Non small cell lung cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2],Maria Fernanda Villarreal, M.D. [3],Furqan M M. M.B.B.S[4]

Non-small cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). Non-small cell lung cancer may be classified according to the WHO histological classification system into 3 main types; Squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Other less common subtypes include adenosquamous lung carcinoma, pulmonary sarcomatoid carcinoma, carcinoid tumors of the lung, and carcinomas of the lung of salivary gland type. Non-small cell lung cancer arises from the epithelial cells of the lung of the bronchi to the alveoli, which are normally involved in the protection of the airways. Non-small cell lung cancer is an invasive and rapidly growing cancer which may metastasize to different organs of the body. Genes involved in the pathogenesis of non-small cell lung cancer include multiple oncogenes, such as EGFR, KRAS, HER2, BRAF, ROS-1, ALK, AKT1, MEK1, MET, NRAS, PIK3CA, and RET. The primary cause of non-small cell lung cancer is DNA damage. Non-small cell lung cancer is the leading cause of cancer-related death among both men and women, and the most common cancer among the adult population in the United States. Non-small cell lung cancers account for about 85% of all lung cancers. The incidence rate of non-small cell lung cancer is approximately 42.6 per 100 000 individuals in the United States. Common risk factors in the development of non-small cell lung are smoking, family history of lung cancer, high levels of air pollution, radiation therapy to the chest, radon gas, asbestos, occupational exposure to chemical carcinogens, and previous lung disease. Non-small cell lung cancer is a locally aggressive tumor, commonly occurs in patients between 65 to 74 years. Common sites of metastasis include adrenal gland, bone, brain, and liver. The 5-year relative survival of patients with non-small cell lung cancer is approximately 50%. Features associated with worse prognosis are genetic markers, tumor size, associated conditions, clinical fitness for surgery, the presence of lymphatic invasion, the location of the lesion, the presence of satellite lesions, and presence of regional or distant metastases. Prognosis is generally regarded as poor with an all-stage average survival rate of 50%. The 5-year recurrence rate of non-small cell lung cancer is 24%. Chemotherapy is indicated for non-small cell lung cancer stage (IB, II, and III) as adjuvant therapy. The main therapy for non-small cell lung cancer is surgical resection. Chemotherapy and chemo-radiation may be required upon histological subtype of non-small cell lung cancer, location, size, and lymph node involvement.

Lung cancer was not identified as a disease until 1700. Morgagni GB, an Italian anatomist, first described lung cancer in his book “De sedibus et causis morborum per anatomen indagatis (1761). In 1761, Dr. John Hill of London, proved the relationship between the use of tobacco and cancer in his case study. In 1879, Harting and Hesse, two German physicians, first described the association between lung cancer and working in mines, and later radon gas was identified as the cause. In 1929, Fritz Lickint, a German physician first described the association between smoking and lung cancer. In 1965, U.S. Congress adopted the Federal Cigarette Labeling and Advertising Act and the Public Health Cigarette Smoking Act of 1969 as a preventive measure against lung cancer.

Non-small cell lung cancer may be classified according to the WHO histological classification system into 3 main types; Squamous cell carcinoma, lung adenocarcinoma, and large cell carcinoma. Other less common subtypes include adenosquamous lung carcinoma, pulmonary sarcomatoid carcinoma, carcinoid tumors of the lung, and carcinomas of the lung of salivary gland type.

Non-small cell lung cancer arises from the epithelial cells of the bronchioles and alveoli, which are normally involved in the protection of the airways. Non-small cell lung cancer is an invasive and rapidly growing cancer which may metastasize to different organs of the body. Genes involved in the pathogenesis of non-small cell lung cancer include EGFR, KRAS, HER2, BRAF, and ALK. Findings on gross pathology depend on the histological subtypes of non-small cell lung cancer. On microscopic histopathological analysis non-small cell lung cancer usually demonstrates large cells with abundant cytoplasm and no stippled chromatin.

Cancers are caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes. DNA mutations can be acquired or hereditary. Non-small cell lung cancer may develop by acquired genetic mutation of the TP53 or p16 tumor suppressor genes and the K-RAS or ALK oncogenes as result of exposure to environmental factors such as smoking, asbestos exposure, ionizing radiation, and air pollution, which are considered as risk factors for NSCLC. Hereditary factors in development of lung cancer is poorly understood because they are masked by the influence of environmental factors.

Non-small cell lung cancer must be differentiated from other diseases that cause chronic cough, weight loss, hemoptysis, and dyspnea among adults such as tuberculosis, pulmonary fungal disease, lung abscess, and secondary metastases.

