Lung cancer is the most common primary malignant tumor of the lung.
Lung cancer is the most common primary malignant tumor of the lungs, which may have symptoms such as cough, blood in sputum or hemoptysis, wheezing, chest pain, etc. Prognosis is related to the tumor stage, pathology type and other factors. Chest CT is the commonly used examination tool, but pathology is the “gold standard” for diagnosis.
Understanding Lung Cancer
Lung cancer is the most common primary malignant tumor of the lung.
Lung cancer is broadly defined to include primary lung cancer that develops in the lungs and secondary or metastatic lung cancer that has metastasized to the lungs from other sites.
This term refers to primary lung cancer, for more on metastatic lung cancer, please read Metastatic Lung Cancer.
Staging classification
The staging classification of lung cancer can be carried out in three main dimensions: site of occurrence, histologic classification and molecular staging.
Classification by site of occurrence
According to the site of occurrence of lung cancer, it can be classified into central lung cancer and peripheral lung cancer.
Central lung cancer
The tumor occurs in the bronchus above the opening of the segmental bronchus.
Most of them are squamous lung cancer and small cell lung cancer.
Fiberoptic bronchoscopy and sputum cytology are more accurate.
Surgery is often more difficult than for peripheral lung cancer.
Peripheral lung cancer
Tumors occur in the bronchi below the opening of the segmental bronchi, i.e. from the subsegmental bronchi to the alveoli.
The vast majority are lung adenocarcinomas.
Classification by histology
The main tissue types of lung cancer are adenocarcinoma and squamous cell carcinoma (referred to as squamous carcinoma), accounting for about 80% of all primary lung cancers. This is followed by small cell carcinoma, which accounts for about 15%.
Other rare types of primary lung cancer include adenosquamous carcinoma, large cell carcinoma, carcinoma of salivary gland origin (adenoid cystic carcinoma, mucoepidermoid carcinoma, etc.), and so on.
Lung adenocarcinoma
It accounts for about 40% to 55% of lung cancer and is the most common type of lung cancer.
Patients may have a history of smoking and many have no smoking history, especially women.
Squamous lung cancer
Lung squamous carcinoma accounts for about 30% to 40% of lung cancer.
Most of the patients are men aged 50 to 70 years old, and more than 90% of them have long-term smoking history.
Small cell lung cancer
Small cell neuroendocrine carcinoma accounts for about 15% of lung cancer.
Most of the patients are middle-aged or old men, and most of them are smokers. The tumor grows rapidly and is prone to early metastasis.
Molecular typing
Driver genes are important genes related to the development of cancer. Currently, the main driver genes studied in lung cancer include EGFR, ALK, ROS1, BRAF, NTRK, MET, RET, KRAS, and HER-2. According to the different driver genes, lung cancer can be divided into different molecular subtypes.
Targeted therapy for driver gene mutations has gradually become the main treatment method for lung cancer, especially lung adenocarcinoma, and has achieved remarkable efficacy. Examples of common mutation types are as follows.
EGFR-mutant lung cancer
This type of lung cancer can be treated with EGFR-TKIs (tyrosinase inhibitors), including molecularly targeted drugs such as gefitinib, erlotinib, erlotinib, axitinib, afatinib, daclatinib, and ositinib.
For more information, please refer to reading EGFR Mutant Lung Cancer
ALK fusion lung cancer
This type can be treated with molecularly targeted drugs such as alectinib, crizotinib and ceritinib.
For more information, please refer to ALK Fusion Lung Cancer.
ROS1 fusion lung cancer
This type can generally be treated with molecularly targeted drugs such as crizotinib.
For more information, please refer to ROS1 fusion lung cancer.
Other Molecular Types
In addition to the above molecular typing, some molecular typing has been gradually proposed, such as BRAF, NTRK, MET, RET, KRAS, HER-2 and other genes.
Advanced lung cancer patients with MET14 exon skipping mutation cannot tolerate chemotherapy and can use cevotinib.
Patients with BRAF V600 mutation-positive advanced lung cancer can use dabrafenib in combination with trametinib.
Incidence
According to the National Cancer Center’s National Cancer Report 2022, the incidence of lung cancer in China in 2016 was as follows:
Lung cancer is still the most common malignant tumor in China, and about 657,000 people lost their lives in 2016 due to lung cancer.
The number of new cases of lung cancer reached 828,000 in 2016, an increase of 41,000 from 2015.
The incidence of lung cancer is estimated to be 49.78/100,000 in the male population and 23.70/100,000 in females.
In urban areas, the incidence rate of lung cancer is 36.7/100,000, and in rural areas, it is 35.2/100,000.
[Special Reminder] Due to the general lag of data from the National Tumor Registry, the data released for the 2022 report is the 2016 registry information from the National Tumor Registry collected and summarized by the National Tumor Registry.
Questions you may be concerned about
Are lung nodules lung cancer?
Lung nodules are not necessarily lung cancer.
Lung nodules are focal, round-like, increased density solid or subsolid lung shadows with a diameter of ≤3 cm on imaging, which can be seen in a variety of diseases, such as spherical foci of tuberculosis (tuberculomas), lung abscesses, spherical pneumonias, and lung misshapen tumors.
In other words, lung nodule is a diagnostic imaging term, strictly speaking belongs to the diagnosis without pathological confirmation, there are many possibilities for this kind of lung nodule, only some of them may be malignant nodules, and the vast majority of these malignant nodules are lung cancer. According to the data, more than 90% of lung nodules are benign.
Is excessive white sputum a symptom of lung cancer?
Excessive white sputum is not a typical symptom of lung cancer because lung cancer patients usually have irritating dry cough with no sputum or a little white mucus sputum.
White sputum is a common clinical symptom, which is not unique to lung cancer patients. It can be seen in respiratory tract infections and other diseases, such as sputum that is white and thick and in the form of filaments, which is generally suggestive of fungal infections and so on.
However, lung cancer can be manifested as blood in sputum, etc. It is recommended to consult doctor as soon as possible when discomfort occurs.
