest dimension.

T2b:tumor ＞4 cm but ≤5 cm in greatest dimension.

T3:tumor ＞5 cm but ≤7 cm in greatest dimension or directly invading any of the following:parietal pleura(PL3),chest wall (including superior sulcus tumors),phrenic nerve,parietal pericardium;or separate tumor nodule(s) in the same lobe as the primary tumor.

T4:tumor ＞7 cm or tumor of any size invading one or more of the following:diaphragm,mediastinum,heart,great vessels,trachea,recurrent laryngeal nerve,esophagus,vertebral body,carina;separate tumor nodule(s) in an ipsilateral lobe different from that of the primary tumor.

N regional lymph nodes

NX:regional lymph nodes cannot be assessed.

N0:no regional lymph node metastasis.

N1:metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes,including involvement by direct extension.

N2:metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).

N3:metastasis in contralateral mediastinal,contralateral hilar,ipsilateral or contralateral scalene,or supraclavicular lymph node(s).

M distant metastasis

M0:no distant metastasis.

M1:distant metastasis.

M1a:separate tumor nodule(s) in a contralateral lobe;tumor with pleura or pericardial nodules or malignant pleural or pericardial effusion.

M1b:single extrathoracic metastasis in a single organ(including involvement of a single non-regional node).

M1c:multiple extrathoracic metastases in a single organ or in multiple organs.

Clinical stage

Occult carcinoma:TXN0M0

Stage 0:TisN0M0

Stage IA1:T1miN0M0,T1aN0M0

Stage IA2:T1bN0M0

Stage IA3:T1cN0M0

Stage IB:T2aN0M0

Stage IIA:T2bN0M0

Stage IIB:T1a?cN1M0,T2aN1M0,T2bN1M0,T3N0M0

Stage IIIA:T1a?cN2M0,T2a?bN2M0,T3N1M0,T4N0M0,T4N1M0

Stage IIIB:T1a?cN3M0,T2a?bN3M0,T3N2M0,T4N2M0

Stage IIIC:T3N3M0,T4N3M0

Stage IVA:any T,any N,M1a;any T,any N,M1b

Stage IVB:any T,any N,M1c

4.Lung cancer treatment

Lung cancer treatment should follow the principle that combines the multidisciplinary team (MDT) and personalized treatment together,according to the patient’s performance status (PS),histologic type,molecular profiling,tumor involvement and prognosis.Multiple modalities are commonly used properly either alone or in combination,including surgery,radiotherapy,chemotherapy,targeted therapy and immunotherapy,with an aim to maximize tumor control,improve survival results and minimize treatment toxicity.

4.1 Surgery

In general,anatomic lung resection is the essential approach for stage I or II disease.The resections are defined as complete,incomplete and uncertain resection.Complete resection is preferred to reduce the incidence of tumor recurrence and metastasis,and secure the accurate pathologic staging and molecular types,thus determining the postoperative treatment.

4.1.1 Surgical anatomy of bronchi and lung system

The trachea is a ventilation pipe connecting the throat and bronchoalveolar system.The length of the trachea is about 10?13 cm.From the inferior margin of the cricoid cartilage(about the level of lower margin of the 6th cervical vertebra) to the carina (about the level of the 4th thoracic vertebra),there are usually 18?22 cartilage rings.The blood supply of the trachea is segmental:the upper part of the trachea mainly comes from the branches of the inferior thyroid artery and the lower part from the branches of the bronchial artery.Therefore,isolating trachea too long would affect the blood supply and healing of the reserved trachea.

The trachea is divided into the left and right main bronchi at the carina level.In terms of the angle between the main bronchus,the trachea is straighter on the right side than on the left side,so the foreign body inhaled into the trachea by mistake is more likely to enter the right main bronchus.The right main bronchus bifurcates into the right upper lobe bronchus and the intermediate bronchus,and the latter further bifurcates into the middle lobe and the lower lobe bronchus.The right upper lobe bronchus is further divided into 3 segments of bronchus:apex,posterior and anterior.The middle lobe bronchus is further divided into 2 segments of bronchus:medial and lateral.The lower lobe bronchus consists of 1 superior and 4 basal bronchi:dorsal,internal,anterior,lateral and posterior.The length of the left main bronchus is about 4.5?5.0 cm,which bifurcates into the upper lobe and the lower lobe bronchus.The left upper lobe bronchus is further divided into the intrinsic upper lobar bronchus and the lingual lobar bronchus.The former is usually divided into anterior bronchus and posterior apical bronchus,while the latter is divided into upper lingual bronchus and lower lingual bronchus.The lower lobe bronchus also consists of dorsal bronchus and basal bronchi:internal anterior,lateral and posterior.The right lung is divided into 3 lobes by horizontal and oblique fissure and 10 segments,accounting for 55% of the respiratory function.The left lung is divided into 2 lobes by oblique fissure and 8 segments,accounting for 45% of the respiratory function.

The blood supply of the lung includes the pulmonary circulation system in pulmonary arteriovenous pattern and body circulation system in bronchial vessels pattern.The bronchial artery is mainly emanated from the descending aorta or intercostal artery,accompanied by the bronchi,and eventually forms a network of capillaries supplying the bronchi in adventitia and submucosa.Venous blood mainly flows into the pulmonary vein,a small part into the bronchial vein,and then into the azygos vein and the semiazygos vein.The main trunk of pulmonary artery originates from the right ventricle,ascending to the left,and is divided into left and right pulmonary trunk under the aortic arch.The right pulmonary trunk is longer than the left pulmonary artery,but its branches begin earlier than the left ones.The pulmonary artery is usually accompanied with the corresponding bronchi.Both left and right pulmonary veins consist of superior and inferior pulmonary veins,which go into the left atrium respectively.The right pulmonary middle lobe veins usually join with the right superior lobe veins to form the superior pulmonary veins.

4.1.2 Indications for lung cancer surgery

From the perspective of lung cancer alone,the absolute indication of lung cancer surgery is the T1?3N0?1M0 disease,the relative indication of the surgery is part of T4N0?1M0 disease,and the controversial indication is the T1?3N2M0 disease.Exploratory surgical indications for lung cancer include part of stage T1?3N0?1M1 with solitary metastases.

4.1.3 Contraindications of lung cancer surgery

Contraindications recognized for lung cancer surgery include:1) the stage of lung cancer beyond the scope of surgical indications;2) poor PS,with a Karnofsky score below 60%.It is recommended that the scoring criteria be aligned with international standards and considered in conjunction with ECOG score;3) acute myocardial infarction within 6 weeks;4) severe ventricular arrhythmia or uncontrollable heart failure;5) cardiopulmonary failure to meet the intended operation;6) more than 50% of carotid artery stenosis for patients over 75 years old,or patients under 75 with more than 70% of carotid artery stenosis;7) patients over 80 years old requiring pneumonectomy;8) serious,uncontrollable accompanying diseases continue to impair the patient’s physiological and psychological function;and 9) patients refused surgery.