Non-small cell lung cancer is the most common cancer worldwide and the leading cause of cancer-related mortality in the United States. Non-small cell lung cancer accounted for 1.8 million new cases and 1.6 million deaths of lung cancer in 2012. In the United States, the age-adjusted prevalence of non-small cell lung cancer is 47.2 per 100,000 individuals. The median age at diagnosis of non-small cell lung cancer is 70 years. Non-small cell lung cancer is most frequently diagnosed among people between 65 to 74 years old. Males are more commonly affected by non-small cell lung cancer than females. The male to female ratio is approximately 1.8 to 1. The rate of new cases in 2011 showed that males develop lung cancer more often than females (64.8 and 48.6 per 100,000 individuals). There is a racial preponderance to the development of non-small cell lung cancer, where African American individuals are at a significantly increased risk compared to Caucasian race.

Common risk factors in the development of non small cell lung are smoking, family history of lung cancer, high levels of air pollution, radiation therapy to the chest, radon gas, asbestos, occupational exposure to chemical carcinogens, and previous lung disease.

According to the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography is recommended every year among smokers who are between 55 to 80 years old and who have history of smoke 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation).

If left untreated, non-small cell lung cancer progression occurs slowly and is then followed by local invasion to lymph nodes and distant metastasis. Non-small cell lung cancer is a locally aggressive tumor, which commonly occurs in adult patients between 65 to 74 years. Common sites of metastasis include the adrenal gland, bone, brain, and liver. Complications of non-small cell lung cancer include acute respiratory failure, respiratory acidosis, malignant pleural effusion, metastases, and pneumonia. The 5-year relative survival of patients with non-small cell lung cancer is approximately 50%. Features associated with worse prognosis are presence of lymphatic invasion, location of lesion, gene expression profile, performance status, presence of satellite lesions, and presence of regional or distant metastases. Prognosis is generally regarded as poor with an all-stage average survival rate of 25%. The 5-year recurrence rate of non-small cell lung cancer is approximately 24%.

Chest X-Ray is the initial study performed when non-small cell lung cancer is suspected. Lung CT scan is the diagnostic study of choice for the diagnosis of non-small cell lung cancer. Endobronchial ultrasound is a first-line diagnostic modality for mediastinal staging of the non-small cell lung cancer. The lung biopsy is the gold standard for the diagnosis of the non-small cell lung cancer. The lung biopsy helps to differentiate between the various subtypes of lung cancer.

Staging system classifications for non-small cell lung cancer, include: American Joint Committee on Cancer (AJCC) staging system and International Union Against Cancer (UICC) staging system. According to both institutions, TNM system, which they now develop jointly, classifies cancer by several factors, T for tumor, N for nodes, M for metastasis. TNM determines the stages of cancer based on the extent of involvement of the lung, lymph nodes, and adjacent structures.

The hallmark of non-small cell lung cancer is chronic cough, weight loss, and hemoptysis. A positive history of smoking, exposure to asbestos, tuberculosis infection, or a high risk occupation may be suggestive of non-small cell lung cancer. Symptoms related with non-small cell lung cancer will vary depending on the size and location of the tumor. Common symptoms of non-small cell lung cancer may also include shortness of breath, fatigue, and chest pain.

Physical examination findings of non-small cell lung cancer will depend on the location of the tumor. Non-small cell lung cancer with central location may cause crackling sounds, focal wheezing, voice hoarseness, and tachypnea. Peripheral location can present with pleurisy findings, such as reduced chest expansion. Common physical examination of patients with non-small cell lung cancer, include: crackling or bubbling noises, decreased/absent breath sounds, and whispered pectoriloquy.

The following laboratory tests are required for patients with non-small cell lung carcinoma, including squamous cell carcinoma are complete blood count, electrolytes, calcium, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine, albumin, and lactate dehydrogenase.

On chest X-ray, characteristic findings of non-small cell lung cancer include rounded or spiculated mass, bulky hilum (representing the tumor and local nodal involvement) and lobar collapse.

Computed tomography is the method of choice for the diagnosis of non-small cell lung cancer. On CT, characteristic findings of non-small cell lung cancer include ground-glass opacity, rounded or spiculated mass, local nodal involvement, intraluminal obstruction, and lobar collapse.

On MRI, there are no specific findings of non-small cell cancer. MRI may be done for the pleural effusion assessment, guidance for thoracentesis, and guidance for biopsy of peripheral lung or mediastinal mass.

On endobronchial ultrasound (EBUS) and endoscopic ultrasound, characteristic findings of non-small cell lung cancer include enlarged lymph nodes and local invasion to adjacent bronchial structures and mediastinum. Endobronchial ultrasound is a first-line diagnostic modality for mediastinal staging.

Other imaging findings of non-small cell lung cancer include PET and pulmonary angiography. PET scan is used for general follow-up, monitor treatment response and as a staging modality (in the risk of missing occult disease).

Diagnosis of non-small cell lung cancer can be confirmed by histopathological evaluation and immunohistochemical staining of the tumor specimen obtained from biopsy. Different types of lung tissue biopsy for non-small cell lung cancer include transthoracic needle biopsy, open biopsy, and video-assisted thoracoscopic surgery (VATS). Specimen for histopathological evaluation and immunohistochemical staining can also be obtained by bronchoscopy, mediastinoscopy, transthoracic percutaneous fine needle aspiration or sputum cytology.

