Lung Cancer

Human lungs are two spongy organs located on each side of the heart. During inhalation, air flows from the nose or mouth through the pharynx (throat) and larynx (which contain the vocal cords) into the trachea (wind pipe). The trachea divides into two bronchi, which direct air into the right and left lungs.

Within the lungs, the bronchi divide into several smaller bronchioles. Air flows from bronchioles into tiny air sacs, called alveoli. A group of alveoli is referred to as a lobule. Lobules are, in turn, grouped into lobes. The left lung contains two lobes, whereas the right contains three.

A network of tiny blood vessels, called capillaries, surrounds the alveoli. The lining of these blood vessels is so thin that oxygen and carbon dioxide can move between the capillaries and the alveoli. Carbon dioxide diffuses from the capillaries into the alveoli and is released from the body during exhalation. Oxygen diffuses in the opposite direction, from the alveoli into the blood, and is carried throughout the body by the circulatory system.

Most lung cancers begin in epithelialA type of tissue (epithelium) that covers our exposed surfaces, such as skin. Also lines our hollow or tube-like organs/tissues such as the digestive tract. Since these tissues are often exposed to environmental insults such as chemicals and solar radiation and are often divide rapidly to replace lost cells, many cancers arise in epithelial tissues. cells lining the bronchi.3 Cancers that develop in epithelial cells are known as carcinomas

Types Of

Lung cancer is divided into 2 main types, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The category of the cancer determines the treatment options.

Small Cell Lung Cancer

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers.4 Also known as oat cell carcinomaCancer of epithelial cells, the cells that cover the outside and inside of body surfaces. This is the most common form of cancer. or small cell undifferentiated carcinoma, SCLC tends to be aggressive. The cancer often grows rapidly and spreads to other parts of the body including lymph nodesA grape-like cluster of lymphatic tissue. Lymph nodes (or lymph glands) filter the lymph fluid that flows through the lymphatic system. Lymph nodes collect fluid from discrete regions of the body and are often examined for the presence of metastasizing cancer cells., bone, brain, adrenal glands, and the liver.5 Risk of developing SCLC is highly associated with tobacco smoking. Less than 5% of patients diagnosed with the disease have never smoked.5

Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is divided into three categories, based on appearance and other characteristics of the cancerous cells:

• Squamous cell carcinoma (SCC): SCC accounts for approximately 25-30% of all lung cancer cases. SCC is highly associated with tobacco smoking and usually develops in the central region of the lungs.3
• Adenocarcinoma: Adenocarcinomas account for approximately 40% of all lung cancer cases. This cancer type usually develops in the outer region of the lungs.3
• Large Cell Carcinoma (LCC): LCC accounts for approximately 10-15% of all lung cancer cases. LCC is associated with rapid tumor growth and poor prognosis.3

Other, less common types of lung cancers include carcinoid tumors, adenoid cystic carcinomas, hamartomas, lymphomas, and sarcomas.3

Watch the full interview with Dr. Gerold Bepler.

The risk factors for lung cancer include4:

• Smoking (especially cigarettes, pipes, cigars)
• Secondhand smoke and air pollution
• Radon gas released from soil and building materials
• Family history
• Asbestos
• Metals like chromium, cadmium, arsenic
• Chronic lung diseases such as tuberculosis
• RadiationIn cancer biology: A cancer treatment in which high energy beams are used to kill cancer cells. Radiation can also cause genetic damage that can lead to cancer. As an example, skin cancer is believed to be greatly increased by exposure to ultraviolet (UV) radiation from the sun.
• Diesel exhaust
• Paint

The relative effects of these and other risk factors in any given case of cancer are variable and very difficult to determine with accuracy at this time. Some of these and other risk factors are discussed below.

Family History of Lung Cancer
It is possible to inherit defective genes that lead to the development of a familial form of a particular cancer type. For example, certain genes influence a person's ability to metabolize some of the carcinogenic chemicals in cigarette smoke.6 An individual with inherited susceptibility that chooses to smoke may be at an increased the risk of developing lung cancer compared to other smokers.

Risk is higher if an immediate family member has been diagnosed with lung cancer. The more closely related an individual is to someone with lung cancer, the more likely they are to share the genes that increased the risk of the affected individual. Risk also increases with the number of relatives affected.