Can blood test diagnose lung cancer?
Lung cancer cannot be directly diagnosed by blood test alone.
The so-called blood test is generally serum tumor markers, which commonly include carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1), gastrin-releasing peptide precursor (ProGRP), squamous epithelial cell carcinoma antigen (SCC) and so on.
When suffering from lung cancer, the above indicators can be abnormally elevated, but the elevation does not necessarily mean that it is lung cancer, as it may also be elevated in other malignant tumors or non-neoplastic diseases. The diagnosis of lung cancer needs to be combined with symptoms, signs, imaging manifestations and other preliminary diagnosis, and finally confirmed by pathology.
If physical examination reveals abnormal blood test results, it is recommended to seek medical treatment promptly.
Causes
The cause of lung cancer is still not completely clear. It may be related to genetic abnormality and internal and external environmental cancer-causing factors.
Causative factors
Smoking and passive smoking
Smoking is the most common cause of lung cancer. About 85% of lung cancer patients have a history of smoking, and research shows that the risk of lung cancer is more than 10 times higher in people with a long history of smoking.
The longer you smoke and the more you smoke, the higher the incidence and mortality rate of lung cancer.
History of Chronic Obstructive Pulmonary Disease (COPD)
Studies have shown that the risk of lung cancer in people with chronic obstructive pulmonary disease (COPD) is 1.57 times higher than in people without COPD.
Occupational Exposure
A variety of specific occupational exposures can increase the risk of lung cancer, including asbestos, radon, beryllium, chromium, cadmium, nickel, silica, soot and coal smoke.
Family history and genetic susceptibility to lung cancer
Family aggregation exists among lung cancer patients. These findings suggest that genetic factors may play an important role in populations and/or individuals susceptible to environmental carcinogens.
It is currently believed that genetic polymorphisms may be genetic susceptibility factors for lung cancer, with metabolic enzyme genes and DNA damage repair gene polymorphisms being two of the more studied aspects.
Others
Other factors associated with the development of lung cancer include nutrition and diet, physical exercise, immune status, estrogen levels, infections (human immunodeficiency virus, human papillomavirus), chronic inflammation of the lungs, and economic and cultural levels.
However, the association between the above factors and lung cancer is still controversial and there is no recognized authoritative evidence.
Pathogenesis
The specific pathogenesis of lung cancer is not yet fully understood, but the more studied mechanism is the driver gene-related mechanism.
Driver genes are important genes associated with the development of cancer, and they usually have a transforming effect, which can initiate the evolution of non-cancerous cells to malignant tumors, thus inducing the development of lung adenocarcinoma and contributing to its progression. Currently, the main driver genes studied include EGFR mutation, ALK fusion and ROS1 fusion.
EGFR mutation
EGFR is a tyrosine kinase-type receptor that forms a dimer upon activation by ligands, activating its intracellular kinase pathway, which in turn activates downstream signaling pathways, thereby promoting cell survival and proliferation.
Mutation or overexpression of the EGFR gene encoding the EGFR receptor is associated with tumor cell proliferation, tumor invasion, metastasis and inhibition of apoptosis.
ALK fusion
Mutations in ALK mainly occur when the ALK gene undergoes breakage rearrangement and other genes to form a fusion gene.
It has been found that ALK fusion proteins are more common in younger lung adenocarcinoma patients, especially those younger than 30 years old.
ROS1 Fusion
ROS1 gene fusion is a newer molecular subtype of lung cancer, with a mutation and activation pathway similar to that of ALK, and ROS1 gene rearrangements are present in about 1% to 2% of patients with lung adenocarcinoma.
Symptoms
Lung cancer usually has no obvious symptoms in the early stage, and symptoms appear only after the disease has developed to a certain stage and vary from person to person.
However, it should be noted that any untreated respiratory symptoms for more than two weeks, especially bloody sputum, dry cough, or repeated occurrence of pneumonia in the same area, or changes in the original respiratory symptoms, should be alerted to the possibility of lung cancer.
Some lung cancer patients may consult the doctor because of some atypical first symptoms, such as hoarseness, pestle finger, edema of head and neck or even both upper limbs.
Primary symptoms
Primary symptoms refer to the symptoms caused by the local growth of the primary tumor itself.
Cough and sputum
Cough is the most common symptom of lung cancer patients when they visit the doctor, more than half of the patients have cough symptoms when they visit the doctor.
Most of them have irritating dry cough with no sputum or a little white mucus sputum.
Hemoptysis
About 25% to 40% of lung cancer patients will have hemoptysis symptoms.
It is usually manifested as blood in sputum, hemoptysis is rare.
Hemoptysis is the most suggestive symptom of lung cancer.
Difficulty in breathing
About 10% of lung cancer patients have dyspnea as the first symptom.
It mostly manifests as chest tightness, shortness of breath, and some patients may have chest pain.
Fever
It can be caused by necrosis of tumor tissue or secondary pneumonia (such as obstructive pneumonia).
Fever is characterized by delayed and repeated, sometimes good and sometimes bad, difficult to cure.
Intermittent moderate or low fever is common, and high fever may be present when combined with infection.
Weight loss, malaise
The tumor may cause consumption, loss of appetite, etc., leading to malaise with weight loss.
Wheezing
It is a harsh sound made when inhaling.
If the tumor is located in the large airways, especially in the main bronchial tubes, it can often cause symptoms of restrictive stridor.
Extrinsic symptoms
Extrinsic symptoms are symptoms caused by the primary tumor invading neighboring organs and structures.
Superior vena cava obstruction syndrome
About 10% of lung cancer patients consult the doctor with this as the first symptom.
The main manifestations are edema of the head and neck or even both upper limbs, aneurysm of the veins in the neck and upper chest (the veins are in the shape of cords and are clearly visible), capillary dilatation and so on.
Horner’s syndrome
Sunken eyeballs, drooping upper eyelids, small eye fissures, narrow pupils, and absence of facial sweating on the side where lung cancer occurs.
Pancoast Syndrome
Also known as Pancoast syndrome, it is usually significantly more common in males than females, more common on the right side than on the left side, and can occur at any age.