4.1.4 Complete resection of lung cancer

At present,surgical resection of lung cancer should include anatomical lobectomy (including combined lobectomy),sublobar resection (suitable for some lung cancer in early stage),lobectomy with bronchoangioplasty,pneumonectomy,and systematic mediastinal lymph node dissection.The NCCN guidelines defined criteria for complete resection of lung cancer.Complete resection:1)all incisional margins including bronchi,arteries,veins,peribronchial tissues and tissues adjacent to tumors are negative;2) systemic lymph node dissection must include 6 stations of lymph nodes,3 of which come from intrapulmonary (lobar,interlobar or segmental) and hilar lymph nodes,and the other 3 stations are from mediastinal lymph nodes,including subcarinal lymph nodes;3) no extracapsular nodal extension of the tumor;and 4) the highest mediastinal node removed must be negative.Complete resection requires all the criteria above,otherwise the resection would be defined as incomplete.

4.1.5 Lymph node dissection for lung cancer

Mediastinal,hilar and segmental portal lymph node dissection is indispensable for lung cancer surgery.Lobectomy or pneumonectomy with systemic mediastinal lymph node dissection is considered the standard surgical procedure for lung cancer.However,recent high-level evidence-based medical proof suggests that sublobar resection with lobe-specific lymph nodes dissection has a long-term survival rate that is not inferior to the standard surgical procedure.It may also be an option for some lung cancers in early stage.

So far,the lymph node atlas in 2009 from International Association for the Study of Lung Cancer (IASLC) is used worldwide.In this atlas,the mediastinal lymph nodes consist of 9 stations.Standard mediastinal lymph node dissection,also known as complete mediastinal lymph node dissection,requiresen blocresection of the mediastinal lymph node and its surrounding adipose tissues.

4.1.6 Surgical procedures for lung cancer

Lung cancer surgery can be divided into complete resection(radical resection),incomplete resection (palliative resection) and biopsy for diagnostic purposes,according to the degree of resection completeness.It also can be defined by the removed lung as wedge resection,segmentectomy,lobectomy,combined lobectomy (removal of more than one lobe),pneumonectomy,lobectomy with bronchoangioplasty,and extended resection of organs and tissues involved;According to the size of the incision,lung cancer surgery can be defined as conventional thoracotomy,smallincision thoracotomy,video-assisted thoracic surgery(VATS),etc.Generally,resection of lung cancer specifically refers to complete resection.

The standard procedure of anesthesia for lung cancer resection is double lumen endotracheal intubation,while the operative side is not ventilated.The patient lies on the contra-operative side.Surgical incision is usually performed by the posterolateral incision through the 5th or 6th intercostal spaces.The thoracoscopic incision varies according to the patients and surgeons’ habits.Usually,single-port thoracoscopies are chosen to enter the chest through the 4th or 5th intercostal spaces.The two/threeport thoracoscopic option is more variable.The key to lobectomy is to dissect the fissures between the lobes,ligate the branches of pulmonary arteries and pulmonary veins of the lobe,and cut off all these blood vessels and the bronchus of the lobe,so as to remove the lobe.For lobectomy,the procedure is commonly started with the dissection of fissure.Sleevelobectomy is usually considered when a central disease invades the opening the lobar bronchus,which results in the tumor residual at the margin of bronchus,or the margin that is too close to the tumor.If sleeve lobectomy is not enough for a free margin,pneumonectomy should be considered.The most common reason for pneumonectomy is not the unsafe margin of the bronchus,but the involvement of the pulmonary artery.Basically,the left pneumonectomy is usually performed.Right pneumonectomy is not commonly used in our clinical practice because of the pulmonary function loss,poor quality of life and poor tolerance to adjuvant treatment consequently.Combined lobectomy mainly refers to middle and lower lobe resection and upper and middle lobectomy.The common reason for the former is to secure a safe margin when the tumor involves the root of middle lobe bronchus or the root of the superior bronchus in lower lobe.Since the right middle lobe pulmonary veins usually converge into the superior lobe pulmonary veins to form the superior pulmonary veins,the upper and middle lobectomy may be necessary if the junction of superior lobe veins and the middle lobe veins are invaded.Anatomic sublobar resection mainly includes including segmentectomy,combined segmentectomy,combined subsegmentectomy,etc.,where the anatomy is more delicate and complex.The 3D reconstruction software can help the surgeon to complete the surgery more accurately and smoothly.

4.1.7 Surgical complications of lung cancer

The incidence of postoperative complications of lung cancer is about 8%?35%.The most common complications are related to respiratory and cardiovascular system,whereas air leakage and bronchopleural fistula are particular for lung surgery.

4.1.7.1 Respiratory complications

It usually happens in patients with chronic bronchitis preoperatively.The common problems are atelectasis and obstructive emphysema,resulting from the sputum blocking the airway.The reasons for the formation of sputum thrombus vary,such as intubation by anesthesia,intraoperative manipulation,which caused increased mucous secretion,together with the postoperative pain,bronchial branch of vagus injury,as well as insufficient ventilation,which compromises the effectiveness of cough postoperatively.The clinical symptoms are low breathing,hypopnea,low oxygen saturation and infection with fever.The patients need to be helped to expel sputum,and some patients undergo bronchoscopic aspiration of sputum,while very few patients need tracheotomy.

4.1.7.2 Air leakage of lung

It is most seen in patients with emphysematous bulla preoperatively.It also occurs in some patients who have undergone sublobar resection due to the large wound.Air leakage is mainly caused by air leakage from the lung fracture after dissection of the fissure.The diagnosis is persistent bubbles escaping from the thoracic drainage tube,which should also be differentiated with bronchopleural fistula.The key of the treatment is adequate drainage to ensure the recovery of the reserved lungs and prevent infection.By the postoperative adhesions on the surface of the lung,the volume of air leakage reduced gradually in most of the patients.

4.1.7.3 Bronchopleural fistula

Bronchopleural fistula is a series of clinical symptoms and signs caused by poor healing of bronchial stump that gets the airway into pleural cavity.Vestet al.has reported that the incidence of bronchopleural fistula was 1.6%,based on 2,243 cases of lung surgery in 1991,whereas the incidence in China was about 1% in a large group of cases reported.Most cases occurred about one week after operation.Clinical symptoms include cough,producing sputum,hard breath and fever.Chest X-ray shows encapsulated hydropneumothorax and empyema,while some have the sign of aspiration pneumonia.The early symptoms are markedly increased sputum volume and thinner,reddish pleural effusion,and purulent sputum would be noted in the following days,especially when there is empyema.To confirm the diagnosis,a bronchoscopy examination is necessary.Pleural drainage is the essential treatment for this complication and drainage tube is often placed near the fistula.For postoperative patients in early stage,surgical repair can be tried,otherwise the repair would be very difficult,and the drainage would be the only approach.It has been reported that tracheal stent could be placed to temporarily close the fistula.Some studies also reported that for the cases with limited inflammation,medical biological protein glue could be another method to solve the problem.

