Lung Cancer

What Is Lung Cancer?

Lung cancer is the uncontrolled growth of abnormal cells that start off in one or both lungs; usually in the cells that line the air passages. The abnormal cells do not develop into healthy lung tissue, they divide rapidly and form tumors. As tumors become larger and more numerous, they undermine the lung’s ability to provide the bloodstream with oxygen. Tumors that remain in one place and do not appear to spread are known as “benign tumors”.

Malignant tumors, the more dangerous ones, spread to other parts of the body either through the bloodstream or the lymphatic system. Metastasis refers to cancer spreading beyond its site of origin to other parts of the body. When cancer spreads it is much harder to treat successfully.
Primary lung cancer originates in the lungs, while secondary lung cancer starts somewhere else in the body, metastasizes, and reaches the lungs. They are considered different types of cancers and are not treated in the same way.
According to the National Cancer Institute, by the end of 2012 there will have been 226,160 new lung cancer diagnoses and 160,340 lung-cancer related deaths in the USA.
According to the World Health Organization (WHO), 7.6 million deaths globally each year are caused by cancer; cancer represents 13% of all global deaths. As seen below, lung cancer is by far the number one cancer killer.
Total deaths worldwide caused by cancer each year:

• Lung cancer - 1,370,000 deaths
• Stomach cancer - 736,000 deaths
• Liver cancer - 695,000 deaths
• Colorectal cancer - 608,000 deaths
• Breast cancer - 458,000 deaths
• Cervical cancer - 275,000 deaths

The American Cancer Society says that lung cancer makes up 14% of all newly diagnosed cancers in the USA today. It adds that annually, more patients die from lung cancer alone than prostate, breast and colon cancers combined (in the USA). An American man’s lifetime risk of developing lung cancer is 1 in 13; for a woman the risk is 1 in 16. These risk figures are for all US adults, including smokers, ex-smokers and non-smokers. The risk for a regular smoker is dramatically higher.
Most lung cancer patients are over the age of 60 years when they are diagnosed. Lung cancer takes several years to reach a level where symptoms are felt and the sufferer decides to seek medical help.
Female lung cancer rates set to rise rapidly
Over the next three decades, female lung cancers will increase thirty-five times faster than male lung cancers, scientists from King’s College London reported in October 2012.
In the UK, female lung cancer deaths will reach 95,000 annually in 2040, from 26,000 in 2010 – a rise of more than 350%. Male annual lung cancer deaths will increase by 8% over the same period, to 42,000 in 2040 from 39,000 in 2010.
The authors of the report say that lung cancer will continue being the largest cancer killer over the next thirty years. Twice as many people will be living with lung cancer in 2040 compared to 2010. The main reason for the increase will be longer lifespans - the older you are, the higher your risk of cancer is, including lung cancer.

How is lung cancer classified?

Lung cancer can be broadly classified into two main types based on the cancer's appearance under a microscope: non-small cell lung cancer and small cell lung cancer. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers, while small cell lung cancer accounts for the remaining 20%.
NSCLC can be further divided into four different types, each with different treatment options:

• Squamous cell carcinoma or epidermoid carcinoma. As the most common type of NSCLC and the most common type of lung cancer in men, squamous cell carcinoma forms in the lining of the bronchial tubes.
• Adenocarcinoma. As the most common type of lung cancer in women and in nonsmokers, adenocarcinoma forms in the mucus-producing glands of the lungs.
• Bronchioalveolar carcinoma. This type of lung cancer is a rare type of adenocarcinoma that forms near the lungs' air sacs.
• Large-cell undifferentiated carcinoma. A rapidly growing cancer, large-cell undifferentiated carcinomas form near the outer edges or surface of the lungs.

Small cell lung cancer (SCLC) is characterized by small cells that multiply quickly and form large tumors that travel throughout the body. Almost all cases of SCLC are due to smoking.

What causes cancer?

Cancer is ultimately the result of cells that uncontrollably grow and do not die. Normal cells in the body follow an orderly path of growth, division, and death. Programmed cell death is called apoptosis, and when this process breaks down, cancer begins to form. Unlike regular cells, cancer cells do not experience programmatic death and instead continue to grow and divide. This leads to a mass of abnormal cells that grows out of control.
Lung cancer occurs when a lung cell's gene mutation makes the cell unable to correct DNA damage and unable to commit suicide. Mutations can occur for a variety of reasons. Most lung cancers are the result of inhaling carcinogenic substances.

Carcinogens

Carcinogens are a class of substances that are directly responsible for damaging DNA, promoting or aiding cancer. Tobacco, asbestos, arsenic, radiation such as gamma and x-rays, the sun, and compounds in car exhaust fumes are all examples of carcinogens. When our bodies are exposed to carcinogens, free radicals are formed that try to steal electrons from other molecules in the body. These free radicals damage cells and affect their ability to function and divide normally.
About 87% of lung cancers are related to smoking and inhaling the carcinogens in tobacco smoke. Even exposure to second-hand smoke can damage cells so that cancer forms.

Genes

Cancer can be the result of a genetic predisposition that is inherited from family members. It is possible to be born with certain genetic mutations or a fault in a gene that makes one statistically more likely to develop cancer later in life. Genetic predispositions are thought to either directly cause lung cancer or greatly increase one's chances of developing lung cancer from exposure to certain environmental factors.

How does lung cancer develop? - video

A short video explaining how lung cancer develops. Video by eHow.

What are the symptoms of lung cancer?