It is characterized by persistent pain in the shoulder, forehead, neck, upper arm and even hand on the diseased side, which is progressively aggravated, and some of them even have upper limb dysfunction, and Horner’s syndrome on the diseased side can also be found.
Hoarseness
Involvement of the recurrent laryngeal nerve causes hoarseness.
Some lung cancer patients consult the doctor with this as the first symptom.
Difficulty in swallowing
It is mostly caused by direct invasion of tumor or lymph node metastasis compressing the esophagus.
Pleural effusion
Invasion of pleura can cause pleural effusion (hydrothorax), which is often a large amount of bloody effusion.
At first, patients gradually feel chest tightness and may have chest pain. As the amount of fluid increases, chest pain decreases or disappears, but dyspnea increases.
Distant metastatic symptoms
Metastatic symptoms refer to the symptoms caused by distant metastasis of the tumor. The most common is brain metastasis, followed by bone metastasis, liver metastasis and so on.
Intracranial metastasis (brain metastasis)
Early stage may be asymptomatic.
Frequent central nervous system symptoms:
Headache, vomiting, vertigo.
Diplopia (producing two images when both eyes look at the same object at the same time).
Ataxia (e.g., clumsiness, unsteady walking).
Hemiparesis (impaired movement of the upper and lower limbs on one side).
Seizures, etc.
It is sometimes accompanied by altered mental status and visual disturbances.
Bone metastases
Commonly found in the ribs, spine, pelvis and long bones.
They may be asymptomatic in the early stages, with localized pain and tenderness in the later stages.
If spinal metastasis compresses or invades the spinal cord, it may lead to urinary and fecal incontinence or paraplegia.
Liver metastasis
Hepatomegaly and pain in the liver area may occur.
It may be accompanied by loss of appetite, nausea, emaciation, and elevation of liver enzymes such as aspartate aminotransferase (AST) or bilirubin.
Adrenal metastasis
May present with symptoms of Addison’s disease, with loss of appetite, diarrhea, deepening of skin color, loss of axillary hair, and low blood pressure.
Lymph node metastasis
Often metastasize first to hilar lymph nodes along the lymphatic reflux pathway, followed by mediastinal and supraclavicular lymph nodes.
The enlarged superficial lymph nodes are usually hard and can be fused into a mass, and are not accompanied by pressure pain.
Others
Lung cancer may metastasize to many parts of the body leading to different clinical signs, such as subcutaneous nodules, skin ulcers and abdominal pain.
Malignant stasis, also known as malignant fluid, is seen in some advanced cancer patients. It is characterized by extreme emaciation, weakness, general exhaustion and other symptoms.
Paraneoplastic syndrome
About 10% to 20% of lung cancer patients may have some rare symptoms and signs not caused by direct invasion or metastasis of tumor, but a series of manifestations caused by ectopic endocrine, bone and joint metabolic abnormalities, neuromuscular conduction disorders, etc., which is called paraneoplastic syndrome or paraneoplastic syndrome.
The occurrence of paraneoplastic syndrome is not necessarily positively correlated with the degree of tumor lesions, and sometimes it may precede the clinical diagnosis of lung cancer.
Hypertrophic pulmonary osteoarthropathy
Most commonly seen in patients with lung adenocarcinoma.
The main manifestations are pain in the large joints, pestle-like fingers/toes (abnormal manifestation of hyperplasia and hypertrophy of the ends of the fingers or toes, which are enlarged in the shape of a pestle), and so on.
This manifestation may occur in the early stage of lung cancer or precede the localized symptoms of lung cancer, and may even be the only symptom of lung cancer consultation.
Cushing’s syndrome
Ectopic secretion of adrenocorticotropic hormone can cause Cushing’s syndrome.
Patients usually present with muscle weakness, weight loss, hypertension, hirsutism, and osteoporosis.
Dermatomyositis and Polymyositis
Dermatomyositis and polymyositis are 2 different forms of inflammatory myopathies, both of which clinically present with muscle weakness.
These inflammatory myopathies can be the first symptom of lung cancer or can appear later in the course of lung cancer.
Hypercalcemia
Hypercalcemia in patients with lung cancer may be due to bone metastases and, in a few cases, to tumor-secreted parathyroid hormone-related proteins, osteotriol, or other cytokines, including osteoclast activating factor.
Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, lethargy, polyuria, irritable thirst, and dehydration. Advanced manifestations may show confusion, coma, renal failure and renal calcinosis.
Male breast development
Mostly seen in small cell lung cancer.
It mainly manifests as bilateral or unilateral breast development.
Consultation
Department of Medicine
Respiratory Medicine
Please consult the Department of Respiratory Medicine when symptoms such as cough, blood in sputum or hemoptysis, wheezing and chest pain occur.
Thoracic Surgery
Please consult the Department of Thoracic Surgery when nodules or space-occupying lesions in the lungs are found on chest imaging (X-ray, chest CT, etc.).
Medical Oncology
Consult the Department of Medical Oncology if lung cancer is highly suspected or has already been diagnosed and requires drug treatment.
Preparation
Consultation: Registration, Preparation of Documents, Frequently Asked Questions
Consultation Tips
Chest X-rays or CT scans may be required. Avoid wearing metallic clothing such as shirts with buttons, blouses with sequins, and dresses with zipper openings.
Preparation Checklist
Symptom Checklist
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Is there coughing and sputum, and for how long?
Is there blood in the sputum?
Is there any chest tightness and shortness of breath, and how long has it been?
Is there any unexplained weight loss?
Is there a fever and what is the highest temperature?
List of medical history
Have you smoked, for how long and how many cigarettes per day?
What is your occupation?
Is there a family history of malignant tumors such as lung cancer?
Are there any other concomitant diseases, such as chronic obstructive pulmonary disease (COPD)?
Are there any drug or food allergies?
Checklist
Examination results in the past six months, which can be brought to the doctor’s office
Other tests: magnetic resonance imaging (MRI), PET-CT.