4.1.8 A dvances in surgical treatment of lung cancer

(1) The role of VATS in surgical treatment of lung cancer.VATS is one of the greatest advances and developments in techniques of thoracic surgery over the past twenty years.We attached more and more importance to video-assisted thoracoscopic lung cancer surgery,which is one of the directions of lung cancer surgery development in the future.There are still many different opinions about the indication of VATS,which is associated with the time when the techniques started,the preference of the surgeon,and the proficiency of the surgeon.However,as what has been written in NCCN guidelines,VATS should also follow the principles of lung cancer surgery,that is,the completeness of the resection,as well as the safety of surgery.

(2) Options of surgery for early-stage lung cancer.It has been accepted for a long time that lobectomy is the standard surgical procedure for stage I NSCLC.Recent studies proved that segmentectomy or wedge resection might be the best procedure for less than 2 cm peripheral stage I NSCLC,especially for those ground-glass nodules.

With the increasing number of retrospective reports,the utilization of sublobar resection (lung segmentectomy or wedge resection) for peripheral early-stage lung cancer with a predominant ground-glass component has gradually become the consensus in thoracic surgery.The recent results of the large randomized controlled trial JCOG0802 showed that segmentectomy was superior to lobectomy in terms of 5-year survival and better preservation of lung function for peripheral NSCLC with a solid component of＞50% and a tumor diameter of ≤2 cm.As more similar studies are disclosed,sublobar resection may become the standard procedure for this type of lung cancer.

4.2 Radiotherapy

Radiotherapy for lung cancer includes radical radiotherapy,palliative radiotherapy,adjuvant radiotherapy and preventive radiotherapy.

4.2.1 Principles of radiotherapy

(1) Radical radiotherapy is suitable for patients with Karnofsky score ＞70,including those unresectable earlystage NSCLC (stereotactic body radiation therapy,SBRT),locally advanced NSCLC,and limited stage SCLC who are inoperable due to objective or subjective reasons.

(2) Palliative radiotherapy is suitable for the treatment of primary lung cancer and metastatic lesions from advanced lung cancer.Postoperative whole brain radiotherapy can be performed on patients with NSCLC single brain metastases.SBRT for patients with NSCLC single metastases or oligometastases can be considered.Chestradiotherapy can be performed on extensive stage SCLC patients.

(3) Adjuvant radiotherapy is suitable for patients with positive margins (R1 and R2) postoperatively;patients with uncertain surgical exploration or unsafe surgical margins;and patients with positive pN2 after surgery are encouraged to participate in clinical trials on postoperative radiotherapy.Based on non-randomized findings,the NCCN guidelines (2021.Version 4) recommend postoperative radiotherapy.

(4) The plan of postoperative radiotherapy should refer to patient’s postoperative pathology report and operation record.

(5) Preventive radiotherapy of whole brain is suitable for limited stage SCLC patients who performed complete response after chemotherapy and radical radiotherapy.Patients with extensive stage SCLC after an effective chemotherapy can choose the prophylactic whole-brain radiotherapy or a close follow-up using brain MRI.

(6) Indication of concurrent chemoradiation:For patients with locally advanced NSCLC,concurrent chemoradiation is recommended.If the patient cannot tolerant the complications,sequential radiotherapy can be performed.The recommended regimen for concurrent chemotherapy is EP (etoposide+cisplatin) or TC (paclitaxel +carboplatin),and regimen of pemetrexed +cisplatin/carboplatin may also be one of the preferred regimens for concurrent or sequential administration of non-squamous cell NSCLC.

(7) Consolidation therapy with the immune checkpoint inhibitor durvalumab (PD-L1 monoclonal antibody) after concurrent chemoradiotherapy for locally advanced NSCLC has been shown to significantly prolong overall survival and progression-free survival (PACIFIC study,class 1 evidence).PD-L1 expression testing is not mandatory,but there may be no significant benefit in overall survival in patients with negative PD-L1 expression.The incidence of severe adverse reactions of grade 3?4(including pneumonia of grade 3 and above) is not statistically significant compared with the control group.

(8) Patients with chemoradiation will have more potential adverse reactions and should be informed before treatment.We should lay more emphasis on the protection of lung,heart,esophagus and spinal cord when designing and implementing radiotherapy.During the treatment,we should avoid the unplanned interruption of radiotherapy due to improper treatment of toxic side effects.

(9) It is suggested that SBRT should be carried out under the condition of excellent radiophysical techniques by using advanced radiotherapy techniques such as 3D conformal radiotherapy,intensity modulated radiotherapy (IMRT) or image-guided radiotherapy.

(10) Enhanced CT localization or PET-CT localization is recommended for radiotherapy target area delineation.We can refer to the tumor biological image of PET-CT and delineate tumor radiotherapy target in enhanced CT imaging.

(11) Patients undergoing radiotherapy or chemoradiation should be given adequate monitoring and supportive treatment during rest.

4.2.2 Indications for NSCLC radiotherapy

Radiotherapy can be used for radical treatment of early NSCLC patients who are medically inoperable or refused surgery;preoperative and postoperative adjuvant therapy in operable patients;local therapy in patients with locally advanced lesions that cannot be resected;palliative care for incurable patients at an advanced stage.

For stage I NSCLC patients with contraindications for surgery or refusing surgery due to medical conditions,large fractionation radiotherapy is an effective radical therapy,and SBRT is recommended.The principle should be high dose,less fractionation and short course of treatment.The segmentation scheme can be considered comprehensively according to the location of the lesion,distance from the chest wall and other factors,and the total dose is usually given ≥100 Gy.Radiotherapy tolerance doses of organs and tissues should be fully considered and carefully assessed in SBRT planning,such as spinal cord,esophagus,trachea,heart,chest wall and brachial plexus.

For NSCLC patients who undergo surgery,if the pathology of surgical margin is negative and the mediastinal lymph node is positive (pN2 stage),besides routine postoperative adjuvant chemotherapy,adjuvant radiotherapy can be used,and chemotherapy followed by sequential radiotherapy is recommended.For patients with obvious residues (R2 resection),postoperative concurrent chemoradiation is recommended,if patients are physically permitted.

If the physical conditions permit,conformal radiotherapy combined with concurrent chemotherapy should be used in patients with stage II?III NSCLC who are unable to undergo surgery for physical reasons.For patients who are expected to be cured,more conformal radiotherapy plans and more active supportive care should be recommended to avoid interruptions or dosage reductions during radiotherapy or concurrent chemoradiation.For stage IV NSCLC patients with extensive metastasis,some patients can receive radiotherapy on primary and metastatic lesions to achieve palliative reduction.When the benefit from systemic therapy is apparent,SBRT technique can be used on the residual primary and/or oligometastatic lesions,so as to obtain potential curative effect.