Learn more about the genetics of lung cancer here.

Watch the full interview with Dr. Gerold Bepler.

Smoking
Smoking is, by far, the leading risk factor for lung cancer. Risk increases with both quantity and duration of smoking.4 In 2004, the United States Surgeon General released a report addressing the harmful effects of smoking on health (The Health Consequences of Smoking: A Report of the Surgeon General). Included in the report were the following statements:

• "The evidence is sufficient to infer a causal relationship between smoking and lung cancer."
• "Smoking causes genetic changes in cells of the lung that ultimately lead to the development of lung cancer."
• "Although characteristics of cigarettes have changed during the last 50 years and yields of tar and nicotine have declined substantially...the risk of lung cancer in smokers has not declined."

There are more than 60 molecules in cigarette smoke that are thought to be carcinogenic in humans and laboratory animals.7 Two carcinogens highly associated with lung cancer are benzo[a]pyrene and N-nitrosamine NNK. These molecules bind to DNAAbbreviation for deoxyribonucleic acid. Composed of very long strings of nucleotides, which are abbreviated as A, C, G and T. DNA is the storage form of our genetic material. All of the instructions for the production of proteins are encoded in our DNA. and proteins; the toxin and the DNA are together called an adduct. The presence of adducts increases the chance of DNA mutation and interferes with the proper function of proteins. Learn more about DNA mutations. The presence of adducts is directly related to smoking status. Studies show that the level of adducts drops when a person quits smoking.8

Second-Hand Smoke
Exposure to second-hand smoke also greatly increases the risk of lung cancer. In 2006, the Surgeon General released a report addressing the harmful effects of second-hand smoke on health (The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General). According to the report, second-hand smoke contains over 50 cancer-causing chemicals and can lead to many health problems, including lung cancer. The effects of second-hand smoke are especially harmful to the developing lungs of infants and children.9

Radon
Radon is a naturally occurring, colorless, odorless gas. Exposure to radon is one of the leading risk factors for lung cancer, possibly contributing to 10% of all lung cancer cases.10 The mechanism by which radon leads to cancer is still unclear. Laboratory studies with radon have shown cellular damage that appears comparable to the damage caused by tobacco smoke, suggesting a similar mechanism of action. The production of reactive oxygen intermediates that can cause DNA damage is a likely event in mutagenicCausing alterations to DNA. If the alterations are not repaired exactly, changes in the DNA can lead to altered gene expression or gene products. Many mutagens are also carcinogens, agents that can cause cancer. Since cancer results from mutations in key genes, an agent that can cause changes has the potential to cause the changes that lead to cancer. Ironically, radiation and many of the chemotherapy agents used to treat cancer also have the potential to cause mutations and lead to cancer themselves. process caused by radon.11

Asbestos
Asbestos is a naturally occurring mineral that was frequently used in commercial construction throughout the 1950s and 1960s. The long, thin fibers of asbestos are fragile and have a tendency to break down into dust particles. Asbestos particles are easily inhaled into the lungs, where they cause damage to lung tissue that can lead to lung cancer.

Individuals who are exposed to asbestos and tobacco smoke are at a significantly increased risk of lung cancer. Studies suggest that asbestos particles may help deliver concentrated tobacco carcinogens to cells lining the lungs.12However the exact mechanism by which asbestos, alone or in combination with tobacco smoke, leads to lung cancer is still uncertain.

Chronic Lung Diseases
Chronic lung diseases such as asbestosis (scarring of lung tissue caused by asbestos), asthma, chronic bronchitis, emphysema, pneumonia, and tuberculosis have been suggested to increase risk of lung cancer.13 All of these diseases damage lung tissue and can result in scar tissue on the lungs.

As often is the case, it is difficult to distinguish between correlation (a relationship) and causation (an actual cause). As an example: the increased incidence of lung cancer in individuals with a history of chronic bronchitis (or emphysema) may be due to a genetic predisposition that increases susceptibility to both the bronchitis (or emphysema) AND cancer. In this instance, the first disease does not CAUSE the second.
On the other hand, the chronic diseases may aid in the accumulation of harmful toxins in the lungs, resulting in cell/tissue damage and CAUSING an increase in cancer.13 Further studies are needed to clearly determine if the observed correlation is actually a causative one.

