Lung cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2];Kim-Son H. Nguyen M.D.;Saarah T. Alkhairy M.D;Cafer Zorkun, M.D., Ph.D. [3]

Prior to the introduction of cigarette smoking and industrial carcinogens, lung cancer was thought to be a rare disease. Of all the tumors detected on autopsy, lung cancer accounted for only 1% of cancers in the 1800s. The majority of cases of lung cancer were associated with occupational hazards due to radon exposure. The association between lung cancer and smoking was not defined until the mid-20th century. Primary lung cancers may be classified into small cell lung cancer (~15%) and non small cell lung cancer (~85%). Non small cell lung cancer are a heterogeneous group of lung cancers that are often grouped together because they share similar clinical features (e.g. prognosis and management). The 2015 WHO histological classification of tumors of the lung categorized lung tumors into malignant epithelial tumors, benign epithelial tumors, lymphoproliferative tumors, miscellaneous tumors, and metastatic tumors. The pathophysiology of lung cancer includes both genetic and environmental factors. Causality of the majority of lung cancer is linked to tobacco usage. Carcinogenic effects of tobacco smoking may result in DNA mis-replication and mutation. Smoking starts a cascade of events that leads to cancer development, even decades after smoking cessation. Besides smokers, patients with the history of prior respiratory tract or gastrointestinal tract cancer comprise a high-risk population. Other environmental factors include radon, asbestos, viral infections, and states of chronic lung inflammation, all of which may predispose to cellular damage and DNA mutations that predispose to the development of lung cancers. The direct cause of lung cancer is DNA mutations that often result in either activation of proto-oncogenes (e.g. K-RAS) or the inactivation of tumors suppressor genes (e.g. TP53) or both. The risk of these genetic mutations may be increased following exposure to environmental insults. Lung cancer must be differentiated from other conditions that cause hemoptysis, cough, dyspnea, wheezing, chest pain, dysphonia, dysphagia, unexplained weight loss, unexplained loss of appetite, and fatigue. These conditions include pneumonia, bronchitis, metastatic cancer from a non-thoracic primary site, infectious granuloma, pulmonary tuberculosis, tracheal tumors, and a thyroid mass. Lung cancer is the most common cause of cancer-associated mortality and the second most common type of cancer among both genders. Individuals > 50 years of age who have a history of smoking are at increased risk. Historically, the incidence of lung cancer is significantly higher among males compared to females. This increased ratio is thought to be attributed to the increased rates of smoking among men. However, more women are being diagnosed with lung cancer due to the increased rate of smoking among women. In 2014, the incidence of lung cancer in the United States was approximately 70 cases per 100,000. The most potent risk factor in the development of lung cancer is tobacco smoking. Other risk factors include second hand smoke, air pollution, family history of lung cancer, radiation therapy to the chest, and exposure to radon, asbestos and other chemical carcinogens. Lung cancer screening is a strategy used to identify early lung cancer in people, before they develop symptoms. Screening refers to the use of medical tests to detect disease in asymptomatic people. Screening studies for lung cancer have only been done in high risk populations, such as smokers and workers with occupational exposure to certain substances. This is because radiation exposure from screening could actually induce carcinogenesis in a small percentage of screened subjects, so this risk should be mitigated by a (relatively) high prevalence of lung cancer in the population being screened. A pulmonary nodule larger than 5 – 6 mm is considered a positive result for screening with x-ray or computed tomography. The majority of lung cancers present with advanced disease because the symptoms tend to occur later in the course of the disease. Patients experience non-specific symptoms such as cough, hemoptysis, dyspnea, chest pain, difficulty speaking, difficulty swallowing, lack of appetite, weight loss, and fatigue from 3 weeks to 3 months before seeking medical attention. There are a variety of complications associated with lung cancer, such as pleural effusion, leg weakness, paresthesias, bladder dysfunction, seizures, hemiplegia, cranial nerve palsies, confusion, personality changes, skeletal pain, pleuritic pain, atelectasis, and bronchopleural fistula. The prognosis of lung cancer is poor if diagnosed at the advanced stages. Chest CT scan is the modality of choice in the diagnosis of lung cancer. Findings on CT scan suggestive of lung cancer include a solitary pulmonary nodule, centrally located masses, mediastinal invasion CT scans help stage the lung cancer. A CT scan of the abdomen and brain can help visualize the common sights of metastases such as adrenal glands, liver, and brain. CT scans diagnose lung cancer by providing anatomical detail to locate the tumor, demonstrating proximity to the nearby structures, and deciphering whether lymph nodes are enlarged in the mediastinum. Common symptoms of lung cancer include difficulty breathing, hemoptysis, chronic coughing, chest pain, weakness and wasting, difficulty speaking, and symptoms related to paraneoplastic syndromes. Common physical examination findings of lung cancer include decreased/absent breath sounds, pallor, low-grade fever, and tachypnea. The laboratory findings associated with lung cancer are the following neutropenia, hyponatremia, hypokalemia, hypercalcemia, respiratory acidosis, hypercarbia, hypoxia, and tumor cells in sputum and pleural effusion cytology. Performing a chest x-ray is the first step if a patient reports symptoms that may be suggestive of lung cancer. Lung cancers are usually detected on a routine chest x-ray in a person experiencing no symptoms. There are no echocardiography/ultrasound findings associated with lung cancer. Chest CT scan is the modality of choice in the diagnosis of lung cancer. Findings on CT scan suggestive of lung cancer include a solitary pulmonary nodule, centrally located masses, mediastinal invasion CT scans help stage the lung cancer. A CT scan of the abdomen and brain can help visualize the common sights of metastases such as adrenal glands, liver, and brain. CT scans diagnose lung cancer by providing anatomical detail to locate the tumor, demonstrating proximity to the nearby structures, and deciphering whether lymph nodes are enlarged in the mediastinum. The indication of MRI in lung cancer is when there is a suspicion of spinal cord canal invasion and/or in the presence of pancoast tumor (superior sulcus tumor) and brachial plexus tumors. There are no other imaging findings associated with lung cancer. Other diagnostic studies include bone scintigraphy, PET scan, and molecular tests. Medical therapy for lung cancer consists of radiation therapy, chemotherapy, and targeted therapy. Lung cancer surgery involves the surgical excision of the cancerous tissue. It is used mainly in non-small cell lung cancer with the intention of curing the patient. Effective measures for the primary prevention of lung cancer include smoking cessation and avoidance of second hand smoking. Lifestyle changes, such as healthy diet rich with fruits and vegetables and regular exercise, might decrease the risk of developing cancer in general. Secondary prevention of lung cancer consists of smoking cessation and screening. Secondary chemoprevention focuses on blocking the development of lung cancer in individuals in whom a precancerous lesion has been detected.

Prior to the introduction of cigarette smoking and industrial carcinogens, lung cancer was thought to be a rare disease. Of all the tumors detected on autopsy, lung cancer accounted for only 1% of cancers in the 1800s. The majority of cases of lung cancer were associated with occupational hazards due to radon exposure. The association between lung cancer and smoking was not defined until the mid-20th century.

Primary lung cancers may be classified into small cell lung cancer (~15%) and non small cell lung cancer (~85%). Non small cell lung cancer are a heterogeneous group of lung cancers that are often grouped together because they share similar clinical features (e.g. prognosis and management). The 2015 WHO histological classification of tumors of the lung categorized lung tumors into malignant epithelial tumors, benign epithelial tumors, lymphoproliferative tumors, miscellaneous tumors, and metastatic tumors.

The pathophysiology of lung cancer includes both genetic and environmental factors. Causality of the majority of lung cancer is linked to tobacco usage. Carcinogenic effects of tobacco smoking may result in DNA mis-replication and mutation. Smoking starts a cascade of events that leads to cancer development, even decades after smoking cessation. Besides smokers, patients with the history of prior respiratory tract or gastrointestinal tract cancer comprise a high-risk population. Other environmental factors include radon, asbestos, viral infections, and states of chronic lung inflammation, all of which may predispose to cellular damage and DNA mutations that predispose to the development of lung cancers.

The direct cause of lung cancer is DNA mutations that often result in either activation of proto-oncogenes (e.g. K-RAS) or the inactivation of tumors suppressor genes (e.g. TP53) or both. The risk of these genetic mutations may be increased following exposure to environmental insults.

