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 Anatomy and functions of Lungs [1]

lung1The lungs are a pair of sponge-like cone shaped organs in the chest.  These are part of our respiratory system. The left lung is smaller because the heart occupies space on left side.  The lungs are slightly different on each side; Right lung has three lobes, whereas the left lung has two lobes. Lungs are covered by a thin covering called ‘pleura’ which   protects and helps lungs move back and forth as they expand and contract during breathing.

A thin, dome-shaped muscle below the lungs called ‘diaphragm’ separates the chest from the abdomen. The diaphragm moves up and down during breathing forcing air in and out of the lungs.

Main function of the lungs is to exchange gases between the air we breathe and the blood. When we breathe in (inhale), oxygen enters into the body through the lungs and when we breathe out (exhale) carbon dioxide is sent out of the body.

Air enters the lungs through nose or mouth via windpipe (trachea) which divides into two airways going into right and left lungs. These airways are called ‘bronchi (singular, bronchus). Inside each lung the bronchus   divides into smaller tubes, the ‘secondary bronchi’ which further subdivide into smaller branches called bronchioles. At the end of the bronchioles are tiny air sacs known as ‘alveoli’. Many tiny blood vessels that run through these alveoli perform the function of exchange of gases.

What is Lung Cancer?   

lung2

Lung cancer is a type of cancer that arises in the lungs [2]. It may spread to lymph nodes or other organs in the body, such as the brain.

Lung cancers usually are grouped into two main types, non-small cell lung cancer (NSCLC) and small cell lung cancers (SCLC) based on appearance of tumor cells under the microscope [3].  Non-small cell lung cancer (75-80 % of cases) is more common than small cell lung cancer (15-20%) [4]

Epidemiology

Epidemiology 

 Table : Lung cancer in India ( Globocan 2012) [5]

 Incidence  Mortality
 Lung cancer (Men)  54,000  49,000
 Women  17,000  15,000
 Both sexes  70,000  64,000

Table : Age of gender wise risk of lung cancer [6]

 Male  Female  Both sexes
 Risk of getting cancer before age 75 (%)  10.2   10.8  10.4
 Risk of dying from cancer before age 75 (%)  8.0   7.1   7.5 

The mean age : 54.6 years 
Males predominate with a M:F ration of 4.5:1 and this ratio varies with age and smoking status. 

The ratio increased progressively upto 51-60 years and then remained same. 

The smoker to non-smoker ratio is high up to 20:1 in various studies. 

Upto 40 years of age small cell type predominates and has less association with smoking. After the age of 40 years squamous cell type is commonest in smokers and adenocarcinoma in non-smokers.

Risk Factors

Risk Factors

A number of factors are known to increase risk of lung cancer. Of these, some can be controlled by making lifestyle changes, like by quitting smoking, while other risk factors, such as family history of cancer can't be controlled.

Risk factors for lung cancer include:

Tobacco Smoking: Tobacco use in any form is harmful, whether smoked or smokeless. Cigarette and beedi smoking is the number one risk factor for lung cancer [7,8]. Smokeless tobacco use is associated with cancers of the lip, oral cavity, pharynx, digestive, respiratory and intrathoracic organs [7]. The toxic chemicals in tobacco damage the cells in the lungs, causing them cells to grow abnormally [8]

Cigarette smoking increases a person’s chance of getting lung cancer by 15 to 30 times and these persons are more likely to die from lung cancer than people who do not smoke [9]. Lung cancer risk increases with the number of cigarettes smoked each day and with increasing duration of time the person has been smoking. The risk decreases if the person quits smoking [7,10]

In addition to lung cancer, smoking can cause cancer almost anywhere in the body such as head and neck region, stomach, liver, pancreas, colon, rectum, bladder, kidney, cervix, blood, and cancer in the bone marrow [11] .

In India, 87% of males and 85% of females patients with lung cancer have history of active tobacco smoking and history of passive tobacco exposure has been found in 3% of patients. Beedi has been found to be more carcinogenic than cigarette smoke [12, 13, 14] and the relative risk of developing lung cancer is more (2.64) for beedi smokers compared to that of cigarette smokers (2.23) [4]. Hookah smoking has also been associated with lung cancer [15].