Diagnosis
Lung cancer is mainly diagnosed initially based on medical history, clinical manifestations, laboratory tests and imaging tests, etc. The final diagnosis requires pathologic examination to confirm the diagnosis.
Medical history
Some patients may have the following medical history:
History of smoking and passive smoking (secondhand smoke).
History of COPD.
History of occupational exposure to asbestos, radon, beryllium, chromium, cadmium, nickel, silica, soot and coal fumes.
Family history of lung cancer.
Clinical manifestations
Clinical manifestations of lung cancer are diversified but lack of specificity. Early stage of lung cancer may not show any symptoms, especially peripheral lung cancer, which is mostly detected during physical examination or chest imaging examination for other diseases.
Symptoms
There are no obvious symptoms in the early stage of lung cancer. As the disease progresses, symptoms such as coughing, coughing up sputum, blood in sputum or hemoptysis, dyspnea, wheezing, fever, weight loss, generalized weakness and so on may appear.
Physical signs
Most early stage lung cancer patients have no obvious related positive signs.
They may show extrapulmonary signs of unknown cause and prolonged duration, such as pestle-like fingers (toes), non-wandering joint pain, male breast development, dark skin or dermatomyositis, ataxia and phlebitis.
In patients with high clinical suspicion of lung cancer, physical examination reveals vocal cord paralysis, superior vena cava obstruction syndrome, Horner’s syndrome, and suprapulmonary sulcus tumor syndrome, etc., suggesting the possibility of local invasion and metastasis.
In patients with highly suspected lung cancer, physical examination reveals hepatomegaly with nodules, subcutaneous nodules, enlarged lymph nodes in supraclavicular fossa, etc., suggesting the possibility of distant metastasis.
Laboratory examination
Serological examination of lung cancer, especially the detection of tumor markers, is helpful for the auxiliary diagnosis of lung cancer, judgment of curative effect and follow-up monitoring.
Currently, the commonly recommended lung cancer markers include carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1), gastrin-releasing peptide precursor (ProGRP), and squamous epithelial cell carcinoma antigen (SCC).
Ancillary diagnosis
NSE and ProGRP are ideal indicators to aid in the diagnosis of small cell lung cancer (SCLC). When histologic findings are inconclusive, elevation of both can assist in supporting the diagnosis of small cell lung cancer.
The specificity of ProGRP for the diagnosis of small cell lung cancer is superior to other individual markers, and it positively correlates with the stage of small cell lung cancer, allowing its level to differentiate small cell lung cancer from benign lung disease.
Elevated levels of CEA, SCC and CYFRA21-1 contribute to the diagnosis of non-small cell lung cancer (NSCLC).
Determination of efficacy and follow-up monitoring
Tumor marker levels have a certain correlation with tumor load and stage, it is recommended to take tumor marker tests to know the baseline levels before the first diagnosis and the start of treatment, and to monitor the dynamic changes after the treatment can play a role in monitoring the efficacy of the tumor and judging the prognosis.
Determination of therapeutic efficacy: If one of the above tumor markers is elevated before treatment and decreases after treatment, it suggests that the therapeutic efficacy is better.
Follow-up monitoring: If one of the above tumor markers is found to be elevated in the course of follow-up, it suggests that there may be signs of recurrence, and it is recommended to consult a doctor for timely investigation.
Imaging
Chest X-ray
It is still the basic examination method to detect lung lesions including lung cancer, especially in primary hospitals.
It has limited diagnostic value for early stage lung cancer. Once lung cancer is suspected, chest CT examination should be performed promptly.
CT examination
Chest CT is the most important and commonly used imaging examination method for lung cancer diagnosis, staging, evaluation of therapeutic effect and follow-up after treatment.
It can effectively detect early stage lung cancer and further evaluate the location of tumor, extent of involvement and lymph node metastasis, which can help the clinical staging of lung cancer.
For lung lesions that are difficult to be diagnosed qualitatively, percutaneous lung puncture biopsy can be performed under CT guidance, and lung tissues can be removed for pathological biopsy.
Low-dose spiral CT is recommended for regular screening of high-risk groups for lung cancer because it has a low radiation dose without compromising diagnostic quality.
CT examination of other parts of the body, including brain, liver and adrenal gland, can help doctors clarify whether there are distant metastases.
Magnetic Resonance Imaging (MRI)
MRI of the chest
It can help determine whether the chest wall or mediastinum has been invaded by tumors, and distinguish the boundary between hilar masses and atelectasis and obstructive pneumonia.
It is also valuable in distinguishing fibrosis from tumor recurrence after radiotherapy.
MRI of other parts
It is especially suitable for determining whether there is metastasis in brain and spinal cord.
Brain-enhanced MRI is a routine preoperative staging examination for lung cancer.
MRI is helpful in determining the metastasis of bone marrow cavity.
Ultrasonography
Ultrasonography for lung cancer patients is mainly applied to the observation of metastasis in supraclavicular lymph nodes, liver, adrenal glands, kidney and other parts and organs to provide information for tumor staging.
Ultrasound-guided puncture can be used for puncture biopsy of subpleural lung tumors, supraclavicular lymph nodes, and metastases of parenchymal organs, and specimens can be obtained for histological examination.
Bone nuclear scan
Abbreviated as bone scan, it is a routine examination to determine whether lung cancer has bone metastasis or not.
When bone scanning suggests suspected bone metastasis, MRI, CT or PET-CT should be performed on the suspected area for verification.
Positron emission computed tomography (PET-CT)
PET-CT is the best method for lung cancer diagnosis, staging and re-staging, efficacy evaluation and prognosis assessment.
According to domestic and international guidelines as well as the consensus of domestic experts, PET-CT is recommended for the following conditions when available.
Diagnosis and differential diagnosis of isolated lung nodules (≥8mm solid nodules, partially solid nodules persisting with internal solid components ≥6mm);
For pre-treatment staging of lung cancer, PET has better diagnostic efficacy for lymph node metastasis and extra-thoracic metastasis (except brain metastasis);
Lung cancer radiotherapy localization and target area outlining;
Assisting in identifying postoperative scarring and tumor recurrence that cannot be determined by conventional CT;
Assisting in identifying post-radiotherapy fibrosis and tumor residual/recurrence that cannot be determined by conventional CT;
To assist in evaluating the efficacy of lung cancer treatment (especially molecular targeted therapy).