4.2.3 Indications for SCLC radiotherapy

Combined chemoradiation is the standard treatment for limited stage SCLC.Patients with limited diseases are recommended to receive concurrent chemoradiation at the initial treatment or two cycles of induction chemotherapy followed by concurrent chemoradiation.If patients are intolerant,sequential chemoradiation is also feasible.Radiotherapy for limited stage SCLC should begin as early as possible if the condition permits,and concurrent with chemotherapy in the first or second cycle.If the lesion is large and the risk of radiation-induced lung injury is too high,concurrent radiotherapy during the third cycle of chemotherapy may also be considered.

For patients with SCLC in extensive stage,if distant metastases have been controlled by chemotherapy,chestradiotherapy can also increase tumor control and prolong survival.Whether chest radiotherapy can further improve efficacy in patients with chemotherapy combined with immunotherapy has currently no evidence of prospective randomized controlled clinical trials.Participation in clinical studies is encouraged.

4.2.4 Prophylactic cranial irradiation (PCI)

PCI is recommended for limited stage SCLC patients after complete response in primary lesions,and is also recommended for patients with partial response.PCI can also reduce the risk of brain metastasis in extensive stage SCLC when chemotherapy is effective.The recommended time for PCI is about 3 weeks after the end of all chemoradiation.Enhanced magnetic resonance imaging should be performed before PCI to rule out brain metastasis,and a dose of 25 Gy in 10 fractions within 2 weeks is recommended.An adequate and effective communication between the doctor and the patient is necessary before making decision of PCI,weighing the pros and cons of each patient’s situation.

4.2.5 Patients with oligometastasesat stage IV

The definition is not yet uniform,with no more than three metastatic organs,no more than five metastatic lesions,the feasibility of radical treatment,etc.being recognized as the important factors in defining the status of oligometastses.If systemic therapy is effective (chemotherapy,targeted therapy,etc.),active local treatment (SBRT,surgery,etc.)for residual primary and/or oligometastatic foci may prolong disease control and patient survival.It has a potential curative effect.Due to the lack of high-level evidence,the decision of local consolidation therapy on patients with oligometastatic at stage IV should be made through MDT discussions.Clinical studies are recommended.

4.2.6 Palliative radiotherapy for patients with advanced lung cancer

The main purpose of palliative radiotherapy for advanced lung cancer patients is to relieve the local compression symptoms caused by primary or metastatic lesions,the pain caused by bone metastasis,and neurological symptoms caused by brain metastasis.For such patients,lowfractionation irradiation can be considered,so that it would be more convenient for treatment and more rapid for symptom relief.

4.2.7 Treatment effect evaluation

The short-term efficacy of radiotherapy is evaluated according to WHO response evaluation criteria in solid tumors (RECIST).

4.2.8 Radiation protection

Advanced techniques of radiotherapy should be used as much as possible to protect the lungs,heart,esophagus and spinal cord from serious radiation damage.Acute radiation lung injury refers to the international radiation therapy cooperation group acute radiation injury classification standard.

4.3 Medication

Systemic therapy for lung cancer includes chemotherapy,molecular targeted therapy and immunotherapy.Chemotherapy can be defined as neoadjuvant chemotherapy,adjuvant chemotherapy and palliative chemotherapy.Clinical indications should be strictly controlled and carried out under the guidance of oncologists.Chemotherapy should give full consideration to the stage of the disease,physical condition,adverse effect,quality of life and patients’ desire,so as to avoid overtreatment or inadequate treatment.After evaluating clinical response and monitoring adverse effects,the administration and/or dose should be adjusted in time.Molecular targeted therapy should be used after identifying the gene mutation status.In recent years,immune checkpoint inhibitors (such as PD-1 monoclonal antibody or PD-L1 monoclonal antibody,etc.) have been shown to improve the survival of lung cancer patients.Currently,several PD-1 mAb and/or PD-L1 mAb have been approved and marketed for use in advanced and locally advanced NSCLC and SCLC.More clinical indications are still being explored.

4.3.1 Medication for advanced NSCLC

4.3.1.1 First-line systemic therapy

For patients with negative driver genes,platinum-doublet regimens are the standard first-line chemotherapy regimen,and for patients with non-squamous carcinoma,they can be combined with anti-angiogenic therapy such as bevacizumab or endostatin on the basis of chemotherapy.It is recommended that camrelizumab,pembrolizumab,tislelizumab,sintilimab or atezolizumab in combination with pemetrexed platinum-based chemotherapy regimen can be administrated.For squamous cell carcinoma,pembrolizumab,tislelizumab in combination with paclitaxel or sintilimab in combination with gemcitabine platinum-doublet regimen is recommended.If the patient has positive PD-L1 expression (TPS≥1%),pembrolizumab monotherapy is feasible.Moreover,patients with high PDL1 expression (TPS≥50%) benefit more from immunotherapy.Patients with high PD-L1 expression (TC≥50% or IC≥10%) may also receive atezolizumab monotherapy.For patients with positive driver gene,such as those withEGFRgene mutations (including exon19 deletions,exon21 L858R and L861Q,exon18 G719X,and exon20 S768I),treatment with epidermal growth factor receptor tyrosine kinase inhibitors,including gefitinib,erlotinib,icotinib,dacomitinib,afatinib,or osimertinib,may be selected.Combined chemotherapy may also be considered for the first-line therapy of gefitinib or erlotinib,and bevacizumab can also combine with erlotinib.Patients with positiveALKgene fusion may choose treatment with alectinib,ceritinib,or crizotinib.Patients who are positive forROS1gene fusion may be treated with crizotinib.Patients withCMETex14 skipping mutation or who cannot tolerate chemotherapy can choose savolitinib.The current therapeutic options are detailed inTables 3,4.

Table 3 First-line chemotherapy and immunotherapy regimen for NSCLC

Table 3 (continued)

Maintenance therapy is optional for patients who have achieved disease control (complete response,partial response and stable disease) with first-line treatment.So far,pemetrexed (non-squamous cell carcinoma),bevacizumab (non-squamous cell carcinoma) and gemcitabine have been proved by medical evidence as options for continuation maintenance therapy.If there is no disease progression or intolerable adverse effects when using immune checkpoint inhibitors,the recommended cycle of use is 2 years.Pemetrexed (non-squamous cell carcinoma) has been proved effective as switch maintenance therapy.EGFR-TKI can be selected for maintenance therapy in patients with sensitiveEGFRgene mutation.

4.3.1.2 Second-line systemic therapy

Alternative drugs for second-line treatment include docetaxel,pemetrexed,etc.Patients with positiveEGFRmutations,ALKgene fusion,orROS1gene fusion can choose the appropriate molecular targeted drugs.Immunotherapy includes nivolumab,etc.