 

Tobacco Related Cancers

 

Second-hand smoking (SHS): Regular exposure to smoke from other’s cigarettes, can increase a person’s risk of getting lung cancer, even if the person himself/herself does not smoke. This is called ‘second-hand smoke (SHS) or passive or environmental smoking’ [13].

 

The Global Adult Tobacco Survey (GATS) India, shows that 52% of the adults (rural-58%, urban-39%) are exposed to SHS at home [16]. Toxic chemical particles from smoke cling to household items like, curtains, clothes, rugs, food, furniture and other materials used commonly by other family members causing SHS [17]. The risk increases with increase in number of smokers in the house and with the duration of exposure. Environmental tobacco smoke exposure during childhood is strongly associated with risk of developing lung cancer [18,19].

 

Asbestos: Asbestos is classified as a known human carcinogen, and has been directly and scientifically linked to lung cancer and other respiratory conditions [20]. Asbestos is a set of six naturally occurring fibrous mineral widely used in house construction materials, automobiles parts and textiles due to its extremely durable and fire resistant property [20]. Asbestos fibres are microscopic in nature and when inhaled, they get lodged in the soft internal tissue of respiratory system and can irritate the lungs. There is no safe level or no safe type of asbestos.
The combination of smoking and occupational exposure to asbestos is very dangerous [11].

 

Occupational exposure to chemical carcinogens: Workplace exposure to arsenic, chromium, diesel exhaust, silica and nickel can also increase risk of developing lung cancer and the risk is even higher for those who also smoke [21, 22]. Chemicals used in rubber manufacturing, iron and steel founding and painting have also been considered as risk factors but the exact constituents which trigger carcinogenesis are not known [21].

 

Read more [23] 

 

Radon: Exposure to radon has been associated with an increased risk of some types of cancer, including lung cancer. Radon is an invisible, odourless gas released naturally from dirt and rocks by the breakdown of uranium that gets mixed with the air we breathe eventually [20, 22-25]. The main sources of indoor radon are soil, construction material, tap water, and the natural gas used for cooking. This gas can get accumulated in homes and buildings to unsafe levels. A preventive measure to reduce radon accumulation is to ventilate basements well [20, 24, 25].

 

Family/Personal History of Lung Cancer: People with a family history of lung cancer in first degree relatives have an increased risk of lung cancer [26]There is a risk of developing lung cancer in the other lung, if you have had lung cancer on one side [27] . Cancer survivors who have been given radiation therapy to chest area are also at a higher risk [10]. The risk may be even higher if there is a positive family history since they share the same living space, and the exposure to radon [10].  

 

Indoor burning of coal: There is sufficient evidence that indoor combustion of coal, either for cooking or heating, increases the risk of lung cancer [28].  In poorly ventilated houses, cooking or heating with coal on open fires in traditional stoves results in high levels of indoor air pollution due to a wide range of  pollutants that damage health [28]

 

Infections in lung: Having had infections like chlamydia pneumoniae or disease like tuberculosis (TB) that can lead to scar tissue formation in the lungs may have an increased risk for adenocarcinoma of the lung, a type of lung cancer [29, 30]. Research indicates that people who have had TB have double the risk of lung cancer [31]

 

Diet: Evidence suggests that some dietary factors may be protective for lung cancer and some may increase the risk of lung cancer. Persons with the low intake of foods rich in beta-carotene, such as carrots, have a higher risk for lung cancer [32] .

 

Vitamin A deficiency increases the chance of developing squamous cell carcinoma of lung in smokers [33]. Also, arsenic in drinking water (primarily from private wells) can increase the risk of lung cancer [34] 

Prevention

 Prevention of Lung Cancer  [35, 36, 37]

 

There is no proven way to completely prevent lung cancer, but there are steps to lower the risk of getting lung cancer. You can help lower your risk of getting lung cancer in the following ways:

 

1. Not Smoking: The best way to prevent lung cancer is to not smoke. People who have never smoked have the lowest risk of lung cancer. Talk to your children about harmful effects of smoking so that they know how to face peer pressure and do not start smoking.

 

2. Quitting Smoking: However long you have been smoking, it is always worthwhile to quit smoking. If you stop smoking before you attain 50 years of age, you can reduce your risk of getting lung cancer by half in the next 10-15 years. Your doctor can help you in strategies and stop-smoking aids that can help you quit effectively. 