The optimal management approach of non-small cell lung cancer will depend on a series of characteristics, which includes: pre-treatment evaluation, location, and adequate staging. Common treatment options for management of non-small cell lung cancer include surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, and radiation therapy.

Therapies for non-small cell lung cancer stage I include surgery, radiation therapy, or surgery and chemotherapy (if the tumor size is larger than 4cm).

Therapies for non-small cell lung cancer stage II include surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, and radiation therapy. If the tumor is resectable, the preferred treatment for stage II non small cell lung cancer, includes: surgical resection with lymph node dissection and pathological evaluation. If evidence of lymph node extension of the disease is present adjutant chemotherapy should be administered.

Therapies for non-small cell lung cancer stage III, depends on 4 categories; Resectable tumors, unresectable tumors, superior sulcus tumors, and tumors that invade the chest wall. Therapies for resectable tumors include surgery, neoadjuvant therapy, and adjuvant therapy. Alternatively, therapies for unresectable disease only include radiation therapy, and chemoradiation therapy. Therapies for superior sulcus tumors include radiation therapy alone, radiation therapy and surgery, concurrent chemotherapy with radiation therapy and surgery. Lastly, therapies for tumors that invade the chest wall include surgery, surgery and radiation therapy, radiation therapy alone, and chemotherapy combined with radiation therapy and/or surgery. The treatment of stage III non-small cell lung cancer will be contingent on the extension of the tumor. Chemotherapy and/or radiation therapy should be considered for patients with stage IIIB.

Therapies for non-small cell lung cancer stage IV include cytotoxic combination chemotherapy (first line), combination chemotherapy with bevacizumab or cetuximab, EGFR tyrosine kinase inhibitors, EML4–ALK inhibitors in patients with EML–ALK translocation, and immune checkpoint inhibition with nivolumab for selected patients with squamous or non-squamous metastatic. Maintenance therapy following first-line chemotherapy, include endobronchial laser therapy or brachytherapy (for obstructing lesions) and external beam radiation therapy (primarily for palliation of local symptomatic tumor growth). Local therapies (ambulatory catheter drainage, pleurodesis or mediastinal window) plus therapy for systemic metastasis is the preferred combination for patients with stage IV M1a non-small cell lung cancer. Patients with solitary site metastasis (stage IV M1b) should be treated according to the site of metastasis.

Therapies for non-small cell lung cancer stage IV include radiation therapy (for palliation) and palliative chemotherapy. The treatment of metastatic non-small cell lung cancer depends on the site and extension of the disease. If specific mutations are diagnosed, targeted treatment should be administered.

Chemotherapy is indicated for non-small cell lung cancer stage (IB, II, and III) as adjuvant therapy. The predominant therapy for non-small cell lung cancer is surgical resection. Chemotherapy and chemo–radiation may be required upon histological subtype of non-small cell lung cancer, location, size, and lymph node involvement. Commonly used chemotherapeutic agents include gemcitabine, paclitaxel, docetaxel, pemetrexed, etoposide or vinorelbine.

Chemotherapeutic regimens are based on platinum agents such as cisplatin, carboplatin, oxaliplatin, and satraplatin. Alternative regimens include paclitaxel, gemcitabine, or etoposide. Chemotherapeutic regimens are adjusted based on individual characteristics and body surface. The regimen adjustment according to tumor evolution has demonstrated longer survival rates, optimal symptom control, and higher quality of life.

Radiation therapy can be applied to any stage of non-small cell lung cancer. In general, radiation therapy is recommended as palliative care treatment among patients who develop an advanced stage of non-small cell lung cancer or symptomatic patients with local involvement (pain, vocal cord paralysis, and hemoptysis). Curative radiation therapy may be indicated in patients who are not suitable for surgery with early-stage non-small cell lung cancer. The main goal of radiation therapy for non-small cell lung cancer is maximum tumor control with minimal tissue toxicity. The two main types of radiation therapy for non-small cell lung cancer are external beam radiation therapy (thoracic radiotherapy), and brachytherapy (internal radiation therapy).

Surgery is the mainstay of therapy for early-stage non-small cell lung cancer. Common surgical procedures for the treatment of non-small cell lung cancer, include lung resection with lobectomy, lung resection with pneumonectomy with or without lymph node dissection. The preferred surgical procedure is thoracotomy with the removal of the entire lung or lobe (lobectomy) along with regional lymph nodes and contiguous structures.

Primary prevention of non-small cell lung cancer includes avoidance of smoking, smoking exposure, exposure to asbestos, and other high-risk occupational jobs.

