Lung cancer, also known as primary bronchogenic carcinoma or primary bronchogenic lung cancer, is a malignant tumor originating from respiratory epithelial cells in bronchi, bronchioles, and alveoli, and is the most common primary lung malignant tumor. According to pathological changes of lung tissues, lung cancer can be divided into small cell lung cancer and non-small cell lung cancer. The peak incidence occurs between the ages of 55 and 65, and males are more affected than females, with a male-to-female ratio of 2.1:1. Clinical symptoms are mostly latent and include cough, expectoration, hemoptysis, and emaciation, and chest x-ray shows mainly lung nodule and mass. Since about 75% of patients are in the late stage of lung cancer when they have symptoms and seek medical treatment, the overall 5-year survival is about 20%. Therefore, attention should be paid to to early diagnosis and standardized treatment.

Etiology and pathogenesis

The etiology and pathogenesis of lung cancer have not yet been clarified, but there is evidence that they are associated with the following factors.

Cigarette smoking

Cigarette smoking is the most common cause of lung cancer. About 85% of lung cancer patients have a history of cigarette smoking, including smokers and ex-smokers. Individuals with 20 - 30 pack-year smoking (1 pack per day x 20 - 30 years) have a significantly increased risk of lung cancer. Both intrauterine exposure to tobacco and cigarette smoking after birth increase the risk of lung cancer, and the risk of lung cancer occurrence is inversely proportional to the age of initial cigarette smoking. The risk of lung cancer is 10 times in smokers and 10 - 25 times in heavy smokers higher than that in never smokers. After acquiring smoking behavior in childhood, adolescence, and adulthood, the risk of lung cancer occurrence increases by 14 times, 8 times, and 5 times respectively, and the risk of death caused by lung cancer also increases. Ex-smokers have a lower risk of lung cancer than those who continue to smoke, but still have 9 times higher risk than never smokers. Tobacco has been classified as a group 1 carcinogen, and cigarette smoking is associated with the risk of all pathological types of lung cancer.

Environmental tobacco smoke

Environmental tobacco smoke (ETS), also known as secondhand tobacco smoke or passive smoking, is also one cause of lung cancer. The risk from ETS is lower than that from active smoking. Non-smokers who have married and lived with smokers for many years have a 20% - 30% increased risk of lung cancer, and their risk of lung cancer increases with the amount of smoking of their spouses. Tobacco has been classified as a Class A carcinogen, and cigarette smoking is associated with the risk of all pathological types of lung cancer. Since only about 11% of heavy smokers develop lung cancer, genetic sensitivity may play a role.

Occupational carcinogens

There are many carcinogens in the working environment of certain occupations. Confirmed carcinogens include asbestos, arsenic, chromium, mustard gas, nickel, polycyclic aromatic hydrocarbons, radon and radon gas produced by the decay of radioactive substances such as uranium and radium, ionizing radiation, and microwave radiation. Silica and soot are also definite carcinogens for lung cancer. These factors can increase the risk of lung cancer by 3 - 30 times. Since the formation of lung cancer is a long process, its incubation period can be up to 20 years or more, many patients develop lung cancer a long time after they stop contacting carcinogens.

Air pollution

Industrial waste gas and automobile exhaust in cities contain carcinogens, such as benzopyrene, arsenous oxide, radioactive substances, nickel, chromium compounds, SO₂, NO, and incombustible aliphatic hydrocarbons. PM2.5, also known as fine particulate matter or inhalable pulmonary particulate matter, is one of the most harmful pollutants composed of most complex chemical compositions in the atmospheric environment, and is related to the incidence and mortality of lung cancer that increase with the elevation of PM2.5 concentration. Data show that the incidence of lung cancer in cities is significantly higher than that in rural areas.

Fuel combustion and cooking can produce carcinogens. Indoor exposure to coal smoke or its incomplete combustion products is a risk factor for lung cancer, especially adenocarcinoma in females. The fume released by heating during cooking is also a carcinogenic factor that cannot be ignored.

Ionizing radiation

Ionizing radiation can be occupational or non-occupational, and can come from outside the body or is caused by inhalation of radioactive dust and gas. Different rays produce different effects. For example, the atomic bomb in Hiroshima, Japan released neutrons and alpha rays, while only alpha rays in Nagasaki, the former has a higher risk of lung cancer than the latter.

Diet and physical activity

Studies have shown that low intake of fruits and vegetables in adulthood increases the risk of lung cancer. Persons with low levels of beta-carotene in their serum have a high risk of lung cancer. Other studies have shown that moderate to vigorous intensity physical activity reduces the risk of lung cancer by 13% - 30%.

Genetics

The correlation between genetic factors and lung cancer has received attention. For example, relatives with a family history of early lung cancer (before the age of 60) have a 2-fold increased risk of lung cancer; with the same cigarette smoking exposure, females have a higher risk of lung cancer than males. Only about 11% of heavy smokers suffer from lung cancer. Genetic sensitivity may play a certain role. Lung cancer may be caused by external factors acting on internal factors. External factors can induce malignant transformation of cells and irreversible genetic changes, including activation of proto-oncogenes, inactivation of tumor suppressor genes, activation of autocrine feedback loops, and inhibition of cell apoptosis. The occurrence of lung cancer is a multi-stage gradual evolutionary process involving a series of genetic changes. The accumulation of multiple genetic changes causes the disordered control mechanism of cell growth and differentiation, leading to uncontrolled cell growth and carcinogenesis. The oncogenes that are closely related to the occurrence of lung cancer, mainly include HER family gene, RAS gene family, MYC gene family, ALK fusion gene, Sox gene, and MDM2 gene. Related tumor suppressor genes include TP53, RB1, CDKN2A, NME1, and PTEN genes. The molecular pathogenesis related to the occurrence and development of lung cancer also includes activation of growth factor signaling pathways, tumor angiogenesis, cell apoptosis disorders, and immune escape.

Other factors

Tuberculosis is one cause of lung cancer, the risk of lung cancer in tuberculosis patients is 10 times more than that in normal population, and the main histological type is adenocarcinoma. Certain chronic lung diseases such as chronic obstructive pulmonary disease, sarcoidosis, idiopathic pulmonary fibrosis, scleroderma, viral infection, and mycotoxins may also have a certain relationship with the occurrence of lung cancer.