Bronchoscopy
For central lung cancer, bronchoscopy can directly observe the lesions inside the bronchus, and more than 95% of them can obtain clear pathological diagnosis through cytological brushing and histological biopsy.
Puncture biopsy of hilar and mediastinal lymph nodes adjacent to the bronchus can be performed for qualitative diagnosis of lung cancer and mediastinal lymph node staging diagnosis.
Pathologic diagnosis
Pathological diagnosis of lung biopsy specimens is mainly to clarify the presence or absence of tumor and the histological type of tumor, which is the “gold standard” for final diagnosis of lung cancer.
For advanced inoperable patients, pathological diagnosis should carry out subtype classification as far as possible, and for cases with atypical morphology, immunohistochemical staining should be combined to further clarify the diagnosis.
Cytologic examination
Cytologic examination can be performed by sputum exfoliated cells or by bronchoscopic brushing of cells from the diseased bronchial tubes. This examination is simple, non-invasive and one of the simple and effective methods for the qualitative diagnosis of lung cancer.
Histologic examination
Histologic examination of lung cancer is generally divided into two types: small specimen and large specimen.
Small specimen
Small specimen refers to the biopsy specimen obtained by bronchoscopy or CT-guided percutaneous lung puncture.
Large specimens
Generally speaking, large specimen refers to the specimen obtained after surgical resection of lung cancer and its pathological and histological examination, which is also known as postoperative pathological report of lung cancer.
The contents of the report generally include tumor site, histological typing, extent of involvement (bronchus, pleura, vasculature, nerves, type of concomitant lesions, foci of intrapulmonary dissemination, lymph node metastasis, etc.), margins of incision and special staining if necessary, immunohistochemistry results, or molecular pathology test results.
Immunohistochemistry
Immunohistochemistry, referred to as immunohistochemistry (IHC), is mainly used for the diagnosis, differential diagnosis and guidance of treatment of lung cancer, and can help determine the subtype of lung cancer.
Lung squamous carcinoma: usually expresses P40, P63 and CK5/6. P40 is the most specific indicator for squamous cell carcinoma, usually diffusely positive, but usually negative for TTF1.
Lung adenocarcinoma: the vast majority express TTF-1 and NapsinA.
Small cell lung cancer: tumor cells express neuroendocrine markers such as Syn, CgA, CD56.
Special reminder: In the pathology report, the expression of a certain immunohistochemical index is generally represented by “+”, the more “+”, the higher the degree of expression, which is more helpful to assist in the diagnosis, and there can be up to 3 “+”. Up to 3 “+”.
Genetic testing
Genetic testing of tumor tissues is conducive to individualized targeted therapy for lung cancer.
Routine testing
Routine molecular biology testing for EGFR, ALK, and ROS1 is recommended for all non-small cell lung cancers with adenocarcinoma components, regardless of the stage at diagnosis.
For advanced non-small cell lung cancer, testing for genes EGFR, ALK, ROS1, MET, BRAF V600E, KRAS, HER-2, RET, and NTRK is recommended.
Drug resistance monitoring
For patients with EGFR tyrosine kinase inhibitor (EGFR-TKI) resistance, secondary biopsy is recommended for secondary resistance testing.
For patients in whom tissue is not available, plasma circulating tumor DNA (ctDNA) can be used for EGFR T790M testing.
When the blood test is negative, patients should still be advised to undergo tissue testing to clarify the mutation status to guide more appropriate targeted drug selection.
Staging
Staging of lung cancer can help to reasonably formulate treatment plan, correctly evaluate the efficacy and judge the prognosis.
TNM staging
Currently, TNM staging of lung cancer is a staging system jointly developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC), which is mainly based on the three elements of T, N and M. The TNM staging system is based on the following three elements
T: represents the extent of primary tumor, mainly referring to the size of the primary tumor foci and the degree of extravasation.
N: represents regional lymph node metastasis, including the number of metastases and regional extent.
M: represents distant metastasis.
Special reminder: T, N, M will be followed by Arabic numerals, the larger the number, the more serious.
Overall staging
According to the different TNM staging, the overall staging (prognostic grouping) of the patient is finally determined, which is indicated by the Roman letters I, II, III and IV.
Overall staging TNM staging
Stage 0 TisN0M0
Stage 0
TisN0M0
Stage IA TisN0M0
ⅠA stage
T1N0M0
ⅠB period T2aN0M0
ⅠB period
T2aN0M0
ⅡA stage T2bN0M0
ⅡA stage
T2bN0M0
IIB stage T1a~cN1M0T2aN1M0T2bN1M0T3N0M0
Phase IIB
T1a～cN1M0T2aN1M0T2bN1M0T3N0M0
Phase IIIA T1a～cN2M0T2a～bN2M0T3N1M0T4N0M0T4N1M0
Stage IIIA
T1a～cN2M0T2a～bN2M0T3N1M0T4N0M0T4N1M0
Phase IIIB T1a～cN3M0T2a～bN3M0T3N2M0T4N2M0
Stage IIIB
T1a～cN3M0T2a～bN3M0T3N2M0T4N2M0
Stage IIICT3N3M0T4N3M0
Stage IIIC
T3N3M0T4N3M0
Phase IVAAny T, any N, M1a～b
Stage IVA
Any T, any N, M1a～b
Phase IVB Any T, any N, M1c
Stage IVB
Any T, any N, M1c
Differential Diagnosis
Typical lung cancer is relatively easy to detect and diagnose. However, some of the symptoms of lung cancer, such as symptoms and imaging tests, may sometimes be confused with other lung diseases.
Tuberculosis
Similarities: Patients with tuberculosis may also have symptoms of coughing, coughing up sputum or blood in sputum, or even hemoptysis, and it is more difficult to distinguish the tuberculosis balls it forms from peripheral lung cancer in imaging examinations.
