What is Lung Cancer?

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Lung cancers are tumours arising from cells lining the airways of the respiratory system. Adenocarcinoma of the

lung is one of the main types of lung cancers. Adenocarcinoma of the lung arises from the secretory (glandular) cells

located in the epithelium lining the bronchi.

Statistics on Lung CancerLung cancer is common. One in every 28 Australians will develop lung cancer during their lifetime. Lung

cancer is also deadly: it is the commonest cause of cancer death in Australia, accounting for around 23% of

male and 15% of female cancer deaths. Lung cancer is more than twice as common in men as in women.

Geographically, the tumour is found worldwide, but it is especially common in countries with a high tobacco

consumption. Adenocarcinoma of the lung is the commonest type of lung cancer, accounting for 32% of all

cases of lung cancer.

Risk Factors for Lung CancerCigarette smoking is the main predisposing factor. In recent years, it has been recognised that passive

smoking (e.g. from a first degree relative in a house of smokers) can also put people at risk. Generally, the

risk increases with the number of cigarettes smoked. The link between cigarette smoking and

adenocarcinoma is weaker than the link between smoking and other types of lung cancer, but is still the

most significant risk factor identified.

Exposure to asbestos increases the risk of developing this tumour. The combination of asbestos exposure

plus cigarette smoking is particularly harmful. Other occupational exposures such as exposure to metals

including arsenic, chromium and nickel can also increase risk.

Some studies have suggested that diet can play a role in lung cancer risk. Though it is not known how it

works, diets high in fruits and vegetables seem to decrease risk.

Radiation exposure damages the DNA material within the cells and can also cause lung cancer. Radon (a

radioactive gas) exposure from our normal surrounding environment, if higher than normal, can predispose

to lung cancer. This evidence is mainly based upon population studies which show that people living in areas

with a high radon content are prone to increased incidences of a variety of cancers.

Progression of Lung Cancer

Adenocarcinomas tend to be slow-growing. Spread of the tumour can occur by

thelymphatic vessels to lymph nodes located within the lung, mediastinum

and thorax. If spread by the blood stream, it can lead to deposits of tumour in

the liver, opposite lung, bone and brain.

Example of Lung Cancer. The image to the right is that of a cancerous lung

post mortem, showing local growth of the tumour.

Symptoms of Lung CancerPatients with adenocarcinoma of the lung may notice:

Coughing  (8-75%)

Weight loss  (0-68%)

Shortness of breath  (3-60%)

Chest pain  (20-49%): if the tumour involves the chest wall, pain may be localised to this area

Haemoptysis (coughing up blood) : sputum may be streaked with blood

Non-specific symptoms: fever, weakness, lethargy.

Rarely, patients may present with difficulty swallowing or wheezing.

How is Lung Cancer Diagnosed?Blood tests:

Full blood picture : this may reveal anaemia (low haemoglobin).

Liver function tests : abnormal liver function tests may suggest that the tumour has spread to the

liver.

Urea and electrolytes: low levels of sodium in the blood may indicate inappropriate secretion of ADH

(SIADH), a complication of some types of lung cancer.

Imaging tests:

Chest x-ray: lung cancer may be seen on chest x-ray as a solitary pulmonary nodule or mass. As

many as 80% of solitary pulmonary nodules (<4cm diameter) in the over-50 age group are cancer. Chest x-

ray may also be used to evaluate the size of the tumour and possible involvement of lymph nodes in the

chest. See the example image below.

CT scanning : this is more accurate than chest x-ray, and may be particularly useful in identification

of lymph node involvement. See the example image below.

PET scanning  can help to distinguish between benign and malignant solitary pulmonary nodules

seen on chest x-ray. PET scanning may also be used in the assessment of nodal spread and metastatic

disease.

Imaging of other organs: if it is suspected that the cancer has spread to other organs, scans of the

liver, brain or bone may be required. While imaging tests are helpful in raising the suspicion of lung cancer,

diagnosis requires that cancer cells are seen under a microscope. There are a number of ways of obtaining

samples of suspected cancer cells:

Fine needle aspiration  biopsy through the skin may be used to investigate suspected lung tumours

located on the outside of the lungs.

Sputum cytology: cells from the sputum (spit) are examined for signs of malignancy (cancer).

Sputum cytology may not be very useful in adenocarcinoma of the lung, because the tumours are usually in

the periphery of the lung, meaning tumour cells are less likely to be coughed up.

Bronchoscopy with washings, brushings and biopsy: a bronchoscopy is a camera tube placed

through the throat into the airways of the lungs. Samples of the cells from the airways can be taken with

washing, brushing, or biopsy.

Prognosis of Lung CancerThe prognosis (probable outcome) depends on the stage of the tumour. Cancer staging is a tool which allows

prediction of patient outcomes, and helps decide on the best treatment options. It takes into account various

features of a tumour in an individual patient, which can then be compared to other patients with similar

tumour features. Staging of adenocarcinoma of the lung is based on the TNM (Tumour, Node, Metastasis)

system. 'Tumour' refers to tumour size, which is measured in centimetres. 'Node' refers to the presence of

cancerous cells in regional lymph nodes. 'Metastasis' refers to the spread of cancer beyond regional lymph

nodes to other organs of the body.

Tumour size (T):

Tx: Primary tumour not able to be assessed

T0: No evidence of primary tumour, ie. cancer cells seen on sputum sampling or bronchial washing

only

Tis: Carcinoma in situ

T1: Tumour 3 cm or less, surrounded by pleura, without evidence of invasion more proximal than the

lobar bronchus.

T2: Tumour with any of the following features:

o >3cm in greatest dimension

o Involves main bronchus, 2cm or more distal to the carina

o Invades visceral pleura

o Associated with atelectasis or obstructive pneumonitis, extending to the hilar region but not

involving the entire lung.

T3: Tumour of any size,

o directly invading the chest wall, diaphragm, mediastinal pleura or parietal pericardium; or

tumour in the main bronchus; or

o in the main bronchus, less than 2cm distal to the carina, but without involvement of the

carina; or

o with associated atelectasis or obstructive pneumonitis of the entire lung

T4: Tumour of any size, invading the mediastinum, heart, great vessels, trachea, oesophagus,

vertebral body, carina; or with separate tumour nodules in one lobe, or with malignant pleural effusion

Regional lymph nodes (N):

NX: Regional lymph nodes not able to be assessed

N0: No regional lymph node metastasis

N1: Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary

nodes, including involvement by direct extension

N2: Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes

N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or

supraclavicular lymph nodes

Distant Metastasis (M):

MX: Distant metastasis not able to be assessed

M0: No distant metastasis

M1: Distant metastasis, including separate tumour nodule(s) in a different lobe (ipsi- or

contralateral).

Using this classification, non-small cell lung cancers are grouped into stages as follows:

Stage 0: TIS N0 M0

Stage Ia: T1 N0 M0

Stage Ib: T2 N0 M0

Stage IIa: T1 N1 M0

Stage IIb: T2 N1 M0, T3 N0 M0

Stage IIIa: T1 N2 M0, T2 N2 M0, T3 N1 M0, T3 N2 M0

Stage IIIb: any T N3 MO, T4 any N M0

Stage IV: any T any N M1

Using this system, outcomes are best for patients with early stages of disease, with small tumours, no

spread to lymph nodes, and no distant spread (metastasis) to other organs. Outcomes are also better for

younger patients. Overall, despite treatment, 5-year survival for all types of lung cancer in Australia is not

good: 11% for males and 14% for females. Adenocarcinoma has the best prognosis of any type of lung

cancer.

How is Lung Cancer Treated?Surgical treatment:

Surgery offers the best chance of cure, but is usually only possible with small tumours that have not

yet spread (stage I or II). In some cases, lobectomy may be more appropriate than limited resection.

If surgical treatment is to be given, the lymph nodes draining the tumour should be sampled and

removed if the cancer has spread.