In patients with positive driver genes,if no corresponding molecular targeting drugs are used for first-line and maintenance therapy,molecular targeting drugs should be given priority in second-line treatment.In patients with first-line EGFR-TKIs resistance and harboringEGFR T790Mmutation,the third-generation EGFR-TKIs including osimertinib,almonertinib and furmonertinib should be given priority in second-line treatment.ForALKmutation patients who develop drug resistance after firstline crizotinib,ceritinib or alectinib can be used sequentially during second-line treatment.If there is oligoprogressive lesion or central nervous system progression after resistance to first-line molecular targeted therapy,a combination of local therapy based on targeted therapy,such as radiotherapy or surgery,can be continued.

For patients with resistance to EGFR-TKI or ALK inhibitor in the first line,platinum-doublet or monotherapy regimen can be selected according to the Eastern Cooperative Oncology Group (ECOG) PS score of patients.It can be combined with anti-angiogenic drugs,such as bevacizumab,on this basis for patients with nonsquamous cell carcinoma.

Chemotherapy should be given priority in patients with negative driver genes,and afatinib may be used in patients without driver genes and with histologic type of squamous cell carcinoma (Table 5).

Table 4 Anti-angiogenic therapy,immunotherapy and targeted therapy for NSCLC

Table 5 Commonly used second-line chemotherapy regimens for NSCLC

Immune checkpoint inhibitors can be considered for NSCLC patients who fail to respond to platinum-doublet chemotherapy or targeted therapy.

4.3.1.3 Third-line systemic therapy

Clinical trials are optional.Oral monotherapy of VEGFRTKI can be used in third-line treatment.If immune checkpoint inhibitors are not used in the first and second lines,nivolumab may be considered.Current third-line treatment with VEGFR-TKI with evidence-based medical evidence supports anlotinib.

4.3.1.4 Other systemic therapies

Patients with locally advanced or metastatic NSCLC harboring METex14 skipping mutations,who have diseaseprogression after chemotherapy or who are intolerant to standard platinum-based chemotherapy,may be treated with savolitinib.Patients with locally advanced or metastatic NSCLC harboring positiveRETgene fusion,who have received previous platinum-based chemotherapy,can be treated with pralsetinib.For other driver mutations,such asBRAF V600Emutation,NTRKgene fusion,etc.,there are some new targeted drugs that have been tested in clinical trials and achieved good efficacy.Therefore,patients with rare mutations are encouraged to participate in clinical trials and the corresponding drugs can be considered as the treatment in some clinical situations.

4.3.2 Systemic therapy for unresectable NSCLC

Combination of radiotherapy and chemotherapy is recommended.Concurrent or sequential chemoradiotherapy can be chosen according to specific circumstances.Recommended regimens for concurrent chemotherapy include etoposide combined with cisplatin (EP) or carboplatin (EC),pemetrexed combined with cisplatin or carboplatin,paclitaxel or docetaxel combined with platinum.Sequential chemotherapy regimens include cisplatin+etoposide,cisplatin+paclitaxel,cisplatin +docetaxel,cisplatin or carboplatin+pemetrexed (nonsquamous cell NSCLC).The multidisciplinary team should discuss and evaluate the possibility of surgery for downstaging patients after induction therapy.Surgical treatment should be considered if complete resection could be achieved.Sequential durvalumab treatment for 1 year can be considered for patients with unresectable stage III NSCLC if there is no disease progression after concurrent chemoradiation.

4.3.3 Perioperative chemotherapy for NSCLC

Postoperative adjuvant chemotherapy:Completely resected stage II?III NSCLC is recommended for 4 cycles of adjuvant chemotherapy with platinum-doublet regimen.Adjuvant chemotherapy begins with the patient’s postoperative physical condition returning to normal,generally starting at 4?6 weeks and not exceeding 3 months after surgery.

Neoadjuvant chemotherapy:For resectable stage III NSCLC,2?3 cycles of preoperative neoadjuvant chemotherapy can be carried out with platinum-doublet.The responses should be evaluated in time,and adverse reactions should be monitored and treated to avoid the increase of surgical complications.Surgery is usually performed 2?4 weeks after chemotherapy.Postoperative adjuvant chemotherapy should be adjusted according to the preoperative staging and the efficacy of neoadjuvant chemotherapy.The effective ones should continue the original regimen or adjust according to the patient’s tolerance.The ineffective ones should adjust the treatment regimen.The overall perioperative chemotherapy is recommended for 4 cycles.

Perioperative immunotherapy:Evidence-based medical evidence shows that neoadjuvant therapy of platinum-based chemotherapy combined with PD-1 mAb neoadjuvant therapy,or postoperative PD-L1 mAb may improve pathologic complete response rates or prolong relapse-free survival.Therefore,we encourage patients to participate in clinical trials of perioperative immunotherapy.

4.3.4 Systemic therapy for SCLC

4.3.4.1 First-line treatment

Limited stage (T1?2,N0) SCLC is recommended for lobectomy+hilar and mediastinal lymph node dissection,and postoperative adjuvant chemotherapy.Limited stage(more than T1?2,N0) SCLC is recommended for radiation and chemotherapy-based comprehensive treatment.The recommended regimens include EP or EC.Extensive stage SCLC is recommended for chemotherapy or chemotherapy (EP or EC) combined with immunotherapy.Those with local symptoms or brain metastases are recommended to combine radiotherapy or other treatments based on chemotherapy.The recommended regimens include EP,EC,irinotecan combined with cisplatin (IP),irinotecan combined with carboplatin (IC),or etoposide combined with lobaplatin (EL).

4.3.4.2 Second-line treatment

Topotecan,irinotecan,gemcitabine,vinorelbine,temozolomide,or paclitaxel is recommended for patients with recurrence or progression within 6 months after firstline chemotherapy.Patients who relapse or progress after 6 months can choose the initial treatment plan.Patients are encouraged to participate in clinical trials of new drugs.

4.3.4.3 Third-line treatment

Anlotinib or participating in clinical trials is available.

4.3.5 Principles of lung cancer chemotherapy

(1) Lung cancer patients with KPS＜60 or ECOG＞2 are not suitable for chemotherapy.Terms can be appropriately eased for patients with SCLC.

(2) Lung cancer patients with leukocytes less than 3.0×109/L,neutrophils less than 1.5×109/L,platelets less than 100×109/L,red blood cells less than 2×1012/L,and hemoglobin lower than 80 g/L should not be treated with chemotherapy in principle.

(3) Lung cancer patients with severely abnormal liver function,kidney function and/or laboratory indicators,or with serious complications and infections,fever,bleeding tendency should not be treated with chemotherapy.

(4) Discontinuing or replacing regimens should be considered:If the disease progresses after 2 cycles of treatment or deteriorates again during the interval of the chemotherapy cycle,the original regimen should be discontinued and alternative regimens should be chosen in the following treatment.If the adverse reaction of chemotherapy reaches grade 3?4,and the patient’s life is obviously threatened,the drug should be discontinued,and alternative regimens should be used in the following treatment.If serious complication occurs,the drug should be discontinued and alternative regimens should be used in the following treatment.