Differences: Tuberculosis is prevalent in young people, with special symptoms such as low afternoon fever and night sweats, which can be alleviated or disappeared after anti-tuberculosis treatment. It can be determined by pathological examination, in which Mycobacterium tuberculosis is visible in tuberculosis and cancer cells are visible in lung cancer.
PneumoniaSimilarities: the same symptoms such as fever, cough and sputum. Chronic inflammation in the lungs acts for a long time, forming lumpy inflammatory pseudotumor, which is also easy to be confused with lung cancer.Differences: Antibiotic treatment for pneumonia is effective. When pneumonia occurs repeatedly in the same area, the possibility of lung cancer should be considered, and biopsy samples can be taken from the lesion area for pathologic differential diagnosis.Benign lung tumorsBenign tumors of the lungs commonly include malignant tumors, chondrosarcoma, fibroma, etc., which are mostly asymptomatic clinically.Similarity: they have similar occupying manifestations with lung cancer on imaging.
重播Differences: Pathologic examination is usually needed to identify them.
Treatment
Treatment principle
Multidisciplinary comprehensive treatment (MDT) model
The treatment of lung cancer generally adopts the principle of combining multidisciplinary comprehensive treatment and individualized treatment for the whole management.
According to the patient’s physical condition, the pathological and histological type and molecular typing of the tumor, the extent of invasion and the tendency of development, the mode of multidisciplinary comprehensive treatment is adopted.
Through the planned and rational application of surgery, radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy, etc., in order to achieve the purpose of maximizing the survival time of the patients, improving the survival rate, controlling the tumor progression and improving the quality of life of the patients.
Treatment Methods
Generally speaking, non-small cell lung cancer is treated with multidisciplinary comprehensive treatment including surgery, while small cell lung cancer is treated with comprehensive treatment based on radiotherapy and chemotherapy.
Pharmacological treatments for lung cancer include chemotherapy, targeted therapy and immunotherapy.
Special Reminder
Drug treatment, especially chemotherapy, kills tumor cells and damages normal body cells at the same time, so it is necessary to choose the appropriate plan under the guidance of professional doctors and carry out individualized diagnosis and treatment.
Surgical treatment
The first choice of treatment for lung cancer is surgical treatment, which is the only possible way to cure lung cancer.
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Surgery Classification
According to the amount of lung tissue removed, it can be divided into wedge resection, segmental resection, lobectomy, total lung resection and extended resection.
According to the size of incision and trauma, it can be divided into conventional open-heart surgery, small incision open-heart surgery and thoracoscopic minimally invasive surgery.
Main indications for surgery
Those who are highly suspected of lung cancer, but the diagnosis cannot be confirmed after various examinations, and it is estimated that the lesion can be completely resected.
Clinical stage Ⅰ, Ⅱ and some stage ⅢA (T3N1M0) non-small cell lung cancer.
Stage IIIB and IIIC lung cancer that can be surgically resected after neoadjuvant therapy at a reduced stage.
Those who have achieved remission after chemotherapy for limited stage small cell lung cancer.
Surgical methods
Open-heart surgery
Open thoracic surgery is mainly performed by incision into the chest through posterior lateral incision, small chest incision and other incisions.
It can visually expose the diseased lung tissue for lobectomy and systematic lymph node dissection.
Usually, the surgical incision is 20 to 30 centimeters long, which makes the surgery traumatic and the patient’s recovery after surgery slower.
Assisted Thoracoscopic Surgery (VATS)
VTAS only uses 1 to 3 incisions, each about 1 to 3 cm long, replacing the 20 to 30 cm incision of traditional open thoracic direct surgery, with less trauma, faster recovery, and good results, and has become the main surgical method for lung cancer surgical treatment in China.
The disadvantages of thoracoscopic lung resection are longer operation time and easy to cause hemorrhage. At present, it is mainly suitable for earlier peripheral lung cancer, or elderly patients whose lung function does not tolerate open surgery.
A more advanced technology is 3D thoracoscopy with robotic-assisted thoracoscopy (RATS), also known as da Vinci robotic-assisted thoracoscopy, which has the advantage of fine operation under high-definition stereoscopic vision and higher surgical safety.
Chemotherapy
Chemotherapy is a systemic treatment that utilizes cytotoxic drugs to destroy cancer cells. According to the purpose of treatment, it can be divided into neoadjuvant chemotherapy, adjuvant chemotherapy and palliative chemotherapy.
Generally speaking, non-small cell lung cancer is less sensitive to chemotherapy than small cell lung cancer.
Chemotherapy for non-small cell lung cancer
Adjuvant chemotherapy can be used for early stage lung cancer, neoadjuvant chemotherapy, adjuvant chemotherapy or simultaneous radiotherapy for locally advanced lung cancer, and palliative chemotherapy for advanced lung cancer.
Commonly used first-line chemotherapy regimens include:
NP regimen: vincristine + cisplatin or carboplatin, 1 cycle in 21 days, 4-6 cycles.TP regimen: paclitaxel + cisplatin or carboplatin, 1 cycle in 21 days, 4 to 6 cycles.GP regimen: gemcitabine + cisplatin or carboplatin, 1 cycle of 21 days, 4 to 6 cycles.DP regimen: docetaxel + cisplatin or carboplatin, 1 cycle of 21 days, 4 to 6 cycles.PP regimen: pemetrexed (non-squamous) + cisplatin or carboplatin, 1 cycle of 21 days, 4 to 6 cycles.Chemotherapy for small cell lung cancer
重播For limited stage small cell lung cancer of T1～2N0, lobectomy + hilar and mediastinal lymph node dissection is recommended, followed by postoperative adjuvant chemotherapy.
For limited stage small cell lung cancer beyond T1～2N0, radiotherapy and chemotherapy-based combination therapy is recommended.
Commonly used first-line chemotherapy regimens for limited stage
EP regimen: etoposide + cisplatin.
EC regimen: etoposide + carboplatin.
