Lung cancer pathophysiology

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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., M.P.A., Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA, Cafer Zorkun, M.D., Ph.D. [2] Dildar Hussain, MBBS [3]Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S.

Overview

The pathophysiology of lung cancer includes both genetic and environmental factors. Genetic mutations, namely mutations in K-ras oncogene and TP53 tumor-suppressor gene, are associated with the development of lung cancers. Environmental factors often include smoking (most important carcinogen), 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.

Pathophysiology

The pathophysiology of lung cancer includes both genetic and environmental factors.

Genetics

• Lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.
• Mutations in the K-ras proto-oncogene are responsible for 20% to 30% of non-small cell lung cancer cases.
• Chromosomal damage may also result in 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.
• Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for:
  • Interleukin-1
  • Cytochrome P450, such as
  • caspase-8, an apoptosis promoter and s such as
  • XRCC1, a DNA repair molecule.
• Individuals with these polymorphisms are thought to be more likely to develop lung cancer following exposure to carcinogens.

Environment

Although genetics play a significant role in the pathogenesis of lung cancer, it is thought that exposure to environmental risk factors plays an equally improtant 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.

Smoking

• Cigarette smoking is a leading cause of lung cancer:
• 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 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. Nonetheless, it is thought that the risk of lung cancer among ever-smokers (even when stopped) is always higher than those who never smoked.

Radon gas

The association of radon gas exposure to lung cancer is described below:

• 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

• Asbestos exposure is associated with many lung diseases, including lung cancer.
• Tiny asbestos fibers are 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

• Viruses are known to be associated with the development of lung cancer in animals and humans which include:
  • 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.

Infection and Inflammation

• There may be a correlation between general inflammation of lung tissue and the development of lung cancers.
• 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.

Gross Pathology

Cross section of a human lung. The white area in the upper lobe is cancer; the black areas indicate the patient was a smoker

Microscopic Pathology

Small cell lung carcinoma (microscopic view of a core needle biopsy)