Definition: Lung cancer, a malignancy of the lungs, is defined as an uncontrolled growth of abnormal cells in one or more of the lungs.

Etiology

Over 165,000 people die of lung cancer every year in the United States. Lung cancer composes 28% of all cancer deaths in the United States. It is the leading cause of cancer deaths in men and women in the United States and worldwide.

The median age of patients receiving a lung cancer diagnosis is 70 years.

Smoking is the chief risk factor of lung cancer with over 85% of lung cancers attributed to smoking. Female smokers are at a higher risk (approximately twice as likely to develop lung cancer) than male smokers, although there are not yet any clinical indicators as to why. 

Other risk factors for lung cancer include: second-hand smoke, a family history of cancer, radiation exposure, asbestos exposure (asbestos workers are seven times more likely to develop lung cancers than non-asbestos workers), air pollution, and exposure to radon, uranium, arsenic, coal products, nickel chromates, gasoline, and diesel exhaust.

Types of lung cancer

The two most common types of lung cancer are Small Cell Lung Cancer (SCLC) and
Non-small Cell Lung Cancer (NSCLC). Each type of lung cancer has different behaviors and clinical patterns, is composed of different types of cells, and responds to different types of treatments. Clinical staging also differs among different types of lung cancer.

Small cell lung cancer: Small cell lung cancer, also called oat cell carcinoma and small cell undifferentiated carcinoma, accounts for approximately 20% of all lung cancer cases. SCLC is characterized by an aggressive clinical pattern involving distinct cells that grow and metastasize more rapidly than those involved in other types of lung cancer. In addition to rapid growth, the cancer cells involved with SCLC are also more sensitive to chemotherapy and radiation therapy. Surgery is rarely used in this type of treatment due to the rapid onset of SCLC, its likelihood of spreading to organs outside of the lungs, and its sensitivity to other treatments. SCLC is highly associated with smoking.

Non-small cell lung cancer: Non-small cell lung cancer composes approximately 75% of all lung cancers. Although surgery is the preferred treatment for NSCLC, most patients are diagnosed too late for surgery to be effective.

Like there are different types of lung cancer, there are also different types of NSCLC,
depending on the type of tumor existing in each case. Each carcinoma group arises in a distinct part of the lungs, varies in cell size/shape, and/or varies in treatment options. When localized, all groups have a potential of cure with surgical resection.

Adenocarcinoma: Adenocarcinoma is the most common type of lung cancer and composes approximately 40% of all lung cancers. This type of lung cancer has no relationship with smoking. It originates on the outer boundaries of the lungs.

Squamous cell carcinoma: Squamous cell carcinoma, also called Epidermoid cancer, is the
second most common lung cancer. It composes approximately 20-30% of all lung cancers. Squamous cell carcinoma usually originates in the bronchial tubes and the bronchial epithelium. Squamous cell carcinoma spreads locally and later metastasizes throughout the body.

Large cell carcinoma: Large cell carcinoma composes approximately 10% of all lung cancers. This type of cancer is composed of large, abnormal cells and beings along the outer edges of the lungs.

Secondary Lung Cancer: Secondary lung cancer is a malignancy of the lung that has spread from other parts of the body (where lung is not the area of primary cancer). Secondary lung cancer does not have the same characteristics or clinical pattern as primary lung cancers and is not treated or stages as such.

Clinical manifestations

Symptoms:  Symptoms of lung cancer that may present while lung cancer is still localized to the lung area are: persistent cough, loss of appetite, weight loss, shortness of breath, blood in phlegm, and recurring respiratory infections. Symptoms that may occur after metastases include: bone pain, jaundice, dizziness, swelling of the neck or face, headaches, neurological changes, and palpable masses near the skin. Unfortunately, once these symptoms present themselves, cancer has usually spread a substantial amount and prognosis is not good. The time of onset to manifestations varies and depends on the type of cancer as well as the location.

Lung nodules can be detected on chest x-rays (routine physical examinations and
pre-operative testing) before clinical manifestations occur. Screening may occur after certain symptoms present themselves, or as a routine screening due to risk factors. Many nodules found on x-rays and during lung cancer screening are benign. Currently, it is difficult to assess the possible malignancy of such nodules, as further assessment tends to be costly and/or invasive (this is discussed in the Diagnosis, monitoring & staging procedures section of this article).