Radiotherapy:

Patients with tumours which are not suitable for surgical resection can benefit from radiotherapy to

the chest.

Patients with early disease (Stage I or II cancer) who have had the tumour completely surgically

removed do not usually need radiotherapy.

Chemotherapy:

Chemotherapy can increase survival for patients with advanced cancer who are otherwise medically

fit. Chemotherapy may also have improve quality of life for these patients.

If chemotherapy is to be used, combination regimes (using more than one drug together) are better

than single-drug regimes. Chemotherapy using platinum-based drugs produces the best results.

New classes of treatment agents, such as biological therapies, are finding a place alongside chemotherapy.

Watch this site for breaking news regarding this treatment.

Palliative care

Lung symptoms commonly reported by patients with incurable lung cancer include shortness of

breath from pleural effusion, coughing, or haemoptysis (coughing up blood). Pain may be from the lung

tumour itself, or from spread (metastasis) to other organs, including bone. Treatment is available for all of

these symptoms. In some cases,radiotherapy may be used to manage cancer pain. Spinal cord

compression is a complication of bony metastasis which requires urgent treatment.

What is lung adenocarcinoma?

Lung adenocarcinoma is the most common kind of lung cancer, both in smokers and nonsmokers and in people under age 45. Adenocarcinoma accounts for about 30 percent of

primary lung tumors in male smokers and 40 percent in female smokers. Among non-smokers,

these percentages approach 60 percent in males and 80 percent in females. This disease also

is more common among Asian populations.

Overall, less than 10 percent of people with primary lung cancer survive five years after

diagnosis. However, five-year survival rates can be as high as 35 to 40 percent for those who

have localized lung cancer removed in its early

stages. These five-year survival rates approach 85

percent for patients under age 30.

Who is most likely

to have lung adenocarcinoma?

Smoking frequently causes this type of cancer. Both

how much and how long a time you smoke increase

the chances of lung cancer. If you quit smoking, your

risk decreases over time. Secondary risk factors

include age, family history, and exposure to secondhand smoke, mineral

and metal dust, asbestos, or radon.

What characterizes lung adenocarcinoma?

This type of non-small cell lung cancer usually develops in the

peripheral portion of the lungs. Lung adenocarcinoma cells form recognizable glandular

patterns. This type of cancer is more likely than other kinds of lung cancer to be contained

in one area of the body. Slow growing, lung

adenocarcinoma can take years to develop from

a confined tumor to metastatic cancer. Symptoms

develop slowly as well. They include coughing,

shortness of breath, wheezing, chest pain, and

bloody sputum. Sometimes, this illness may appear

to be pneumonia or a collapsed lung.

What tests can help

to identify lung adenocarcinoma?

The practical first steps are a thorough physical examination and the

testing of a sample of sputum for bacteria, infectious organisms, and

cancer cells. If the sputum test does not provide a definite diagnosis,

your primary care physician may prescribe further tests, which may include a chest x-ray or

bronchoscopy. A chest x-ray can detect a mass in the lungs or enlarged lymph nodes in the

chest. Bronchoscopy is an examination of the windpipe and lung branches with a

flexible scope.

If there appears there may be a mass in your lungs, your primary care physician or cancer

specialist may order a CT or MRI scan or a needle biopsy. CT (computed tomography) or

MRI (magnetic resonance imaging) scans produce chest images that assist physicians to

better determine the nature, position, or extent of the mass. CT is used to guide a needle

biopsy, which gathers cell samples from a suspicious area using a slim, hollow needle attached

to a syringe.

(continued on next page)

Definitions

Adenocarcinoma:

A type of cancerous,

or malignant, tumor

that forms glandular

structures.

Lobe: A spongy,

saclike respiratory

compartment in the

lung that removes

carbon dioxide from

the blood and supplies

it with oxygen. The

right lung has three

lobes, and the left

has two.

Malignant: Cancerous

and capable of

spreading.

Pathologist: A

physician who

examines tissues and

fluids to diagnose

disease in order

to assist in making

treatment decisions.

Biopsy: Removal of a

tissue sample.

Sputum: Mucus

coughed up from

the lungs.

Lung Cancer

Lung Adenocarcinoma

Copyright © 2011.

College of American

Pathologists. For use and

reproduction by patients

and CAP members only.

Normal lung cells.

Lung adenocarcinoma

is a slow-growing

cancer that can take

years to develop into

invasive cancer.(continued from previous page)

How does a pathologist diagnose lung adenocarcinoma?

Your pathologist reviews the results of the sputum sample or biopsy. Through this review, your

pathologist is able to confirm a diagnosis of cancer.

What else does the pathologist look for?

Your pathologist may examine additional blood tests ordered by your primary care physician

or specialist. These tests identify lung cancer markers–elements in the blood associated with

lung cancer. Finding particular types of markers helps the pathologist determine the exact type

of cancer. Also, if fluid has accumulated in the chest, a pathologist may examine a sample

obtained through a procedure called thoracentesis, in which a needle withdraws a

fluid sample.

How do doctors determine what surgery or treatment will be necessary?

If cancer is found by the pathologist, your primary care physician or specialist may order a

bone scan to see if the cancer has spread into your bones. If the cancer has not spread, a

procedure called mediastinoscopy may be recommended. In this procedure, a physician

examines tissues and organs in the middle chest with an endoscope, which is a small, flexible

device with a camera. The endoscope is inserted into the chest through a small incision at the

top of the breastbone. Lymph nodes from the middle chest area are usually removed during

this procedure. If the pathologist does not find cancer cells in these nodes, your primary care

physician or specialist may recommend surgery.

After reviewing the results of all your tests and procedures, your pathologist assigns a

pathologic stage to your lung cancer. Stage 1 lung adenocarcinomas are small and confined to

the lungs, and stage 4 tumors have spread beyond tissues and organs near the lungs. Stages

between 2 and 3 describe conditions in between these two extremes.

Once the stage has been determined, your primary care physician or cancer specialist

will discuss treatment options with you. If the cancer is located only in the lungs, surgery

is generally recommended. Common lung cancer surgical procedures include thoractomy

(opening the chest wall) or median sternotomy (cutting through the breastbone) during

which lung tissue, one lobe, or an entire lung will be removed, depending on the size of the

tumor. Recently, surgeons have developed less-invasive procedures to remove cancerous

tissue. Most appropriate for stage 1 and 2 cancers localized in the chest area, video-assisted

thoracic surgery (VATS) enables surgeons to remove tissue through smaller incisions.

For aggressive and widespread tumors, physicians recommend chemotherapy and

radiation therapy. Chemotherapy delivers drugs throughout the body, slows the cancer’s

progression, and reduces pain. Chemotherapy can be used before and after surgery and can

be combined with other treatments. Radiation therapy–pinpointed high-energy beams–can be

used to shrink tumors or to destroy cancer cells that remain after surgery. This treatment is

also used to relieve the symptoms of advanced lung cancer.

Clinical trials of new treatments for lung adenocarcinoma may be found at www.cancer.

gov/clinicaltrials. These treatments are highly experimental in nature but may be a potential

option for advanced cancers.

For more information, go to www.cancer.gov (National Cancer Institute) or www.cancer.org

(American Cancer Society). Type the keywords lung adenocarcinoma or lung cancer into

the search box.

What kinds of

questions should I

ask my doctors?

Ask any question you

want. There are no

questions you should

be reluctant to ask.

Here are a few to

consider:

• Please describe the

type of cancer I have

and what treatment

options are available.

• What is the stage of

my cancer?

• What are the

chances for full

remission?

• What treatment

options do you

recommend? Why do

you believe these are

the best treatments?

• What are the pros

and cons of these

treatment options?

• What are the side

effects?

• Should I receive a

second opinion?

• Is your medical team

experienced in treating

the type of cancer I

have?

• Can you provide me

with information about

the physicians and

others on the medical

team?