Classification

According to the anatomical site, lung cancer can be divided into central lung cancer and peripheral lung cancer.

Central lung cancer occurs in the bronchi, mainly squamous cell carcinoma and small cell lung cancer.

Peripheral lung cancer occurs in the bronchioles, mostly adenocarcinoma.

According to histopathology, lung cancer is divided into non-small cell lung cancer and small cell lung cancer, mostly non-small cell lung cancer, accounting for about 85%. Atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) are classified as glandular precursor lesions.

Non-small cell lung cancer (NSCLC)

Squamous cell carcinoma

Squamous cell carcinoma is currently divided into squamous cell carcinoma, not otherwise specified (keratinizing, non-keratinizing, and basaloid squamous cell carcinoma), and lymphoepithelial carcinoma. Typical squamous cell carcinoma shows squamous cell metaplasia derived from bronchial epithelium, often with cell keratinization and/or intercellular bridges. Non-keratinizing squamous cell carcinoma lacks cell keratinization and/or intercellular bridges, and immunohistochemistry is often required to confirm the presence of squamous differentiation. In basaloid squamous cell carcinoma, the basaloid cancer cell component is at least > 50%. Lymphoepithelial carcinoma is a poorly differentiated squamous cell carcinoma with infiltration of lymphocytes and plasma cells; more than 90% of Asian cases are related to the Epstein-Barr virus (EBV), while the correlation with EBV is low in the European and American populations; in situ hybridization EBER is mostly positive; attention should be paid to the differentiation from nasopharyngeal carcinoma. Cancer cells CK5/6, p40, and p63 are positive in immunohistochemistry.

Squamous cell carcinoma mostly originates from the segmental or subsegmental bronchial mucosa and tends to grow into the lumen. In the early stage, it often causes bronchial stenosis, leading to atelectasis or obstructive pneumonia. Cancerous tissue is prone to degeneration and necrosis, forming cavity or cancerous lung abscess. It is common in older males, with slow growth and late metastasis. There are some opportunities for surgical resection and a higher 5-year survival rate, but it is not as sensitive as small cell lung cancer to chemotherapy and radiotherapy.

Adenocarcinoma

Minimally invasive adenocarcinoma (MIA) is mainly characterized by lepidic growth. The diameter of MIA tumor is ≤ 3 cm, the maximum diameter of stroma is ≤ 5 mm, and there is no bronchial, vascular, and pleural invasion, tumor necrosis, and intrapulmonary dissemination.

Invasive non-mucinous adenocarcinoma has morphological or immunohistochemical evidence of glandular differentiation, with different subtypes recorded using a 5% threshold, and is no longer necessary to be classified as adenocarcinoma dominated by any specific subtype. Common subtypes include lepidic, acinar, papillary, micropapillary, and solid adenocarcinoma, and a mixture of multiple subtypes is often present. Based on the predominant histology and presence or absence of high-grade components, this type of adenocarcinoma can be well differentiated, moderately differentiated, and poorly differentiated. Well differentiated adenocarcinoma is composed of mainly lepidic adenocarcinoma, without high-grade components, or with < 20% high-grade components; moderately differentiated adenocarcinoma is composed of mainly acinar or papillary adenocarcinoma, without high-grade components, or with < 20% high-grade components; poorly differentiated adenocarcinoma is composed of any histological type of adenocarcinoma, with ≥ 20% high-grade components.

Invasive mucinous adenocarcinoma accounts for 3% of lung adenocarcinomas. The tumor cells are in the form of goblet cells or columnar cells, containing abundant intracellular mucus. The nuclei of the tumor cells are small and pushed to one side of the cells. The alveoli around the tumor are often filled with mucus. Lepidic growth is often seen, and this type of adenocarcinoma includes acinar, papillary, micropapillary, solid, and cribriform adenocarcinoma, and can coexist with non-mucinous adenocarcinoma. Immunohistochemistry shows positive CK7, partially positive CK20 and CDX2, and mostly negative TTF-1 and Napsin A.

Colloid adenocarcinoma is with an incidence rate of about 0.14% - 0.25% in lung cancer, is characterized by massive destruction of mucoprotein in the alveolar walls, and the mucus content is generally > 50%. Immunohistochemistry shows positive CDX-20, CK20, and Villin.

Fetal adenocarcinoma of the lung (FLAC) accounts for 0.1% - 0.5% of lung cancers. Pathological changes show glandular structures formed by tubules analogous to fetal lung tubules and composed of glycogen-rich and non-ciliated cells. FLAC is divided into low-grade and high-grade FLAC. High-grade FLAC is more common in older males, mainly occurs in individuals age 60 - 70, with a history of heavy smoking, with possible elevation of serum AFP, and is mostly at stage III - IV when seeking medical attention. Low-grade FLAC is more common in young females, mostly aged 30 - 40, and is mostly at stage I - II when seeking medical attention.

Enteric adenocarcinoma has a low incidence. The morphology of the cancer tissue is analogous to that of colorectal adenocarcinoma. It This type of adenocarcinoma can be regularly or irregularly tubular, papillary, and cribriform, as well as solid nested in poor differentiation. Dusty necrotic substances or significant nuclear fragmentation, sometimes accompanied by little mucinous substances, in the glandular cavity can be seen. Some enteric adenocarcinomas express intestinal differentiation markers such as CK7, CK20, CDX-2, Villin, MUC2, and HNF4a, while some cases only have the morphology of enteric adenocarcinoma but lack the expression of intestinal markers. It is often necessary to complete clinical examinations to exclude gastrointestinal adenocarcinoma.

Adenocarcinoma is the most common type of lung cancer, mostly in females, and mainly originates from bronchial mucous glands. Adenocarcinoma can occur in bronchioles or the central airway, and is mostly peripheral lung cancer in clinical practice. Adenocarcinoma can grow outside the trachea, and spread along the alveolar walls, often forming nodules or masses with a diameter of 2 - 4 cm at the edges of the lungs. Because adenocarcinoma is rich in blood vessels, local invasion and hematogenous metastasis occur early, and is prone to involvement of the pleura, causing pleural effusion.