Cancer symptoms are quite varied and depend on where the cancer is located, where it has spread, and how big the tumor is. Lung cancer symptoms may take years before appearing, usually after the disease is in an advanced stage.
Many symptoms of lung cancer affect the chest and air passages. These include:

• Persistent or intense coughing
• Pain in the chest shoulder, or back from coughing
• Changes in color of the mucus that is coughed up from the lower airways (sputum)
• Difficulty breathing and swallowing
• Hoarseness of the voice
• Harsh sounds while breathing (stridor)
• Chronic bronchitis or pneumonia
• Coughing up blood, or blood in the sputum

If the lung cancer spreads, or metastasizes, additional symptoms can present themselves in the newly affected area. Swollen or enlarged lymph nodes are common and likely to be present early. If cancer spreads to the brain, patients may experience vertigo, headaches, or seizures. In addition, the liver may become enlarged and cause jaundice and bones can become painful, brittle, and broken. It is also possible for the cancer to infect the adrenal glands resulting in hormone level changes.
As lung cancer cells spread and use more of the body's energy, it is possible to present symptoms that may also be associated with many other ailments. These include:

• Fever
• Fatigue
• Unexplained weight loss
• Pain in joints or bones
• Problems with brain function and memory
• Swelling in the neck or face
• General weakness
• Bleeding and blood clots

How is lung cancer diagnosed and staged?

Physicians use information revealed by symptoms as well as several other procedures in order to diagnose lung cancer. Common imaging techniques include chest X-rays, bronchoscopy (a thin tube with a camera on one end), CT scans, MRI scans, and PET scans.

Physicians will also conduct a physical examination, a chest examination, and an analysis of blood in the sputum. All of these procedures are designed to detect where the tumor is located and what additional organs may be affected by it.
Although the above diagnostic techniques provided important information, extracting cancer cells and looking at them under a microscope is the only absolute way to diagnose lung cancer. This procedure is called a biopsy. If the biopsy confirms lung cancer, a pathologist will determine whether it is non-small cell lung cancer or small cell lung cancer.
After a diagnosis is made, an oncologist will determine the stage of the cancer by finding out how far the cancer has spread. The stage determines which choices will be available for treatment and informs prognosis. The most common cancer staging method is called the TNM system. T (1-4) indicates the size and direct extent of the primary tumor, N (0-3) indicates the degree to which the cancer has spread to nearby lymph nodes, and M (0-1) indicates whether the cancer has metastasized to other organs in the body. A small tumor that has not spread to lymph nodes or distant organs may be staged as (T1, N0, M0), for example.
For non-small cell lung cancer, TNM descriptions lead to a simpler categorization of stages. These stages are labeled from I to IV, where lower numbers indicate earlier stages where the cancer has spread less. More specifically:

• Stage I is when the tumor is found only in one lung and in no lymph nodes.
• Stage II is when the cancer has spread to the lymph nodes surrounding the infected lung.
• Stage IIIa is when the cancer has spread to lymph nodes around the trachea, chest wall, and diaphragm, on the same side as the infected lung.
• Stage IIIb is when the cancer has spread to lymph nodes on the other lung or in the neck.
• Stage IV is when the cancer has spread throughout the rest of the body and other parts of the lungs.

Small cell lung cancer has two stages: limited or extensive. In the limited stage, the tumor exists in one lung and in nearby lymph nodes. In the extensive stage, the tumor has infected the other lung as well as other organs in the body.

Screening for lung cancer - video

A video tutorial discussing Lung Cancer and screening. Video by OncologyPodCasting.

How is lung cancer treated?

Lung cancer treatments depend on the type of cancer, the stage of the cancer (how much it has spread), age, health status, and additional personal characteristics. As there is usually no single treatment for cancer, patients often receive a combination of therapies and palliative care. The main lung cancer treatments are surgery, chemotherapy, and/or radiation. However, there also have been recent developments in the fields of immunotherapy, hormone therapy, and gene therapy.

Surgery

Surgery is the oldest known treatment for cancer. If a cancer is in stage I or II and has not metastasized, it is possible to completely cure a patient by surgically removing the tumor and the nearby lymph nodes. After the disease has spread, however, it is nearly impossible to remove all of the cancer cells.

Lung cancer surgery is performed by a specially trained thoracic surgeon. After removing the tumor and the surrounding margin of tissue, the margin is further studied to see if cancer cells are present. If no cancer is found in the tissue surrounding the tumor, it is considered a "negative margin." A "positive margin" may require the surgeon to remove more of the lung tissue.
Lung cancer surgery can be curative or palliative. Curative surgery aims to cure a patient with early stage lung cancer by removing all of the cancerous tissue. Palliative surgery aims to remove an obstruction or open an airway, making the patient more comfortable but not necessarily removing the cancer.
Surgery carries side effects - most notably pain and infection. Lung cancer surgery is an invasive procedure that can cause harm to the surrounding body parts. Doctors will usually provide several options for alleviating any pain from surgery. Antibiotics are commonly used to prevent infections that may occur at the site of the wound or elsewhere inside the body.

Radiation

Radiation treatment, also known as radiotherapy, destroys or shrinks lung cancer tumors by focusing high-energy rays on the cancer cells. This causes damage to the molecules that make up the cancer cells and leads them to commit suicide. Radiotherapy utilizes high-energy gamma-rays that are emitted from metals such as radium or high-energy x-rays that are created in a special machine. Radiation can be used as the main treatment for lung cancer, to kill remaining cells after surgery, or to kill cancer cells that have metastasized.