(5) Emphasis must be placed on the standardization and individualization of treatment protocols.The basic requirements of chemotherapy should be mastered.Besides the routine use of antiemetic drugs,hydration and diuresis are required during the use of platinum drugs other than carboplatin.Routine blood tests should be performed two times a week after chemotherapy.

(6) The efficacy of chemotherapy is assessed according to RECIST criteria.

4.4 Endobronchoscopic interventional therapy

With the increasing popularity of bronchoscopy in clinical applications,the following local treatments are optional for patients unable to undergo surgery or radiotherapy:bronchoscope-mediated laser,high-frequency electrotome,radiofrequency ablation,argon plasma coagulation (APC),microwave,laser,photodynamic therapy,cryotherapy,airway stent,balloon dilatation,submucosal or intratumoral drug injection,etc.Endobronchial interventional therapy should be based on strict indications,with accurate treatment purpose and objective assessment of whether a certain treatment technology can achieve a desired goal.The treatment should be carried out in qualified hospitals.

(1) For intracavitary polypoid tumors,trap removal or carbon dioxide cryosurgery is feasible,and APC is performed at the root of tumor.

(2) For wall-infiltrated tumors,photodynamic therapy can be performed after the resection of intraluminal tumor,and then radiation and chemotherapy particles can be considered in patients contraindicated of external radiation.

(3) Endoscopic interventional therapy may be considered for patients with central airway stenosis who cannot be or refuse to be operated on.The technologies include thermal ablation (high frequency electrotome,radiofrequency ablation,APC,microwave,laser,etc.),photodynamic therapy,cryotherapy,airway stent,submucosal or intratumoral drug injection,etc.

(4) For airway stenosis and airway fistula that cannot be relieved by conventional treatment,internal stent implantation should be considered as the main treatment.The endotracheal stent can be divided into metal stent and non-metallic stent.The metal stent can be divided into the membrane stent and the non-membrane stent (bare stent).Non-metallic stent can be divided into silicone stent,plastic stent,etc.

(5) Endoscopic interventional therapy should be carefully chosen if distal lung function is lost or small airway obstruction occurs simultaneously.

Selection of individualized endobronchoscopic interventional therapy is very important.It needs to be discussed in multidisciplinary treatment (MDT) and to combine with the equipment performance of the proposed technology and personnel conditions at the same time.The ideal treatment is a combination of several methods,such as thermocoagulation or cryosurgery to remove large lesions in the lumen,and freeze-thaw treatment to remove basal lesions.

4.5 Staged treatment mode of NSCLC

4.5.1 Comprehensive treatment for patients with stage I NSCLC

(1) Surgical treatment is preferred,including lobectomy plus systemic pulmonary hilus and mediastinal lymph node dissection,sublobar resection plus selective lymph node dissection.Minimally invasive operations such as VATS,robotic surgery or thoracotomy can be used.

(2) For partial stage IA NSCLC patients with advanced age or low lung function,anatomical segmental or wedge resection plus systemic hilar or mediastinal lymph node dissection or sampling should be considered.

(3) Postoperative adjuvant chemotherapy,radiotherapy and targeted therapy are not recommended for completed resected stage IA,IB NSCLC patients.

(4) Reoperation is recommended for stage I lung cancer with positive margin.Postoperative radiotherapy is recommended for patients who are unable to reoperation for any reason.

(5) SBRT is available for patients with severe medical complications,advanced age and those who refuse surgery.

4.5.2 Comprehensive treatment for patients with stage II NSCLC

(1) Surgical treatment is preferred,including lobectomy plus systemic pulmonary hilus and mediastinal lymph node dissection.

(2) For patients with advanced age or low lung function,anatomical segmental or wedge resection plus systemic hilar or mediastinal lymph node dissection or sampling should be considered.

(3) Postoperative adjuvant chemotherapy using platinumdoublet regimen is recommended for patients with completely resected stage II NSCLC.

(4)En blocresection of chest wall should be carried out when the tumor invades the parietal pleura or chest wall.The resection range should be at least 2 cm from the upper and lower edges of the ribs nearest to the lesion,and the resection length of the invaded ribs should be at least 5 cm from the tumor.

(5) Reoperation is recommended for stage II lung cancer with positive margin.If physically permitted,postoperative concurrent chemoradiotherapy is recommended for patients who are unable to receive reoperation for any reason.Radiotherapy should start as soon as possible.

4.5.3 Comprehensive treatment for patients with stage III NSCLC

Locally advanced NSCLC refers to patients with TNM stage III.MDT is the best choice for stage III NSCLC.Locally advanced NSCLC can be divided by resectable and non-resectable NSCLC.

4.5.3.1 Resectable locally advanced NSCLC

(1) Surgical treatment+adjuvant chemotherapy or radical chemotherapy are recommended in T3?4N1 or T4N0 patients,and neoadjuvant treatment is worth considering.

(2) For stage N2 NSCLC patients with imaging findings of a single group of mediastinal lymph nodes with diameter less than 3 cm,or two groups of mediastinal lymph nodes enlarged but not fused and a complete resection could be expected to achieve,MDT is recommended,neoadjuvant chemotherapy +/? radiotherapy+surgery,or surgery +chemotherapy +/? radiotherapy is also recommended.For patients withEGFRmutation,surgery+adjuvant EGFRTKI treatment +/? postoperative radiotherapy is adopted.Preoperative mediastinoscopy examination,EBUS-TBNA or EUS-guided fine needle aspiration (EUS-FNA),after N2 staging,preoperative neoadjuvant chemotherapy or neoadjuvant chemo-radiotherapy was performed,followed by surgical treatment.As for lung cancer with N2 lymph metastasis,and predictable completely excision,concurrent chemoradiotherapy was recommended for the risk of recurrence higher than mono-lymph metastasis.Simultaneously,the neoadjuvant chemotherapy +/?radiotherapy+surgery +/? adjuvant chemotherapy +/?postoperative radiotherapy should also be considered as the combined treatment.Some patients have lung cancers withEGFRmutation,the treatment of surgery+combined adjuvant EGFR-TKI treatment +/? postoperative radiotherapy should also be recommended.

(3) NSCLC in stage II?IIIA,according to the benefit treatment data of ADAURA,EVIDENCE,ADJUVANT and EVAN trials,EGFRmutation test was recommended for patients with non-squamous NSCLC at stage II?IIIA(N1?2).

4.5.3.2 Unresectable locally advanced NSCLC includes:

(1) Part of IIIa (N2) NSCLC patients with enlarged and fused mediastinal lymph nodes,which were confirmed positive by mediastinoscopy,EBUS-TBNA or EUS-FNA should be identified as unresectable after discussion of the chest tumor MDT.

(2) Stage IIIB/IIIC patients.