Lung cancer must be differentiated from other conditions that cause hemoptysis, cough, dyspnea, wheezing, chest pain, dysphonia, dysphagia, unexplained weight loss, unexplained loss of appetite, and fatigue. These conditions include pneumonia, bronchitis, metastatic cancer from a non-thoracic primary site, infectious granuloma, pulmonary tuberculosis, tracheal tumors, and a thyroid mass.

Lung cancer is the most common cause of cancer-associated mortality and the second most common type of cancer among both genders. Individuals > 50 years of age who have a history of smoking are at increased risk. Historically, the incidence of lung cancer is significantly higher among males compared to females. This increased ratio is thought to be attributed to the increased rates of smoking among men. However, more women are being diagnosed with lung cancer due to the increased rate of smoking among women. In 2014, the incidence of lung cancer in the United States was approximately 70 cases per 100,000.

The most potent risk factor in the development of lung cancer is tobacco smoking. Other risk factors include second hand smoke, air pollution, family history of lung cancer, radiation therapy to the chest, and exposure to radon, asbestos and other chemical carcinogens.

Lung cancer screening is a strategy used to identify early lung cancer in people, before they develop symptoms. Screening refers to the use of medical tests to detect disease in asymptomatic people. Screening studies for lung cancer have only been done in high risk populations, such as smokers and workers with occupational exposure to certain substances. This is because radiation exposure from screening could actually induce carcinogenesis in a small percentage of screened subjects, so this risk should be mitigated by a (relatively) high prevalence of lung cancer in the population being screened. A pulmonary nodule larger than 5 – 6 mm is considered a positive result for screening with x-ray or computed tomography.

The majority of lung cancers present with advanced disease because the symptoms tend to occur later in the course of the disease. Patients experience non-specific symptoms such as cough, hemoptysis, dyspnea, chest pain, difficulty speaking, difficulty swallowing, lack of appetite, weight loss, and fatigue from 3 weeks to 3 months before seeking medical attention. There are a variety of complications associated with lung cancer, such as pleural effusion, leg weakness, paresthesias, bladder dysfunction, seizures, hemiplegia, cranial nerve palsies, confusion, personality changes, skeletal pain, pleuritic pain, atelectasis, and bronchopleural fistula. The prognosis of lung cancer is poor if diagnosed at the advanced stages.

Chest CT scan is the modality of choice in the diagnosis of lung cancer. Findings on CT scan suggestive of lung cancer include a solitary pulmonary nodule, centrally located masses, mediastinal invasion CT scans help stage the lung cancer. A CT scan of the abdomen and brain can help visualize the common sights of metastases such as adrenal glands, liver, and brain. CT scans diagnose lung cancer by providing anatomical detail to locate the tumor, demonstrating proximity to the nearby structures, and deciphering whether lymph nodes are enlarged in the mediastinum.

Common symptoms of lung cancer include difficulty breathing, hemoptysis, chronic coughing, chest pain, weakness and wasting, difficulty speaking, and symptoms related to paraneoplastic syndromes.

Common physical examination findings of lung cancer include decreased/absent breath sounds, pallor, low-grade fever, and tachypnea.

Chest CT scan is the modality of choice in the diagnosis of lung cancer. Findings on CT scan suggestive of lung cancer include, a solitary pulmonary nodule, centrally located masses, mediastinal invasion. A CT scan of the abdomen and brain can help visualize the common sites of metastases: adrenal glands, liver, and brain. CT scans diagnose lung cancer by providing anatomical detail to locate the tumor, demonstrating proximity to nearby structures, and deciphering whether lymph nodes are enlarged in the mediastinum.

The laboratory findings associated with lung cancer are the following neutropenia, hyponatremia, hypokalemia, hypercalcemia, respiratory acidosis, hypercarbia, hypoxia, and tumor cells in sputum and pleural effusion cytology.

ECG is a simple method for finding evidence of pulmonary artery stenosis in metastatic lung cancer and should be routinely performed in such patients. Findings on ECG associated mediastinal metastatic of lung cancer led to pulmonary artery stenosis and right ventricular strain include right axis deviation, deepened S wave in lead 1, sustantial R wave in lead avR, inverted/flattened T waves in limb and precordial leads.

Performing a chest x-ray is the first step if a patient reports symptoms that may be suggestive of lung cancer. Lung cancers are usually detected on a routine chest x-ray in a person experiencing no symptoms.

There are no echocardiography/ultrasound findings associated with lung cancer.

Chest CT scan is the modality of choice in the diagnosis of lung cancer. Findings on CT scan suggestive of lung cancer include a solitary pulmonary nodule, centrally located masses, mediastinal invasion CT scans help stage the lung cancer. A CT scan of the abdomen and brain can help visualize the common sights of metastases such as adrenal glands, liver, and brain. CT scans diagnose lung cancer by providing anatomical detail to locate the tumor, demonstrating proximity to the nearby structures, and deciphering whether lymph nodes are enlarged in the mediastinum.

The indication of MRI in lung cancer is when there is a suspicion of spinal cord canal invasion and/or in the presence of pancoast tumor (superior sulcus tumor) and brachial plexus tumors.

There are no other imaging findings associated with lung cancer.

Other diagnostic studies include bone scintigraphy, PET scan, and molecular tests.

Medical therapy for lung cancer consists of radiation therapy, chemotherapy, and targeted therapy.

Lung cancer surgery involves the surgical excision of the cancerous tissue. It is used mainly in non-small cell lung cancer with the intention of curing the patient.

Effective measures for the primary prevention of lung cancer include smoking cessation and avoidance of second hand smoking. Lifestyle changes, such as healthy diet rich with fruits and vegetables and regular exercise, might decrease the risk of developing cancer in general.

Secondary prevention of lung cancer consists of smoking cessation and screening. Secondary chemoprevention focuses on blocking the development of lung cancer in individuals in whom a precancerous lesion has been detected.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2] Yazan Daaboul, M.D.

Prior to the introduction of cigarette smoking and industrial carcinogens, lung cancer was thought to be a rare disease. Of all the tumors detected on autopsy, lung cancer accounted for only 1% of cancers in the 1800s. The majority of cases of lung cancer were associated with occupational hazards due to radon exposure. The association between lung cancer and smoking was not defined until the mid-20th century.

• The historical data on lung cancer is described below:^{[1][2][3][4][5][6][7][8]}
• The majority of cases of lung cancer were associated with occupational hazards. Death among miners was reported to be caused by Bergkrankheit (mountain sickness).
• During World War 1, cigarette smoking gained popularity because the soldiers used to smoke in trenches to relieve stress, so did the civilians and the women at home. General John J. (“Black Jack”) Pershing reportedly stated: “You ask me what it is we need to win this war. I answer tobacco as much as bullets.”
• In 1924, radon gas was first reported to be a prominent cause of lung cancer among miners.
• In 1929, Fritz Lickint, a German physician, published a paper and suggested that lung cancer patients were likely to be smokers.
• In 1929, Fritz Lickint launched an anti-tobacco campaign in Germany.
• In the 1930s, clinicians started suspecting the association between cigarette smoking and lung cancer due to an increased number of cases.
• The association between lung cancer and smoking was not defined until the mid-20th century. The first reports between lung cancer and smoking were often confounded by gender, given that men were more likely to be smokers compared to women.
• In the 1950s, Doll and Hill in England provided additional corroboration for a causal association between smoking and lung cancer.
• In the 1950s, Cuyler Hammond and Ernest Wynder in the U.S provided additional corroboration for a causal association between smoking and lung cancer.
• In 1961, the first case of adenocarcinoma of the lung was reported.
• The 1969, Springer Handbook of Special Pathology is considered to be the landmark publication that highlighted the role of smoking in the development of lung cancer in over 25 pages.
• In 1969, the first surgeon general warning suggesting cigarette smoking to be a hazard for lung cancer was issued.
• In the 1980s, cisplatin-based chemotherapy emerged and demonstrated modest efficacy in the reduction of tumor related symptoms and the improvement of quality of life.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kim-Son H. Nguyen M.D. Cafer Zorkun, M.D., Ph.D. [2] Rim Halaby, M.D. [3] Dildar Hussain, MBBS [4]

Primary lung cancers may be classified into small cell lung cancer (~15%) and non small cell lung cancer (~85%). Non small cell lung cancer are a heterogeneous group of lung cancers that are often grouped together because they share similar clinical features (e.g. prognosis and management). The 2015 WHO histological classification of tumors of the lung categorized lung tumors into malignant epithelial tumors, benign epithelial tumors, lymphoproliferative tumors, miscellaneous tumors, and metastatic tumors.