The secondary prevention of non-small cell lung cancer is based on the stage of non-small cell lung cancer at diagnosis. Secondary prevention includes chest CT along with a periodic evaluation of alert signs in second-hand smokers or active smokers.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2] Maria Fernanda Villarreal, M.D. [3]

Lung cancer was not identified as a disease until 1700. Morgagni GB, an Italian anatomist, first described lung cancer in his book “De sedibus et causis morborum per anatomen indagatis (1761)”. In 1761, Dr. John Hill of London, proved the relationship between the use of tobacco and cancer in his case study. In 1879, Harting and Hesse, two German physicians, first described the association between lung cancer and working in mines, and later radon gas was identified as the cause. In 1929, Fritz Lickint, a German physician first described the association between smoking and lung cancer. In 1965, U.S. Congress adopted the Federal Cigarette Labeling and Advertising Act and the Public Health Cigarette Smoking Act of 1969 as a preventive measure against lung cancer.

• In 1761, Dr. John Hill of London, proved the relationship between the use of tobacco and cancer in his case study.^[1]
• In between 1876 to 1938 miners working in silver, later nickel, cobalt, bismuth, and arsenic mines were dying from a disease called “Bergkrankheit” (mountain sickness) that lasted for about 25 years, which later confirmed was the lung cancer.^[2]
  • Later in 1924 German physics journal confirmed the cause behind the deaths in miners was radon gas.
• In 1879, Harting and Hesse, two German physicians, first described the association between lung cancer and working in mines.^[3]
• In 1929, Fritz Lickint, a German physician first described the association between smoking and lung cancer.
  • This discovery led to anti-smoking movement in Germany.
• In 1950, “The British Doctors Study” was the first solid epidemiological evidence of the link between lung cancer and smoking.^[4]
• In 1965, the first preventive measures against lung cancer were implemented in The United States.^[5]
  • U.S. Congress adopted the Federal Cigarette Labeling and Advertising Act of 1965 and the Public Health Cigarette Smoking Act of 1969. These laws:
  • Required a health warning on cigarette package.
  • Banned cigarette advertising in the broadcasting media.
  • Called for an annual report on the health consequences of smoking.
• In 1982, Geoffrey Cooper, an American pathologist first used the NIH 3T3 focus assay to identify the activated K-ras oncogene in lung cancer cell lines.^[6]
• In 1987, it was established that a receptor on cancer cells called the epidermal growth factor receptor (EGFR) plays an important role in the growth and spread of non small cell lung cancer.^[7]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

Non-small cell lung cancer may be classified according to the WHO histological classification system into 3 main types; Squamous cell carcinoma, lung adenocarcinoma, and large cell carcinoma. Other less common subtypes include adenosquamous lung carcinoma, pulmonary sarcomatoid carcinoma, carcinoid tumor of the lung, and carcinomas of the lung of salivary gland type.

• There are 3 main types of non–small cell lung cancer:^[1][2][3]
  • Adenocarcinoma
  • Squamous cell carcinoma
  • Large cell carcinoma
• The table below summarizes the WHO histological classification system for non small cell lung cancer.^[4]

WHO histological classification system Adapted from WHO/IARC (2006)
Main types	Subtypes	Prevalence
Adenocarcinoma	Adenocarcinoma, mixed Acinar adenocarcinoma Papillary adenocarcinoma Bronchioloalveolar carcinoma Nonmucinous Mucinous Mixed nonmucinous and mucinous or indeterminate Solid adenocarcinoma with mucin production Fetal adenocarcinoma Mucinous (“colloid”) carcinoma Mucinous cystadenocarcinoma Signet ring adenocarcinoma Clear cell adenocarcinoma	40% of lung cancers
Squamous cell carcinoma	Papillary Clear cell Small cell Basaloid	25% of lung cancers
Large cell carcinoma	Large cell neuroendocrine carcinoma Basaloid carcinoma Lymphoepithelioma-like carcinoma Clear cell carcinoma Large cell carcinoma with rhabdoid phenotype	10% of lung cancer
Less common types
Adenosquamous carcinoma	No subtypes	Less than 5%
Sarcomatoid carcinoma	Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma	Less than 5%
Carcinoid tumor	Typical carcinoid Atypical carcinoid	Less than 5%
Salivary gland tumor	Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma	Less than 5%

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2],Maria Fernanda Villarreal, M.D. [3]

Non-small cell lung cancer arises from the epithelial cells of the bronchioles and alveoli, which are normally involved in the protection of the airways. Non-small cell lung cancer is an invasive and rapidly growing cancer which may metastasize to different organs of the body. Genes involved in the pathogenesis of non-small cell lung cancer include EGFR, KRAS, HER2, BRAF, and ALK. Findings on gross pathology depends on the histological subtypes of non-small cell lung cancer. On microscopic histopathological analysis non-small cell lung cancer usually demonstrates large cells with abundant cytoplasm and no stippled chromatin.

The pathogenesis of non-small cell lung cancer depends on the type of histological subtype of lung cancer.^[1]

• Non-small cell lung cancer arises from the epithelial cells of the bronchioles and alveoli, which are normally involved in the protection of the airways.
• The genetic pathogenesis of non-small cell lung cancer is due to the amplification of oncogenes and inactivation of tumor suppressor genes.
• Non-small cell lung cancer is an invasive and rapidly growing cancer which may metastasize to different organs of the body.