(3) The preferred treatment for unresectable locally advanced NSCLC,such as ECOG PS score 0?1,is concurrent chemoradiotherapy.If there is no disease progression after concurrent chemoradiotherapy,the addition of durvalumab for maintenance therapy may be considered.

4.5.4 Comprehensive treatment for patients with stage IV NSCLC

Patients with stage IV NSCLC should first obtain tumor tissues forEGFR,ALKandROS1gene detection before treatment,and then decide the appropriate treatment strategy according to the above gene status.Stage IV NSCLC is mainly treated by systemic therapy with the aim of improving the quality of life and prolonging the survival of patients.

4.5.4.1 Treatment of stage IV NSCLC patients with solitary metastases to brain,adrenal gland or lung

(1) In NSCLC patients with solitary metastases to brain and resectable lung lesions,brain lesions can be resected surgically or treated with stereotactic radiotherapy and the primary pulmonary lesions should be performed according to the principle of staged treatment.

(2) In NSCLC patients with solitary adrenal metastases and resectable lung lesions,adrenal lesions can be considered surgical removement and the primary pulmonary lesions should be performed according to the principle of staged treatment.

(3) For solitary nodules in the contralateral lung or other lobes of the ipsilateral lung,if the primary lung lesion can be surgically removed,they can be treated as two primary tumors with respective staging.If surgery is performed,adjuvant therapy is guided by pathology.

4.5.4.2 Systemic treatment for stage IV NSCLC treatment

(1) First-line EGFR-TKI treatment is recommended for stage IV NSCLC patients with EGFR-sensitive mutation.Patients with positiveALKgene fusion are recommend first-line treatment with ALK inhibitor like crizotinib,alectinib and ceritinib.Patients with positiveROS1fusion gene are recommend first-line treatment with crizotinib.

(2) Stage IV NSCLC patients whoseEGFR,ALKandROS1gene fusion are negative or whose mutation status is unknown should receive platinum-doublet as soon as possible if the ECOG PS score is 0?1.This can be combined with immune checkpoint inhibitors (e.g.,PD-1 mAb) or systemic treatment with bevacizumab (nonsquamous carcinoma).For patients with positive PD-L1(TPS≥1%),pembrolizmab monotherapy is feasible,and patients with high PD-L1 expression (TPS≥50%) benefit more from it.Patients with high PD-L1 expression (TC≥50% or IC≥10%) may also be treated with atezolizumab monotherapy.For patients who are not suitable for platinum treatment,non-platinum doublets may be considered.

(3) Patients with advanced NSCLC with ECOG PS score=2 should be given single-drug chemotherapy,but those with ECOG PS score ＞2 are not recommended to use cytotoxic drugs.

(4) For elderly patients,the evidence does not support age as the sole criterion for choosing chemotherapy regimens,and a comprehensive assessment of organ function and ECOG PS status is required.If organ function indicators meet the requirements of chemotherapy,patients with ECOG PS 0?1 can still consider platinum-doublet regimens.Patients with ECOG PS score=2 can consider single-drug chemotherapy.Patients with severe organ dysfunction or ECOG PS score ＞2 should not be recommended systemic chemotherapy.

(5) Second-line treatment options include docetaxel,pemetrexed,PD-1 mAb,and targeted therapy.Targeted therapy should be given priority in second-line treatment if it is not used in first-line and maintenance therapy in patients with positive driver genes.For patients with resistance after first-line EGFR-TKIs and harboringEGFRT790Mmutation,second-line treatment should be given priority to third-generation EGFR-TKI,such as osimertinib,almonertinib or fumonertinib.For patients withALKgene fusion who develop resistance after first-line treatment with crizotinib,ceritinib or alectinib may be chosen for second-line treatment.In case of oligoprogression or CNS progression after the first-line drug resistance,targeted therapy can be continued in combination with local therapy,such as radiotherapy or surgery.For patients with resistance to first-line EGFRTKI or ALK inhibitors,second-line therapy using platinum-doublets or single-drug chemotherapy can also be chosen based on the patient’s ECOG PS score.For nonsquamous cell cancer,anti-angiogenic drugs such as bevacizumab can be added to the above regimen.For patients with negative driver genes,nivolumab can be considered as second-line therapy if PD-1 mAb is not used as the first-line treatment.

(6) Patients with stage IV NSCLC with an ECOG PS score ＞2 do not benefit from chemotherapy generally,and the best supportive treatment is recommended.On the basis of systemic treatment,appropriate local treatment can be selected to improve symptoms and the quality of life.

(7) HTS has been widely used in clinical practice.It can be used for gene mutation detection,tumor mutation burden assessment,as well as assistance in determining the mechanism of resistance to targeted drugs and guidance to the next step of treatment.

4.6 Staged treatment mode of SCLC

The staging of SCLC has been followed by the two-stage method of The Veterans Administration Lung Study Group (VALG),mainly based on the importance of radiotherapy in the treatment of SCLC.The American Joint Committee on Cancer (AJCC) TNM staging system is suitable for selecting T1?2N0 patients who are suitable for surgery.TNM staging system should be given priority in clinical research,because it can assess prognosis more accurately and guide treatment.

4.6.1 T1?2N0 limited stage SCLC

For T1?2N0 SCLC after systematic staging examination showing no mediastinal lymph node metastasis,surgery +adjuvant chemotherapy (EP or EC regimen,4?6 cycles) is recommended.If diagnosis of mediastinal lymph node metastasis is still uncertain after systematic staging examination,mediastinoscopy,endoscopic ultrasonography or pathological examination may be used to exclude potential mediastinal lymph node metastasis.Postoperative adjuvant radiotherapy is recommended for patients with N1 and N2.PCI is recommended after surgery.

4.6.2 Limited stage (more than T1?2,N0) SCLC

Combined chemotherapy and radiotherapy should be used.PCI is recommended if disease (complete remission or partial remission) is controlled.

4.6.2.1 ECOG PS 0?2

Concurrent chemoradiation is preferred.Sequential chemoradiation is also an option if patients cannot tolerate concurrent chemoradiation.

4.6.2.2 ECOG PS score 3?4 caused by SCLC

All factors should be considered comprehensively,and the therapeutic regimen should be carefully chosen.The single-drug regimen or combined regimen with dose reduction should be considered.If the ECOG PS score of patients reaches 2 points or less after treatment,sequential radiotherapy can be considered.If the ECOG PS score remains more than 2 points,thoracic radiotherapy should be considered according to the specific circumstances.

4.6.2.3 ECOG PS 3?4 score not induced by tumor

The best supportive treatment is given in principle.4.6.3 Extensive stage SCLC

Patients with ECOG PS score 0?2 or ECOG PS score 3?4 caused by SCLC should receive comprehensive therapy including chemotherapy.First-line recommendations are EC regimen combined/not combined with atezolizumab,EP regimen,IP or IC regimen for 4?6 cycles chemotherapy.Patients with ECOG PS 3?4 score that are not induced by tumors should be given the best supportive treatment.