Large cell carcinoma

Large cell carcinoma is an undifferentiated non-small cell carcinoma, relatively less common, and accounts for less than 10% of lung cancer. It lacks the characteristics of small cell carcinoma, adenocarcinoma, and squamous cell carcinoma in terms of cytology, tissue structure, and immunophenotype. Only surgically resected specimens are used to diagnose large cell carcinoma, and small biopsy and cytology specimens are not applicable. Immunohistochemistry and mucin staining show negative squamous epithelial and adenoid differentiation markers. Large cell carcinoma is with late metastasis and there are some chances of surgical resection.

Other cancers include adenosquamous carcinoma, sarcomatoid carcinoma, lymphoepithelioma-like carcinoma, NUT (nuclear protein in testis) carcinoma, and salivary gland carcinoma (adenoid cystic carcinoma, mucoepidermoid carcinoma).

Small cell lung cancer (SCLC)

Pulmonary neuroendocrine tumor includes carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma. SCLC is a poorly differentiated neuroendocrine tumor, including small cell carcinoma and combined small cell carcinoma. Small cell carcinoma cells are small, round or oval, with little cytoplasm and unclear cell edges. There are finely granular or hyperchromatic nucleus, absent or inapparent nucleolus, and common nuclear division. The cytoplasm of small cell lung cancer contains neuroendocrine granules, which have endocrine and chemical receptor functions, can secrete substances such as 5-hydroxytryptamine, catecholamine, histamine, and kinin, and can cause carcinoid syndrome. Cancer cells often express neuroendocrine markers such as CD56, neural cell adhesion molecule, synaptophysin, and chromogranin. Ki-67 immunohistochemistry is very helpful in distinguishing SCLC from carcinoid. Ki-67 proliferation index of SCLC is usually 50% - 100%.

SCLC is characterized by rapid proliferation and early extensive metastases. In the initial diagnosis, 60% - 88% of patients have metastases in the brain, liver, bone, or adrenal glands, and the cancer is confined to the chest in only about 1/3 of patients. SCLC is mostly central, and typical manifestations are cough and dyspnea caused by hilar mass and enlarged mediastinal lymph nodes. SCLC is sensitive to chemotherapy and radiotherapy. In all epithelial lung cancers, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma are the main types, accounting for about 90% of all lung cancers.

Clinical manifestations

Clinical manifestations are closely related to tumor size, type, stage of development, site, and presence or absence of complications or metastasis. 5% - 15% of patients are asymptomatic and are only found during routine physical examinations and chest imaging examinations.

Primary tumor

Cough is an early symptom, often an irritating dry cough with little or no sputum. Cough may be exacerbated when the tumor causes bronchial stenosis, usually persistent, and is high-pitched brassy cough or irritating paroxysmal cough. Mucinous adenocarcinoma may have excessive mucous sputum. When accompanied by secondary infection, sputum is increased and is mucopurulent.

Bloody expectoration or hemoptysis is more common in central lung cancer. Patients with tumor in the lumen may have intermittent or persistent bloody expectoration. If the surface erosion severely erodes the large blood vessels, massive hemoptysis may occur.

Tumor growing into the trachea and bronchi can cause partial airway obstruction. Metastasis in the hilar lymph nodes causes the enlarged lymph nodes to compress the main bronchi or carina. Metastasis can cause large amounts of pleural effusion, pericardial effusion, diaphragmatic paralysis, and superior vena cava obstruction. Extensive lung invasion can cause dyspnea, tachypnea, wheezing, and occasionally stridor. Localized or unilateral wheezing may be heard on auscultation.

There may be dull chest pain, which is related to the metastasis of tumor or direct invasion of the chest wall.

Tumor tissue necrosis can cause fever. Fever is mostly caused by obstructive pneumonia resulting from tumor, and antibiotic treatment is ineffective.

Emaciation is a common manifestation of malignant tumor. In the late stage, due to anorexia caused by infection and pain, emaciation or cachexia may occur.

Local expansion of tumor

When tumor invades the pleura or chest wall, irregular dull pain or severe pain occurs and aggravates during respiration and cough. There may be tenderness when the ribs and spine are invaded. If tumor compresses the intercostal nerves, thoracodynia may involve the distribution area.

Tumor or metastasis in the mediastinal lymph nodes compresses the recurrent laryngeal nerve (mostly on the left side) to paralyze the vocal cords, resulting in hoarseness.

Tumor invades or compresses the esophagus, causing dysphagia, and can also cause tracheoesophageal fistula, leading to mediastinal or pulmonary infection.

Tumor or metastasis involving the pleura or pulmonary lymphatic circulation obstruction can cause pleural effusion.

Tumor can extend and invade the pericardium, and can also obstruct the lymphatic circulation of the heart, resulting in pericardial effusion. Rapid production or large amounts of pericardial effusion may cause cardiac tamponade.

Tumor directly invading the mediastinum, metastatic enlarged lymph nodes compressing the superior vena cava, and tumor thrombus obstructing the vena cava can cause venous return obstruction. Symptoms include edema of the upper limbs, neck, and face, and varicose veins of the chest wall. Severe patients have dark purple skin, congested conjunctiva, blurred vision, dizziness, and headache.

Pancoast tumor is a lung cancer at the apex of the lung, can compress the cervical sympathetic nerves, causing ptosis, miosis, enophthalmos on the affected side, and anhidrosis on the forehead on the same side, which is termed Horner syndrome.

Distant metastasis of tumor

Pathological anatomy reveals that extrathoracic metastasis occurs in more than 50% of patients with squamous cell carcinoma, 80% of patients with adenocarcinoma and large cell carcinoma, and more than 95% of patients with small cell carcinoma. About 1/3 of patients with symptoms are caused by extrathoracic metastasis. Lung cancer can metastasize to any organ, and the involved part presents corresponding symptoms and signs.

Brain metastasis can cause symptoms of increased intracranial pressure such as headache, nausea, and emesis, and can be also manifested by vertigo, ataxia, diplopia, personality changes, and epileptic seizures, as well as lateral asthenia or even hemiplegia. If the spinal cord is compressed, there may be back pain, lower limb weakness, paresthesia, and dysfunction of bladder or intestinal tract.

Bone metastasis is manifested by local pain and tenderness, and pathological fracture may also occur, mostly osteolytic. Common sites are the ribs, spine, pelvis, and long bones of the limbs.