Pathogenesis according to histopathological subtypes:

• Adenocarcinoma of the lung:^[2]
  • Adenocarcinoma arises from the bronchial mucosal glands of the lung (main, lobar, or segmental bronchi, or lung parenchyma), which are normally involved in eliminating microbes and avoiding microbial growth in the epithelial cells of the lung.
  • Lung adenocarcinoma usually occurs in a peripheral location within the lung.
  • In the majority of the patients, cancer arises from precursor lesions, such as pre-existing scars or inflammation (chronic infections).
  • Lung adenocarcinoma can also result from multiple genetic mutations.
  • For more information about adenocarcinoma of the lung pathogenesis, click here.
• Large cell carcinoma of the lung:
  • Large cell carcinoma of the lung arises from large polygonal and anaplastic cells.
  • It is difficult to differentiate large cell carcinoma from other types of non small cell lung cancer.
  • Large cell carcinoma of the lung usually occurs in a peripheral location within the lung.
  • For more information about large cell carcinoma of the lung pathogenesis, click here.
• Squamous cell carcinoma of the lung:^[3]
  • Squamous cell carcinoma of the lung arises from bronchial epithelial cell damage, commonly caused by smoking.
  • Squamous cell carcinoma usually occurs in a central location within the lung.
  • For more information about squamous cell carcinoma of the lung pathogenesis, click here.

Development of non-small cell lung cancer is the result of multiple genetic mutations. Genetic mutations also play an important role in the treatment selection for non small cell lung cancer.^[4]

• The table below describes the genes involved in the pathogenesis of non small cell lung cancer.

Genes	Presence in non small cell-lung cancers
EGFR	EGFR mutations are present in approximately 10% to 15% of all non-small cell lung cancers
KRAS	Mutations are present in approximately 30% of pulmonary adenocarcinomas Mutations are present in approximately 5% of pulmonary squamous cell carcinomas Associated with carcinomas with mucinous histology
ALK	Mutations are present in approximately 5% of all non-small cell lung cancers
HER2	Mutations are present in approximately 4% of adenocarcinomas
BRAF	Mutations are present in less than 2% of adenocarcinomas
ROS-1	Mutations are present in less than 2% of adenocarcinomas

Other conditions associated with non-small cell lung cancer, include:

• Genetic conditions
  • Li–Fraumeni syndrome^[5]
  • Von Hippel-Lindau disease ^[6]
• Infections
  • Human papillomavirus (HPV) infection ^[7]
  • Pulmonary tuberculosis ^[8]

On gross pathology, findings will depend on the histological subtype of non-small cell lung cancer.

• Adenocarcinoma of the lung:^[2][9]
  • Spherical tumor with well-defined borders
  • Homogeneous gray-white cut surface
  • Involvement of the thoracic wall
  • Usually found in the peripheral lung
  • For more information on the gross pathological findings of adenocarcinoma of the lung, click here.
• Large cell carcinoma of the lung:^[10]
  • Well-defined borders
  • Resemblance to gross findings in adenocarcinoma
  • No signs of anthracosis
  • Involvement of the thoracic wall
  • For more information on the gross pathological finding of large cell carcinoma of the lung, click here.
• Squamous cell carcinoma of the lung:^[11]
  • Lung mass
  • Usually centrally located
  • Associated with a large airway
  • Usually have a central cavitation
  • For more information on the gross pathological finding of squamous cell carcinoma of the lung, click here.

On microscopic pathology, findings will depend on the histological type of non-small cell lung cancer.

• Adenocarcinoma of the lung:^[12]
  • Nuclear atypia
  • Eccentrically placed nuclei
  • Abundant cytoplasm with mucin vacuoles
  • Often conspicuous nucleoli
  • Lack of intercellular bridges
  • Different patterns, include: acinar, lepidic, micropapillary, papillary, and solid
  • For more information on microscopic pathological findings of adenocarcinoma of the lung, click here.

• Large cell carcinoma of the lung:^[10]
  • Large polygonal cells and anaplastic cells
  • No squamous or glandular differentiation
  • Moderately abundant cytoplasm
  • Vesicular nuclei, prominent nucleoli
  • For more information on microscopic pathological findings of large cell carcinoma of the lung, click here.

• Squamous cell carcinoma of the lung:^[13]
  • Central nucleus
  • Dense appearing cytoplasm, usually eosinophilic
  • Small nucleolus
  • Intercellular bridges (classic feature)
  • For more information on microscopic pathological findings of squamous cell carcinoma of the lung, click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2],Maria Fernanda Villarreal, M.D. [3]

Cancers are caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes. DNA mutations can be acquired or hereditary. Non-small cell lung cancer may develop by acquired genetic mutation of the TP53 or p16 tumor suppressor genes and the K-RAS or ALK oncogenes as result of exposure to environmental factors such as smoking, asbestos exposure, ionizing radiation, and air pollution, which are considered as risk factors for NSCLC. Hereditary factors in development of lung cancer is poorly understood because they are masked by the influence of environmental factors.