Primary lung cancers may be classified into two main categories:^[1]

• Small cell lung cancer (~15%)
• Non small cell lung cancer (~85%).

Lung Cancer

Small cell lung cancer (~15%)

Non small cell lung cancer (~85%) Squamous cell carcinoma (25% of lung cancers) Adenocarcinoma (40% of lung cancers). Large cell carcinoma (10% of lung cancers) Other non-small cell lung carcinomas: Adenosquamous carcinoma Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements Carcinoid tumor Lung carcinoma of salivary gland type Unclassified carcinoma

The World Health Organization (WHO) classifies tumors of the lungs as follows:^[1][2]

WHO Classification of Lung Tumors
Histological type	Subtype
Epithelial tumors
Adenocarcinoma	Lepidic adenocarcinoma Acinar adenocarcinoma Papillary adenocarcinoma Micropapillary adenocarcinoma Solid adenocarcinoma Invasive mucinous adenocarcinoma Mixed invasive mucinous Nonmucinous adenocarcinoma Colloid adenocarcinoma Fetal adenocarcinoma Enteric adenocarcinoma Minimally invasive adenocarcinoma Nonmucinous Mucinous Pre-invasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ Nonmucinous Mucinous
Squamous cell carcinoma	Keratinizing squamous cell carcinoma Nonkeratinizing squamous cell carcinoma Basaloid squamous cell carcinoma Pre-invasive lesion Squamous cell carcinoma in situ
Neuroendocrine tumors
Small cell carcinoma	Combined small cell carcinoma
Large cell neuroendocrine carcinoma	Combined large cell neuroendocrine carcinoma
Carcinoid tumors	Typical carcinoid tumor Atypical carcinoid tumor
Pre-invasive lesion	Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Large cell carcinoma	N/A
Adenosquamous carcinoma	N/A
Sarcomatoid carcinomas	Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma
Other and Unclassified carcinomas	Lymphoepithelioma-like carcinoma NUT carcinoma
Salivary gland-type tumors	Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial–myoepithelial carcinoma Pleomorphic adenoma
Papillomas	Squamous cell papilloma Exophytic Inverted Glandular papilloma Mixed squamous and glandular papilloma
Adenomas	Sclerosing pneumocytoma Alveolar adenoma Papillary adenoma Mucinous cystadenoma Mucous gland adenoma
Mesenchymal tumors
Pulmonary hamartoma	N/A
Chondroma	N/A
PEComatous tumors	Lymphangioleiomyomatosis PEComa (benign) Clear cell tumor PEComa (malignant)
Congenital peribronchial myofibroblastic tumor	N/A
Diffuse pulmonary lymphangiomatosis	N/A
Inflammatory myofibroblastic tumor	N/A
Epithelioid hemangioendothelioma	N/A
Pleuropulmonary blastoma	N/A
Synovial sarcoma	N/A
Pulmonary artery intimal sarcoma	N/A
Pulmonary myxoid sarcoma with EWSR1–CREB1 translocation	N/A
Myoepithelial tumors	Myoepithelioma Myoepithelial carcinoma
Lymphohistiocytic tumors
Extranodal marginal zone lymphomas of mucosa-associated Lymphoid tissue (MALT lymphoma)	N/A
Diffuse large cell lymphoma	N/A
Lymphomatoid granulomatosis	N/A
Intravascular large B cell lymphoma	N/A
Pulmonary Langerhans cell histiocytosis	N/A
Erdheim-Chester disease	N/A
Tumors of ectopic origin
Germ cell tumors	Mature teratoma Immature teratoma
Intrapulmonary thymoma	N/A
Melanoma	N/A
Meningioma, NOS	N/A

• Adenocarcinoma is the most common histologic subtype in nonsmoking individuals, accounting for approximately 60%–80% of cases.
• Squamous cell carcinoma represents about 17% of lung cancers in nonsmokers.
• Small cell lung cancer is uncommon in nonsmoking individuals, comprising fewer than 10% of cases.
• Lung cancers in nonsmoking individuals more frequently contain actionable oncogenic alterations.

• EGFR mutations and ALK rearrangements are particularly enriched in tumors from nonsmoking individuals.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kim-Son H. Nguyen M.D. Cafer Zorkun, M.D., Ph.D. [2] Dildar Hussain, MBBS [3] Michael Maddaleni, B.S.

The pathophysiology of lung cancer includes both genetic and environmental factors. Causality of the majority of lung cancer is linked to tobacco usage. Carcinogenic effects of tobacco smoking may result in DNA mis-replication and mutation. Smoking starts a cascade of events that leads to cancer development, even decades after smoking cessation. Besides smokers, patients with the history of prior respiratory tract or gastrointestinal tract cancer comprise a high-risk population. Other environmental factors include radon, asbestos, viral infections, and states of chronic lung inflammation, all of which may predispose to cellular damage and DNA mutations that predispose to the development of lung cancers.

The pathophysiology of lung cancer includes both genetic and environmental factors.^[1][2][3]

• Lung cancer consists of several histological types.
• Main histological types of lung cancer include:
  • Small cell lung cancer
  • Non small cell lung cancer
    • Adenocarcinoma of the lung
    • Squamous cell carcinoma of the lung
    • Large cell carcinoma of the lung
    • Sarcomatoid carcinoma of the lung
• Smoking starts a cascade of events that leads to cancer.

• Lung cancer pathogenesis can be understood with the help of the following hypothesis:

• • 6q23–25 locus has been identified as a susceptibility gene for familial lung cancer.

• • Tumors of organs such as skin, lung and colon are developed through a process called multistep tumorigenesis.
  • As with other epithelial malignancies, lung cancers are believed to arise from preneoplastic or precursor lesions in the respiratory mucosa.
  • Multistep tumorigenesis is the development of tumor through a series of progressive pathologic events such as preneoplastic or precursor lesions with corresponding genetic and epigenetic aberrations.
  • Hyperplasia, squamous metaplasia, squamous dysplasia, and carcinoma in situ (CIS) comprise changes in the large airways that precede or accompany invasive squamous cell carcinoma of the lung.^[4]
  • Multistep tumorigenesis explains pathogenesis of centrally located squamous cell carcinoma of the lung very well but fails to explain the pathogenesis of large cell lung carcinomas, lung adenocarcinomas, and small cell lung cancer.

• • Another theory on the pathogenesis of lung cancer is the accumulation of molecular abnormalities beyond a certain threshold point, rather than the sequence of alterations.
  • There are no known preneoplastic lesions for the most common type of neuroendocrine lung tumors, small cell carcinoma of the lung,
  • Atypical adenomatous hyperplasia (AAH) is the only sequence of morphologic change identified leading to the development of invasive adenocarcinoma of the lung.
• Pathogenesis of lung cancer is thought to be result of both due to stepwise, sequence-specific and multistage molecular pathogenesis and due to accumulation and combination of genetic and epigenetic abnormalities.

• Preneoplastic lung lesions frequently extend throughout the respiratory epithelium, indicating a field effect in which much of the respiratory epithelium has been mutagenized, presumably from exposure to tobacco-related carcinogens.^[5][6][7]
• Epithelial cells lining the entire respiratory tract that have been exposed to smoking show molecular alterations that may signify the onset of lung cancer, a paradigm known as the “airway field of injury”.
• Premalignant airway fields in the molecular pathogenesis of lung cancer:
  • Smoking induces widespread molecular alterations, such as gene expression changes in exposed epithelia throughout the respiratory tract.
  • The airway field of injury can be seen in smokers with or without lung cancer and is highly relevant for the identification of markers for minimally invasive and early detection of lung cancer.
  • The adjacent airway field of carcinoma represents the field in normal appearing airways adjacent to lung tumors.
  • It has been suggested that in this adjacent field of tumor, there is closer molecular genealogy between lung cancers and airways that are in closest proximity to the tumors compared to airways that are more distant from the tumors.
  • The progression of the molecular airway field of injury to preneoplasia and lung malignancy is still not clear.
  • Molecular changes involved in the development of the airway field of injury and changes mediating progression of this field to lung preneoplasia may help the identification of early markers for lung cancer detection and chemoprevention.