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Early radiation treatments caused severe side-effects because the energy beams would damage normal, healthy tissue, but technologies have improved so that beams can be more accurately targeted. Radiation oncologists can focus the radiation in precise locations in the body for certain lengths of time, reducing the risk of damage to surrounding healthy tissue. Treatments occur intermittently over weeks or months depending on the size and extent of the tumor, the dosage of radiation, and how much damage is being done to noncancerous tissue.
Common side effects of radiation therapy include fatigue, nausea, loss of appetite, hair loss, and skin affectations that cause skin to become dry, irritated, and sensitive.

Chemotherapy

Chemotherapy utilizes strong chemicals that interfere with the cell division process - damaging proteins or DNA - so that cancer cells will commit suicide. These treatments target any rapidly dividing cells (not just cancer cells), but normal cells usually can recover from any chemical-induced damage while cancer cells cannot. Chemotherapy is considered systemic because its medicines travel throughout the entire body, killing the original tumor cells as well as cancer cells that have spread throughout the body.

A medical oncologist will usually prescribe chemotherapy drugs for lung cancer to be taken intravenously, but there are also drugs available in tablet, capsule, and liquid form. Chemotherapy treatment occurs in cycles so the body has time to heal between doses, and dosages are determined by the type of lung cancer, the type of drug, and how the person responds to treatment. Medicines may be administered daily, weekly, or monthly, and can continue for months or even years.
Combination therapies often include multiple types of chemotherapy, and chemotherapy is also given as adjuvant therapy as a complement to surgery and radiation. Adjuvant therapy is designed to reduce the risk of cancer recurrence after surgery and killing any cancer cells that exist after surgery. Chemotherapy can be given before surgery, called neo-adjuvant therapy, to shrink tumors and to make surgery more successful.
Chemotherapy carries several common side effects, but they depend on the type of chemotherapy and the health of the patient. These include nausea and vomiting, appetite loss, diarrhea, hair loss, fatigue from anemia, infections, bleeding, and mouth sores. Many of these side effects are only temporarily felt during treatment, and several drugs exist to help patients cope with the symptoms.

Other lung cancer treatments

Researchers continue to search for ways to improve lung cancer treatments and find new methods of treating the disease.
Targeted therapies are designed to only treat cancer cells while leaving alone normal and healthy lung cells. These include monoclonal antibodies that travel directly to the cancer cells and release drugs or radiation, anti-angiogenesis agents that interfere with the blood supply creation mechanism of cancer cells, and growth factor inhibitors that block the effects of growth factors and disallow the cancerous cells to grow.
PARP (poly ADP ribose polymerase) inhibitors - approximately 50% of PARP inhibitors could help treat patients with non-small-cell lung cancer, researchers from The Institute of Cancer Research, London, reported in the journal Oncogene.
PARP inhibitors are currently used for treating patients with ovarian or breast cancer caused by mutated BRCA1 or BRCA2 genes. This type of medication targets two DNA repair systems simultaneously - destroying the cancerous cells while leaving the healthy ones alone.
There is also some research in the area of lung cancer vaccines that first transform cancer cells so they are no longer cancerous. However, the cells will exist such that the body's immune system can recognize the cancerous cells as foreign and attack them. These targeted therapies are also called immunotherapies because the treatment tweaks the body's natural immune responses.

How can lung cancer be prevented?

Cancers that are closely linked to certain behaviors are the easiest to prevent. For example, choosing not to smoke tobacco or drink alcohol significantly lowers the risk of several types of cancer - most notably lung, throat, mouth, and liver cancer. Even if you are a current tobacco user, quitting can still greatly reduce your chances of getting cancer. The most important preventive measure you can take to avoid lung cancer is to quit smoking.
Quitting smoking will also reduce your risk of several other types of cancer including esophagus, pancreas, larynx, and bladder cancer. If you quit smoking, you will usually reap additional benefits such as lower blood pressure, enhanced blood circulation, and increased lung capacity.
Exposure to tobacco smoke is not the only risk factor for lung cancer though. Those who have come into contact with asbestos, radon, and secondhand smoke also have an increased risk of developing lung cancer. In addition, having a family member who developed lung cancer without being exposed to carcinogens could mean that you have a genetic predisposition for developing the disease, increasing your overall risk.
Eating raw garlic reduces lung cancer risk - a research team from the Jiangsu Provincial Center for Disease Control and Prevention, China, reported in the journal Cancer Prevention Research that people who eat raw garlic twice a week could be cutting their lung cancer risk in half.
The authors said "Protective association between intake of raw garlic and lung cancer has been observed with a dose-response pattern, suggesting that garlic may potentially serve as a chemo-preventive agent for lung cancer."
Screening techniques are designed to find cancer at the earliest stage so that the most treatment options are available, increasing survival rates and avoiding highly invasive procedures. Most lung cancers are detected in the late stages of the disease after they have spread and are harder to treat. Although there currently do not exist approved screening tests for lung cancer that improve survival or detect localized disease, there is promising research underway. Advocates of screening recommend that certain high risk groups be screened. This includes persons age 60 or older with a history of smoking, previous lung tumors, or chronic obstructive pulmonary disease (COPD). Possible lung cancer screening tests include analysis of sputum cells, fiberoptic examination of bronchial passages (bronchoscopy), and low-dose spiral CT scans.

Lung cancer - the future of healthcare delivery

Stephen C Schimpff, MD has written an article on lung cancer and how technologies now and in the future are offering hope to this devastating disease. You can read this article in our special section entitled The Future Of Healthcare Delivery For Lung Cancer.