Non-small cell lung cancer is caused by DNA mutations as a result of exposure to environmental risk factors.^[1]

• Genes involved in the pathogenesis of non small cell cancer of the lung include:^[2][3][4]
  • Activation of EGFR (7p11)
  • KRAS (12p12) mutation
  • BRAF (7q34)
  • HER2^[5]
  • PIK3CA (3q26)^[6]
  • ERBB2 (17q12)
  • Fusion between EML4 and ALK^[7]
  • Tyrosine kinase fusions
  • ALK (2p23)
  • ROS1 (6q22) alteration^[8]
  • RET (10q11)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Non-small cell lung cancer must be differentiated from other diseases that cause chronic cough, weight loss, hemoptysis, and dyspnea among adults such as tuberculosis, pulmonary fungal disease, lung abscess, and secondary metastases.

• The table below summarizes the findings that differentiate non small cell lung cancer from other conditions that cause chronic cough, weight loss, hemoptysis, and dyspnea.^[1][2][3]

Differential Diagnosis	Similar Features	Differentiating Features
Pulmonary tuberculosis	Chronic cough, weight loss, hemoptysis, nocturnal diaphoresis, dyspnea	In pulmonary tuberculosis, differentiating features include: resolution (or decrease in size) after medical therapy, patients age is usually younger, hemoptisis is an early feature, and CXR anatomical predilection for upper lobes
Lung abscess	Chronic cough, weight loss, hemoptysis, and dyspnea	In lung abscess, differentiating features include: acute or subacute onset, CXR anatomical predilection for upper lobes, and usually resolve with antibiotic
Pneumonia	Cough, fatigue, and dyspnea	In pneumonia, differentiating features include: high grade fever, good response to antibiotics, acute onset, predilection on CXR is consolidation, laboratory markers indicate infection
Fungal infection	Chronic cough, weight loss, hemoptysis, and dyspnea	In fungal infection, differentiating features include: CXR findings (air-cresecent sign), no response to antibioitcs, and mimcs tuberculosis
Chronic eosinophilic pneumonia	Chronic cough, weight loss, hemoptysis, and dyspnea	In chronic eosinophilic pneumonia , differentiating features include: parasite infection or medication exposure, and increased serum IgE levels

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

Non-small cell lung cancer is the most common cancer worldwide and the leading cause of cancer-related mortality in the United States. Non-small cell lung cancer accounted for 1.8 million new cases and 1.6 million deaths of lung cancer in 2012. In the United States, the age-adjusted prevalence of non-small cell lung cancer is 47.2 per 100,000 individuals. The median age at diagnosis of non-small cell lung cancer is 70 years. Non-small cell lung cancer is most frequently diagnosed among people between 65 to 74 years old. Males are more commonly affected by non-small cell lung cancer than females. The male to female ratio is approximately 1.8 to 1. The rate of new cases in 2011 showed that males develop lung cancer more often than females (64.8 and 48.6 per 100,000 individuals). There is a racial preponderance to the development of non-small cell lung cancer, where African American individuals are at a significantly increased risk compared to Caucasian race.

• In the United States, the age-adjusted prevalence of non-small cell lung cancer is 47.2 per 100,000 indivudals.^[1]
• About 85%–90% of all lung cancers are non-small cell lung cancer.^[2]
• The most common type of lung cancer is non-small cell lung cancer.^[3][4]
  • Non-small cell lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012.
  • Adenocarcinoma of the lung is the most common non-small cell lung cancer subtype in the United States.

• The age-adjusted incidence of non-small cell lung cancer in 2012 was estimated to be 58.7 per 100,000 individuals in the United States.^[1]
  • The incidence rate of lung adenocarcinoma is 22.1 per 100,000 individuals a year.
  • The incidence rate of lung squamous-cell carcinoma is 14.4 per 100,000 individuals a year.

• The incidence of non small cell lung cancer increases with age; the median age at diagnosis is 70 years.^[5]
  • Non small cell lung cancer is most frequently diagnosed among people among 65 to 74 years old.
  • Shown below is an image that demonstrates the age-adjusted incidence of non-small cell lung cancer in the United States. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.

• Males are more commonly affected with non-small cell lung cancer than females. The male to female ratio is approximately 1.8 to 1.^[5]
  • The rate of new cases in 2011 showed that males develop lung cancer more often than females (64.8 and 48.6 per 100,000 individuals).
  • Shown below is an image that demonstrates the relative proportions of common types of non-small cell lung cancer in the United States, by histology and gender. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.

• There is a racial preponderance to the development of non small cell lung cancer, where African American individuals are at a significantly increased risk compared to Caucasian race.^[4]
  • There is a higher prevalence of lung adenocarcinoma among Asian female patients with EGFR mutation (51.4%).
• Shown below is an image that demonstrates the mortality rate of non-small cell lung cancer among different ethnic groups in the United States. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

Common risk factors in the development of non small cell lung are smoking, family history of lung cancer, high levels of air pollution, radiation therapy to the chest, radon gas, asbestos, occupational exposure to chemical carcinogens, and previous lung disease.