• Lung cancer development is initiated by the activation of oncogenes or inactivation of tumor suppressor genes.^[8]
• Mutations in the K-ras proto-oncogene are responsible for 20% to 30% of non-small cell lung cancer cases.^[9][10]
• Chromosomal damage may also result in the loss of heterozygosity, which subsequently leads to the inactivation of tumor suppressor genes.
• Damage to the following chromosomes are particularly common in small cell lung carcinoma:
  • Chromosome 3p
  • Chromosome 5q
  • Chromosome 13q
  • Chromosome 17p
• The TP53 tumor suppressor gene, located on chromosome 17p, is often mutated in lung cancers.^[11]
• Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for:^{[12][13][14][15]}
  • Interleukin-1
  • Cytochrome P450
  • Caspase-8, an apoptosis promoter
  • XRCC1, a DNA repair molecule
• Individuals with these polymorphisms are thought to be more likely to develop lung cancer following exposure to carcinogens.

Although genetics play a significant role in the pathogenesis of lung cancer, it is thought that exposure to environmental risk factors plays an equally important role in the development of lung cancer. The main causes of lung cancer include carcinogens (such as those present in tobacco smoke), ionizing radiation, and viral infections. Chronic exposure results in cumulative alterations to the DNA in the tissue lining the bronchi of the lungs (the bronchial epithelium). Irreversible DNA changes following exposure to carcinogens are directly associated with the development of lung cancer.^[16]

• Cigarette smoking is a leading cause of lung cancer.^{[17][18][19][20][21][22][23][24][25][26]}
• Cigarette smoke contains over 60 known carcinogens including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene.
• Nicotine is thought to reduce the immune response to malignant growths in the exposed tissue. The length of time an individual smokes, as well as the amount, significantly increases the person’s chance of developing lung cancer.
• Among individuals who stopped smoking, the risk of lung cancer steadily decreases as lung tissue repairs itself and as contaminant particles are eliminated from the lungs.
• It is thought that the risk of lung cancer among persons with a history of smoking (even when stopped) is always higher than those who never smoked.

The association of radon gas exposure to lung cancer is described below:^[27][28]

• Radon is a colorless and odorless gas generated by the breakdown of radioactive radium (decay product of uranium) found in the Earth’s crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous.
• Radon exposure is the second major cause of lung cancer following smoking.
• The mechanism of lung damage following radon exposure is not thought to be due to the radon gas itself, but due to the short-lived alpha decay products that cause cellular damage and DNA mutations.

• Asbestos exposure is associated with many lung diseases, including lung cancer.^[29]
• Tiny asbestos fibers released into the air are breathed into the lungs. The fibers become lodged in the lungs and are stuck for an indefinite amount of time. They can eventually lead to scarring and inflammation.

• Viruses known to be associated with the development of lung cancer in animals and humans include:^{[30][31][32][33][34][35]}
  • Human papillomavirus
  • JC virus
  • Simian virus 40 (SV40)
  • BK virus
  • Cytomegalovirus
  • HIV
• These viruses may affect the cell cycle and inhibit apoptosis, allowing uncontrolled cell division.
• HIV has also been thought to increase the risk of developing lung cancer. Although the mechanism is unknown, HIV is thought to be associated with a state of chronic lung inflammation that may potentiate cellular damage and DNA mutations.

• There may be a correlation between general inflammation of lung tissue and the development of lung cancer.^[35]
• Neutrophils are released in response to bacterial infection and are considered to be the initial responders during inflammation.
• The hypothesis is that neutrophils may activate reactive oxygen or nitrogen species, which can bind to DNA and lead to genomic alterations. Accordingly, inflammation may be thought of as an initiator or promoter of lung cancer development. Also, tissue repair from inflammation is associated with cellular proliferation. During cellular proliferation there may be errors in chromosomal replication that can cause further DNA mutation.
• Angiogenesis, a significant process during tumor growth, may be promoted by chronic states of inflammation, which often require increased blood flow to sites of inflammation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kim-Son H. Nguyen M.D. Cafer Zorkun, M.D., Ph.D. [2] Dildar Hussain, MBBS [3]

The direct cause of lung cancer is DNA mutations that often result in either activation of proto-oncogenes (e.g. K-RAS) or the inactivation of tumors suppressor genes (e.g. TP53) or both. The risk of these genetic mutations may be increased following exposure to environmental insults.

• The direct cause of lung cancer is DNA mutations that often result in either activation of proto-oncogenes (e.g. K-RAS) or the inactivation of tumors suppressor genes (e.g. TP53) or both.^[1][2]
• The risk of these genetic mutations may be increased following exposure to environmental insults, which are regarded as risk factors that predispose to the development of lung cancer.

• To view a comprehensive list of risk factors that increase the risk of lung cancer, click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2] , Eiman Ghaffarpasand, M.D. [3],

Lung cancer must be differentiated from other conditions that cause hemoptysis, cough, dyspnea, wheezing, chest pain, dysphonia, dysphagia, unexplained weight loss, unexplained loss of appetite, and fatigue. These conditions include pneumonia, bronchitis, metastatic cancer from a non-thoracic primary site, infectious granuloma, pulmonary tuberculosis, tracheal tumors, and a thyroid mass.