Metastasis in the liver, pancreas, and gastrointestinal tract is manifested by anorexia, pain in the liver, abdominal pain, jaundice, hepatomegaly, abdominal effusion, and pancreatitis. Adrenal metastasis is also common.

The supraclavicular fossa lymph nodes are commonly involved, and metastasis is mostly in the lower posterior part of the attachment of the sternocleidomastoid muscle. There can be single or multiple, fixed, indurated, gradually enlarged, increased in number and size, fusible metastases, usually without pain and tenderness. Retroperitoneal lymph node metastasis is also common.

Extrathoracic manifestations of lung cancer

Extrathoracic manifestations of lung cancer are the non-metastatic extrathoracic manifestations of lung cancer, can appear before or after the discovery of lung cancer, and are termed paraneoplastic syndrome. Paraneoplastic syndrome is more common in SCLC, and can be the initial symptoms or early signs of recurrence. Its pathophysiology may be clear (abnormal hormone secretion), and can be also unknown (anorexia, cachexia, emaciation, fever, and immunosuppression).

Paraneoplastic endocrine syndrome occurs in 12% of lung cancer patients. Endocrine syndrome is caused by some bioactive peptides and amines generated by tumor cells, such as adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), antidiuretic hormone (ADH), and gonadotropin.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is manifested by hyponatremia, hypoosmolarity, anorexia, nausea, emesis, gradually exacerbated drowsiness, irritability, disorientation, epileptic seizures, and coma. Hyponatremia can also be caused by increased atrial natriuretic peptide (ANP). Symptoms can be mostly relieved within 1 - 4 weeks after initial chemotherapy.

Ectopic ACTH syndrome presents Cushing syndrome, caused by SCLC or carcinoid. The manifestations include pigmentation, edema, amyotrophy, hypokalemia, metabolic alkalosis, hyperglycemia, and hypertension, but the manifestations are mostly atypical, and centripetal obesity and livid striae are rare.

Hypercalcemia presents with polydipsia and polyuria in mild patients, and nausea, emesis, abdominal pain, constipation, lethargy, and coma in severe patients. It is the most common life-threatening metabolic complication of malignant tumors, mainly in patients with squamous cell carcinoma. Calcium level in blood can return to normal after tumor resection.

Ectopic secretion of gonadotropin causes mild breast development in males, often accompanied by hypertrophic pulmonary osteoarthropathy, mostly in large cell carcinoma. Carcinoid syndrome caused by excessive secretion of 5-hydroxytryptamine is manifested by wheezing, skin flushing, watery diarrhea, and paroxysmal tachycardia, predominantly in SCLC and adenocarcinoma.

Primary hypertrophic osteoarthropathy presents clubbed fingers (toes) in 30% of patients, mostly NSCLC patients. The involved bones may develop periostitis, manifested by pain, tenderness, and swelling, mostly at the distal ends of the long bones of the limbs. X-ray shows thickening of the periosteum and new bone formation, and bone scintigraphy shows radionuclide concentration at the lesion site.

Paraneoplastic neurological syndrome and paraneoplastic myopathic syndrome may be associated with autoimmune reactions or humoral substances produced by tumors.

Eaton-Lambert myasthenic syndrome presents with myasthenic pelvic girdle muscles and proximal muscles of the lower limbs in the early stage, and muscle strength can be temporarily improved after repeated activities. Physical examination shows weakened tendon reflexes. Symptoms in some patients can improve after chemotherapy. More than 70% of patients respond poorly to neostigmine test. Low-frequency repetitive stimulation shows a decrease in the amplitude of the action potential, while high-frequency stimulation causes a temporary increase in the amplitude, which can be used to distinguish from myasthenia gravis, mostly in SCLC.

Multiple peripheral neuritis, subacute cerebellar degeneration, cortical degeneration, and polymyositis can be caused by various types of lung cancer; while paraneoplastic encephalomyelitis, sensory neuropathy, cerebellar degeneration, limbic encephalitis, and brainstem encephalitis are caused by small cell lung cancer, and are often accompanied by various anti-neuronal antibodies, such as anti-Hu, anti-CRMP5, and ANNA-3 antibodies.

1% - 8% of patients have hematological abnormalities such as coagulopathy and thrombosis, including migratory thrombophlebitis (Trousseau syndrome), nonbacterial thrombotic endocarditis with atrial thrombus, disseminated intravascular coagulation with hemorrhage, anemia, granulocytosis, and leukoerythroblastosis. The prognosis of lung cancer with thrombotic diseases is poor. Dermatomyositis and acanthosis nigricans are with an incidence of about 1%, and the incidence of nephrotic syndrome and glomerulonephritis is less than 1%.

Imaging and other auxiliary examinations

X-ray

In central lung cancer, the tumor grows in the main bronchi, lobar bronchi, or segmental bronchi. The growth of tumor in the lumen can cause bronchial obstruction, manifested by unilateral hilar round opacity, with rough edges, with or without lobulation. When the tumor coexists with atelectasis or obstructive pneumonia, the lower edge may show Golden S sign, which is a typical sign of central lung cancer in the right upper lobe. The growth of tumor in the bronchus can partially or completely obstruct the bronchus, forming localized emphysema, atelectasis, obstructive pneumonia, and secondary lung abscess.

Figure 1 Central lung cancer
Male, 60 years old. Chest x-ray shows central lung cancer with obstructive atelectasis and obstructive pneumonia in the right upper lobe; the cancer is pathologically confirmed lung squamous cell carcinoma.

In peripheral lung cancer, tumor occurs in the bronchioles. In the early stage, there is mostly localized, small, hazy, poorly marginated, patchy opacity, but also nodular, spherical, reticular, or ground-glass opacity, and the tumor is easily mistaken for inflammation or tuberculosis. As the tumor grows, the opacity gradually increases in size and density, and is rounded or subrounded, with lobulated edges, spicules, and pleural retraction. If the tumor metastasizes to the hilar lymph nodes, the involved lymphatic vessels can be thickened and show irregular linear opacities with enlarged hilar lymph nodes. Necrotizing cancerous tissue connected with the bronchus presents with thick-walled, eccentric, cancerous cavity with rough edges. In secondary infection, fluid level may appear in the cavity. Adenocarcinoma disseminated through the bronchi shows patchy infiltration. Invasion of the pleura causes pleural effusion. Invasion of the ribs causes bone destruction.