4.6.3.1 Patients without local symptoms and no brain metastases

For patients with first-line chemotherapy reaching CR/PR,thoracic radiotherapy is feasible.Patients with no brain metastasis after effective initial treatment should receive PCI.

4.6.3.2 Patients with local symptoms

Selective local treatment should be carried out on symptomatic conditions based on first-line chemotherapy.Patients with superior vena cava syndrome or obstructive atelectasis or spinal cord compression can be given selective local radiotherapy.In addition to selective palliative external irradiation,patients with bone metastases can also perform local orthopedic fixation on sites at high risk of fracture if necessary.Patients with no brain metastasis after effective initial treatment should receive PCI.

4.6.3.3 Patients with brain metastases

Besides first-line systemic chemotherapy,whole brain radiotherapy is recommended.For patients with first-line chemotherapy reaching CR/PR,thoracic radiotherapy is feasible.Stereotactic radiotherapy (SRT/SRS) is recommended for patients with small tumor size (less than 4 cm in diameter),or oligometastasis,or recurrent metastasis after whole brain radiotherapy,or if the patient has poor physical condition and is unable to tolerate conventional radiotherapy or surgery.

4.6.3.4 Follow-up treatment for relapsed/drug-resistant SCLC patients

Patients who relapse or progress within 6 months after first-line chemotherapy can be treated with topotecan,irinotecan,gemcitabine,vinorelbine,temozolomide or paclitaxel.For those who relapse or progress after 6 months can choose the initial treatment regimen.Anlotinib or participating in clinical trials may be chosen as third-line therapy.

4.7 Palliative treatment

Palliative care,as a special way of treatment,aims to improve the quality of life of patients and their families who are suffering from diseases and facing death threats by controlling pain,relieving symptoms and providing spiritual and social support.In our country,with the expected progress of population aging and increased cancer incidence and mortality,the number of patients requiring palliative care also increased significantly.Therefore,to provide palliative treatment within the criteria of WHO and NCCN has become more and more important.

Palliative treatment includes treatment on the body,mental,psychological and social needs of cancer patients.Palliative care can be initiated as soon as cancer is diagnosed and in early stage,and can be adjusted to meet the changing needs of patients.Studies have shown that early introduction of palliative care can not only improve the quality of life of patients with advanced cancer,but also improve their survival rate.It can reduce the depression and stress score of nurses.There is ample evidence that palliative care combined with standard anticancer therapies,or as a focus of treatment,can lead to better outcomes for patients and caregivers.Therefore,for patients with any metastatic cancer,and/or with a high burden of symptoms,the combination of standard anticancer therapy and palliative care should be considered at an early stage of treatment.Palliative care for lung cancer patients includes palliative surgery,chemotherapy,radiotherapy,endocrine therapy,targeted therapy,immunotherapy,and/or other means of relieving symptoms such as pain and dyspnea.

Patient comfort is a priority problem at all stages of treatment.Hospice care may be considered if physicians and patients both believe that treatment can no longer delay or prevent cancer progression.

The aim of palliative care is to relieve symptoms,relieve pain and improve the quality of life.All lung cancer patients should receive palliative screening,evaluation and treatment.Screening symptoms include not only pain,dyspnea,fatigue,anorexia and nausea,nausea and vomiting,constipation,diarrhea and other common physical symptoms,but also sleep disorders,anxiety and depression,delirium and other psychological problems.

Evaluation of quality of life should be included in the overall evaluation system of lung cancer patients and palliative treatment evaluation.The European Organization for Research and Treatment of Cancer quality of life-C30(EORTC QLQ-C30) is recommended for overall assessment.EORTC QLQ-LC13 can also be used to screen and assess the common symptoms of lung cancer patients.

5.Prognosis

The prognosis of patients with lung cancer (including NSCLC and SCLC) is based on the comprehensive clinical pathological features of patients.According to the existing research results,the clinical pathological stage of the tumor,patients’ physical condition,age and gender are important prognostic factors;in addition,some biochemical indicators (such as white blood cell count and hypercalcemia) and blood tumor marker levels (such as CEA) have also shown to be significantly associated with the prognosis of lung cancer patients.At present,clinicalpathological staging,TNM staging,is still the most important and stable indicator for predicting the survival time of patients with lung cancer.The prognosis of patients with lung cancer largely depends on the TNM stage of the tumor at the time of disease discovery.There is a significant difference in the prognosis of patients with different clinical stages.According to the eighth edition of the Tumor Staging Manual of AJCC reported in 2017 on the meta-analysis of 94,703 patients with NSCLC.For NSCLC,the 5-year survival rate of stage IA patients is approximately 80%,of which,the 5-year survival rate of patients with stage IA1,IA2 and IA3 is 92%,83% and 77%,respectively;the 5-year survival rate of patients with stage IB is 68%;the 5-year survival rate of patients with stage II is approximately 55%;for patients with stage III,the 5-year survival rate drops to about 20%;for patients with stage IV,the 5-year survival rate is less than 5%,and the median survival time is only 7 months.The malignancy of SCLC is higher than that of NSCLC,and recurrence and metastasis are more likely to occur.Therefore,the survival of patients with SCLC is significantly shorter than that of NSCLC.The 5-year survival rate of patients with stage I SCLC is about 50%;stage II is about 25%;stage III is about 10%;and stage IV is less than 3%.The prognostic data of each TNM staged lung cancer patient reported in China are similar to that of the AJCC statistics.A comprehensive analysis of several large-scale statistical results from 2000 to 2012 shows that the 5-year survival rate of stage I in NSCLC patients in China is about 75%;stage II is about 55%,stage III is about 20%,and stage IV is about 5%.For patients with SCLC in China,the above data are 45%,25%,8% and 3%,respectively.

6.Follow-up

Regular review of lung cancer is required after treatment.The purpose of the review is to monitor the efficacy and discover early recurrence and metastasis.The inspection is based on image examination.For the early-and middlestage lung cancer after comprehensive treatment including surgery,reexamination is generally recommended every 3 months within 2 years after treatment,once every half year from 2 to 5 years,and once every 1 year after 5 years.

Working group members

Group leader:Jie He

Associate group leaders:Yilong Wu,Shugeng Gao,Jie Wang

Group members:Zhijie Wang,Jun Wang,Zhehai Wang,Lvhua Wang,Hui Tian,Nan Bi,Lunxu Liu,Lin Xu,Hecheng Li,Ning Wu,Jianxing He,Jianming Ying,Qibin Song,Li Zhang,Lanjun Zhang,Shun Lu,Ming Chen,Haiquan Chen,Yun Fan,Caicun Zhou,Lujun Zhao,Yushun Gao,Yunchao Huang,Cheng Huang,Hong Ge,Ying Cheng,Xiaolong Fu,Fengwei Tan,Qi Xue

Translation group members

Nan WuKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Jia WangKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Quanne WangCheeloo College of Medicine,Shandong University