Commonly used first-line chemotherapy regimen for extensive stage
For extensive stage small cell lung cancer, chemotherapy-based comprehensive treatment is recommended. For those with localized symptoms or brain metastasis, it is recommended to combine radiotherapy or other treatment methods on the basis of chemotherapy.
EP regimen: etoposide + cisplatin.
EC program: etoposide + carboplatin.
IP regimen: irinotecan + cisplatin.
IC regimen: irinotecan + carboplatin.
EL regimen: Etoposide + Lopatin.
Targeted therapy
Before starting treatment for lung cancer patients, it is generally recommended to obtain tumor tissues for driver gene mutation testing, such as EGFR, ALK and ROS1, etc., and decide the corresponding treatment strategy according to the above driver gene status.
According to different clinical efficacy and drug characteristics, targeted drugs for driver gene positivity can be divided into three generations at present, and some of them may be the fourth generation, but they are still in clinical trials and have not been approved for marketing at the moment.
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EGFR PositivePatients who are positive for ECFR mutations (including exon 19 deletion, exon 21 L858R and L861Q, exon 18 G719X, and exon 20 S768I) can be treated with an EGFR-TKI, which can be categorized into three generations.Representative drugsFirst-generation gefitinib, erlotinib, ectinibFirst generationGefitinib, erlotinib, ectinib
Targeted drugs against ALK fusion gene positivity (ALK inhibitors) are currently categorized into three generations.
Representative drugs
First-generation crizotinib
First generation
Crizotinib
Second generation Ceritinib, Aleitinib, Ensatinib, Bugatinib
Second Generation
Ceritinib, Aleitinib, Ensatinib, Bugatinib
Third Generation Loratinib
Third Generation
Loratinib
ROS1-positive
Since the current research for ROS1 enzyme-specific inhibitors is not successful, and ALK kinase inhibitors may also inhibit ROS1 kinase activity, ALK inhibitors are mainly applied at present.
Currently, the only ALK inhibitor recommended by domestic guidelines is crizotinib, and foreign approved drugs include entrectinib (Entrectinib).
Other gene positivity
Patients with advanced non-squamous cell carcinoma with MET14 exon skipping mutation who cannot tolerate chemotherapy can use Sevortinib.
Patients with BRAF V600E mutation-positive advanced NSCLC may use dabrafenib in combination with trametinib.
Those with other rare mutations may receive platinum-containing two-drug chemotherapy or participate in clinical trials.
Immunotherapy
At present, in the immunotherapy of lung cancer, the main application is immune checkpoint inhibitors, and the common ones are PD-1 inhibitors (e.g., pabolizumab, navulizumab, cindolizumab, tirilizumab, carilizumab, etc.) and PD-L1 inhibitors (e.g., dovarilizumab, atirilizumab, sugilizumab, etc.).
Immune checkpoint inhibitors are currently used in advanced and locally advanced non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and can be used as a single agent or in combination with other therapeutic modalities. More clinical indications are being explored, and the specific regimen needs to be formulated by the doctor based on the patient’s actual condition.
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Advanced/locally advanced non-small cell lung cancer
Negative for driver mutations
Currently commonly used immunotherapy regimens include, but are not limited to, the following:
Immuno-combination chemotherapy: platinum-containing two-agent chemotherapy based on carilizumab, pembrolizumab, tirilizumab, sindilizumab, or atilizumab in combination with pemetrexed is feasible.
Stage III driver mutation-negative unresectable NSCLC
Patients with stage III NSCLC who do not show disease progression after concurrent radiotherapy and are not resectable may be considered for sequential divalizumab treatment for 1 year.
Driver gene mutation-positive NSCLC
There is insufficient evidence for immunotherapy for driver gene-positive NSCLC, and it is recommended to consult a medical professional or participate in a clinical trial to determine whether immunotherapy can be used.
Advanced small cell lung cancer
Combination of immunotherapy with chemotherapy (EP or EC regimen) is an option for extensive stage small cell lung cancer.
Radiotherapy
Radiotherapy, referred to as radiotherapy, is an important treatment method for lung cancer, especially for patients with clinical stage I or II lung cancer who cannot or do not want to have surgery for various reasons.
The sensitivity of lung cancer to radiotherapy is highest in small cell lung cancer, followed by squamous and adenocarcinoma, so the irradiation dose of small cell lung cancer is the smallest and that of adenocarcinoma is the largest.
Radiotherapy for lung cancer includes radical radiotherapy, palliative radiotherapy and comprehensive radiotherapy.
Radical radiotherapy
The purpose is to eliminate the primary lung cancer foci and its regional metastatic lymph nodes, so as to restore the patient’s health as much as possible.
It is suitable for patients in good physical condition (KPS score ≥70), including early stage non-small cell lung cancer that cannot be operated for various reasons, unresectable locally advanced non-small cell lung cancer and limited stage small cell lung cancer.
Palliative radiotherapy
The purpose is to inhibit tumor growth, reduce patients’ pain as much as possible and improve their quality of life.
It is suitable for tumor reduction treatment for primary and metastatic foci of advanced lung cancer.
For patients with non-small cell lung cancer with single brain metastases surgically resected, local radiotherapy or stereotactic radiotherapy in the operation area can be observed or performed. For patients with extensive stage small cell lung cancer, chest radiotherapy is feasible.
Integrated radiotherapy
Adjuvant radiotherapy: it is suitable for patients with preoperative radiotherapy, positive postoperative margins or surgical pathology suggesting multiple mediastinal lymph node metastases.
Prophylactic radiotherapy: after small cell lung cancer reaches complete remission by chemotherapy and radical radiotherapy and other comprehensive treatments, prophylactic whole brain radiotherapy is performed.
Synchronized radiotherapy: Synchronized radiotherapy is recommended for stage IIIA and IIIB patients who cannot be operated.
Interventional therapy
Tumor interventional therapy is a therapeutic method to kill tumor by gathering physical energy (radiofrequency, microwave, ultrasound, etc.) or chemical substances to the tumor site with the help of imaging technology guidance (angiography, ultrasound, CT, magnetic resonance, lumenscope, etc.).