Lung cancer

From Wikipedia, the free encyclopedia

Lung cancer

Classification and external resources

Cross section of a human lung. The white area in the upper lobe is cancer; the

black areas are discoloration due to smoking.

ICD-10 C 33. -C 34.

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 and, eventually, into other parts of the body. Most cancers that start in lung, known as primary lung

cancers, are carcinomas that derive from epithelial cells. Worldwide, lung cancer is the most common cause of cancer-related death in men and

women, and is responsible for 1.3 million deaths annually, as of 2004.[1] The most common symptoms are shortness of breath, coughing

(including coughing up blood), and weight loss.[2]

The main types of lung cancer are small-cell lung cancer (SCLC), also called oat cell cancer, and non-small-cell lung cancer (NSCLC). The most

common cause of lung cancer is long-term exposure to tobacco smoke.[3] Nonsmokers account for 15% of lung cancer cases,[4] and these cases are

often attributed to a combination of genetic factors,[5][6] radon gas,[7] asbestos,[8] and air pollution [9] [10] [11]  including secondhand smoke.[12][13]

Lung cancer may be seen on chest radiograph and computed tomography (CT scan). The diagnosis is confirmed with a biopsy. This is usually

performed bybronchoscopy or CT-guided biopsy. Treatment and prognosis depend on the histological type of cancer, the stage (degree of spread),

and the patient's general wellbeing, 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 radiation therapy. This is partly because SCLC often

spreads quite early, and these treatments are generally better at getting to cancer cells that have spread to other parts of the body.[14]

Survival depends on stage, overall health, and other factors, but overall 14% of people diagnosed with lung cancer survive five years after the

diagnosis.[2]

Contents

[hide]

1 Signs and symptoms

2 Causes

o 2.1 Smoking

o 2.2 Radon gas

o 2.3 Asbestos

o 2.4 Viruses

o 2.5 Particulate

matter

3 Pathogenesis

4 Diagnosis

o 4.1 Classification

o 4.2 Staging

5 Prevention

o 5.1 Screening

6 Treatment

o 6.1 Surgery

o 6.2 Radiotherap

y

o 6.3 Chemothera

py

o 6.4 Intervention

al radiology

o 6.5 Palliative

care

7 Prognosis

8 Epidemiology

9 History

10 References

11 External links

[edit]Signs and symptoms

Symptoms that may suggest lung cancer include:[15]

dyspnea  (shortness of breath)

hemoptysis  (coughing up blood)

chronic coughing or change in regular coughing pattern

wheezing

chest pain  or pain in the abdomen

cachexia  (weight loss), fatigue, and loss of appetite

dysphonia  (hoarse voice)

clubbing  of the fingernails (uncommon)

dysphagia  (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. Many lung cancers have a rich blood supply. The surface of the cancer may be fragile, leading to bleeding

from the cancer into the airway. This blood may subsequently be coughed up.

Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease.[16] In lung cancer, these phenomena

may include Lambert-Eaton myasthenic syndrome (muscle weakness due to auto-antibodies), hypercalcemia, or syndrome of inappropriate antidiuretic

hormone (SIADH). Tumors in the top (apex) of the lung, known as Pancoast tumors,[17]may invade the local part of the sympathetic nervous system,

leading to changed sweating patterns and eye muscle problems (a combination known as Horner's syndrome) as well as muscle weakness in the

hands due to invasion of the brachial plexus.

Many of the symptoms of lung cancer (bone pain, fever, and weight loss) are nonspecific; in the elderly, these may be attributed to comorbid illness.

[14] In many patients, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Common

sites of metastasis include the brain, bone, adrenal glands, contralateral (opposite) lung, liver,pericardium, and kidneys.[18] About 10% of people with

lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest radiograph.[2]

[edit]Causes

The main causes of any cancer include carcinogens (such as those in tobacco smoke), ionizing radiation, and viral infection. This exposure causes

cumulative changes to the DNA in the tissue lining the bronchi of the lungs (the bronchial epithelium). As more tissue becomes damaged, eventually a

cancer develops.[14]

[edit]Smoking

NIH graph showing the correlation and time-lag between tobacco smoking and lung cancer rate in the U.S. male population.

Smoking, particularly of cigarettes, is by far the main contributor to lung cancer.[19] Cigarette smoke contains over 60 known carcinogens,

[20] includingradioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune

response to malignant growths in exposed tissue.[21] Across the developed world, 91% of lung cancer deaths in men during the year 2000 were

attributed to smoking (71% for women).[22] In the United States, smoking is estimated to account for 87% of lung cancer cases (90% in men and 85% in

women).[23] Among male smokers, the lifetime risk of developing lung cancer is 17.2%; among female smokers, the risk is 11.6%. This risk is

significantly lower in nonsmokers: 1.3% in men and 1.4% in women.[24]

Women who smoke (former smokers and current smokers) and take hormone therapy are at a much higher risk of dying of lung cancer. In a study by

Chlebowski et al. published in 2009, the women taking hormones were about 60% more likely to die of lung cancer than the women taking a placebo.

Not surprisingly, the risk was highest for current smokers, followed by past smokers, and lowest for those who have never smoked. Among the women

who smoked (former or current smokers), 3.4% of those taking hormone therapy died of lung cancer compared to 2.3% for women taking the placebo.

[25]

The time a person smokes (as well as rate of smoking) increases the person's chance of developing lung cancer. If a person stops smoking, this

chance steadily decreases as damage to the lungs is repaired and contaminant particles are gradually removed.[26] In addition, there is evidence that

lung cancer in never-smokers has a better prognosis than in smokers,[27] and that patients who smoke at the time of diagnosis have shorter survival

times than those who have quit.[28]

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 U.S.,[29] Europe,[30] the UK,[31] and Australia[32] have consistently shown a significant increase

in relative risk among those exposed to passive smoke. Recent investigation of sidestream smoke suggests that it is more dangerous than direct

smoke inhalation.[33]

10–15% of lung cancer patients have never smoked.[34] That means between 20,000 to 30,000 never-smokers are diagnosed with lung cancer in the

United States each year. Because of the five-year survival rate, each year in the U.S. more never-smokers die of lung cancer than do patients of

leukemia, ovarian cancer, or AIDS.[35]

[edit]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 ionizegenetic material, causing mutations that sometimes turn cancerous. Radon exposure is the second

major cause of lung cancer in the general population, after smoking[7] with the risk increasing 8–16% for every 100 Bq/m³ increase in the radon

concentration.[36] 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 that one in 15 homes in the U.S. has radon levels above the

recommended guideline of 4 picocuries per liter (pCi/L) (148 Bq/m³).[37] Iowa has the highest average radon concentration in the United States; studies

performed there have demonstrated a 50% increased lung cancer risk, with prolonged radon exposure above the EPA's action level of 4 pCi/L.[38][39]

[edit]Asbestos

Ferruginous bodies the histopathologicfinding associated with asbestosis.

Asbestos can cause a variety of lung diseases, including lung cancer. There is a synergistic effect between tobacco smoking and asbestos in the

formation of lung cancer.[8] In the UK, asbestos accounts for 2–3% of male lung cancer deaths.[40] Asbestos can also cause cancer of the pleura,

called mesothelioma(which is different from lung cancer).

[edit]Viruses

Viruses are known to cause lung cancer in animals,[41][42] and recent evidence suggests similar potential in humans. Implicated viruses include human

papillomavirus,[43] JC virus,[44] simian virus 40 (SV40), BK virus, and cytomegalovirus.[45] These viruses may affect the cell cycle and inhibit apoptosis,

allowing uncontrolled cell division.