Figure 2 Peripheral lung cancer
Male, 52 years old. Chest x-ray shows peripheral lung cancer in the right lower lobe with metastases to the right hilar lymph nodes and both lungs; the cancer is pathologically confirmed well differentiated adenocarcinoma.

Figure 3 Cancerous cavity

CT

CT has a higher resolution and can detect small lung lesions that are difficult to display on conventional chest x-ray (lesions behind the heart, beside the spine, at the apex of the lung, at the costophrenic angle, and at the head of ribs). Contrast-enhanced CT can sensitively detect enlarged lymph nodes in the hilum and mediastinum, which is helpful for the clinical staging of lung cancer. Spiral CT can show small nodules with a diameter of less than 5 mm in the central airways, 6th to 7th generation of bronchi, and small blood vessels; and can clarify the relationship between the lesions and the peripheral airways and blood vessels. Low-dose CT can effectively detect early lung cancer and has replaced chest x-ray as a more sensitive tool for evaluating lung nodules. CT-guided percutaneous puncture biopsy of lung lesions is an important histological diagnostic technique. CT simulation can guide the bronchoscope to perform biopsy of lesions in the airway or through the bronchial wall.

Figure 4 Small cell lung cancer
Male, 59 years old. CT shows central lung cancer in the left lung, involved left main bronchus and bronchi of the upper and lower lobes, obstructive pneumonia in the left lung, and multiple metastases in the lung; the cancer is small cell lung cancer pathologically confirmed in bronchoscopic biopsy.

Figure 5 Adenocarcinoma in the left lower lobe
Male, 61 years old. CT shows peripheral lung cancer in the left lower lobe; the cancer is pathologically confirmed lung adenocarcinoma.

Figure 6 Adenocarcinoma in the right lower lobe
Male, 32 years old. CT shows peripheral lung cancer in the right lower lobe; the cancer is pathologically confirmed lung adenocarcinoma.

MRI

Compared with CT, MRI is superior in clarifying the relationship between tumors and large blood vessels and detecting metastasis in the brain parenchyma or meninges, but is not as sensitive as CT in detecting small lung lesions (<5 mm).

Radionuclide scintigraphy

Bone γ scintigraphy can be used to detect the presence or absence of bone metastasis. Its sensitivity, specificity, and accuracy are 91%, 88%, and 89%, respectively. Radiolabeled somatostatin analog is more helpful for the staging and diagnosis of SCLC.

PET and PET-CT

PET tracks the transfer and transformation of positron-labeled radionuclide compounds in the body, shows the physiological changes of metabolites in the body, noninvasively shows the function of internal tissues and organs of the human body, and can perform quantitative analysis. PET-CT is a combination of PET and CT; CT anatomical images and PET functional metabolic images can be simultaneously obtained, biological metabolic information and precise anatomical positioning can be simultaneously obtained, and PET-CT is superior to any other existing imaging examinations in detection of early lung cancer and metastatic lesions in other parts of the body, tumor staging, and efficacy evaluation. It should be noted that patients with positive PET-CT still need cytological or pathological examinations for final diagnosis.

Examination for pathological diagnosis

Exfoliative sputum cytology is is the simplest and most convenient non-invasive diagnostic method for central lung cancer, but there is a certain possibility of false positives and false negatives. To improve the positive rate, sputum in the deep airway must be obtained and sent for examination quickly, and at least three examinations are needed. The sensitivity is less than 70%, but the specificity is high.

Thoracentesis can be used to obtain pleural effusion for cytological examination, with a detection rate of 40% - 90%, clarifying the pathology and stage of lung cancer. Paraffin embedding, sectioning, and staining of the cell blocks from centrifuged and precipitated pleural effusion can increase the positive diagnostic rate of pathology. For metastatic serous effusion in other parts, puncture can also be performed to obtain pathological evidence.

Bronchoscopy is one of the main methods for diagnosis of lung cancer. Bronchoscopy can reach the 4th to 5th generation of bronchi, helping to visually observe approximately 1/3 of the proximal bronchial mucosa. Histological or cytological samples can be obtained through biopsy, brushing, and lavage. The combination application of biopsy, brushing, and lavage can increase the detection rate. Fluorescence bronchoscopy is developed based on the principle that tumor tissues are different from normal tissue in autofluorescence. Fluorescence bronchoscopy in combination with conventional bronchoscopy can significantly improve the diagnosis of epithelial cell carcinogenesis and invasive lung cancer.

For lesions that cannot be observed in conventional bronchoscopy, pathological specimens can be obtained through thin or ultrafine bronchoscopy, fluoroscopy, radial ultrasound probes, electromagnetic navigation bronchoscopy, and other guided bronchoscopy techniques. Endobronchial ultrasound (EBUS)-guided needle aspiration biopsy is helpful to clarify the nature of airway wall infiltration lesions, space-occupying lesions outside airway, and mediastinal lymph nodes, and is also helpful for the TNM classification of lung cancer; peripheral lesions can be biopsied under the guidance of small ultrasound probes.

Thoracoscopy is used for subpleural lesions that cannot be obtained in bronchoscopy, and can show whether there are metastatic lesions in the pleura, providing a reliable basis for formulating a comprehensive treatment plan.

Mediastinoscopy can obtain more samples, and is an effective method for differentiation of benign and malignant diseases with mediastinal lymph node enlargement. It is also one of the methods for assessment of the stage of lung cancer and preoperative assessment of lymph node stage. However, the operational trauma and risk are relatively large.

Under the guidance of x-ray fluoroscopy, chest CT, or ultrasound, core needle biopsy of the lesion can be performed, and is suitable for pulmonary lesions close to or adjacent to the chest wall.

Fine needle aspiration, surgical biopsy, or resection of the enlarged superficial lymph nodes in the clavicle or axilla can be performed.

If the diagnosis cannot be confirmed after the above multiple examinations, open lung biopsy can be prudently considered.

Tumor marker detection

There is no tumor marker with high diagnostic sensitivity and specificity so far. Detection or combined detection of carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and pro-gastrin-releasing peptide (ProGRP) has certain reference value for the diagnosis and monitoring of lung cancer.