Common risk factors non-small cell lung cancer may include:^[1][2]

• Smoking
• Second-hand smoke
• Family history of non-small cell lung cancer
• High levels of air pollution
• Radiation therapy to the chest
• Radon gas
• Asbestos
• High levels of arsenic in drinking water
• Occupational exposure to chemical carcinogens
• Previous lung disease
• Indoor burning of coal
• Weakened immune system
• Systemic lupus erythematosus

Smoking

• Cigarette smoking is the leading cause of non-small cell lung cancer.^[3][4][5][6]
  • Both active and passive smoking are associated with increased risk of non-small cell lung cancer.
  • The risk of non-small cell 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.
  • There is a parallel correlation between the amount of cigarettes and the proportional risk of non-small cell 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 non-small cell lung cancer due to the presence of formaldehyde.^[7]
• In the United States, smoking is estimated to account for 87% of non-small cell lung cancer cases (90% in men and 85% in women).^[8]
• There is approximately a 20 year lag period between smoking and death due to non-small cell lung cancer (in men).

Shown below is an image depicting the correlation between smoking and non-small cell 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 or passive smoking.^[9]
  • Second-hand smoke contains the same chemicals as smoke that is actively inhaled.
  • People exposed to second-hand smoke have an increased risk of non-small cell lung cancer.
  • Second-hand smoke is the main risk factor for non-small cell lung cancer among non-smokers.
• There is no established amount of exposure to correlate safety and the risk of second-hand smoke.^[9]

Air Pollution

• Emissions from automobiles, factories and power plants are thought to pose potential risks.^[10]
• Researchers have shown that individual components of outdoor air pollution cause cancers (PAHs).^[11]
• Components include diesel engine exhaust, benzene, particulate matter and some polycyclic aromatic hydrocarbon.

Family History of Lung Cancer

A positive family history of non-small cell lung cancer may increase the risk of non-small cell lung cancer.^[1]

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

Radiation Therapy to the Chest

Positive history of radiation therapy to the chest increases the risk of non-small cell lung cancer due to the development of cellular damage and DNA mutations.^[1]

• The risk of non-small cell 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 for non-small cell lung cancer.

Radon Exposure

Radon is a colorless, odorless, tasteless gas that comes from the natural breakdown of uranium in rocks and soil.^[12]

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

Asbestos Exposure

Exposure to asbestos fibers in the air increases the risk of non-small cell lung cancer.^[12]

• The risk of asbestos exposure is highest for people who work with asbestos, such as miners.
• Studies have shown that the combination of smoking and asbestos exposure is especially hazardous.
• Patients that are exposed to asbestos and smoke are at even greater risk of developing non-small cell lung cancer.

Exposure to Other Chemical Carcinogens

Other chemical carcinogens associated with small cell lung cancer include:^[12]

• Arsenic and inorganic arsenic compounds
• Beryllium and beryllium compounds
• Cadmium and cadmium compounds
• Chemicals used in:
  • Rubber manufacturing
  • Iron
  • Steel founding
  • Paints
• Chloromethyl ethers and bis-chloromethyl ether
• 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

Less common risk factors non small cell lung cancer may include:^[13][12]

• Occupational exposure to certain chemicals
• Vinyl chloride
• Dioxin
• Cobalt–tungsten carbide
• Inorganic acid mists
• Smoking marijuana
• Indoor burning of wood
• High-temperature frying
• Meat-diet
• Physical inactivity

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2],Maria Fernanda Villarreal, M.D. [3]

The U.S. Preventive Services Task Force (USPSTF) recommends annual screening for lung cancer by low-dose computed tomography. The screening test is recommended to the smokers who are between 55 to 80 years old and who have a history of smoking 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation).

According to the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography is recommended every year among smokers who are between 55 to 80 years old and who have history of smoke 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation).^[1][2]

Guidelines

• According to the clinical practice guideline by the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography (LDCT) is recommended every year 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 within the past 15 years (grade B recommendation).^[3]

• According to the clinical practice guideline issued by the American College of Chest Physicians (CHEST) in 2013, screening for lung cancer by low-dose CT (LDCT) is recommended every year among smokers and former smokers who are age 55 to 74 and who have smoked for 30 pack-years or more and either continue to smoke or have quit within the past 15 years.^[4]

Strategies

• Low-dose helical computed tomography:^[5]
  • Pros:
    • There is evidence that screening persons aged 55 to 74 years who have cigarette smoking histories of 30 or more pack-years and who, if they are former smokers, have quit within the last 15 years reduce lung cancer mortality by 20% and all-cause mortality by 6.7%.
  • Cons:
    • The majority of all positive low-dose helical computed tomography screening exams do not result in a lung cancer diagnosis. False-positive exams may result in unnecessary invasive diagnostic procedures.