[edit]Particulate matter

Studies of the American Cancer Society cohort directly link the exposure to particulate matter with lung cancer. For example, if the concentration of

particles in the air increases by only 1%, the risk of developing a lung cancer increases by 14%.[46][47] Further, it has been established that particle size

matters, as ultrafine particles penetrate further into the lungs.[48]

[edit]Pathogenesis

Main article: Carcinogenesis

Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.[49] Oncogenes

are genes that are believed to make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to

particular carcinogens.[50] Mutations in the K-ras proto-oncogene are responsible for 10–30% of lung adenocarcinomas.[51][52] The epidermal growth

factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion.[51] 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.[51] 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.[53] Other genes

that are often mutated or amplified are c-MET, NKX2-1, LKB1, PIK3CA, and BRAF.[51]

Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for interleukin-1,[54] cytochrome P450,

[55] apoptosis promoters such as caspase-8,[56]and DNA repair molecules such as XRCC1.[57] People with these polymorphisms are more likely to

develop lung cancer after exposure to carcinogens.

A recent study suggested that the MDM2 309G allele is a low-penetrant risk factor for developing lung cancer in Asians.[58]

[edit]Diagnosis

Chest radiograph showing a cancerous tumor in the left lung.

Performing a chest radiograph is the first step if a patient reports symptoms that may suggest lung cancer. This may reveal an obvious mass, widening

of themediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (pneumonia), or pleural effusion. If there are no

radiographic findings but the suspicion is high (such as a heavy smoker with blood-stained sputum), bronchoscopy and/or a CT scan may provide the

necessary information. Bronchoscopy or CT-guided biopsy is often used to identify the tumor type.[2]

Abnormal findings in cells ("atypia") in sputum are associated with an increased risk of lung cancer. Sputum cytologic examination combined with other

screening examinations may have a role in the early detection of lung cancer.[59]

CT scan showing a cancerous tumor in the left lung.

The differential diagnosis for patients who present with abnormalities on chest radiograph includes lung cancer as well as nonmalignant diseases.

These include infectious causes such as tuberculosis or pneumonia, or inflammatory conditions such as sarcoidosis. These diseases can result

in mediastinal lymphadenopathy or lungnodules, and sometimes mimic lung cancers.[14] Lung cancer can also be an incidental finding: a solitary

pulmonary nodule (also called a coin lesion) on a chest radiograph or CT scan taken for an unrelated reason. The definitive diagnosis of lung cancer

and its classification (described above) is based on examination of the suspicious tissue under the microscope by a pathologist.

[edit]Classification

Lung cancers are classified according to histological type. This classification has important implications for clinical management and prognosis of the

disease. The vast majority of lung cancers are carcinomas—malignancies that arise from epithelial cells. The two most prevalent histological types of

lung carcinoma, categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: non-small-

cell and small-cell lung carcinoma.[60] The non-small-cell type is the most prevalent by far (see accompanying

table).

Frequency of histological types of lung cancer[60]

Histological type Frequency (%)

Non-small-cell lung carcinoma 80.4

Small-cell lung carcinoma 16.8

Carcinoid [61] 0.8

Sarcoma [62] 0.1

Unspecified lung cancer 1.9

Cancer found outside of the lung may be determined to have arisen within the lung, as lung cancers that metastasize, i.e. spread, often retain a cell

marker profile that allow a pathologist to say, with a good deal of certainty, that the tumor arose from the lung, i.e. is a primary lung cancer. Primary

lung cancers of adenocarcinoma histology typically have nuclear immunostaining with TTF-1.[63][64]

[edit]Non-small-cell lung carcinoma

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

The non-small-cell lung carcinomas (NSCLC) are grouped together because their prognosis and management are similar. There are three main sub-

types: squamous cell lung carcinoma,adenocarcinoma, and large-cell lung carcinoma.

Sub-types of non-small-cell lung cancer insmokers and never-smokers[65]

Histological sub-type Frequency of non-small-cell lung cancers

(%)

Smokers Never-smokers

Squamous cell lung carcinoma 42 33

Adenocarcinoma

Adenocarcinoma (not otherwise specified)

39 35

Bronchioloalveolar carcinoma 4 10

Carcinoid 7 16

Other 8 6

Pie chart of the incidence of lung cancer types in the Nurses' Health Study, sorted by histological subtypes, in turn sorted into how

many are non-smokers versus smokers[66]

Accounting for 25% of lung cancers,[67] squamous cell lung carcinoma usually starts near a central bronchus. A hollow cavity and

associated necrosis are commonly found at the center of the tumor. Well-differentiated squamous cell lung cancers often grow more slowly than other

cancer types.[14]

Adenocarcinoma accounts for 40% of non-small-cell lung cancers.[67] It usually originates in peripheral lung tissue. Most cases of adenocarcinoma are

associated with smoking; however, among people who have never smoked ("never-smokers"), adenocarcinoma is the most common form of lung

cancer.[68] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have different

responses to treatment.[69]

[edit]Small-cell lung carcinoma

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

Small-cell lung carcinoma (SCLC) is less common. It was formerly referred to as "oat-cell" carcinoma.[70]Most cases arise in the larger airways (primary

and secondary bronchi) and grow rapidly, becoming quite large.[71] The small cells contain dense neurosecretory granules

(vesicles containing neuroendocrine hormones ), which give this tumor an endocrine/paraneoplastic syndrome association.[72] While initially more

sensitive to chemotherapy and radiation, it is often metastatic at presentation, and ultimately carries a worse prognosis. Small-cell lung cancers have

long been dichotomously staged into limited and extensive stage disease. This type of lung cancer is strongly associated with smoking.[73]

[edit]Others

Lung cancers are highly heterogeneous malignancies, with tumors containing more than one subtype being very common.[74]

Currently, the most widely recognized and utilized lung cancer classification system is the 4th revision of the Histological Typing of Lung and Pleural

Tumours, published in 2004 as a cooperative effort by the World Health Organization and the International Association for the Study of Lung Cancer. It

recognizes numerous other distinct histopathological entities of non-small-cell lung carcinoma, organized into several additional subtypes,

including sarcomatoid carcinoma, salivary gland tumors, carcinoid tumor, and adenosquamous carcinoma. The latter subtype includes tumors

containing at least 10% each of adenocarcinoma and squamous cell carcinoma. When a tumor is found to contain a mixture of both small-cell

carcinoma and non-small-cell carcinoma, it is classified as a variant of small-cell carcinoma and called a combined small-cell carcinoma. Combined

small-cell carcinoma is the only currently recognized variant of small-cell carcinoma.

In infants and children, the most common primary lung cancers are pleuropulmonary blastoma and carcinoid tumor.[75]

[edit]Metastasis

Micrograph of a lung lymph node biopsyshowing metastatic colorectal adenocarcinoma. Field stain.

The lung is a common place for metastasis 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 breast cancer. Metastases often have a characteristic round appearance on chest radiograph.[76] Solitary

round lung nodules are not infrequently of an uncertain etiology and may prompt a lung biopsy.

In children, the majority of lung cancers are secondary.[75]

Primary lung cancers themselves most commonly metastasize to the adrenal glands, liver, brain, and bone.[14]

[edit]Staging

See also: Lung cancer staging

Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. In most studies, it is the most important factor

affecting the prognosis and potential treatment of lung cancer.

Staging varies for the two major cell types of lung cancer (non-small cell lung carcinoma and small cell lung carcinoma). It is normally done prior to

attempts at curative therapy, and usually consists of an extensive battery of tests, to include physical examination, laboratory tests, imaging studies,

and/or biopsies and other invasive procedures (such as mediastinoscopy). Non-small cell lung carcinoma is usually staged from IA ("one A"; best

prognosis) to IV ("four"; worst prognosis).[77] Small cell lung carcinoma 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).

For both NSCLC and SCLC, there are two general types of staging evaluations:

Clinical Staging: evaluated prior to definitive surgery, and typically based on the results of physical examination, imaging studies, and pertinent

laboratory findings. Does not necessarily involve apathologist.