Symptoms

Symptoms

There are no symptoms associated with early stage lung cancer. The American Cancer Society lists the following symptoms associated with advanced stage lung cancer.4 A physician should be consulted if they persist. It is important to note, however, that these symptoms may be caused by factors unrelated to cancer:

• Persistent cough
• Sputum streaked with blood
• Chest pain
• Voice change
• Recurrent pneumonia or bronchitis

Detection
Despite ongoing investigation into screening technology, research shows that lung cancer death rates have not improved. At the time they are diagnosed, the majority of lung cancers have progressed to an advanced state.14 Lung cancer screening is not currently routine practice.15 The disease is sometimes caught in its early stages by tests that are performed for other reasons. The most common methods of lung cancer detection include:

• chest x-ray
• chest CT (computer tomography) scan,
• bronchoscopy (insertion of a tube into the bronchi), and
• sputum cytology (examination of cells in the phlegm).16

These links will take you to the Detection and Diagnosis section.  Return to view the rest of the lung cancer information.

For more information about cancer detection, refer to the Detection and Diagnosis section.

The Pathology Report

If there is suspicion that a patient may have lung cancer, a sample of tissue (biopsyA medical procedure in which a sample of tissue is removed for examination. Biopsies can range from a small sample drawn into a needle to samples taken during more invasive surgery. ) may be taken for examination. After a biopsy is taken, the physician who performed the biopsy sends the specimen to a pathologist. The pathologist examines the specimen at both the macroscopic (visible with the naked eye) and microscopic (requiring magnification) levels and then sends a pathology report to the physician. The report contains information about the tissue's appearance, cellular makeup, and state of disease or normalcy. For more information about pathology reports, refer to the Diagnosis & Detection section.

Staging

Staging a cancer is a way of describing the extent of the disease. One of the most common methods used for cancer staging is called the T/N/M system, which assigns a degree of severity based on the size, location, and spread of cancer in the body. Staging of non-small cell lung cancer (NSCLC) follows the TNM criteria. Details of this system can be found in the Diagnosis and Detection section.

Because small cell lung cancer (SCLC) is often diagnosed at a more advanced state, the T/N/M system is not used. Instead small cell lung cancer is usually staged using the Veterans Administration Lung Study Group System, a 2-stage system based on location of the cancer. Most small cell lung cancers are diagnosed in the extensive stage.5

• Limited-stage: The cancer is located in only one lung and lymph nodes on the same side of the body
• Extensive-stage: The cancer has spread to the other lung and/or other regions of the body

Genetic changes that occur in cancer include mutation of key regulatory genes, changes in proteinOne of the four basic types of biomolecule. Proteins are polymers made up of strings of amino acids. Proteins serve many functions in organisms including transport of molecules, structure, cell adhesion and as signaling molecules such as hormones. Many transcription factors, including p53 and Rb are proteins. products, and changes in the amount of product produced by genes (gene expressionThe act of transcription and, if needed, translation of a gene. Regulation of gene expression is tightly regulated. Genes must only be expressed in the correct cells, at the right time and in the correct amount. Abnormal gene expression is always found in cancer cells.). As changes accumulate, cells become more abnormal and cancer progresses. Details of genetic change associated with cancer can be found in the Mutation section. There are over 100 genes known to be associated with the development of lung cancer. 17Some of the most frequently altered genes are listed below and discussed in the following sections:

• RasA proto-oncogene that is found to be mutated in many different kinds of cancer. The ras protein is involved in transmitting signals through the cell that drive the cell into the division process.
• Myc
• RbA tumor suppressor. The Rb gene is mutated in many different cancers but was initially described due to its role in the development of an eye cancer, retinoblastoma, which usually strikes young children. The protein product of the gene is a transcription factor that controls the expression of genes important in driving cells into the division process.
• TP53
• Epidermal Growth FactorA substance that stimulates cell division. Growth factors are usually small proteins or steroid hormones. They may be secreted by the same cells on which they act or by cells that reside in a different part of the body than the target cells. Some examples of growth factors include estrogen, a growth factor for breast cells, and VEGF, a growth factor that causes the development of blood vessels. Several different anti-cancer treatments are designed to inhibit the activity of growth factors. Receptor (EGFR)