 

3. Avoid second hand smoke: If you live or work with someone who smokes, urge him/ her to quit. If not, request them to smoke outside. Avoid smoking zones in public places like restaurants and bars. 

 

4.  Lower your exposure to radon: If you live in an area where radon is a known problem, get the radon levels in your house checked and take measures to reduce exposure. 

 

5.  Lower exposure to workplace risk factors: Follow your employers’ precautions to protect yourself from toxic chemicals at work. 

 

The following help in reducing the risk of cancer in general, not specifically for lung cancer:
• Diet rich in fruits and vegetables
• Regular physical activity

 

New ways to prevent lung cancer are being studied in clinical trials and may become available in near future. 

Signs and Symptoms

Signs and Symptoms [38]

Lung cancer typically does not cause any specific signs and symptoms in its initial stages. The patients may just have general symptoms of not feeling well.   In most people with lung cancer, the symptoms arise only when the disease is advanced.  The common symptoms include:
1.    Persistent cough that gets worse despite usual treatment. 
2.    Shortness of breath 
3.    Coughing up phlegm (sputum) with traces of blood in it
4.    Coughing up frank blood
5.    Wheezing 
6.    An ache or pain in the chest or shoulder
7.    Unexplained weight  loss
8.    Feeling of extreme tiredness
9.    Loss of appetite

Less Common Symptoms of Lung Cancer

These symptoms are usually associated with more advanced lung cancer
•    Difficulty in swallowing 
•    Hoarseness in  voice
•    Swelling in the neck caused by enlarged lymph nodes. 
•    Repeated attacks  of pneumonia 
•    Rise in platelet count (thrombocytosis)
•    Pain  under the  ribs on the right side
•    Changes in the shape of  fingers and nails, called finger clubbing
•    Severe shoulder pain or pain that travels down the arm

Screening and Diagnosis

Screening and Diagnosis of Lung Cancer

The symptoms of lung cancer usually do not appear until the disease is fairly advanced and in a non-curable stage. The early symptoms of lung cancer (persistent cough, chest pain and shortness of breath) are similar to other lung problems such as an infection or long-term effects of smoking and are not taken notice of. This often delays the diagnosis.

Screening for Lung Cancer

Screening means use of tests to detect a disease in patients who do not have symptoms of the disease. For lung cancer, three tests have been studied for use as screening tests:

1. Chest X-ray: It is an X-ray of the organs and bones inside the chest.

2. Sputum cytology: This is a procedure where a sample of sputum (mucus coughed up from lungs) is viewed under a microscope by a pathologist to look for cancer cells.

3. Low-dose spiral/ helical CT scan: This involves a CT scan with low-dose radiation to make a series of detailed pictures of the organs inside the body.

Of these three tests, chest X-ray and sputum cytology have been found to have a low sensitivity for detection of lung cancer. Only low-dose spiral/ helical CT scan has been recommended to be used in high-risk patients for lung cancer screening.[39]

There are no recommended guidelines for lung cancer screening in India.

As per the guidelines of The American Cancer Society, if you meet all the following criteria, you should go for lung cancer screening [40]:

1. Your age is between 55 and 74 years
2. You have a 30-pack-year smoking history (calculated as number of packs of cigarettes multiplied by the number of years you have been smoking)
3. You are either still smoking or have quit in the last 15 years
4. You are in fairly good health (you should not have symptoms of lung cancer or serious medical problems or metal implants or prior history of lung cancer treated)

Low Dose Computed Tomography (Low Dose CT or LDCT) is better than plain X-ray of the chest at finding small abnormalities in the lungs. LDCT uses a much lower dose of radiation than a normal chest CT. Screening is to be done every year till the age of 74 years or till symptoms appear.

Though screening can detect lung cancer better than X-ray chest, one must remember that not all lung cancers are found by LDCT screening and not all lesions detected by LDCT are cancer.

Diagnosis of Lung Cancer

If you have one or more symptoms indicative of lung cancer, you should visit your doctor, who will examine you and ask for relevant tests.

Medical history and physical exam: If your doctor suspects you might have lung cancer, he will ask you about the presence of risk factors like smoking, your occupation, etc. He will also examine you for signs of lung cancer and other health problems. 
Depending upon the findings, the doctor might advise certain tests.