Genetic diagnosis of lung cancer

It is believed that lung cancer is caused by the activation of proto-oncogenes and the absence of tumor suppressor genes. Therefore, oncogene products such as MYC gene amplification, RAS gene mutation, and abnormalities of tumor suppressor gene RB1 and TP53 are helpful in diagnosing early lung cancer. Genetic testing can identify the best population for targeted drugs. Currently, the main tests for NSCLC patients are EGFR gene mutation, rearrangement of anaplastic lymphoma kinase (ALK) fusion gene and ROS1 fusion gene, BRAF V600 mutation, RET rearrangement, MET exon 14 skipping mutation, NTRK1/2/3 rearrangement. extended genes including MET amplification or overexpression, and HER-2. Drug resistance genes, such as EGFR T790M and C797S mutations, can also be detected. When it is difficult to obtain tumor tissue specimens, cell-free circulating tumor DNA (ctDNA) can be used as a supplementary specimen to evaluate gene mutation status, which is the so-called liquid biopsy. Programmed death ligand 1 (PD-L1) immunohistochemistry can screen NSCLC patients who may benefit from immune checkpoint inhibitors. Tumor mutation burden (TMB) may be another biomarker for predicting the effect of immunotherapy, but currently there are no uniform standards for the selection of its detection methods and thresholds.

Diagnosis

The diagnosis of lung cancer can be carried out according to the following steps.

CT to determine the site

In patients with clinical symptoms or radiological signs of suspected lung cancer, chest and abdominal CT can be performed to find the site of the primary tumor, mediastinal lymph node invasion, and dissemination of other anatomical sites.

Histopathological diagnosis

In patients with suspected lung cancer, histological specimens should be obtained for diagnosis. Tumor tissue can often be obtained through minimally invasive techniques, such as bronchoscopy and thoracoscopy. However, sputum cytology is not recommended for the diagnosis of lung cancer. Superficial palpable lymph nodes or skin metastases should also be biopsied. If distant metastatic lesions, such as soft tissue masses, osteolytic lesions, bone marrow lesions, pleural lesions, and liver lesions, are suspected, tissue specimens should also be obtained. In pleural effusion, sufficient cell mass should be obtained, or thoracoscopy can be performed. It is currently recommended that direct surgical resection can be performed in patients with stage I and stage II lung cancer.

Molecular pathological diagnosis

If conditions permit, EGFR gene mutation, ALK fusion gene, ROS1 fusion gene, BRAF V600, RET, MET exon 14 skipping mutation, KRAS, and NTRK of the tumor tissue should be tested during pathological diagnosis. In NSCLC, the detection of PD-L1 expression can be also considered to facilitate the development of an individualized treatment plan.

Differential diagnosis

Lung cancer often coexists with certain lung diseases, and its imaging manifestations are analogous to those of certain diseases, so misdiagnosis and missed diagnosis are common.

Pulmonary tuberculosis

Pulmonary tuberculoma is seen in young patients, mostly asymptomatic. The lesion is mostly in the posterior segment of the apex of the upper lobe and the dorsal segment of the lower lobe, with clear edges, high density, capsules, and sometimes calcification. It is surrounded by irregular linear lesions and remain unchanged for many years.

Hilar lymph node tuberculosis is easily confused with central lung cancer, mostly in children and young individuals, with fever and diaphoresis. Tuberculin test is often positive, and anti-tuberculosis treatment is effective.

Acute miliary tuberculosis is mainly in young individuals, with fever and diaphoresis. Chest x-ray shows small, homogeneous, hazy, miliary nodular lesions. Adenocarcinoma has nodular disseminated lesions of varying sizes in both lungs, with clear boundaries, high density, and progressive development and enlargement.

Pneumonia

Pneumonia has symptoms such as fever, cough, and expectoration, and is effectively treated with antibiotics. If the lung lesion subsides slowly after antibiotic treatment, or pneumonia occurs repeatedly at the same site, lung cancer should be considered. Chronic inflammation of the lungs can lead to the formation of inflammatory pseudotumor, which is also easily confused with lung cancer. However, inflammatory pseudotumor is often irregular in shape, with rough edges and high core density, and is easily accompanied by pleural thickening; the lesion has no significant changes for a long time.

Lung abscess

Lung abscess has acute onset and severe symptoms, including rigors, high fever, cough, and purulent and odorous expectoration.

Homogeneous patchy opacity can be seen on imaging, and fluid level is often seen in the cavity. Patients with cancerous cavity generally do not have fever; when secondary infection occurs, they may have clinical manifestations of lung abscess; imaging shows the cancerous cavity is eccentric, thick-walled, with rough inner wall. Bronchoscopy and exfoliative sputum cytology are helpful for differentiation.

Tuberculous pleurisy

Tuberculous pleurisy should be differentiated from cancerous pleural effusion.

Pulmonary cryptococcosis

Pulmonary cryptococcosis may have single or multiple nodules and masses in the lungs, mostly under the pleura; single lesion is easily confused with peripheral lung cancer. Lung biopsy and serum cryptococcal capsular polysaccharide antigen detection are helpful for differentiation.

Others

Others such as benign lung tumor and lymphoma need to be differentiated in histopathology.

Stage

There are TNM and clinical stages and their relationship as follows.

Table 1 TNM stage

Table 2 Relationship of TNM stage and clinical stage

Treatment

The treatment of lung cancer should be based on the physical condition, pathological type (including molecular pathological diagnosis), and scope of invasion (clinical staging); and multidisciplinary comprehensive individualized treatment can be considered. Surgery, chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy should be used in a planned and reasonable manner to achieve radical cure or tumor control, improve cure rate, improve quality of life, and prolong survival.

Surgical treatment

Surgery is the best treatment for early lung cancer, and is divided into radical and palliative surgery. Radical resection should be preferred in order to reduce metastasis and recurrence, and TNM staging can be performed to guide postoperative comprehensive treatment.