                           Lung cancer

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Lung cancer
Classification and external resources
A chest X-ray showing a tumor in the lung (marked by arrow)
ICD-10	C33-C34
ICD-9	162
DiseasesDB	7616
MedlinePlus	007194
eMedicine	med/1333 med/1336 emerg/335 radio/807 radio/405 radio/406
MeSH	D002283

Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue or other parts of the body. Most cancers that start in lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. The main types of lung cancer are small-cell lung carcinoma (SCLC), also called oat cell cancer, and non-small-cell lung carcinoma (NSCLC). The most common symptoms are coughing (including coughing up blood), weight loss and shortness of breath.^[1]
The most common cause of lung cancer is long-term exposure to tobacco smoke,^[2] which causes 80–90% of lung cancers.^[1] Nonsmokers account for 10–15% of lung cancer cases,^[3] and these cases are often attributed to a combination of genetic factors,^[4] radon gas,^[4] asbestos,^[5] and air pollution^[4] including second-hand smoke.^[6][7] Lung cancer may be seen on chest radiograph and computed tomography (CT scan). The diagnosis is confirmed with a biopsy^[8] which is usually performed by bronchoscopy or CT-guidance. Treatment and long-term outcomes depend on the type of cancer, the stage (degree of spread), and the person's overall health, measured by performance status.
Common treatments include surgery, chemotherapy, and radiotherapy. NSCLC is sometimes treated with surgery, whereas SCLC usually responds better to chemotherapy and radiotherapy.^[9] Overall, 15% of people in the United States diagnosed with lung cancer survive five years after the diagnosis.^[10] Worldwide, lung cancer is the most common cause of cancer-related death in men and women, and is responsible for 1.38 million deaths annually, as of 2008.^[11]

Contents

• 1 Signs and symptoms
• 2 Causes
  • 2.1 Smoking
  • 2.2 Radon gas
  • 2.3 Asbestos
  • 2.4 Air pollution
  • 2.5 Genetics
  • 2.6 Other causes
• 3 Pathogenesis
• 4 Diagnosis
  • 4.1 Classification
  • 4.2 Staging
• 5 Prevention
  • 5.1 Screening
• 6 Management
  • 6.1 Surgery
  • 6.2 Radiotherapy
  • 6.3 Chemotherapy
  • 6.4 Palliative care
• 7 Prognosis
• 8 Epidemiology
• 9 History
• 10 References
• 11 External links

Signs and symptoms

Signs and symptoms that may suggest lung cancer include:^[1]

• respiratory symptoms: coughing, coughing up blood, wheezing or shortness of breath
• systemic symptoms: weight loss, fever, clubbing of the fingernails, or fatigue
• symptom due to local compress: chest pain, bone pain, superior vena cava obstruction, difficulty swallowing

If the cancer grows in the airway, it may obstruct airflow, causing breathing difficulties. The obstruction can lead to accumulation of secretions behind the blockage, and predispose to pneumonia.^[1]
Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease.^[12] In lung cancer, these phenomena may include Lambert–Eaton myasthenic syndrome (muscle weakness due to autoantibodies), hypercalcemia, or syndrome of inappropriate antidiuretic hormone (SIADH). Tumors in the top of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to Horner's syndrome (dropping of the eyelid and a small pupil on that side), as well as damage to the brachial plexus.^[1]
Many of the symptoms of lung cancer (poor appetite, weight loss, fever, fatigue) are not specific.^[8] In many people, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Common sites of spread include the brain, bone, adrenal glands, opposite lung, liver, pericardium, and kidneys.^[13] About 10% of people with lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest radiography.^[10]

Causes

Cancer develops following genetic damage to DNA. This genetic damage affects the normal functions of the cell, including cell proliferation, programmed cell death (apoptosis) and DNA repair. As more damage accumulates, the risk of cancer increases.^[14]

Smoking

Graph showing how a general increase in sales of tobacco products in the USA in the first four decades of the 20th century (cigarettes per person per year) led to a corresponding rapid increase in the rate of lung cancer during the 1930s, '40s and '50s (lung cancer deaths per 100,000 male population per year)

Cross section of a human lung: The white area in the upper lobe is cancer; the black areas are discoloration due to smoking.

Smoking, particularly of cigarettes, is by far the main contributor to lung cancer.^[15] Cigarette smoke contains over 60 known carcinogens,^[16] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune response to cancerous growths in exposed tissue.^[17] Across the developed world, 90% of lung cancer deaths in men during the year 2000 were attributed to smoking (70% for women).^[18] Smoking accounts for 80–90% of lung cancer cases.^[1]
Passive smoking—the inhalation of smoke from another's smoking—is a cause of lung cancer in nonsmokers. A passive smoker can be classified as someone living or working with a smoker. Studies from the US,^[19][20][21] Europe,^[22] the UK,^[23] and Australia^[24] have consistently shown a significantly increased risk among those exposed to passive smoke.^[25] Those who live with someone who smokes have a 20–30% increase in risk while those who work in an environment with second hand smoke have a 16–19% increase in risk.^[26] Investigations of sidestream smoke suggest it is more dangerous than direct smoke.^[27] Passive smoking causes about 3,400 deaths from lung cancer each year in the USA.^[21]