Pathological Staging: usually evaluated either intra- or post-operatively, and based on the combined results of surgical and clinical findings.[71]

[edit]Prevention

See also: Smoking ban

Prevention is the most cost-effective means of fighting lung cancer. 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.[78] Of utmost importance are prevention programs that target the young. In 1998 the Master

Settlement Agreement entitled 46 states in the USA to an annual payout from the tobacco companies.[79] Between the settlement money and tobacco

taxes, each state's public health department funds their prevention programs, although none of the states are living up to the Center for Disease

Control's recommended amount by spending 15 percent of tobacco taxes and settlement revenues on these prevention efforts.[79]

Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western

countries, with California taking a lead in banning smoking in public establishments in 1998. Ireland played a similar role in Europe in 2004, followed by

Italy and Norway in 2005, Scotland as well as several others in 2006, England in 2007, France in 2008 and Turkey in 2009. New Zealand has banned

smoking in public places as of 2004. The state of Bhutan has had a complete smoking ban since 2005.[80] In many countries, pressure groups are

campaigning for similar bans. In 2007, Chandigarh became the first city in India to become smoke-free. India introduced a total ban on smoking in

public places on 2 October 2008.

Arguments cited against such bans are criminalization of smoking, increased risk of smuggling, and the risk that such a ban cannot be enforced.[81]

The long-term use of supplemental multivitamins—such as vitamin C, vitamin E, and folate—does not reduce the risk of lung cancer. Indeed long-term

intake of high doses of vitamin E supplements may even increase the risk of lung cancer.[82] However, eating at least five servings of fruits and

vegetables per day and following a diet that conforms to the American Cancer Society's guidelines may help lower risk.[83]

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 already instituted.[84]

[edit]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 chest

radiograph, or computed tomography (CT). As of December 2009, screening programs for lung cancer have not demonstrated any benefit.[85][86]

[edit]Treatment

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 patient's performance status. Common treatments

include palliative care,[87] surgery, chemotherapy, and radiation therapy.[2][88]

[edit]Surgery

Main article: Lung cancer surgery

Pneumonectomy specimen containing asquamous cell carcinoma, seen as a white area near the bronchi.

If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localized

and amenable to surgery or whether it has spread to the point where it cannot be cured surgically.

Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry

reveals poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated.

Surgery for lung cancer has an operative death rate of about 4.4%, depending on the patient's lung function and other risk factors.[89] In non-small-cell

lung carcinoma, surgery is usually only an option if the cancer is limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed

tomography, positron emission tomography). A sufficient preoperative respiratory reserve must be present to allow adequate lung function after the

tissue is removed.

Procedures include wedge resection (removal of part of a lobe), segmentectomy (removal of an anatomic division of a particular lobe of the

lung), lobectomy(one lobe), bilobectomy (two lobes), or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the

preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge resection may be

performed.[90] Radioactiveiodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy.[91]

Video-assisted thoracoscopic surgery and VATS lobectomy have allowed for minimally invasive approaches to lung cancer surgery that may have the

advantages of quicker recovery, shorter hospital stay and diminished hospital costs.[92]

Early studies suggested that small-cell lung carcinoma (SCLC) fared better when treated with chemotherapy and/or radiation than when treated

surgically.[93][94] While this approach to treating SCLC remains the current standard of care,[95] the role of surgery in SCLC is being reconsidered, recent

reviews indicating that surgery might improve outcomes when added to chemotherapy and radiation in early stage SCLC[96] and combined forms of

SCLC and NSCLC.[97]

[edit]Radiotherapy

Radiotherapy is often given together with chemotherapy, and may be used with curative intent in patients with non-small-cell lung carcinoma who are

not eligible for surgery. This form of high intensity radiotherapy is called radical radiotherapy.[98] 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.[99] For small-cell lung

carcinoma cases that are potentially curable, chest radiation is often recommended in addition to chemotherapy.[100] The use of adjuvant thoracic

radiotherapy following curative intent surgery for non-small-cell lung carcinoma is not well established and is controversial. Benefits, if any, may only be

limited to those in whom the tumor has spread to the mediastinal lymph nodes.[101][102]

For both non-small-cell lung carcinoma and small-cell lung carcinoma patients, smaller doses of radiation to the chest may be used for symptom

control (palliative radiotherapy). Unlike other treatments, it is possible to deliver palliative radiotherapy without confirming the histological diagnosis of

lung cancer.

Brachytherapy (localized radiotherapy) may be given directly inside the airway when cancer affects a short section of bronchus.[103] It is used when

inoperable lung cancer causes blockage of a large airway.[104]

Patients with limited-stage small-cell lung carcinoma are usually given prophylactic cranial irradiation (PCI). This is a type of radiotherapy to the brain,

used to reduce the risk of metastasis.[105] More recently, PCI has also been shown to be beneficial in those with extensive small-cell lung cancer. In

patients whose cancer has improved following a course of chemotherapy, PCI has been shown to reduce the cumulative risk of brain metastases within

one year from 40.4% to 14.6%.[106]

Recent improvements in targeting and imaging have led to the development of extracranial stereotactic radiation in the treatment of early-stage lung

cancer. In this form of radiation therapy, very 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.[107]

[edit]Chemotherapy

The chemotherapy regimen depends on the tumor type.

[edit]Small-cell lung carcinoma

Even if relatively early stage, small-cell lung carcinoma is treated primarily with chemotherapy and radiation.[108] In small-cell lung carcinoma, cisplatin

and etoposide are most commonly used.[109]Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan are also

used.[110][111] Celecoxib showed a potential signal of response in a small study.[112]

[edit]Non-small-cell lung carcinoma

Primary chemotherapy is also given in advanced and metastatic non-small-cell lung carcinoma.

Testing for the molecular genetic subtype of non-small-cell lung cancer may be of assistance in selecting the most appropriate initial therapy[113] For

example, mutation of the epidermal growth factor receptor gene[114] may predict whether initial treatment with a specific inhibitor or with chemotherapy

is more advantageous.[115]

Advanced non-small-cell lung carcinoma is often treated with cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide,

or vinorelbine.[116] Bevacizumab improves results in non-squamous cancers treated with paclitaxel and carboplatin in patients less than 70 years old

who have reasonable general performance status.[117]

Pemetrexed has been approved for use in non-small-cell lung cancer.[118] For adenocarcinoma and large-cell lung cancer, cisplatin with pemetrexed

was more beneficial than cisplatin and gemcitabine; squamous cancer had the opposite results.[119] As a consequence, subtyping of non-small lung

cancer histology has become more important.[120]

The U.S. Food and Drug Administration (FDA) approved erlotinib (Tarceva)[121] for the treatment of locally advanced or metastatic non-small cell lung

cancer that has failed at least one priorchemotherapy regimen,[122] and has also approved its use as maintenance treatment in locally advanced or

metastatic non-small cell lung cancer that has not progressed after four cycles of platinum-based first-line chemotherapy.[122]

The U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung

cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.[123]

Bronchoalveolar carcinoma is a subtype of non-small-cell lung carcinoma that may respond to gefitinib [124]  and erlotinib.[125]

[edit]Maintenance therapy

In advanced non-small-cell lung cancer there are several approaches for continuing treatment after an initial response to therapy.[126] Switch

maintenance changes to different medications than the initial therapy and can use pemetrexed,[127] erlotinib,[128] and docetaxel,[129] although pemetrexed

is only used in non-squamous NSCLC.[130]

[edit]Adjuvant chemotherapy

Adjuvant chemotherapy refers to the use of chemotherapy after apparently curative surgery to improve the outcome. In non-small-cell lung cancer,

samples are taken during surgery of nearby lymph nodes. If these samples contain cancer, the patient has stage II or III disease. In this situation,

adjuvant chemotherapy may improve survival by up to 15%.[131][132] Standard practice has often been to offer platinum-based chemotherapy (including

either cisplatin or carboplatin).[133] However, the benefit of platinum-based adjuvant chemotherapy was confined to patients who had tumors with

lowERCC1 (excision repair cross-complementing 1) activity.[134]

Adjuvant chemotherapy for patients with stage IB cancer is controversial, as clinical trials have not clearly demonstrated a survival benefit.[135][136] Trials

of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable non-small-cell lung carcinoma have been inconclusive.[137]