Abrevations: HPV: human papillomavirus; CEA: Carcino embryogenic antigen; TTF1: Thyroid transcription factor-1; EMA: Epithelial membrane antigen; CK: Cyto keratin; CD: Cluster differentiation; NCAM: Neural Cell Differentiation Molecule; MMP’s: Mettaloprotineases matrix ; GFAP: Glial fibrocilliary acid protein
Benign Lung Tumors[2]
Benign lung tumor			Risk/Epidemiology	Pleuripotent cells	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Papilloma[3]	Squamous cell papilloma		HPV 6 and 11 Men Median age of diagnosis is 54 years	Epithelial cells	Endobronchial	Cauliflower-like lesions Tan-white soft to semifirm protrutions	Loose fibrovascular core Stratified squamous epithelium Acanthosis Binucleate forms and perinuclear halos Koilocytosis	N/A	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
	Glandular papilloma		Rare Mean age of diagnosis is 68 years	Goblet cells of respiratory epithelium	Endobronchial	White to tan endobronchial polyps that measure from 0.7-1.5 cm	Thick arborizing stromal stalks Thin-walled blood vessels Non-ciliated or ciliated epithelium	N/A	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
Adenoma[4]	Alveolar adenoma		Mean age of diagnosis is 53 years Female predominance	Alveolar pneumocytes Septal mesenchyme	All lung lobes Lower lobes Hilar	0.7-6.0 cm Well demarcated smooth Lobulated, multicystic Soft to firm Pale yellow to tan cut surfaces	Non-encapsulated Multicystic masses Cuboidal cell linning Squamous metaplasia Myxoid and collagenous interstitium	Keratin CEA Surfactant protein TTF-1 Actin	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
	Papillary adenoma[5]		Mean age of diagnosis is 32 years Male predominance	Bronchioloalveolar cell	No lobar predilection Involves alveolar parenchyma	Well defined Encapsulated Soft, spongy to firm mass Granular gray white/ brown 1.0- 4.0 cm	Infiltration Papillary growth pattern Fibrovascular cores Cuboidal to columnar epithelial linning Cilitated and oxyphilic cells Occasional eosinophilic intranuclear inclusions	Cytokeratin Clara cell protein TTF-1 Surfactant apoprotein CEA	Incidental finding	N/A
	Mucinous cystadenoma		No sex predilection Mean age of diagnosis is 52 years	Mucus glands of the bronchus	Central	White-pink to tan Smooth and shiny tumors Gelatinous mucoid solid core 0.7-7.5 cm	Numerous mucin-filled cystic spaces Non-dilated microacini, glands, tubules and papillae	EMA Cytokeratins CEA	Coin lesion Air-meniscus sign	N/A
Malignant Lung Tumors[6]
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Squamous cell carcinoma (SCC)[7]	Papillary		Cigarette smokers Arsenic	Epithelial cells	Central	White or grey lesions Focal carbon pigment deposits Cavitations Intraluminal polypoid masses Infiltration	Exophytic Intra-epithelial Without invasion	Keratin Cytokeratins CEA Thyroid transcription factor-1 (TTF-1)	Lobar or entire lung collapse Shift of the mediastinum to the ipsilateral side Hilar, perihilar or mediastinal masses	Liver Breast Bone
	Clear cell						Cells with clear cytoplasm
	Basaloid						Peripheral palisading of nuclei. Poor differentiation
Small cell carcinoma[8]			Smoking Radon exposure	Bronchial precursor cell	Peripheral	White-tan, soft, friable perihilar masses Extensive necrosis 5% peripheral coin lesions	Sheet-like growth Nesting Trabeculae Peripheral palisading Rosette formation High mitotic rate	CD56 Chromogranin Synaptophysin TTF-1	Hilar or perihilar masses Mediastinal lymphadenopathy Lobar collapse	Bone marrow Liver
Adenocarcinoma[9][10][11]	Acinar adenocarcinoma		Smoking	Columnar cells of bronchioles	Peripheral	Single or multiple lesions Different in size Peripheral distribution Gray-white central fibrosis Pleural puckering Anthracotic pigmentation Necrosis Cavitation Hemorrhage Lobulated or ill defined edges	Irregular-shaped glands Malignant cells: Hyperchromatic nuclei Fibroblastic stroma	Epithelial markers CEA CK7 TTF-1	Peripheral nodules under 4.0 cm in size Central location as a hilar or perihilar mass Rarely show cavitations. Hilar adenopathy Adenocarcinomas account for the majority of small peripheral cancers identified radiologically.	Aerogenous spread is characteristic Brain Bone Adrenal glands Liver Kidney Gastrointestinal Tract
	Papillary adenocarcinoma						Papillae Necrosis Surrounding invasion Cuboidal to columnar epithelial linning Mucinous or non-mucinous
	Bronchio-alveolar carcinoma	Non-mucinous					Clara cells Type II cells
		Mucinous					Low grade differentiation Composed of: Tall columnar cells Basal nuclei Pale cytoplasm resembling goblet cells Varying amounts of cytoplasmic mucin Cytologic atypia
		Mixed non-mucinous and mucinous or indeterminate					Mixed type of cells Low to high grade differentiated cells.
	Solid adenocarcinoma with mucin production	Fetal adenocarcinoma					Consists glandular elements: Tubules of glycogen-rich Non-ciliated cells Subnuclear and supranuclear glycogen vacuoles Rounded morules of polygonal cells with abundant eosinophilic and finely granular cytoplasm
		Mucinous (“colloid”) carcinoma					Dissecting pools of mucin containing neoplastic cells
		Mucinous cystadenocarcinoma					Partial fibrous tissue capsule Central cystic change with mucin pooling Neoplastic mucinous epithelium grows along alveolar walls
		Signet ring adenocarcinoma					Focal Cells with nuclei displaced to sides Components of other cells are present.
		Clear cell adenocarcinoma					Clear cells with no nuclei
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Large cell carcinoma[12]	Basaloid large cell carcinoma of the lung		Approximately 10% of lung cancers Smoking	Neuro endocrine cells Suprabasal bronchial cells	Peripheral masses Bronchi	Soft, pink-tan tumor Necrosis and occasional hemorrhage Cavitations Exophytic bronchial growth	Invasive growth pattern Peripheral palisading Small, monomorphic, cuboidal fusiform	Chromogranin Synaptophysin CD56  Cytokeratin	Large, peripheral masses	Pleura Liver Bone Brain Abdominal lymph nodes Pericardium
	Clear cell carcinoma of the lung						Clear cells
	Lymphoepithelioma-like carcinoma of the lung						Syncytial growth pattern Eosinophilic nucleoli Lymphocytic infiltration Invasive Amyloid deposition
	Large-cell lung carcinoma with rhabdoid phenotype						Eosinophilic cytoplasmic globules Small foci of adenocarcinoma Eosinophilic inclusions
	Mixed type						Mixture of: Adenocarcinoma Squamous cell carcinoma Giant cell carcinoma Spindle cell carcinoma
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Sarcomatoid carcinoma[13]	Carcinosarcoma		Accounts for only 0.3-1.3% of all lung malignancies Mean age at diagnosis is 60 years Tobacco smoking Asbestos exposure	Undifferentiated epithelial cells	Central or peripheral Upper lobes	> 5 cm Well circumscribed Grey, yellow or tan creamy, gritty, Mucoid and/or hemorrhagic with significant necrosis Sessile or pedunculated Infiltrative	Biphasic Mixture of carcinomatous and sarcomatous cells	Keratin S-100	No specific imaging features	Aggressive tumor Esophagus, jejunum, and rectum Kidney
	Spindle cell carcinoma						Only spindle shaped tumor cells Lymphoplasmacytic infiltrates	Keratin EMA Cytokeratin Vimentin CEA TTF-1
	Giant cell carcinoma						Multi- and/or mononucleated tumor giant cells
	Pleomorphic carcinoma						Poorly differentiated Mixture of spindle cells and/or giant cells Fibrous or myxoid stroma
	Pulmonary blastoma						Biphasic Mixture of epithelial and mesenchymal stroma	Keratin EMA CEA Chromogranin A
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Carcinoid tumor[14]	Typical carcinoid Atypical carcinoid		Most common in males Mean age of diagnosis 45	Neuroendocrine cells of lung	Typical carcinoids are throughout the lungs Atypical carcinoid is more commonly peripheral	Firm, well demarcated, tan to yellow tumors	Uniform polygonal cells Nuclear atypia Pleomorphism The most common patterns are the organoid and trabecular Highly vascularized fibrovascular stroma Focal necrosis	Cytokeratin Chromogranin Synaptophysin CD57 CD56 S-100 protein	Well defined pulmonary nodules Calcifications is often seen. Intense contrast enhancement	Liver Bone
Salivary gland tumors[15]	Mucoepidermoid carcinoma		Most patients presents in the third and fourth decade Constitutes of less than 1% tumor No association with cigarette smoking or other risk factors	Primitive cells of tracheobronchial origin	Bronchial glands	Ranging in size from 0.5-6 cm Soft, polypoid, and pink-tan in colour High-grade lesions are infiltrative	Exophytic endobronchial growth Surface epithelium lacking changes of in-situ carcinoma Absence of individual cell keratinization Transitional areas to low grade mucoepidermoid carcinoma	GFAP	Well-circumscribed oval or lobulated mass Calcifications Post-obstructive pneumonic infiltrates	Rare Liver Bones Adrenal gland Brain
	Adenoid cystic carcinoma		Constitutes less than 1% of all lung tumors Most commonly seen in fourth and fifth decades of life	Primitive cells of tracheobronchial origin	Trachea	Gray-white or tan polypoid lesions Size ranges from 1–4 cm Infiltrative margins	Invades other cell layers Heterogeneous cellularity Cribriform pattern Perineural invasion	Immunoperoxidase Cytokeratin Vimentin Actin Calponin S-100 protein p53 GFAP	Well circumscribed Nodule	Liver Brain Bone Spleen Kidney Adrenal glands
	Epithelial-myoepithelial carcinoma		Age ranges from 33 to 71 years No association with smoking	Myoepithelial cells	Endobronchial	Solid to gelatinous in texture White to gray in colour	Myoepithelial cells Dual layer of cells lining ducts Low mitotic activity	MNF116 EMA SMA and S-100	Reflects airway obstruction	Breast
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Preinvasive lesions[16]	Squamous carcinoma in situ		Most commonly seen in fifth or sixth decades Mostly seen in women	Basal cells of squamous epithelium	Bronchi	Focal or multi-focal plaque-like greyish lesions Nonspecific erythema Even nodular or polypoid lesions	Goblet cell hyperplasia Basal cell hyperplasia Squamous dysplasia Angiogenic squamous dysplasia Micropapillomatosis	EGFR HER2/neu p53 MCM2 Ki-67 Cytokeratin 5/6 Bcl-2 VEGF Folate binding protein p16	Cauliflower like Mosaic pattern	Liver Brain Bone Spleen
	Atypical adenomatous hyperplasia			Surfactant apoprotein Clara cell specific 10kDd protein	Pleura Upper lobes	Multiple grey to yellow foci 1mm to 10mm in size	Intranuclear inclusions Clara cells and type II pneumocytes Thickened alveolar walls Discontinuous lining of cells Moderate atypia Pseudopapillae	CEA MMPs E-cadherin ß-catenin CD44v6 TTF-1 TP53	Typically not visualized on radiographs Small non-solid nodules Ground-glass opacity
	Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia			Pulmonary neuroendocrine cells	Endobronchial	Early lesions are: Small, gray-white nodules Resembling ‘miliary bodies’ Larger carcinoid tumors are: Firm Homogeneous Well-defined Grey or yellow-white masses	Nodular aggregates Fibrosis due to proliferation Invade locally Fibrous stroma aggregates to form ‘tumorlets’. Carcinoids are tumorlets >5cm.	Keratin CEA	Mosaic pattern of air trapping Sometimes with nodules Thickened bronchial and bronchiolar walls
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Mesenchymal tumors[17]	Epithelioid haemangioendothelioma / Angiosarcoma		Caucasian 80% are women	Endothelial cells	Intravascular	0.3-2.0 cm circumscribed mass Gray-white or gray-tan firm tissue Yellow flecks Central calcifications Cut surface has a cartilaginous consistency	Round to oval-shaped nodules Central sclerosis Hypocellular zone Peripheral cellular zone Calcifications Intranuclear cytoplasmic inclusions	CD31 CD34 Factor VIII (von Willebrand factor) Cytokeratin	Multiple Bilateral Small nodules 1-2 cm in size Can mimic pulmonary Langerhans’ cell histiocytosis. Calcifications	Liver Bone Soft tissue
	Pleuropulmonary blastoma		Most common in children Median age of diagnosis is 2 years	Thoracic splanchnopleural mesenchyme	Pleura Lung	Purely cystic Thin-walled Rarely solid Firm to gelatinous Upto 15 cm	Type I Purely cystic Lined by respiratory type epithelium Underneath malignant cells Type II Partial or complete overgrowth of the septal stroma Type III Mixed cells	Vimentin S-100 protein	Unilateral Localized airfilled cysts Septal thickening or an intracystic mass	Brain Spinal cord Skeletal system Eyes Pancreas
	Chondroma		Young women	Chondrocytes Cartilaginous cells	Peripheral lesions in lung Primary lesion seen in Stomach Bone Paraganglia	Peripheral Solid lesions Calcified	Capsulated lobules Hypocellular Features of malignancy are absent	N/A	Multiple Well circumscribed lesions “Pop-corn” calcifications	Benign in nature
	Congenital peribronchial myofibroblastic tumor		Rare Sporadic Complicated by Polyhydramnios Non-immune hydrops fetalis	Spindle cells	Along the bronchi	5-10 cm Well-circumscribed Non-encapsulated Smooth or multinodular surface The cut surface has a tann-grey to yellow-tan fleshy appearance Hemorrhage Necrosis	Fascicles of spindle cells Bronchial invasion Peribronchial distribution Cystic foci of hemorrhage	Vimentin	Well circumscribed Opaque hemithorax Heterogeneous mass	Rare
	Diffuse pulmonary lymphangiomatosis		Children Young adults of both sexes	Smooth muscle cells of lymphatic vessels	Along the lymphatic distribution	Prominence of the bronchovascular bundles along Pleura Interlobular pulmonary septa Mediastinum	Anastomosing endothelial-lined cells along lymphatic routes Spindle cells Intra alveolar siderophages	Vimentin	Increased interstitial markings Thickening of the: Interlobular septa Fissures Central airways Pleura	Skin Bone
	Inflammatory myofibroblastic tumor		Previous viral infections HHV8 Children	Myofibroblastic cells	Localized to bronchi	Solitary Round rubbery masses Yellowish-gray discoloration Average size of 3.0 cm Non-encapculated Calcifications No local invasion	Mixture of spindle cells Fibroblastic Myofibroblastic Arranged in fascicles Cytologic atypia Touton type giant cells Plasma cells Lymphoid follicles	Vimentin Actin p80	Solitary mass Regular borders Spiculated appearance Accompanied by Post-obstructive pneumonia Atelectasis	Rare
	Pulmonary artery sarcoma		Mean age of diagnosis is 49.3 years Commonly misdiagnosed as pulmonary embolism	Mesenchymal cells of the intima Primitive cells of the bulbus cordi in the trunk of pulmonary artery	Pulmonary trunk most commonly involving: Right pulmonary artery Left pulmonary artery Pulmonary valve Right ventricular outflow tract	Mucoid or gelatinous clots filling vascular lumens The cut surface may show Firm fibrotic areas Bony/gritty or chondromyxoid foci Hemorrhage and necrosis are common in high-grade tumors	Spindle cells in A myxoid background Collagenized stroma Recanalized thrombi	Vimentin Osteopontin Factor VIII CD31 CD34	Findings overlap with those of chronic thromboembolic disease Decreased vascularity Heterogeneous soft tissue density Smooth vascular tapering	Lung parenchyma Mediastinum
	Pulmonary vein sarcoma		Most common in women Mean age of diagnosis is 49	Smooth muscle	Pulmonary vein	Fleshy-tan tumor Can occlude the lumen of the involved vessel 3.0- 20.0 cm Invasion of wall of the vein	Smooth muscle differentiation Moderate to highly cellular spindle cell neoplasms Epithelioid morphology	Vimentin Desmin Actin Keratin		N/A