Bronchial artery perfusion chemotherapy
It is suitable for advanced patients who have lost the indication for surgery and the systemic chemotherapy is ineffective.
This method has few toxic side effects, relieves symptoms and reduces pain.
Hematoporphyrin dye laser therapy and YAG laser excision therapy
Suitable for patients with centralized airway stenosis who are inoperable or refuse surgery.
It can remove the tumor in the airway lumen, relieve airway obstruction and control bleeding, thus prolonging the survival of patients.
Transbronchoscopic endoluminal radiotherapy
For patients with airway stenosis and lung atelectasis due to lung cancer.
It is usually radioactive particle implantation, such as radioactive iodine particles (125I), which can relieve the symptoms of obstruction and hemoptysis caused by tumor.
Stent placement therapy
For patients with airway stenosis and airway fistula that cannot be relieved by conventional treatment.
Intra-airway stents can be divided into metal stents and non-metal stents, and non-metal stents can be divided into silicone stents and plastic stents.
Generally, after electronic bronchoscopy-guided placement of tracheobronchial stent treatment, the patient’s dyspnea and other symptoms can be relieved, and the quality of recent survival can be significantly improved.
Traditional Chinese Medicine Treatment
Therapeutic effect
Chinese medicine treatment can be used as an auxiliary treatment for lung cancer, which can help reduce the adverse reactions of radiotherapy, chemotherapy and immunotherapy.
It can help regulate the immune function and physical condition of patients, improve the quality of life of cancer, and play a certain role in improving the long-term survival rate of lung cancer patients.
Commonly used medicines
Individual Chinese medicine tablets are not usually used as therapeutic drugs.
Commonly used proprietary Chinese medicines include Kang Lai Te soft capsule, compound red bean curd capsule and so on.
Special reminder] Secret prescriptions, partial remedies, folk remedies and other methods of treatment do not have a scientific basis, the indications, effectiveness is not clear, safety is difficult to guarantee, and is not recommended to use.
Prognosis
The prognosis of lung cancer patients mainly depends on the survival period, recurrence and metastasis, which are determined by the comprehensive clinicopathological characteristics of patients.
Survival
Survival of lung cancer patients can generally be evaluated by 5-year survival rate, which depends largely on the clinical stage and pathological type of the tumor at the time of disease discovery.
The 5-year survival rate refers to the proportion of patients whose tumors survive for more than 5 years after various comprehensive treatments, and does not mean that patients can only survive for 5 years.
Survival rates are statistics used in clinical research, usually based on the results of previous studies of large populations with a particular cancer (e.g., stage), and these statistics do not predict or represent the survival of any individual.
[Tip] With the introduction of related drugs, patients with driver gene-positive lung cancer may achieve longer survival. For more information about survival in this population, please refer to reading EGFR mutant lung cancer, ALK fusion lung cancer and ROS1 fusion lung cancer.
Lung Cancer Survival Data in China
A study synthesizing and analyzing several larger-scale statistics from 2000 to 2012 showed that the 5-year survival rates of non-small cell lung cancer and small cell lung cancer in China at all stages are as follows [1].
Non-small cell lung cancer (NSCLC)
Stage 5-year survival rate
Stage I 75%
Stage I
75%
Stage II 55
Stage II
55%
Stage III 20
Stage III
20%
Stage IV 5%
Stage IV
5%
Small Cell Lung Cancer (SCLC)
Staged 5-year survival rate
Stage I 45%
Stage I
45%
Stage II 25%
Stage II
25%
Stage III 8%
Stage III
8%
Stage IV 3
Stage IV
3 percent
American Joint Committee on Cancer (AJCC) Lung Cancer Survival Data
According to the results of the meta-analysis of the AJCC 8th Edition Tumor Staging Manual 2017, the survival rates for lung cancer are as follows [13]:
Non-small cell lung cancer (NSCLC)
The 5-year survival rate of patients with stage IA was about 80%, of which, the 5-year survival rates of patients with stage IA1, IA2, and IA3 were 92%, 83%, and 77%, respectively; the 5-year survival rate of patients with stage IB was 68%.
For stage II patients, the 5-year survival rate was about 55%.
In stage III patients, the 5-year survival rate drops to about 20%.
For stage IV patients, the 5-year survival rate is just under 5%.
Small cell lung cancer (SCLC)
For stage I patients, the 5-year survival rate is about 50%; for stage II, about 25%; for stage III, it drops to about 10%; and for stage IV, less than 3%.
Recurrence and Metastasis
Recurrence and metastasis of lung cancer are closely related to pathological type and clinical stage.
Currently, more studies have been conducted on the data after surgery. The recurrence rate of lung cancer in stage I and II NSCLC is about 30% about 5 years after surgery, while the recurrence rate or metastasis of stage III NSCLC is about 60% about 5 years after surgery.
SCLC is more malignant than NSCLC and is more prone to recurrence and metastasis.
Prognostic factors
Prognostic factors are factors that have an impact on the overall survival and quality of life of a patient.
Non-small cell lung cancer
Currently, it is believed that the stage at the time of consultation, clinical factors, and pathological type are important prognostic factors, with the stage having the greatest impact on prognosis.
In addition, age and daily physical status have also been shown to have an important correlation with the prognosis of lung cancer patients.
Generally speaking, patients with early staging, early and standardized treatment, and better personal physical fitness before the onset of disease have relatively good prognosis.
There is no uniform conclusion on whether the difference between adenocarcinoma and squamous carcinoma affects the prognosis.
Small cell lung cancer
The most important prognostic factor is the extent of the lesion at the time of consultation (disease stage). In addition, poorer daily physical status and/or weight loss are associated with shorter survival.
Daily
Just because lung cancer has been treated with surgery, radiotherapy or chemotherapy does not mean that you can let your guard down. Active and rigorous daily management can help patients to better beat the cancer.
Daily Management
Mindset and Emotional Adjustment
Good emotion and mindset cannot be replaced by drugs.