Radon gas

Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the Earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon is the second-most common cause of lung cancer in the USA, after smoking.^[21] The risk increases 8–16% for every 100 Bq/m³ increase in the radon concentration.^[28] Radon gas levels vary by locality and the composition of the underlying soil and rocks. For example, in areas such as Cornwall in the UK (which has granite as substrata), radon gas is a major problem, and buildings have to be force-ventilated with fans to lower radon gas concentrations. The United States Environmental Protection Agency (EPA) estimates one in 15 homes in the US has radon levels above the recommended guideline of 4 picocuries per liter (pCi/l) (148 Bq/m³).^[29]

Asbestos

Asbestos can cause a variety of lung diseases, including lung cancer. Tobacco smoking and asbestos have a synergistic effect on the formation of lung cancer.^[5] Asbestos can also cause cancer of the pleura, called mesothelioma (which is different from lung cancer).^[30]

Air pollution

Outdoor air pollution has a small effect on increasing the risk of lung cancer.^[4] Fine particulates (PM_2.5) and sulfate aerosols, which may be released in traffic exhaust fumes, are associated with slightly increased risk.^[4][31] For nitrogen dioxide, an incremental increase of 10 parts per billion increases the risk of lung cancer by 14%.^[32] Outdoor air pollution is estimated to account for 1–2% of lung cancers.^[4]
Tentative evidence supports an increased risk of lung cancer from indoor air pollution related to the burning of wood, charcoal, dung or crop residue for cooking and heating.^[33] Women who are exposed to indoor coal smoke have about twice the risk and a number of the by-products of burning biomass are known or suspected carcinogens.^[34] This risk affects about 2.4 billion people globally,^[33] and is believed to account for 1.5% of lung cancer deaths.^[34]

Genetics

It is estimated that 8 to 14% of lung cancer is due to inherited factors.^[35] In relatives of people with lung cancer, the risk is increased 2.4 times. This is likely due to a combination of genes.^[36]

Other causes

Numerous other substances, occupations, and environmental exposures have been linked to lung cancer. The International Agency for Research on Cancer (IARC) states there is "sufficient evidence" to show the following are carcinogenic in lung:^[37]

• Some metals (aluminum production, cadmium and cadmium compounds, chromium(VI) compounds, beryllium and beryllium compounds, iron and steel founding, nickel compounds, arsenic and inorganic arsenic compounds, underground hematite mining)
• Some products of combustion (incomplete combustion, coal (indoor emissions from household coal burning), coal gasification, coal-tar pitch, coke production, soot, diesel engine exhaust)
• Ionizing radiation (X-radiation, radon-222 and its decay products, gamma radiation, plutonium)
• Some toxic gases (methyl ether (technical grade), Bis-(chloromethyl) ether, sulfur mustard, MOPP (vincristine-prednisone-nitrogen mustard-procarbazine mixture), fumes from painting)
• Rubber production and crystalline silica dust

Pathogenesis

See also: Carcinogenesis

Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.^[38] Oncogenes are believed to make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens.^[39] Mutations in the K-ras proto-oncogene are responsible for 10–30% of lung adenocarcinomas.^[40][41] The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion.^[40] Mutations and amplification of EGFR are common in non-small-cell lung cancer and provide the basis for treatment with EGFR-inhibitors. Her2/neu is affected less frequently.^[40] Chromosomal damage can lead to loss of heterozygosity. This can cause inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q, and 17p are particularly common in small-cell lung carcinoma. The p53 tumor suppressor gene, located on chromosome 17p, is affected in 60-75% of cases.^[42] Other genes that are often mutated or amplified are c-MET, NKX2-1, LKB1, PIK3CA, and BRAF.^[40]

Diagnosis

CT scan showing a cancerous tumor in the left lung

Performing a chest radiograph is one of the first investigative steps if a person reports symptoms that may suggest lung cancer. This may reveal an obvious mass, widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (pneumonia), or pleural effusion.^[2] CT imaging is typically used to provide more information about the type and extent of disease. Bronchoscopy or CT-guided biopsy is often used to sample the tumor for histopathology.^[10]
Lung cancer often appears as a solitary pulmonary nodule on a chest radiograph. However, the differential diagnosis is wide. Many other diseases can also give this appearance, including tuberculosis, fungal infections, metastatic cancer, or organizing pneumonia. Less common causes of a solitary pulmonary nodule include hamartomas, bronchogenic cysts, adenomas, arteriovenous malformation, pulmonary sequestration, rheumatoid nodules, Wegener's granulomatosis, or lymphoma.^[43] Lung cancer can also be an incidental finding, as a solitary pulmonary nodule on a chest radiograph or CT scan done for an unrelated reason.^[44] The definitive diagnosis of lung cancer is based on histological examination of the suspicious tissue in the context of the clinical and radiological features.^[1]

Classification

Age-adjusted incidence of lung cancer by histological type^[4]

Histological type	Incidence per 100,000 per year
All types	66.9
Adenocarcinoma	22.1
Squamous-cell carcinoma	14.4
Small-cell carcinoma	9.8

Lung cancers are classified according to histological type.^[8] This classification is important for determining management and predicting outcomes of the disease. The vast majority of lung cancers are carcinomas—malignancies that arise from epithelial cells. Lung carcinomas are categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope. The two broad classes are non-small-cell and small-cell lung carcinoma.^[45]

Non-small-cell lung carcinoma

Micrograph of squamous carcinoma, a type of non-small-cell carcinoma, FNA specimen, Pap stain