NSCLC

Surgery is mainly suitable for patients at stage I and stage II. Radical surgical resection is preferred. Patients at stage III A or T₃N₁, T₄N_0-1, and T_1-3N₂ need to receive comprehensive treatment through multidisciplinary discussion, including surgical treatment in combination with postoperative chemotherapy, sequential chemoradiotherapy, or synchronous chemoradiotherapy. Except for stage I, stage II and III lung cancer require postoperative adjuvant chemotherapy after radical surgery. Preoperative chemotherapy (neoadjuvant chemotherapy) can reduce the TNM stage of patients who were previously inoperable and make surgery possible. After surgery, according to the final pathological TNM stage and resection margin, reoperation, postoperative adjuvant chemotherapy, or radiotherapy can be selected. Wedge resection can also be considered for patients who cannot tolerate lobectomy.

SCLC

More than 90% of SCLC patients have intrathoracic or distant metastases when seeking medical attention, and surgical treatment is generally not recommended. In patients at stage T_1-2N₀ with negative results in pathological mediastinal staging through mediastinoscopy or mediastinotomy, lobectomy and lymph node dissection can be considered. Surgery alone cannot cure SCLC, so all postoperative SCLC patients need to receive two-drug chemotherapy containing platinum for 4 - 6 courses.

Medication therapy

Medication therapy mainly includes chemotherapy, immunotherapy, targeted therapy, and angiogenesis inhibitors, and is used in patients with advanced or recurrent lung cancer. Chemotherapy can also be used in postoperative adjuvant chemotherapy, preoperative neoadjuvant chemotherapy, and comprehensive treatment including radiotherapy. Chemotherapy should strictly follow the indications, the disease stage, physical condition, willingness, adverse reactions, and quality of life should be fully considered, and overtreatment or undertreatment should be avoided. If the performance status is ≤ 2 and important organs can be tolerated, chemotherapy can be given. Common drugs include platinum (cisplatin, carboplatin), gemcitabine, pemetrexed, taxanes (paclitaxel, docetaxel), vinorelbine, etoposide, and camptothecin analogs (irinotecan). Currently, two-drug combination therapy containing platinum is recommended for first-line chemotherapy, and docetaxel or pemetrexed monotherapy is recommended for second-line chemotherapy. Generally, the efficacy is evaluated after 2 courses of treatment, adverse reactions should be closely monitored and prevented, and the drug and/or dose are adjusted if needed.

Targeted therapy targets the driver gene variations in tumor tissues or cells and the specific molecules of tumor-related signaling pathways, specifically blocks the biological functions of these targets with molecular targeted drugs, and selectively reverses the malignant biological behaviors of tumor cells at the molecular level, thereby achieving the goal of inhibition of tumor growth or even promotion of tumor regression. Currently, targeted therapy is mainly applied to patients with adenocarcinoma in non-small cell lung cancer. For example, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) targeting positive EGFR mutation such as erlotinib, gefitinib, afatinib, osimertinib, and almonertinib; medications targeting positive ALK rearrangement such as crizotinib, alectinib, ceritinib, loratinib, and ensartinib; medications targeting positive ROS1 rearrangement such as crizotinib and entrectinib; medication targeting MET exon 14 skipping mutation glumetinib; medications targeting positive BRAF V600 mutation such as dabrafenib and trametinib; and medication targeting positive RET fusion gene selpercatinib can be used for first-line treatment or maintenance treatment after chemotherapy, and has a significant therapeutic effect on locally advanced and metastatic NSCLC that is not suitable for radical treatment, which can prolong the survival of patients. The key to success of targeted therapy is selection of specific target populations.

Furthermore, angiogenesis is one of the most important characteristics of malignant tumors. The signaling pathway mediated by the binding of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) can control the proliferation, survival, and migration of vascular endothelial cells, ultimately leading to angiogenesis. The occurrence, development, and metastasis of tumors all depend on angiogenesis, and anti-VEGF therapy can effectively inhibit tumor growth and prevent its metastasis. Targeted anti-angiogenesis is one of the effective approaches for treatment of lung cancer. Currently, angiogenesis inhibitors targeting the VEGF pathway mainly include VEGF monoclonal antibodies (bevacizumab), VEGFR monoclonal antibodies (ramucirumab), and VEGFR tyrosine kinase inhibitors (sorafenib, anlotinib, nintedanib, apatinib, and regorafenib). Recent studies suggest that anti-angiogenesis therapy alone or in combination with chemotherapy, targeted therapy, and immunotherapy has achieved significant efficacy in advanced lung cancer. Bevacizumab in combination with chemotherapy can significantly improve the chemotherapy effect of advanced NSCLC and prolong the median progression time of tumors. Anlotinib is an orally administered, novel, small-molecule, multi-target tyrosine kinase inhibitor, has dual functions of anti-angiogenesis and inhibition of tumor growth, and can significantly prolong the median progression-free time and survival time in advanced NSCLC patients. Immune checkpoint inhibitors (ICIs) with monoclonal antibodies targeting the immune checkpoint PD-(L)1 can inhibit the binding of PD-1 to PD-L1 on the surface of tumor cells, generating a series of anti-tumor immune effects, thereby achieving the anti-tumor effect. In recent years, ICIs have brought significant breakthroughs in the treatment of advanced driver gene-negative NSCLC, and 5-year survival rate of patients has increased from 5% in the chemotherapy era to 13.4% - 23.2%. ICIs have been the standard treatment for advanced NSCLC. Common immune checkpoint inhibitors include pembrolizumab, atezolizumab, camrelizumab, sintilimab, tislelizumab, sugemalimab, toripalimab, and adebrelimab.

NSCLC

NSCLC has poor response to chemotherapy. In patients with advanced and recurrent NSCLC, combination chemotherapy can relieve symptoms, improve the quality of life, and improve survival. There are partial remission rate of 30% - 40%, complete remission rate of nearly 5%, median survival of 9 - 10 months, and one-year survival rate of 30% - 40%. Currently, first-line chemotherapy is two-drug chemotherapy containing platinum (carboplatin or cisplatin plus paclitaxel, vinorelbine, gemcitabine, pemetrexed, or docetaxel) for 4 - 6 cycles. In patients with tumor remission or stable condition without progression after chemotherapy, maintenance treatment can be given. In patients with failed first-line treatment, docetaxel or pemetrexed monotherapy is recommended as a second-line chemotherapy. In patients with stage IV NSCLC and positive EGFR mutation, first-line EGFR-TKIs (osimertinib, almonertinib, erlotinib, gefitinib, and afatinib) have better treatment response and progression-free survival (PFS) than first-line platinum-containing two-drug chemotherapy, have lower toxicity, and can also be used for second-line or third-line oral treatment when chemotherapy is ineffective. If there is drug resistance (generally 9 - 13 months after treatment) or disease progression, caused by T790M mutation, osimertinib, almonertinib, and furmonertinib can be used. In patients with positive ALK and ROS1 rearrangement, ALK inhibitors such as crizotinib and ceritinib can be selected for treatment. In stage IV non-squamous cell carcinoma, if patients have no hemoptysis and brain metastasis, anti-tumor vascular drugs, such as bevacizumab, in combination with chemotherapy can be considered. If PD-L1 is highly expressed (≥50%) in NSCLC patients with negative driver genes, the benefit from immune checkpoint inhibitor treatment is more obvious, and single-agent immunotherapy can also be used.