Disease	Clinical features Signs & symptoms									Radiological Findings	Characterstic feature
	Fever		Cough		Hemoptysis	Dyspnea	Chest pain	Weight loss	Night sweats
	High-grade	Low grade	Productive	Dry
Acute Lung abscess	+	–	+	–	–	–	+	–	–	Air fluid level	Foul smelling sputum H/o of prior infection or hospitalization Associated with risk factors like aspiration and alcoholism
Malignancy (primary lung cancer)	–	+	–	+	+	–	–	+	+	Coin-shaped lesion Thick wall(>15mm) Ground glass opacities	Long h/o smoking Elderly male or female Broncho-alveolar lavage positive for malignant cells CT guided biopsy is required for confirmation and differentiation
Pulmonary Tuberculosis	+	–	+	–	+	–	–	–	+	Cavitations in the upper lobe of the lung	People in endemic at high risk Cough >2 weeks with hemoptysis Acid fast stain positive for mycobacteria
Necrotizing Pneumonia	+	–	+		+	–	+	–	–	Multiple cavitary lesions	Acute life-threatening condition Complication of pneumonia or lung abscess Multiple organisms responsible Prompt treatment with antibiotics is required Blood culture positive for causative organism
Empyema	+	–	+	–	+	+	+	–	–	Homogeneous consolidations	Blood culture positive for the causative agent
Bronchiectasis	–	–	+	–	+	–	–	–	–	Linear lucencies Tram tracking appearance Clustered cysts Increased pulmonary markings Honeycombing Atelectasis	CT confirms the diagnosis
Wegners granulomatosis	–	–	+		+	+	–	–	–	Pulmonary nodules Cavities Infiltrates	Seen mostly in female age group of 40-55 years Traid of Upper , lower respiratory tract and kidney disease Biopsy of involved organ confirms granulomas
Sarcoidosis	+	–	+	–	+	–	–	+	+	Bilateral adenopathy Coarse reticular opacities	More common in African-american females Restrictive lung disease Biposy findings: epithelioid,granulomas, schaumann, asteroid bodies.
Rheumatoid nodule	–	–	–	–	–	+	–	+	–	Pulmonary nodules Cavitations on the upper lobe of lung	Rheumatoid arthritis Positive for RF and ACP
Langerhans cell Histiocytosis	–	–	–	–	–	+	+	+	–	Thin-walled cystic cavities	Exclusively afflicts smokers Musculoskeletal and skin is involved Biopsy of the involved organ
Bronchiolitis obliterans	–	–	+	–	+	+	+	–	–	Patchy consolidation, Ground-glass opacities Nodules	Biopsy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kim-Son H. Nguyen M.D. Cafer Zorkun, M.D., Ph.D. [2]; Rim Halaby, M.D. [3]; Anum Ijaz M.B.B.S., M.D.[4] Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S.

Lung cancer is the most common cause of cancer-associated mortality and the second most common type of cancer among both genders. Individuals > 50 years of age who have a history of smoking are at increased risk. Historically, the incidence of lung cancer is significantly higher among males compared to females. This increased ratio is thought to be attributed to the increased rates of smoking among men. However, more women are being diagnosed with lung cancer due to the increased rate of smoking among women. In 2014, the incidence of lung cancer in the United States was approximately 70 cases per 100,000. Lung cancer in nonsmoking individuals (defined as <100 lifetime cigarettes) accounts for approximately 15%–20% of all lung cancer cases worldwide, with reported U.S. incidence rates higher in females as compared to males.