Ras

Ras is an oncogeneA defective gene that is involved in triggering cancer cell growth. Oncogenes are altered forms of genes that normally are involved stimulating cell division. These normal genes are mutated and function in an inappropriate manner in cancer cells. An analogy would be that a mutated oncogene is like a car's gas pedal stuck in the on position. All forms of cancer have one or more mutant oncogenes. Examples of oncogenes that are altered in many cancers are myc, ras and Her-2/neu. Contrast with 'tumor suppressor'. that is altered in up to 30% of nonsmall cell lung cancers (NSCLC).17 The ras protein is involved in transmitting signals through the cell that drive the cell into the division process. Learn more about Ras

Myc

The Myc family of oncogenes are expressed abnormally in many types of cancer, including lung cancer. The myc protein acts as a transcription factorA molecule, usually a protein, that binds to DNA at the start of a gene, enabling that gene to be transcribed (copied) to form an RNA molecule. Transcription factors bind to specific parts of genes called promoters, so called because they promote transcription. Transcription factor binding to gene promoters is critical for regulation of the process. Since transcription factors ultimately control what genes are turned 'on' at any given time, they are essential for the proper functioning of the cell. A wide range of transcription factors are known to be associated with cancer. Changes, or mutations, in these genes leads to a deregulation of the whole process. Some key transcription factors are the p53 and Rb proteins. to regulate the expression of several genes. Learn more about transcription and transcription factors. Myc protein expression is altered in up to 80% of small cell lung cancers (SCLC).17Learn more about Myc

Rb

The retinoblastoma gene (Rb) is a tumor suppressorA gene that functions in the control of cell division. Tumor suppressors normally work to limit cell division and may be contrasted with oncogenes. altered in up to 90% of small cell lung cancers (SCLC).17Learn more about tumor suppressors The Rb protein interacts with transcription factors to indirectly control cell division. Learn more about Rb

TP53

TP53 (or P53A tumor suppressor gene that is mutated in over 50% of cancers of all types. The p53 protein is a transcription factor that controls entry into the cell division cycle. Many signals about the health of a cell are relayed to the p53 protein. This results in a decision by the cell as to whether or not cell division should occur. If the cell is damaged and can not be repaired, the p53 protein is involved in triggering a chain of events that causes the cell to kill itself in a process termed apoptosis. Cells defective for p53 do not have these controls and tend to divide even when conditions are not favorable. Like all tumor suppressors, the p53 gene is normally involved in slowing or monitoring cell division.) is a tumor suppressor gene altered in up to 50% of non small cell lung cancers (NSCLC) and 80% of small cell lung cancers (SCLC).17 The p53 protein interacts with DNA and other proteins to play an important role in the regulation cell growth and division, as well as programmed cell death, or apoptosisAlso called programmed cell death. Apoptosis is a natural process that occurs throughout the lives of almost all animals and plants. The death of the cells is a carefully controlled process that does not generate any inflammation.. Learn more about TP53

Epidermal Growth Factor Receptor

EGFR (epidermal growth factor receptor), also known as erbB1 and HER1, is a gene that encodes for a tyrosine kinaseAn enzyme that adds phosphate groups to target molecules. Often the targets of these enzymes are proteins that control the cell division process, so the enzymes play a key role in cell division. See also, kinase. located in the cell membraneA thin barrier between the cytoplasm and the extracellular space. Cell membranes are composed mainly of lipids and proteins. A hallmark of cellular membranes is their selective permeability to certain ions and other molecules. of epithelial cells. The EGFR protein is involved in response to growth factors and, under the right conditions, can stimulate epithelial cell division. OverexpressionA term describing the abnormal regulation of a gene. When the controls on gene expression (transcription) break down, the gene may be turned off inappropriately, or it may be transcribed at high rates. High transcription levels lead to the production of large amounts of mRNA and large amounts of the protein product. If that protein is important in regulating cell division or some other key process, then too much protein can lead to unregulated cell division. An example is the overexpression of the Her2/neu protein on the surface of some breast and ovarian cancers. The presence of large amounts of this protein increases abnormal cell division. of the EGFR protein occurs in approximately 60-85% of squamous cell carcinomas and 50% of large cell and adenocarcinomas. Overexpression of EGFR is seen only infrequently (0-5%) in small cell lung cancer (SCLC).18