Imaging Tests:

• Chest X-ray: This is usually the first test your doctor will get done to look for a mass in the lungs. If something suspicious is seen in the X-ray, further tests will be ordered.

• Computed tomography (CT) scan: A CT (or CAT) scan is more likely to show lung masses than X-ray. CT scans can also provide information about the size, shape and position of lung tumors and help find spread of the cancer to lymph nodes or other organs.[41]

CT-guided needle biopsy: If a suspicious mass is seen in the lung during CT scan, your doctor may perform a guided biopsy to take some tissue for diagnosis.

• Magnetic resonance imaging (MRI) scan: MRI scans are most often used to look for spread of lung cancer to brain and spinal cord to help in staging of the cancer. Unlike CT scans, MRI uses radio waves and strong magnets and there is no exposure to radiation.[42]

• Positron emission tomography (PET) scan: A PET scan can be used to see if the cancer has spread to lymph nodes or other areas. This determines whether surgery can be done or not. PET scan is also useful if your doctor thinks that your lung cancer has spread but does not know where.

Laboratory Tests:

Imaging can help in detecting a mass in the lung, but the actual diagnosis of lung cancer can be made by looking at the cells under a microscope. The cells can be taken from lung secretions (sputum), in fluid removed from area around the lung (pleural fluid) or from a suspicious area using a needle or surgery (biopsy).

• Sputum Cytology: A sample of sputum (mucus that is coughed up from lungs) is viewed under a microscope to look for cancer cells. For this, the best method is to submit early morning sputum samples obtained after a deep cough for 3 days in a row.[43, 44]

• Needle biopsy: This involves the insertion of a hollow needle into the mass to get a small sample for testing. It can be done by fine needle aspiration biopsy (FNAB), where a very fine needle with syringe is used to withdraw or aspirate cells and fragments from the mass; or core biopsy, in which a larger needle is used to remove small cylinders or cores of tissue.[45]

If the suspected tumor is in the outer portion of lung, either kind of needle may be inserted through the chest wall skin (trans-thoracic needle biopsy). This procedure is performed under local anesthesia and radiologist’s guidance.

An FNA biopsy may also be done to look for cancer spread into the lymph nodes in the chest by trans-tracheal or trans-bronchial FNA  (performed during bonchoscopy or endobronchial ultrasound) or EUS-FNA (performed during endoscopic esophageal ultrasound).[46]

A possible complication of the biopsy procedure is air leak from the lung into the space between lung and chest wall (pneumothorax ). When large, it may lead to collapse of a part of the lung and trouble in breathing. This is usually self limiting and gets better without any treatment.

• Bronchoscopy: For this test, a flexible fiber-optic tube (bronchoscope) is passed through the mouth or the nose and down into the windpipe and further. The doctor can look inside the tube and see for tumor or blockage in the major airways or bronchi. Small instruments can also be passed down the bronchoscope to take biopsies. Cells can also be sampled with a small brush (bronchial brushings) or by rinsing the airway with sterile saline (bronchial washings).[47, 48]

• Thoracocentesis: This procedure is performed if there is a buildup of fluid around the lungs (pleural effusion), which can cause difficulty in breathing. A hollow needle is inserted between the ribs to drain the fluid and check for tumor cells in the fluid (effusion cytology).[49]

If there is difficulty in breathing, removal of fluid can help the patient breathe better.

Staging

Staging of Lung Cancer

There are two types of staging system used to stage lung cancer. They are number system and TNM staging system.[50, 51]

I. Number system of staging lung cancer:

Stage 1
The tumor size is less than 5 cms and it is limited to lungs only. There is no involvement of lymph nodes.

Stage 2
If there is presence of any one of these following conditions, it is categorized as stage 2
•    Tumor size is more than 5 cms 
•    Lymph nodes are involved 
•    Larger than 7cm with no involvement of lymph nodes 
•    spread to the following areas – the chest wall, the muscle under the lung (diaphragm), the phrenic nerve, or the layers that cover the heart (mediastinal pleura and parietal pericardium)
•    In the main airway (bronchus) close to where it divides to go into each lung 
•    Making part of the lung collapse
•    Any size but there is more than one tumor in the same lobe of the lung

Stage 3
If there is presence of any one of these following conditions, it is categorized as stage 3
•    Complete lung collapse 
•    Has spread into the chest wall, the muscle under the lung (diaphragm), or the layers that cover the heart (mediastinal pleura and parietal pericardium) 
•    Spread into lymph nodes on the opposite side of the chest 
•    Involvement of major structures in the chest include the heart, the wind pipe (trachea), the food pipe (oesophagus) or a main blood vessel.