• In 2014, the incidence of lung cancer in the US alone was approximately 70 cases per 100,000.^[1]
• Being the most common cancer diagnosed worldwide, it accounted for 2.1 million new cases in 2018.^[2]
• In 2015, the US State Kentucky recorded the highest incidence rate in both men (105.6 per 100,000) and women (77.5 per 100,000) in the country.
• In 2015, the US State Utah recorded the lowest incidence rate in both men (29.6 per 100,000) and women (22.1 per 100,000) in the country.
• Adult cigarette smoking in the United States has declined substantially over the past two decades, accompanied by a parallel reduction in overall lung cancer incidence.
• Lung cancer in nonsmoking individuals (defined as <100 lifetime cigarettes) accounts for 15% to 20% of all lung cancers worldwide.^[3]
• Epidemiologic data from multiple cohorts indicate a rising incidence and proportion of lung cancer among nonsmoking individuals over recent decades (14.4 to 20.8 per 100000 person-years in females and 4.8 to 12.7 per 100000 person-years in males).^[3]

• In the United States, the age-adjusted prevalence of cancer of the lungs and bronchus is estimated to be 100 per 100,000.^[4]
• The prevalence of lung cancer significantly increases among smokers and individuals with chronic exposure to risk factors for lung cancer.

• Being the most common cancer diagnosed worldwide, lung cancer is responsible for 1.8 million deaths in 2018.^[2]

• The American Cancer Society estimates that approximately 142,670 individuals will die of lung cancer in the US in the year 2019.^[5]
• The mortality rate for men is 46.7 per 100,000 individuals.^[6][7]
• The mortality rate for women is 31.9 per 100,000 individuals.^[6][7]

• Lung cancer is more common in older adults. It is rare in people under age of 45 years.
• While the overall age adjusted incidence of cancer of the lungs and bronchus in the United States between 2007 and 2011 is 60 per 100,000, the age-adjusted incidence of lung cancer by age category is:^[4]
  • Under 65 years: 18.1 per 100,000
  • 65 and over: 349.9 per 100,000
  • Lung cancer in nonsmoking individuals is diagnosed at a slightly younger median age (67 years) compared with individuals who have a history of smoking (70 years).

• In the United States, the age-adjusted prevalence of cancer of the lungs and bronchus by race in 2011 was:^[4]
  • Black: 70 – 95 per 100,000
  • White: 50 – 70 per 100,000
  • Asian/Pacific islander: 40 – 50 per 100,000
  • Hispanic: 30 – 40 per 100,000
  • In United States, the age adjusted incidence of lung cancer among nonsmoking women by race during 2000 to 2013 was:
  • Asian: 17.5 per 100,000
  • Non-Hispanic White females: 10.1 per 100,000

• Males are thought to be more predisposed to the development of lung cancer. This gender discrepancy is often attributed to the historically increased rate of smoking among males compared to females.
• The male to female ratio for the incidence of lung cancer is approximately 1.4 to 1.^[4]
• Lung cancer incidence among nonsmoking women has increased substantially over time (0.4 per 100 000 person-years in 1972 to 6.2 per 100 000 person-years in 2015).^[8]
• Lung cancer incidence among nonsmoking men have remained largely stable (6.5 per 100 000 person-years in 1972 vs 6.7 per 100 000 person-years in 2015).^[8]

• The incidence of lung cancer is lower in the developing countries. It is unknown whether this decreased incidence is due to decreased cancer rates or decreased detection rates.^[9]
• Eastern Europe has the highest lung cancer mortality among men.

• Western Europe and the U.S. have the highest incidence of lung cancer and the highest mortality among women.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kim-Son H. Nguyen M.D. Cafer Zorkun, M.D., Ph.D. [2]

The most potent risk factor in the development of lung cancer is tobacco smoking. Other risk factors include second hand smoke, air pollution, family history of lung cancer, radiation therapy to the chest, and exposure to radon, asbestos and other chemical carcinogens.

The following may increase one’s risk of lung cancer:^[1][2][3]

• Smoking
• Second-hand smoke
• Family history of lung cancer
• Air pollution
• Radiation therapy to the chest
• Radon gas exposure
• Asbestos
• High level of arsenic in drinking water
• Occupational exposure to chemical carcinogens
• Previous lung disease
• Indoor burning of coal
• Weakened immune system
• Lupus

Smoking

• Cigarette smoking is the leading cause of lung cancer.^[4][5][6][7]
• Both active and passive smoking are associated with increased risk of lung cancer.
• The risk of lung cancer is associated with increased quantity of cigarette smoking as well as increased duration of smoking.
• There is no evidence that smoking low-tar cigarettes lowers the risk (however lung cancer has occurred in people who have never smoked).
• The more cigarettes you smoke per day and the earlier you started smoking, the greater your risk of lung cancer.
• Recently introduced e-cigarettes, which were thought to be risk-free were recently demonstrated to be also associated with a significantly increased risk of lung cancer due to the presence of formaldehyde.^[8]
• In the United States, smoking is estimated to account for 87% of lung cancer cases (90% in men and 85% in women).^[9]*There is approximately a 20 year lag period between smoking and death due to lung cancer (in men). Shown below is an image depicting the correlation between smoking and lung cancer.

Second-hand Smoke

• Second-hand smoke is what smokers exhale and what rises from a burning cigarette, pipe or cigar. It is also called environmental tobacco smoke (ETS) or involuntary/passive smoking.^[10]

• Second-hand smoke contains the same chemicals as smoke that is actively inhaled.
• Second-hand smoke is a risk factor for lung cancer among non-smokers.
• No amount of exposure to second-hand smoke is safe.^[11]

Air Pollution

• Emissions from automobiles, factories and power plants are thought to pose potential risks.^[12]

• Researchers have shown that individual components of the outdoor air pollution cause cancer. These components include diesel engine exhaust, benzene, particulate matter and some polycyclic aromatic hydrocarbons (PAHs).^[13]

Family History of Lung Cancer^[14]

• Family history of lung cancer may increase the risk of lung cancer.
• First-degree relatives of people who have had lung cancer may have a slightly higher risk of developing lung cancer themselves.
• The increased risk among first-degree relatives could be due to a number of factors, such as shared behaviors or living with the same exposure to carcinogens.
• Studies of families with a strong history of lung cancer have found that the increased risk might be due to a mutation in a lung cancer gene.
• Other studies have shown that the risk of lung cancer in a family increases if a family member developed the disease at an early age.

Radiation Therapy to the Chest

• A history of radiation therapy to the chest increases the risk of lung cancer due to the development of cellular damage and DNA mutations.
• The risk of lung cancer increases for people who have had previous exposure to ionizing radiation.
• People who have been treated with radiation therapy to the chest for cancers such as Hodgkin lymphoma or breast cancer, are at increased risk of developing lung cancer. The risk is further increased in people who smoke.

Radon Exposure

• Radon is a colorless, odorless, and tasteless gas that comes from the natural breakdown of uranium in rocks and soil.

• Radon exposure increases the risk of lung cancer. Radon is the leading cause of lung cancer in non-smokers and the second leading cause of lung cancer in smokers.

• The risk of developing lung cancer depends on how much radon a person is exposed to, how long they are exposed as well as whether or not they smoke. The risk from radon is much higher in people who smoke than in those who don’t.

Asbestos Exposure

• Exposure to asbestos fibers in the air that people breathe increases the risk of lung cancer.

• The risk of asbestos exposure is highest for people who work with asbestos, such as miners or those who work with it in manufacturing.
• Studies have shown that the combination of smoking and asbestos exposure is especially hazardous.

Exposure to Other Chemical Carcinogens

• Arsenic and inorganic arsenic compounds
• Beryllium and beryllium compounds
• Cadmium and cadmium compounds
• Chemicals used in rubber manufacturing, iron and steel founding, and painting
• Chloromethyl ethers and bischloromethylether
• Chromium (VI) compounds
• Cobalt–tungsten carbide
• Diesel engine exhaust
• Mustard gas
• Polycyclic aromatic hydrocarbons (PAHs)
• Radioactive ores, such as uranium and plutonium
• Silica dust and crystalline silica
• Some nickel compounds

• Smoking marijuana
• Indoor burning of wood
• High-temperature frying
• Meat-based diet
• Physical inactivity
• Occupational exposure to certain chemicals
• Removal of both ovaries

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Lung cancer screening is a strategy used to identify early lung cancer in people, before they develop symptoms. Screening refers to the use of medical tests to detect disease in asymptomatic people. Screening studies for lung cancer have only been done in high risk populations, such as smokers and workers with occupational exposure to certain substances. This is because radiation exposure from screening could actually induce carcinogenesis in a small percentage of screened subjects, so this risk should be mitigated by a (relatively) high prevalence of lung cancer in the population being screened. A pulmonary nodule larger than 5 – 6 mm is considered a positive result for screening with x-ray or computed tomography.