Currently, there are two types of therapies directed against EGFR. MonoclonalDerived from a single source. In the context of cancer, the term is used in two ways: 1) to refer to the fact that tumors arise from a single damaged cell and 2) to describe the antibodies used in the treatment of cancer. antibodiesAntibodies are proteins produced by a type of white blood cell (B cells or B lymphocytes). Antibodies are able to stick very tightly to specific targets. Antibodies are currently being used as anti-cancer drugs (i.e. Herceptin). bind to the region of EGFR located outside the cell, preventing other (activating) molecules from binding. Tyrosine kinaseAn enzyme that adds phosphate groups to another molecule. Many key proteins controlling gene expression are kinase targets. Addition of a phosphate group to a protein can alter the activity of the protein and are often used as molecular on/off switches. For example, the retinoblastoma tumor suppressor gene is 'off' when phosphate groups are added to the protein at specific locations. Removal of the phosphate groups turns the protein 'on'. Enzymes that remove phosphate groups are known as phosphatases. Note that all enzymes, regardless of function, end in ASE inhibitors, on the other hand, bind to the section of EGFR located inside the cell, interfering with the activities of the receptor normally induced by the binding of an activator.19

Learn more about the use of antibodies in cancer treatment 
Learn more about kinase inhibitors in cancer treatment

As our focus is on the biology of the cancers and their treatments, we do not give detailed treatment guidelines. Instead, we link to organizations in the U.S. that generate the treatment guidelines.

The National Comprehensive Cancer Network (NCCN) lists the following treatments for lung cancer:

• Surgery
• Radiation Therapy
• ChemotherapyTreatment of cancer patients with anticancer drugs. Commonly called 'chemo'. These drugs work by attacking cell growth or division. Often these agents are used in combination to take advantage of their different modes of attack on cell division.

For more information about how these and other cancer treatments work, refer to the Cancer Treatments section.

Information about clinical trials:

• General clinical trial information from CancerQuest
• Click here for information about clinical trials from the National Cancer Institute.

• Click here for information about clinical trials from Georgia Clinical Trials Online.

   

Introduction

• Lung cancer currently ranks as the leading cause of cancer related death in men and women.
• Most lung cancers begin in epithelial cells lining the bronchi.

Types of Lung Cancer

• Lung cancer is divided into 2 main types, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
• SCLC tends to be an aggressive cancer and is highly associated with tobacco smoking.
• The majority of lung cancer cases are NSCLC which itself is subdivided into three categories: squamous cell carcinoma, adenocarcinoma, and lung cell carcinoma.

Risk Factors

• Smoking and second-hand smoke are, by far, the leading risk factors for lung cancer.
• Lung cancer risk is higher if an immediate family member has been diagnosed with lung cancer.
• Chemicals such as radon and asbestos increase lung cancer risk.
• Chronic lung diseases have also been implicated as a lung cancer risk.

Symptoms

• Advanced stage lung cancer symptoms: persistent cough, sputum streaked with blood, chest pain, voice change, recurrent pneumonia or bronchitis.

Detection and Diagnosis

• Common detection methods are chest x-ray, chest CT scanComputed Tomography. A non-invasive, X-ray based technique for imaging internal structures and identifying disease. May involve the use of an injected 'contrast' agent such as iodine., bronchoscopy, and sputum cytology.

Pathology Report and Staging

• A tissue biopsy of the lung is examined by a pathologist in order to create a pathology report.
• NSCLC uses the T/N/M staging system which assigns a degree of severity based on size, lymph node involvement, and spread of the cancer.
• SCLC is diagnosed as either limited or extensive depending on the spread of the cancer.

Lung Cancer Tumor Biology

• Many genetic changes occur in cancer. Details can be found in the Mutation section.
• Alterations in Ras, Myc, Rb, TP53, and EGFR have been implicated in the development of lung cancer.

Treatment

• Lung cancer treatments include surgery, chemotherapy and radiation therapy.

Know the Flow is an educational game for you to test your knowledge. To play:

• Drag the appropriate choices from the column on the right and place them in order in the boxes on the left. Note that you will only use five of the six choices to complete the game.
• When done, click on 'Check' to see how many you got correct.
• For incorrect answers, click on 'Description' to review information about the processes.
• To try again, choose 'Reset' and start over.