• Chest x-ray and/or sputum cytology:^[6]
  • Pros:
    • Screening with chest x-ray and/or sputum cytology does not reduce mortality from lung cancer in the general population or in ever-smokers.
  • Cons:
    • False positive exams
    • The majority of all positive chest x-ray screening exams do not result in a lung cancer diagnosis.
    • False-positive exams result in unnecessary invasive diagnostic procedures.

Overdiagnosis

• Based on current evidence, the majority of non-small cell lung cancers detected by screening chest x-ray and/or sputum cytology appear to represent overdiagnosed cancer.^[6]
  • The magnitude of overdiagnosis appears to be between 5% and 25%.
  • These cancers result in unnecessary diagnostic procedures and also lead to unnecessary treatment.
  • Harms of diagnostic procedures and treatment occur most frequently among long-term and/or heavy smokers because of smoking-associated comorbidities that increase risk propagation.

• The table below summarizes the screening eligibility for non-small cell lung cancer screening by different organizations.

Screening Guidelines for Non Small Cell Lung Cancer Adapted from Center of Disease Control and Prevention (CDC). 2016 [7]
Organization	Groups eligible for screening	Year
American Academy of Family Practice	Evidence is insufficient to recommend for or against screening	2013
American Association of Thoracic Surgery	1. Age 55 to 79 years with 30 pack year smoking history 2. Long term lung cancer survivors who have completed 4 years of surveillance without recurrence and who can tolerate lung cancer treatment following screening to detect second primary lung cancer until the age of 79 3. Age 50 to 79 years with a 20 pack year smoking history and additional comorbidity that produces a cumulative risk of developing lung cancer ≥ 5% in 5 years	2012
American Cancer Society	Age 55 to 74 years with ≥30 pack year smoking history, who either currently smoke or have quit within the past 15 years, and who are in relatively good health	2015
American College of Chest Physicans	Age 55 to 74 years with ≥30 pack year smoking history,who either currently smoke or have quit within the past 15 years	2013
American Society of Clinical Oncology	Age 55 to 74 years with ≥30 pack year smoking history,who either currently smoke or have quit within the past 15 years	2012
American Lung Association	Age 55 to 74 years with ≥ 30 pack year smoking history and no history of lung cancer	2012
Medicaid Services	Age 55 to 77 years with ≥ 30 pack year smoking history and smoking cessation < 15 years	2015
National Comprehensive Cancer Network	Age 55 to 74 years with ≥30 packyear smoking history and smoking cessation < 15 years OR Age ≥ 50 years and ≥20 pack year smoking history and additional risk factor (other than secondhand smoke exposure	2015
U.S Preventive Services Task Force	Age 55 to 80 years with ≥30 pack year smoking history and smoking cessation < 15 years	2013

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2], Maria Fernanda Villarreal, M.D. [3]

If left untreated, non-small cell lung cancer progression occurs slowly and is then followed by local invasion to lymph nodes and distant metastasis. Non-small cell lung cancer is a locally aggressive tumor, which commonly occurs in adult patients between 65 to 74 years. Common sites of metastasis include the adrenal gland, bone, brain, and liver. Complications of non-small cell lung cancer include acute respiratory failure, respiratory acidosis, malignant pleural effusion, metastases, and pneumonia. The 5-year relative survival of patients with non-small cell lung cancer is approximately 50%. Features associated with worse prognosis are presence of lymphatic invasion, location of lesion, gene expression profile, performance status, presence of satellite lesions, and presence of regional or distant metastases. Prognosis is generally regarded as poor with an all-stage average survival rate of 25%. The 5-year recurrence rate of non-small cell lung cancer is approximately 24%.

The majority of patients with non-small cell lung cancer are initially asymptomatic.^[1]

• The symptoms of non-small cell lung cancer usually develop in adult patients between 65 to 74 years.
• Initially, patients complain of chronic cough, diaphoresis, and weight-loss.^[2][3]
• If left untreated, patients with non-small cell lung cancer may develop local invasion to lymph nodes and distant metastasis.
• Common sites of metastasis include the adrenal gland, bone, brain, and liver.

Common complications of non-small cell lung cancer, include:^[1]

• Acute respiratory failure
• Respiratory acidosis
• Malignant pleural effusion
• Metastases
• Pneumonia

Non-small cell lung cancer prognosis and recurrence depends on the origin of primary tumor, histological type, and stage.^[1]

• Non-small cell lung cancer prognosis is generally regarded as poor.
• Non-small cell lung cancer survival rate ranges from 1% to 52% (stage I to stage IV).
• The recurrence rate of non-small cell lung cancer is 24%.

The development of complications is associated with worse prognosis. The median survival time of non-small cell lung cancer following a cancer-related complication, such as malignant pleural effusion, is approximately 1 to 3 months.^[4]

• Features associated with worse prognosis, include:
  • Presence of lymphatic invasion
  • Unfavorable genetic expression profile
  • Location of lesion
  • Performance status
  • Presence of satellite lesions
  • Presence of regional or distant metastases

• The table below summarizes the 5-year survival rate according to non-small cell lung cancer stage:

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

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