The three main subtypes of NSCLC are adenocarcinoma, squamous-cell lung carcinoma, and large-cell lung carcinoma.^[1]
Nearly 40% of lung cancers are adenocarcinoma, which usually originates in peripheral lung tissue.^[8] Most cases of adenocarcinoma are associated with smoking; however, among people who have smoked fewer than 100 cigarettes in their lifetimes ("never-smokers"),^[1] adenocarcinoma is the most common form of lung cancer.^[46] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have a better long term survival.^[47]
Squamous-cell carcinoma accounts for about 30% of lung cancers. They typically occur close to large airways. A hollow cavity and associated cell death are commonly found at the center of the tumor.^[8] About 9% of lung cancers are large-cell carcinoma. These are so named because the cancer cells are large, with excess cytoplasm, large nuclei and conspicuous nucleoli.^[8]

Small-cell lung carcinoma

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

In small-cell lung carcinoma (SCLC), the cells contain dense neurosecretory granules (vesicles containing neuroendocrine hormones), which give this tumor an endocrine/paraneoplastic syndrome association.^[48] Most cases arise in the larger airways (primary and secondary bronchi).^[10] These cancers grow quickly and spread early in the course of the disease. Sixty to seventy percent have metastatic disease at presentation. This type of lung cancer is strongly associated with smoking.^[1]

Others

Four main histological subtypes are recognized, although some cancers may contain a combination of different subtypes.^[45] Rare subtypes include glandular tumors, carcinoid tumors, and undifferentiated carcinomas.^[1]

Metastasis

Typical immunostaining in lung cancer^[1]

Histological type	Immunostain
Squamous-cell carcinoma	CK5/6 positive CK7 negative
Adenocarcinoma	CK7 positive TTF-1 positive
Large-cell carcinoma	TTF-1 negative
Small-cell carcinoma	TTF-1 positive CD56 positive Chromogranin positive Synaptophysin positive

The lung is a common place for the spread of tumors from other parts of the body. Secondary cancers are classified by the site of origin; e.g., breast cancer that has spread to the lung is called metastatic breast cancer. Metastases often have a characteristic round appearance on chest radiograph.^[49]
Primary lung cancers themselves most commonly metastasize to the brain, bones, liver, and adrenal glands.^[8] Immunostaining of a biopsy is often helpful to determine the original source.^[50]

Staging

See also: Lung cancer staging

Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. It is one of the factors affecting the prognosis and potential treatment of lung cancer.^[1]
The initial evaluation of non-small-cell lung cancer (NSCLC) staging uses the TNM classification. This is based on the size of the primary tumor, lymph node involvement, and distant metastasis. After this, using the TNM descriptors, a group is assigned, ranging from occult cancer, through stages 0, IA (one-A), IB, IIA, IIB, IIIA, IIIB and IV (four). This stage group assists with the choice of treatment and estimation of prognosis.^[51] Small-cell lung carcinoma (SCLC) has traditionally been classified as 'limited stage' (confined to one half of the chest and within the scope of a single tolerable radiotherapy field) or 'extensive stage' (more widespread disease).^[1] However, the TNM classification and grouping are useful in estimating prognosis.^[51]
For both NSCLC and SCLC, the two general types of staging evaluations are clinical staging and surgical staging. Clinical staging is performed prior to definitive surgery. It is based on the results of imaging studies (such as CT scans and PET scans) and biopsy results. Surgical staging is evaluated either during or after the operation, and is based on the combined results of surgical and clinical findings, including surgical sampling of thoracic lymph nodes.^[8]

Prevention

See also: Smoking ban

Prevention is the most cost-effective means of decreasing lung cancer development. While in most countries industrial and domestic carcinogens have been identified and banned, tobacco smoking is still widespread. Eliminating tobacco smoking is a primary goal in the prevention of lung cancer, and smoking cessation is an important preventive tool in this process.^[52]
Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries.^[53] Bhutan has had a complete smoking ban since 2005^[54] while India introduced a ban on smoking in public in October 2008.^[55] The World Health Organization has called for governments to institute a total ban on tobacco advertising to prevent young people from taking up smoking. They assess that such bans have reduced tobacco consumption by 16% where instituted.^[56]
The long-term use of supplemental vitamin A,^[57][58] vitamin C,^[57] vitamin D^[59] or vitamin E^[57] does not reduce the risk of lung cancer. Some studies suggest people who eat diets with a higher proportion of vegetables and fruit tend have a lower risk,^[21][60] but this is likely due to confounding. More rigorous studies have not demonstrated a clear association.^[60]

Screening

Main article: Lung cancer screening

Screening refers to the use of medical tests to detect disease in asymptomatic people. Possible screening tests for lung cancer include sputum cytology, chest radiograph (CXR), and computed tomography (CT). Screening programs using CXR or cytology have not demonstrated benefit.^[61] Screening those at high risk (i.e. age 55 to 79 who have smoked more than 30 pack years or those who have had previous lung cancer) annually with low-dose CT scans may reduce the chance of death from lung cancer by an absolute amount of 0.3% (relative amount of 20%).^[62][63] There is, however, a high rate of falsely positive scans which may result in unneeded invasive procedures as well as substantial financial cost.^[64] For each true positive scan there are more than 19 false positives.^[65] Radiation exposure is another potential harm from screening.^[66]

Management

Main article: Treatment of lung cancer

Treatment for lung cancer depends on the cancer's specific cell type, how far it has spread, and the person's performance status. Common treatments include palliative care,^[67] surgery, chemotherapy, and radiation therapy.^[1]