Stage 4 
The cancer has spread to a distant part of the body such as the liver, bones or the brain.

II. TNM staging of lung cancer [52]:

TNM stands for Tumor, Node and Metastases. This staging system describes

Tumor (T)
T1 – the tumor is contained within the lung and is smaller than 3 cm across
T2 – the tumor is between 3 and 7cm across 
T3 – the tumor is larger than 7cm 
T4 – the tumor has grown into one of the following structures: mediastinum, the heart, a major blood vessel, the wind pipe, food pipe, a spinal bone, the nerve that controls the voice box

Nodes (N)
The N stages for lung cancer are
N0 – there is no cancer in any lymph nodes
N1 – there is cancer in the lymph nodes nearest the affected lung
N2 – there is cancer in lymph nodes in the mediastinum but on the same side as the affected lung or there is cancer in lymph nodes just under where the windpipe branches off to each lung
N3 – there is cancer in lymph nodes on the opposite side of the chest from the affected lung or in the lymph nodes above either collar bone or in the lymph nodes at the top of the lung

Metastases (M)
The M stages for lung cancer are
M0 – there are no signs that the cancer has spread to another lobe of the lung or any other part of the body
M1 – there are signs that the cancer has spread to another lobe of the lung or any other part of the body

Treatment

Treatment of Lung Cancer

The treatment of lung cancer depends on the

•    type of lung cancer (whether its small cell type or non small cell type), 
•    size of the tumor, 
•    whether the cancer is local or metastatic and 
•    general condition of the patient

Treatment Modalities [53] :

Surgery, chemotherapy, radiotherapy and targeted therapy may be used alone or in combination depending on the above mentioned factors. 

Surgery

Surgery is mostly used to treat non small cell lung cancer [54] and rarely for small cell lung cancer when the disease is in very early stage. The surgeon might remove a small section of lung (wedge resection), a larger portion of lung (segmental resection), entire lobe of one lung (lobectomy) or an entire lung (pneumonectomy). 

Chemotherapy

A combination of chemotherapy drugs are usually given in sessions over a period of weeks or months, with breaks in between. It can either be used before (to shrink cancers) or after surgery (to kill any cancer cells that may remain). In some cases, chemotherapy can be used as palliation to relieve pain and other symptoms of advanced cancer.

Some of the chemotherapy drugs used in the treatment of lung cancer are:

•    Paclitaxel
•    Carboplatin
•    Cisplatin
•    Docetaxel
•    Etoposide
•    Gemcitabine
•    Pemetrexed

Radiation therapy

Radiation therapy can be directed at lung cancer from outside the body (external beam radiation ) or it can be administered through needles, seeds or catheters placed inside the body near the cancerous area (brachytherapy).

Radiation therapy can be either used after surgery to kill any cancer cells that may remain or can be used as the palliative therapy to relieve pain and other symptoms in advanced stage lung cancer.

Targeted drug therapy [55] (for non small cell lung cancer)

Targeted therapies are drugs that target specific molecular targets in the tumor cells. They specifically kill cancer cells only, block their growth, prevent cancer from spreading and can stop tumors from growing by blocking signals inside the cancer cells.

Chemotherapy drugs differ from targeted therapies as they act on all rapidly dividing normal and cancerous cells.The side effects from targeted therapy are minimal since they do not have any toxic effects on normal cells.

Some of the available targeted therapy options for treating lung cancer include:

1. Inhibitors of Epidermal growth factor receptor (EGFR)
•    Erlotinib
•    Gefitinib

2. Monoclonal antibody against EGFR
•    Cetuximab

3. Inhibitors of vascular endothelial growth factor (VEGF)
•    Bevacizumab

4. Inhibitor of EML4-ALK
•    Crizotinib
 

References

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