[edit]Interventional radiology

Radiofrequency ablation should currently be considered an investigational technique in the treatment of bronchogenic carcinoma. It is done by inserting

a small heat probe into the tumor to kill the tumor cells.[138]

[edit]Palliative care

In a 2010 study of patients with metastatic non–small-cell lung cancer, early palliative care led to significant improvements in both quality of life and

mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer

survival" (increased by 3 months).[87]

Other studies in advanced cancer also found benefit from palliative care,[139] or found hospice involvement to be beneficial.[140] These approaches allow

additional discussion of treatment options and provide opportunities to arrive at well-considered decisions[141][142] and may avoid unhelpful but expensive

care at the end of life.[142]

Chemotherapy may be combined with palliative care in the treatment of the non-small-cell lung cancer. In advanced NSCLC, a 1994 meta-

analysis found that appropriate chemotherapy improvedaverage survival over supportive care alone,[143] as well as improving quality of life.[144] With

adequate physical fitness, maintaining chemotherapy during lung cancer palliation offers a 1.5 to 3 months prolongation of survival, symptomatic relief

and an improvement in quality of life, with better results seen with modern agents.[145][146] Since 2008, the NSCLC Meta-Analyses Collaborative Group

has recommended that if the recipient wants and can tolerate treatment then chemotherapy should be considered in advanced NSCLC.[147][148]

[edit]Prognosis

Main articles: Non-small-cell lung carcinoma staging and Manchester score

Prognostic factors in non-small-cell lung cancer 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 patients with inoperable disease, prognosis is adversely affected

by poor performance status and weight loss of more than 10%.[149] 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.[150]

For non-small-cell lung carcinoma (NSCLC), prognosis is generally poor. Following complete surgical resection of stage IA disease, five-year survival is

67%. With stage IB disease, five-year survival is 57%.[151] The five-year survival rate of patients with stage IV NSCLC is about 1%.[3]

For small-cell lung carcinoma, prognosis is also generally poor. The overall five-year survival for patients with SCLC is about 5%.[2] Patients with

extensive-stage SCLC have an average five-year survival rate of less than 1%. The median survival time for limited-stage disease is 20 months, with a

five-year survival rate of 20%.[3]

According to data provided by the National Cancer Institute, the median age at diagnosis of lung cancer in the United States is 70 years,[152] and the

median age at death is 72 years.[153]

[edit]Epidemiology

Age-standardized death from tracheal, bronchial, and lung cancers per 100,000 inhabitants in 2004.[154]

   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 (1.1 million new cases per year and 0.95 million deaths in

males and 0.51 million new cases per year and 0.43 million deaths in females).[155] The highest rates are in Europe and North America.[156] The

population segment most likely to develop lung cancer is over-fifties who have a history of smoking. Lung cancer is the second most commonly

occurring form of cancer in most Western countries, and it is the leading cancer-related cause of death. 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.[157] The evolution of "Big Tobacco" plays a significant role in the smoking culture.[158] Tobacco companies have focused their efforts since

the 1970s at marketing their product toward women and girls, especially with "light" and "low-tar" cigarettes.[159] Among lifetime nonsmokers, men have

higher age-standardized lung cancer death rates than women.

Not all cases of lung cancer are due to smoking, but the role of passive smoking is increasingly being recognized as a risk factor for lung cancer—

leading to policy interventions to decrease undesired exposure of nonsmokers to others' tobacco smoke. Emissions from automobiles, factories, and

power plants also pose potential risks.[9][11][160]

Eastern Europe has the highest lung cancer mortality among men, while northern Europe and the U.S. have the highest mortality among women. In the

United States, black men and women have a higher incidence.[161] Lung cancer incidence is currently less common in developing countries.[162] With

increased smoking in developing countries, the incidence is expected to increase in the next few years, notably in China[163] and India.[164]

Lung cancer incidence (by country) has an inverse correlation with sunlight and UVB exposure. One possible explanation is a preventive effect

of vitamin D, which is produced in the skin on exposure to sunlight.[165]

From the 1950s, the incidence of lung adenocarcinoma started to rise relative to other types of lung cancer.[166] 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.

[167] The incidence of lung adenocarcinoma in the U.S. has fallen since 1999. This may be due to reduction in environmental air pollution.[166] However,

in some developing countries like India, there has been little change in the epidemiology with squamous cell carcinoma continuing to be the

predominant histological type.[168][169][170] An absence of change in the type of tobacco smoking or the pattern of tobacco consumption in the population

could be one of the possible reasons.

[edit]History

Lung cancer was uncommon before the advent of cigarette smoking; it was not even recognized as a distinct disease until 1761.[171] Different aspects of

lung cancer were described further in 1810.[172] 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.[173] Case reports in the medical literature numbered only 374 worldwide in 1912,[174] but a review of autopsies showed that the

incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952.[175] In Germany in 1929, physician Fritz Lickint recognized the link

between smoking and lung cancer,[173] which led to an aggressive antismoking campaign.[176] The British Doctors Study, published in the 1950s, was the

first solid epidemiologicalevidence of the link between lung cancer and smoking.[177] As a result, in 1964 the Surgeon General of the United

States recommended that smokers should stop smoking.[178]

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. Miners developed a disproportionate amount of lung disease,

eventually recognized as lung cancer in the 1870s. An estimated 75% of former miners died from lung cancer.[179] Despite this discovery, mining

continued into the 1950s, due to the USSR's demand for uranium.[180]

The first successful pneumonectomy for lung cancer was performed in 1933.[181] Palliative radiotherapy has been used since the 1940s.[182] 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.[183] In 1997, continuous hyperfractionated accelerated radiotherapy (CHART) was seen as an improvement over

conventional radical radiotherapy.[99]

With small-cell lung carcinoma, initial attempts in the 1960s at surgical resection[184] and radical radiotherapy[185] were unsuccessful. In the 1970s,

successful chemotherapy regimens were developed.[186]

General Information About Non-Small Cell Lung Cancer

Key Points for This Section

Non-small cell lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.

There are several types of non-small cell lung cancer.

Smoking can increase the risk of developing non-small cell lung cancer.

Possible signs of non-small cell lung cancer include a cough that doesn't go away and shortness of breath.

Tests that examine the lungs are used to detect (find), diagnose, and stage non-small cell lung cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

For most patients with non-small cell lung cancer, current treatments do not cure the cancer.

Non-small cell lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.

The lungs are a pair of cone-shaped breathing organs in the chest. The lungs bring oxygen into the body as you breathe in. They release carbon dioxide, a waste product of the body’s cells, as you breathe out. Each lung has sections called lobes. The left lung has two lobes. The right lung is slightly larger and has three lobes. Two tubes called bronchi lead from

the trachea (windpipe) to the right and left lungs. The bronchi are sometimes also involved in lung cancer. Tiny air sacs

called alveoli and small tubes calledbronchioles make up the inside of the lungs.

Enlarge

Anatomy of the respiratory system, showing the trachea and both lungs and their lobes and airways. Lymph nodes and the diaphragm are also shown. Oxygen is inhaled into the lungs and passes through the thin membranes of the alveoli and into the bloodstream (see inset).

A thin membrane called the pleura covers the outside of each lung and lines the inside wall of the chestcavity. This creates a sac called the pleural cavity. The pleural cavity normally contains a small amount offluid that helps the lungs move smoothly in the chest when you breathe.

There are two main types of lung cancer: non-small cell lung cancer and small cell lung cancer.

See the following PDQ summaries for more information about lung cancer:

Small Cell Lung Cancer Treatment

Lung Cancer Prevention

Lung Cancer Screening

Smoking Cessation and Continued Risk in Cancer Patients

There are several types of non-small cell lung cancer.