SCLC

SCLC is very sensitive to chemotherapy, which is the basic treatment option. First-line chemotherapy regimen includes etoposide or irinotecan in combination with cisplatin or carboplatin for 4 - 6 cycles. Adjuvant chemotherapy is recommended for patients with surgical resection. In localized SCLC (stage II and III), comprehensive treatment, mainly radiotherapy and chemotherapy, is recommended. In patients with extensive SCLC, comprehensive treatment, mainly chemotherapy, including etoposide + carboplatin + atezolizumab, etoposide + platinum + durvalumab, etoposide + platinum + adebrelimab, and etoposide + platinum + serplulimab, can be given. In patients with extensive SCLC and brain metastases, chemotherapy can be given before or after whole brain radiotherapy, depending on whether patients have neurological symptoms. Most localized and almost all extensive SCLC can relapse. In patients with recurrent SCLC, second-line chemotherapy or first-line treatment can be selected according to the type of recurrence.

Radiotherapy

Radiotherapy can be divided into radical radiotherapy, palliative radiotherapy, adjuvant radiotherapy, neoadjuvant chemoradiotherapy, and preventive radiotherapy. Radical radiotherapy is used for patients with localized lesions, who are inconvenient to undergo surgery due to anatomical reasons or other reasons; If in combination with chemotherapy, the efficacy can be improved. Palliative radiotherapy inhibits the development of tumor, delays tumor extension, and relieves symptoms; has positive effect on intractable cough, hemoptysis, atelectasis, and superior vena cava syndrome caused by lung cancer; and can also relieve bone metastasis pain and symptoms caused by brain metastasis. Adjuvant radiotherapy is indicated in patients who have received preoperative radiotherapy and positive surgical margins. Preventive radiotherapy is appropriate for whole brain radiotherapy in patients with effective systemic treatment of small cell lung cancer.

Radiotherapy is usually in combination with chemotherapy to treat lung cancer. Due to different staging, treatment purposes, and general conditions of patients, the combination regimen includes synchronous chemoradiotherapy and sequential chemoradiotherapy. Patients receiving chemoradiotherapy have increased potential toxicity and side effects, and attention should be paid to the protection of the lungs, heart, esophagus, and spinal cord. During treatment, unplanned interruptions of radiotherapy due to improper treatment of toxicity and side effects should be avoided.

The sensitivity of lung cancer to radiotherapy is highest in SCLC, followed by squamous cell carcinoma and adenocarcinoma, so the irradiation dose is smallest in SCLC and largest in adenocarcinoma. Generally, 40 - 70Gy is appropriate, and radiotherapy can be performed within 5 - 7 weeks. Common radiations include 60Co-γ, electron beam (β-irradiation)，and accelerator-based neutron. Attention should be paid to reduction and prevention of radiotherapy reactions such as leukopenia, radiation pneumonitis, and radiation esophagitis. Radiotherapy is contraindicated in patients with poor systemic conditions and severe insufficiency of heart, lung, liver, and kidney. Safer and advanced technologies, such as three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT), can be reasonably used during radiotherapy,

NSCLC

Radiotherapy is indicated in locally advanced patients, radical treatment of early NSCLC patients who cannot undergo surgery due to physical reasons, selective preoperative and postoperative adjuvant treatment, local recurrence and metastasis, and palliative treatment of incurable patients in the late stage.

SCLC

Radiotherapy is indicated in patients with high risk of intrathoracic recurrence and brain metastasis after systemic chemotherapy for localized SCLC and patients with extensive SCLC.

Interventional treatment

Bronchial arterial infusion chemotherapy is indicated in advanced patients who have lost surgical indications and are ineffective for systemic chemotherapy. This treatment has few toxicity and side effects, and can relieve symptoms and reduce pain.

Photoradiation therapy with hematoporphyrin derivative and YAG laser therapy can remove tumors in the airway, relieve airway obstruction, and control hemorrhage; and can prolong the survival.

Bronchoscopic intratumoural radiotherapy can relieve obstruction and hemoptysis.

Ultrasound-guided interventional therapy can directly inject anticancer drugs into tumor tissue.

Prevention

Lung cancer prevention includes three levels of preventive measures.

Primary prevention is etiological prevention, including enhancement of the resistance to cancer and removal of various carcinogenic and cancer-promoting factors, such as smoking cessation, improvement of air pollution, maintenance of healthy diet, avoidance of overexertion, departure from harmful environments, and change of unhealthy lifestyle.

Secondary prevention is preclinical prevention. The treatment and prognosis of lung cancer depend on early diagnosis and prompt treatment, and early detection of high-risk populations is particularly important. Screening for early diagnosis and treatment of lung cancer in high-risk populations is necessary, and screening has been a method to reduction of mortality. Compared to chest X-ray low-dose computed tomography (LDCT) used in screening in high-risk populations reduces mortality by 20%.

Tertiary prevention is clinical prevention and rehabilitation. Its goal is to reduce complications in cancer patients, prevent disease progression, avoid disability, and improve the quality of life.

All three levels of prevention are essential and interconnected, constituting the entirety of prevention of lung tumors.

Prognosis

The prognosis of lung cancer depends on early detection, diagnosis, and treatment. Insufficient early diagnosis results in poor prognosis, and 86% of patients die within 5 years after diagnosis. Only 15% of patients have localized lesions when diagnosis is established, and 5-year survival of these patients can reach 50%.