Surgery

Main article: Lung cancer surgery

Pneumonectomy specimen containing a squamous-cell carcinoma, seen as a white area near the bronchi

If investigations confirm NSCLC, the stage is assessed to determine whether the disease is localized and amenable to surgery or if it has spread to the point where it cannot be cured surgically. CT scan and positron emission tomography are used for this determination.^[1] If mediastinal lymph node involvement is suspected, mediastinoscopy may be used to sample the nodes and assist staging.^[68] Blood tests and pulmonary function testing are used to assess whether a person is well enough for surgery.^[10] If pulmonary function tests reveal poor respiratory reserve, surgery may not be a possibility.^[1]
In most cases of early-stage NSCLC, removal of a lobe of lung (lobectomy) is the surgical treatment of choice. In people who are unfit for a full lobectomy, a smaller sublobar excision (wedge resection) may be performed. However, wedge resection has a higher risk of recurrence than lobectomy.^[69] Radioactive iodine brachytherapy at the margins of wedge excision may reduce the risk of recurrence.^[70] Rarely, removal of a whole lung (pneumonectomy) is performed.^[69] Video-assisted thoracoscopic surgery and VATS lobectomy use a minimally invasive approach to lung cancer surgery.^[71] VATS lobectomy is equally effective compared to conventional open lobectomy, with less postoperative illness.^[72]
In SCLC, chemotherapy and/or radiotherapy is typically used.^[73] However the role of surgery in SCLC is being reconsidered. Surgery might improve outcomes when added to chemotherapy and radiation in early stage SCLC.^[74]

Radiotherapy

Radiotherapy is often given together with chemotherapy, and may be used with curative intent in people with NSCLC who are not eligible for surgery. This form of high-intensity radiotherapy is called radical radiotherapy.^[75] A refinement of this technique is continuous hyperfractionated accelerated radiotherapy (CHART), in which a high dose of radiotherapy is given in a short time period.^[76] Postoperative thoracic radiotherapy generally should not be used after curative intent surgery for NSCLC.^[77] Some people with mediastinal N2 lymph node involvement might benefit from post-operative radiotherapy.^[78]
For potentially curable SCLC cases, chest radiotherapy is often recommended in addition to chemotherapy.^[8]
If cancer growth blocks a short section of bronchus, brachytherapy (localized radiotherapy) may be given directly inside the airway to open the passage.^[79] Compared to external beam radiotherapy, brachytherapy allows a reduction in treatment time and reduced radiation exposure to healthcare staff.^[80]
Prophylactic cranial irradiation (PCI) is a type of radiotherapy to the brain, used to reduce the risk of metastasis. PCI is most useful in SCLC. In limited-stage disease, PCI increases three-year survival from 15% to 20%; in extensive disease, one-year survival increases from 13% to 27%.^[81]
Recent improvements in targeting and imaging have led to the development of stereotactic radiation in the treatment of early-stage lung cancer. In this form of radiotherapy, high doses are delivered in a small number of sessions using stereotactic targeting techniques. Its use is primarily in patients who are not surgical candidates due to medical comorbidities.^[82]
For both NSCLC and SCLC patients, smaller doses of radiation to the chest may be used for symptom control (palliative radiotherapy).^[83]

Chemotherapy

The chemotherapy regimen depends on the tumor type.^[8] Small-cell lung carcinoma (SCLC), even relatively early stage disease, is treated primarily with chemotherapy and radiation.^[84] In SCLC, cisplatin and etoposide are most commonly used.^[85] Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan are also used.^[86][87] In advanced non-small cell lung carcinoma (NSCLC), chemotherapy improves survival and is used as first-line treatment, provided the person is well enough for the treatment.^[88] Typically, two drugs are used, of which one is often platinum-based (either cisplatin or carboplatin). Other commonly used drugs are gemcitabine, paclitaxel, docetaxel,^[89][90] pemetrexed,^[91] etoposide or vinorelbine.^[90]
Adjuvant chemotherapy refers to the use of chemotherapy after apparently curative surgery to improve the outcome. In NSCLC, samples are taken of nearby lymph nodes during surgery to assist staging. If stage II or III disease is confirmed, adjuvant chemotherapy improves survival by 5% at five years.^[92][93] The combination of vinorelbine and cisplatin is more effective than older regimens.^[93] Adjuvant chemotherapy for people with stage IB cancer is controversial, as clinical trials have not clearly demonstrated a survival benefit.^[94][95] Trials of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable NSCLC have been inconclusive.^[96]

Palliative care

In people with terminal disease, palliative care or hospice management may be appropriate.^[10] These approaches allow additional discussion of treatment options and provide opportunities to arrive at well-considered decisions^[97][98] and may avoid unhelpful but expensive care at the end of life.^[98]
Chemotherapy may be combined with palliative care in the treatment of the NSCLC. In advanced cases, appropriate chemotherapy improves average survival over supportive care alone, as well as improving quality of life.^[99] With adequate physical fitness, maintaining chemotherapy during lung cancer palliation offers 1.5 to 3 months of prolongation of survival, symptomatic relief, and an improvement in quality of life, with better results seen with modern agents.^[100][101] The NSCLC Meta-Analyses Collaborative Group recommends if the recipient wants and can tolerate treatment, then chemotherapy should be considered in advanced NSCLC.^[88][102]

Prognosis

Main articles: Lung cancer staging and Manchester score

Outcomes in lung cancer according to clinical stage^[51]