Each type of non-small cell lung cancer has different kinds of cancer cells. The cancer cells of each type grow and spread in different ways. The types of non-small cell lung cancer are named for the kinds of cells found in the cancer and how the cells look under a microscope:

Squamous cell carcinoma : Cancer that begins in squamous cells, which are thin, flat cells that look like fish scales. This is also called epidermoid carcinoma.

Large cell carcinoma : Cancer that may begin in several types of large cells.

Adenocarcinoma : Cancer that begins in the cells that line the alveoli and make substances such asmucus.

Other less common types of non-small cell lung cancer are: pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma.

Smoking can increase the risk of developing non-small cell lung cancer.

Smoking cigarettes, pipes, or cigars is the most common cause of lung cancer. The earlier in life a person starts smoking, the more often a person smokes, and the more years a person smokes, the greater the risk. If a person has stopped smoking, the risk becomes lower as the years pass.

Anything that increases a person's chance of developing a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. People who think they may be at risk should discuss this with their doctor. Risk factors for lung cancer include the following:

Smoking cigarettes, pipes, or cigars, now or in the past.

Being exposed to second-hand smoke.

Being treated with radiation therapy to the breast or chest.

Being exposed to asbestos, radon, chromium, nickel, arsenic, soot, or tar.

Living where there is air pollution.

When smoking is combined with other risk factors, the risk of developing lung cancer is increased.

Possible signs of non-small cell lung cancer include a cough that doesn't go away and shortness of breath.

Sometimes lung cancer does not cause any symptoms and is found during a routine chest x-ray. Symptoms may be caused by lung cancer or by other conditions. A doctor should be consulted if any of the following problems occur:

A cough that doesn’t go away.

Trouble breathing.

Chest discomfort.

Wheezing.

Streaks of blood in sputum (mucus coughed up from the lungs).

Hoarseness.

Loss of appetite.

Weight loss for no known reason.

Feeling very tired.

Tests that examine the lungs are used to detect (find), diagnose, and stage non-small cell lung cancer.

Tests and procedures to detect, diagnose, and stage non-small cell lung cancer are often done at the same time. The following tests and procedures may be used:

Physical exam  and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits, including smoking, and past jobs, illnesses, and treatments will also be taken.

Laboratory tests : Medical procedures that test samples of tissue, blood, urine, or other substances in the body. These tests help to diagnose disease, plan and check treatment, or monitor the disease over time.

Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.

Enlarge

X-ray of the chest. X-rays are used to take pictures of organs and bones of the chest. X-rays pass through the patient onto film.

CT scan  (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the chest, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

PET scan  (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small

amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.

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PET (positron emission tomography) scan. The patient lies on a table that slides through the PET machine. The head rest and white strap help the patient lie still. A small amount of radioactive glucose (sugar) is injected into the patient's vein, and a scanner makes a picture of where the glucose is being used in the body. Cancer cells show up brighter in the picture because they take up more glucose than normal cells do.

Sputum cytology : A procedure in which a pathologist views a sample of sputum (mucus coughed up from the lungs) under a microscope, to check for cancer cells.

Fine-needle aspiration (FNA) biopsy  of the lung: The removal of tissue or fluid from the lung using a thin needle. A CT scan, ultrasound, or other imaging procedure is used to locate the abnormal tissue or fluid in the lung. A

small incision may be made in the skin where the biopsy needle is inserted into the abnormal tissue or fluid. A sample is removed with the needle and sent to the laboratory. A pathologist then views the sample under a microscope to look for cancer cells. A chest x-ray is done after the procedure to make sure no air is leaking from the lung into the chest.

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Lung biopsy. The patient lies on a table that slides through the computed tomography (CT) machine which takes x-ray pictures of the inside of the body. The x-ray pictures help the doctor see where the abnormal tissue is in the lung. A biopsy needle is inserted through the chest wall and into the area of abnormal lung tissue. A small piece of

tissue is removed through the needle and checked under the microscope for signs of cancer.

Bronchoscopy : A procedure to look inside the trachea and large airways in the lung for abnormalareas.

A bronchoscope is inserted through the nose or mouth into the trachea and lungs. A bronchoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.

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Bronchoscopy. A bronchoscope is inserted through the mouth, trachea, and major bronchi into the lung, to look for abnormal areas. A bronchoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a cutting tool. Tissue samples may be taken to be checked under a microscope for signs of disease.

Thoracoscopy : A surgical procedure to look at the organs inside the chest to check for abnormal areas. An incision (cut) is made between two ribs, and a thoracoscope is inserted into the chest. A thoracoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of cancer. In some cases, this procedure is used to remove part of the esophagus or lung. If certain tissues, organs, or lymph nodes can’t be reached, a thoracotomy may be done. In this procedure, a larger incision is made between the ribs and the chest is opened.

Thoracentesis : The removal of fluid from the space between the lining of the chest and the lung, using a needle. A pathologist views the fluid under a microscope to look for cancer cells.

Light  and electron microscopy: A laboratory test in which cells in a sample of tissue are viewed under regular and high-powered microscopes to look for certain changes in the cells.

Immunohistochemistry study: A laboratory test in which a substance such as an antibody, dye, orradioisotope is added to a sample of cancer tissue to test for certain antigens. This type of study is used to tell the difference between different types of cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

The stage of the cancer (the size of the tumor and whether it is in the lung only or has spread to other places in the body).

The type of lung cancer.

Whether there are symptoms such as coughing or trouble breathing.

The patient’s general health.

What is Cancer? What Causes Cancer?

Cancer is a class of diseases characterized by out-of-control cell growth. There are over 100 different

types of cancer, and each is classified by the type of cell that is initially affected.

Cancer harms the body when damaged cells divide uncontrollably to form lumps or masses of tissue

called tumors (except in the case of leukemia where cancer prohibits normal blood function by abnormal

cell division in the blood stream). Tumors can grow and interfere with the digestive, nervous, and

circulatory systems, and they can release hormones that alter body function. Tumors that stay in one spot

and demonstrate limited growth are generally considered to be benign.

More dangerous, or malignant, tumors form when two things occur:

1. a cancerous cell manages to move throughout the body using the blood or lymph systems,

destroying healthy tissue in a process called invasion

2. that cell manages to divide and grow, making new blood vessels to feed itself in a process called

angiogenesis.

When a tumor successfully spreads to other parts of the body and grows, invading and destroying other

healthy tissues, it is said to have metastasized. This process itself is called metastasis, and the result is a

serious condition that is very difficult to treat.

In 2007, cancer claimed the lives of about 7.6 million people in the world. Physicians and researchers

who specialize in the study, diagnosis, treatment, and prevention of cancer are called oncologists.

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.

What is cancer? - Video

A short, 3D, animated introduction to cancer. This was originally created by BioDigital Systems and used

in the Stand Up 2 Cancer telethon.

Genes - the DNA type

Cells can experience uncontrolled growth if there are damages or mutations to DNA, and therefore,

damage to the genes involved in cell division. Four key types of gene are responsible for the cell division

process: oncogenes tell cells when to divide, tumor suppressor genes tell cells when not to divide, suicide

genes control apoptosis and tell the cell to kill itself if something goes wrong, and DNA-repair genes

instruct a cell to repair damaged DNA.

Cancer occurs when a cell's gene mutations make the cell unable to correct DNA damage and unable to

commit suicide. Similarly, cancer is a result of mutations that inhibit oncogene and tumor suppressor gene

function, leading to uncontrollable cell growth.

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. Theses

free radicals damage cells and affect their ability to function normally.

Genes - the family type

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.

Other medical factors

As we age, there is an increase in the number of possible cancer-causing mutations in our DNA. This

makes age an important risk factor for cancer. Several viruses have also been linked to cancer such as:

human papillomavirus (a cause of cervical cancer), hepatitis B and C (causes of liver cancer), and

Epstein-Barr virus (a cause of some childhood cancers). Human immunodeficiency virus (HIV) - and

anything else that suppresses or weakens the immune system - inhibits the body's ability to fight

infections and increases the chance of developing cancer.