About 50% of smokers meet the criteria of 20 pack years^[1].

Uptake of lung cancer screening is low^[2].

As of 2021, screening for lung cancer is not an implemented quality measure nor reportable^[3].

In 2021, a clinical practice guideline by the U.S. Preventive Services Task Force (USPSTF) recommended screening for lung cancer among smokers and former smokers who are between 50 to 80 years old and who have smoked 20 pack years or more and either continue to smoke or have quit smoking within the past 15 years (grade B recommendation).^[4]

MEDICARE requires that screening include counseling for the benefits of screening and smoking cessation^[5].

• In 2013, a clinical practice guideline by the U.S. Preventive Services Task Force (USPSTF) recommended screening for lung cancer among smokers and former smokers who are between 55 to 80 years old and who have smoked 30 pack years or more and either continue to smoke or have quit smoking within the past 15 years (grade B recommendation).^[6]
• The USPSTF guideline was based on a modeling study using data from the National Lung Screening Trial (NLST) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) randomized controlled trials . The modeling study did not include the MILD randomized controlled trial that suggested harm.^{[7][8][9][10]}.

• Clinical practice guidelines issued by the American College of Chest Physicians in 2013 recommend:^{[11] [12][13]}
  • For smokers and former smokers who are between the age of 55 to 74 years and who have smoked for 30 pack years or more and either continue to smoke or have quit within the past 15 years, it was suggested that annual screening with low dose computed tomography (LDCT) should be offered in settings that can deliver the comprehensive care provided to the National Lung Screening Trial (NLST) participants.

• In 2004, a clinical practice guideline by the U.S. Preventive Services Task Force (USPSTF) gave a grade I recommendation indicating that “the evidence is insufficient to recommend for or against screening asymptomatic persons for lung cancer”.^[14][15]

• In 2007, a clinical practice guideline by American College of Chest Physicians recommended not to screen for lung cancer.^[16]

Lung-RADS version 1.1 by the American College of Radiology guides interpretation of scans.

The Swenson prediction rule can aid prediction^[17].

• Regular chest radiography and sputum examination programs were not effective in reducing mortality from lung cancer.^[18]
• Earlier studies (Mayo Lung Project and Czechoslovakia lung cancer screening study, combining over 17,000 smokers) showed that earlier detection of lung cancer was possible but without any improvement in mortality.
• At present, no professional or specialty organization advocates screening for lung cancer outside of clinical trials.

• A computed tomography (CT) scan can uncover tumors not yet visible on an X-ray.
• CT scanning is now being actively evaluated as a screening tool for lung cancer in high risk patients, and it is showing promising results.
• The USA-based National Cancer Institute is currently completing a randomized trial comparing CT scans with chest radiographs. Several single-institution trials are ongoing around the world.^[19]

• The International Early Lung Cancer Action Project is a cohort study of 31,000 high-risk patients that found benefit from screening.^[20]
  • In this study 85% of the 484 detected lung cancers were stage I and thus highly treatable. Mathematically, these stage I patients would have an expected 10-year survival of 88%. However, there was no randomization of patients (all received CT scans and there was no comparison group receiving only x-rays) and the patients were not actually followed up to 10 years post detection (the median follow up was 40 months).

• A cohort of 3,200 current or former smokers found no benefit. These patients were screened for 4 years and offered 3 or 4 CT scans. Lung cancer diagnoses were 3 times as high, and surgeries were 10 times as high, as predicted by a model, but there were no significant differences between observed and expected numbers of advanced cancers or deaths.^[21]

• The National Lung Screening Trial (NLST) reported reduction in the diagnosis of advanced-stage cancers.^[22]
• The DANTE trial has been inconclusive.^[23]

“1. The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (Grade B)”

The cost per year of life save from smoking cessation^[24][25] is less than the costs per year of life saved from screening for lung cancer with low-dose computed tomography^[26][8].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Michael Maddaleni, Saarah T. Alkhairy M.D, Dildar Hussain, MBBS [2]

The majority of lung cancers present with advanced disease because the symptoms tend to occur later in the course of the disease. Patients experience non-specific symptoms such as cough, hemoptysis, dyspnea, chest pain, difficulty speaking, difficulty swallowing, lack of appetite, weight loss, and fatigue from 3 weeks to 3 months before seeking medical attention. There are a variety of complications associated with lung cancer, such as pleural effusion, leg weakness, paresthesias, bladder dysfunction, seizures, hemiplegia, cranial nerve palsies, confusion, personality changes, skeletal pain, pleuritic pain, atelectasis, and bronchopleural fistula. The prognosis of lung cancer is poor if diagnosed at the advanced stages.

• The majority of lung cancers present with advanced disease because the symptoms tend to occur later in the course of the disease.^[1]
• Patients experience non-specific symptoms such as cough, hemoptysis, dyspnea, chest pain, difficulty speaking, difficulty swallowing, lack of appetite, weight loss, and fatigue from 3 weeks to 3 months before seeking medical attention.
• Depending on the duration of the presence of symptoms, the tumor cells may double 20 times.^[1]
• In more advanced disease, the tumor may spread to other organs such as the spinal cord, brain, and bone.
• These patients may develop symptoms such as leg weakness, paresthesias, bladder dysfunction, seizures, hemiplegia, cranial nerve palsies, confusion, personality changes, skeletal pain, and pleuritic pain.^[1]
• Once the cancer spreads to the other organs, it is most likely fatal.
• Most nonsmoking individuals with lung cancer present with advanced disease at diagnosis( unresectable stage III or metastatic stage IV). 10% – 25% have brain metastases at diagnosis, particularly in the presence of certain genomic alterations such as EGFR mutations.

General Complications

The complications associated with lung cancer are:^[2][3]

• Breathing difficulties

• Lung cancer patients can experience trouble in breathing especially when tumors grow and block the airways. Also, it is possible for fluid to build up in the lungs of the patients which can negatively affect breathing.

• Pneumonia

• If the cancer grows in the airway, it may obstruct airflow, causing breathing difficulties. This can lead to accumulation of secretions behind the blockage, predisposing the patient to pneumonia.

• Hemoptysis

• Occasionally, lung cancer can cause bleeding in the airways which can result in hemoptysis.

• Pain

• It is possible that lung cancer will cause pain as well, especially if it spreads to the pleura or other areas of the body, like the bones.

• Pleural effusion

• Lung cancer can cause fluid to build up in the lungs which can cause breathing difficulties.

• Metastasis

• In many cases, lung cancer will spread to other parts of the body. Some of the more common places lung cancer metastasizes to are the bones, liver, brain, and adrenal glands.

• Horner’s syndrome

• Tumors in the apex of the lung, known as Pancoast tumors, may invade locally into the sympathetic nervous system leading to Horner’s syndrome.

• Superior vena cava syndrome
  • SVCS is a group of symptoms caused by obstruction of the superior vena cava. More than 60% of cases of superior vena cava obstruction are caused by malignancies, especially with a tumor outside the vessel compressing the vessel wall.

Surgical Complications

• Bronchopleural fistula

• It is when air leaks from a pneumonectomy bronchial stump.
• Approximately 2% of the patients that undergo a pneumonectomy experience this.
• It will most commonly occur approximately 7 to 10 days after surgery.

• Hemothorax

• Atelectasis
• Sputum retention

The prognosis of lung cancer is poor and it depends on the following factors:

• Whether or not the tumor can be removed by surgery
• Stage of the cancer
• Patient’s general health
• Whether the cancer has just been diagnosed or has recurred

Non-small Cell Lung Cancer Survival Rate by Stage^[4]

Stage	5-year survival rate
IA	49%
IB	45%
IIA	30%
IIB	31%
IIIA	14%
IIIB	5%
IV	1%

Small Cell Lung Cancer Survival Rate

• To view the prognosis among patients with small cell lung carcinoma, please click Here.

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