Clinical stage	Five-year survival (%)
	Non-small cell lung carcinoma	Small cell lung carcinoma
IA	50	38
IB	47	21
IIA	36	38
IIB	26	18
IIIA	19	13
IIIB	7	9
IV	2	1

Prognosis is generally poor. Of all people with lung cancer, 15% survive for five years after diagnosis.^[2] Stage is often advanced at the time of diagnosis. At presentation, 30–40% of cases of NSCLC are stage IV, and 60% of SCLC are stage IV.^[8]
Prognostic factors in NSCLC include presence or absence of pulmonary symptoms, tumor size, cell type (histology), degree of spread (stage) and metastases to multiple lymph nodes, and vascular invasion. For people with inoperable disease, outcomes are worse in those with poor performance status and weight loss of more than 10%.^[103] Prognostic factors in small cell lung cancer include performance status, gender, stage of disease, and involvement of the central nervous system or liver at the time of diagnosis.^[104]
For NSCLC, the best prognosis is achieved with complete surgical resection of stage IA disease, with up to 70% five-year survival.^[105] For SCLC, the overall five-year survival is about 5%.^[1] People with extensive-stage SCLC have an average five-year survival rate of less than 1%. The average survival time for limited-stage disease is 20 months, with a five-year survival rate of 20%.^[2]
According to data provided by the National Cancer Institute, the median age at diagnosis of lung cancer in the United States is 70 years,^[106] and the median age at death is 72 years.^[107] In the US, people with medical insurance are more likely to have a better outcome.^[108]

Epidemiology

Age-standardized death from tracheal, bronchial, and lung cancers per 100,000 inhabitants in 2004^[109]

no data   ≤ 5   5-10   10-15   15-20   20-25   25-30

30-35   35-40   40-45   45-50   50-55   ≥ 55

Lung cancer distribution in the United States

Worldwide, lung cancer is the most common cancer in terms of both incidence and mortality. In 2008, there were 1.61 million new cases, and 1.38 million deaths due to lung cancer. The highest rates are in Europe and North America.^[11] The population segment most likely to develop lung cancer is people aged over 50 who have a history of smoking. In contrast to the mortality rate in men, which began declining more than 20 years ago, women's lung cancer mortality rates have been rising over the last decades, and are just recently beginning to stabilize.^[110] In the USA, the lifetime risk of developing lung cancer is 8% in men and 6% in women.^[1]
For every 3–4 million cigarettes smoked, one lung cancer death occurs.^[1][111] The influence of "Big Tobacco" plays a significant role in the smoking culture.^[112] Young nonsmokers who see tobacco advertisements are more likely to take up smoking.^[113] The role of passive smoking is increasingly being recognized as a risk factor for lung cancer,^[25] leading to policy interventions to decrease undesired exposure of nonsmokers to others' tobacco smoke.^[114] Emissions from automobiles, factories, and power plants also pose potential risks.^[4]
Eastern Europe has the highest lung cancer mortality among men, while northern Europe and the US have the highest mortality among women. In the United States, black men and women have a higher incidence.^[115] Lung cancer rates are currently lower in developing countries.^[116] With increased smoking in developing countries, the rates are expected to increase in the next few years, notably in China^[117] and India.^[118]
From the 1960s, the rates of lung adenocarcinoma started to rise relative to other types of lung cancer. This is partly due to the introduction of filter cigarettes. The use of filters removes larger particles from tobacco smoke, thus reducing deposition in larger airways. However, the smoker has to inhale more deeply to receive the same amount of nicotine, increasing particle deposition in small airways where adenocarcinoma tends to arise.^[119] The incidence of lung adenocarcinoma continues to rise.^[120]

History

Lung cancer was uncommon before the advent of cigarette smoking; it was not even recognized as a distinct disease until 1761.^[121] Different aspects of lung cancer were described further in 1810.^[122] Malignant lung tumors made up only 1% of all cancers seen at autopsy in 1878, but had risen to 10–15% by the early 1900s.^[123] Case reports in the medical literature numbered only 374 worldwide in 1912,^[124] but a review of autopsies showed the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952.^[125] In Germany in 1929, physician Fritz Lickint recognized the link between smoking and lung cancer,^[123] which led to an aggressive antismoking campaign.^[126] The British Doctors Study, published in the 1950s, was the first solid epidemiological evidence of the link between lung cancer and smoking.^[127] As a result, in 1964 the Surgeon General of the United States recommended smokers should stop smoking.^[128]
The connection with radon gas was first recognized among miners in the Ore Mountains near Schneeberg, Saxony. Silver has been mined there since 1470, and these mines are rich in uranium, with its accompanying radium and radon gas.^[129] Miners developed a disproportionate amount of lung disease, eventually recognized as lung cancer in the 1870s.^[130] Despite this discovery, mining continued into the 1950s, due to the USSR's demand for uranium.^[129] Radon was confirmed as a cause of lung cancer in the 1960s.^[131]
The first successful pneumonectomy for lung cancer was performed in 1933.^[132] Palliative radiotherapy has been used since the 1940s.^[133] Radical radiotherapy, initially used in the 1950s, was an attempt to use larger radiation doses in patients with relatively early-stage lung cancer, but who were otherwise unfit for surgery.^[134] In 1997, continuous hyperfractionated accelerated radiotherapy was seen as an improvement over conventional radical radiotherapy.^[135] With small-cell lung carcinoma, initial attempts in the 1960s at surgical resection^[136] and radical radiotherapy^[137] were unsuccessful. In the 1970s, successful chemotherapy regimens were developed.^[138]