What are the symptoms of cancer?

Cancer symptoms are quite varied and depend on where the cancer is located, where it has spread, and

how big the tumor is. Some cancers can be felt or seen through the skin - a lump on the breast or testicle

can be an indicator of cancer in those locations. Skin cancer (melanoma) is often noted by a change in a

wart or mole on the skin. Some oral cancers present white patches inside the mouth or white spots on the

tongue.

Other cancers have symptoms that are less physically apparent. Some brain tumors tend to present

symptoms early in the disease as they affect important cognitive functions. Pancreas cancers are usually

too small to cause symptoms until they cause pain by pushing against nearby nerves or interfere with liver

function to cause a yellowing of the skin and eyes called jaundice. Symptoms also can be created as a

tumor grows and pushes against organs and blood vessels. For example, colon cancers lead to

symptoms such as constipation, diarrhea, and changes in stool size. Bladder or prostate cancers cause

changes in bladder function such as more frequent or infrequent urination.

As cancer cells use the body's energy and interfere with normal hormone function, it is possible to present

symptoms such as fever, fatigue, excessive sweating, anemia, and unexplained weight loss. However,

these symptoms are common in several other maladies as well. For example, coughing and hoarseness

can point to lung or throat cancer as well as several other conditions.

When 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. Spreading to the lungs

may cause coughing and shortness of breath. In addition, the liver may become enlarged and cause

jaundice and bones can become painful, brittle, and break easily. Symptoms of metastasis ultimately

depend on the location to which the cancer has spread.

How is cancer classified?

There are five broad groups that are used to classify cancer.

1. Carcinomas are characterized by cells that cover internal and external parts of the body such as

lung, breast, and colon cancer.

2. Sarcomas are characterized by cells that are located in bone, cartilage, fat, connective tissue,

muscle, and other supportive tissues.

3. Lymphomas are cancers that begin in the lymph nodes and immune system tissues.

4. Leukemias are cancers that begin in the bone marrow and often accumulate in the bloodstream.

5. Adenomas are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other

glandular tissues.

Cancers are often referred to by terms that contain a prefix related to the cell type in which the cancer

originated and a suffix such as -sarcoma, -carcinoma, or just -oma. Common prefixes include:

Adeno- = gland

Chondro- = cartilage

Erythro- = red blood cell

Hemangio- = blood vessels

Hepato- = liver

Lipo- = fat

Lympho- = white blood cell

Melano- = pigment cell

Myelo- = bone marrow

Myo- = muscle

Osteo- = bone

Uro- = bladder

Retino- = eye

Neuro- = brain

How is cancer diagnosed and staged?

Early detection of cancer can greatly improve the odds of successful treatment and survival. Physicians

use information from symptoms and several other procedures to diagnose cancer. Imaging techniques

such as X-rays, CT scans, MRI scans, PET scans, and ultrasound scans are used regularly in order to

detect where a tumor is located and what organs may be affected by it. Doctors may also conduct an

endoscopy, which is a procedure that uses a thin tube with a camera and light at one end, to look for

abnormalities inside the body.

Extracting cancer cells and looking at them under a microscope is the only absolute way to diagnose

cancer. This procedure is called a biopsy. Other types of molecular diagnostic tests are frequently

employed as well. Physicians will analyze your body's sugars, fats, proteins, and DNA at the molecular

level. For example, cancerous prostate cells release a higher level of a chemical called PSA (prostate-

specific antigen) into the bloodstream that can be detected by a blood test. Molecular diagnostics,

biopsies, and imaging techniques are all used together to diagnose cancer.

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After a diagnosis is made, doctors find out how far the cancer has spread and determine the stage of the

cancer. The stage determines which choices will be available for treatment and informs prognoses. 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.

TNM descriptions then lead to a simpler categorization of stages, from 0 to 4, where lower numbers

indicate that the cancer has spread less. While most Stage 1 tumors are curable, most Stage 4 tumors

are inoperable or untreatable.

How is cancer treated?

Cancer treatment depends on the type of cancer, the stage of the cancer (how much it has spread), age,

health status, and additional personal characteristics. There is no single treatment for cancer, and

patients often receive a combination of therapies and palliative care. Treatments usually fall into one of

the following categories: surgery, radiation, chemotherapy, immunotherapy, hormone therapy, or gene

therapy.

Surgery

Surgery is the oldest known treatment for cancer. If a cancer has not metastasized, it is possible to

completely cure a patient by surgically removing the cancer from the body. This is often seen in the

removal of the prostate or a breast or testicle. After the disease has spread, however, it is nearly

impossible to remove all of the cancer cells. Surgery may also be instrumental in helping to control

symptoms such as bowel obstruction or spinal cord compression.

Radiation

Radiation treatment, also known as radiotherapy, destroys cancer 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. 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. Radiotherapy is used as a standalone

treatment to shrink a tumor or destroy cancer cells (including those associated with leukemia and

lymphoma), and it is also used in combination with other cancer treatments.

Chemotherapy

Chemotherapy utilizes 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 necessarily

just cancer cells), but normal cells usually can recover from any chemical-induced damage while cancer

cells cannot. Chemotherapy is generally used to treat cancer that has spread or metastasized because

the medicines travel throughout the entire body. It is a necessary treatment for some forms of leukemia

and lymphoma. Chemotherapy treatment occurs in cycles so the body has time to heal between doses.

However, there are still common side effects such as hair loss, nausea, fatigue, and vomiting.

Combination therapies often include multiple types of chemotherapy or chemotherapy combined with

other treatment options.

Immunotherapy

Immunotherapy aims to get the body's immune system to fight the tumor. Local immunotherapy injects a

treatment into an affected area, for example, to cause inflammation that causes a tumor to shrink.

Systemic immunotherapy treats the whole body by administering an agent such as the protein interferon

alpha that can shrink tumors. Immunotherapy can also be considered non-specific if it improves cancer-

fighting abilities by stimulating the entire immune system, and it can be considered targeted if the

treatment specifically tells the immune system to destroy cancer cells. These therapies are relatively

young, but researchers have had success with treatments that introduce antibodies to the body that inhibit

the growth of breast cancer cells. Bone marrow transplantation (hematopoetic stem cell transplantation)

can also be considered immunotherapy because the donor's immune cells will often attack the tumor or

cancer cells that are present in the host.

Hormone therapy

Several cancers have been linked to some types of hormones, most notably breast and prostate cancer.

Hormone therapy is designed to alter hormone production in the body so that cancer cells stop growing or

are killed completely. Breast cancer hormone therapies often focus on reducing estrogen levels (a

common drug for this is tamoxifen) and prostate cancer hormone therapies often focus on reducing

testosterone levels. In addition, some leukemia and lymphoma cases can be treated with the hormone

cortisone.

Gene therapy

The goal of gene therapy is to replace damaged genes with ones that work to address a root cause of

cancer: damage to DNA. For example, researchers are trying to replace the damaged gene that signals

cells to stop dividing (the p53 gene) with a copy of a working gene. Other gene-based therapies focus on

further damaging cancer cell DNA to the point where the cell commits suicide. Gene therapy is a very

young field and has not yet resulted in any successful treatments.

How can 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 lower 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.

Skin cancer can be prevented by staying in the shade, protecting yourself with a hat and shirt when in the

sun, and using sunscreen. Diet is also an important part of cancer prevention since what we eat has been

linked to the disease. Physicians recommend diets that are low in fat and rich in fresh fruits and

vegetables and whole grains.

Certain vaccinations have been associated with the prevention of some cancers. For example, many

women receive a vaccination for the human papillomavirus because of the virus's relationship with

cervical cancer. Hepatitis B vaccines prevent the hepatitis B virus, which can cause liver cancer.

Some cancer prevention is based on systematic screening in order to detect small irregularities or tumors

as early as possible even if there are no clear symptoms present. Breast self-examination, mammograms,

testicular self-examination, and Pap smears are common screening methods for various cancers.