Most cancers of the lung (if not detected when still localized) will be fatal within 5 years.

Diagnosis, monitoring, & staging procedures

Physical exam: a physical exam could detect certain symptoms that are sometimes present in lung cancer, such as breathing difficulties, infection in the lungs, or obstruction of the airway.

Sputum cytology: mucous cells (expectorant from the patient) are examined under a microscope to determine if cancerous cells are present.

Biopsy: a sample of tissue or fluid is removed from the patient for examination under a microscope to determine if cancerous cells are present.

Chest x-ray: when respiratory symptoms present themselves, a chest x-ray is the most commonly performed test to evaluate anatomy for abnormalities. Images from the anterior to the posterior are usually taken, as well as lateral images. Not all abnormalities on a chest x-ray will indicate a malignancy, and not all malignancies can be detected from a chest x-ray. If an abnormality is detected on a chest x-ray, further means of lung cancer screening/assessment may be suggested. Most commonly used ways to assess the malignancy of a nodule can be costly (PET or PET/CT imaging) or invasive (biopsy).  

Bronchoscopy: an instrument called a bronchoscope is inserted into the mouth or nose of the patient and allows the doctor to examine the cells and anatomy of the airways and lungs; the doctor can also collect tissue to biopsy using the bronchoscope; some bronchoscopes have video recording devices incorporated into the instrument so the examination can be replayed and analyzed.

Needle aspiration: a needle is inserted through the chest and into the tumor to remove tumor cells for pathological evaluation.

Thoracentesis: a needle is inserted through the chest into the cavity surrounding the lungs and fluid is removed for pathological evaluation.

CT: computerized tomography may be indicated when no abnormalities are found on an x-ray, or when it is necessary to visualize an abnormality in more detail. CT scans take
x-ray images from multiple angles and anatomy can be viewed in 3 planes. CT
scans may also be indicated to assess other parts of the body for metastatic
disease.

MRI: magnetic resonance imaging can be used to visualize detailed anatomy of the lungs and bordering structures and may be indicated when an x-ray has not shown an
abnormality or failed to show necessary detail. More detailed images can be obtained using MRI imaging than chest x-ray, and images can be viewed in 3 planes. MRI shows superior contrast between soft tissues than other imaging procedures such as CT and x-ray. Unlike CT and x-ray, MRI does not use ionizing radiation.

Nuclear bone scan: this imaging is used to detect if lung cancer has spread to the bones, or if it remains in the bones after treatment. A radioisotope attached to a phosphate analogue is injected into the patient’s blood stream and whole-body images are taken using a gamma camera. In areas of increased bone metabolism, the phosphate analogue will accumulate, thereby emitting more radiation than normal bone. The gamma camera detectors will image the bones and the radioactive activity and indicate high levels of bone metabolism, often times an indicator of metastatic activity.

PET: positron emission tomography is used to stage disease and monitor disease progression and effectiveness of treatment. A positron-emitting radioisotope is attached to a glucose molecule and injected into the patient’s blood stream. The glucose molecule will localize in increased areas of metabolic activity, such as tumors. A PET scanner detects the radiation present throughout the body and creates images in 3 planes of the body. Unlike X-ray, MRI and CT, PET images the physiology of the body rather than the anatomy. When used in detection of mediastinal metastasis, PET sensitivity and specificity are found to be higher than that of CT.

PET/CT: when PET and CT are used together, a hybrid camera is used to image both physiology and the anatomy. The detail and high resolution provided by CT is fused with
the metabolic information gathered by the PET to detect not only the size and exact location of abnormalities, but their metabolic activity (malignancy) as
well.

Blood tests: blood tests can be helpful in staging previously diagnosed cancers, or can be an indicator of a possible malignancy. Certain enzymes may exist in the blood, such as
alkaline phosphatase, that can indicate bone metastasis. Elevated calcium levels could also be an indication of bone metastasis. Elevated levels of enzymes found in liver cells, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), could signal liver disease, and possible malignancy of/metastasis to the liver.

Tumor markers, also called biomarkers, are substances that are sometimes found in a specific concentration in the blood (as well as other body fluids or tissues) that may indicate a certain type of cancer is present in the body. Blood is drawn from the patient and tested for biomarkers specific to lung cancer. Researchers have discovered over 400 biomarkers associated with lung cancer to date. Assessment of biomarkers can be used for early detection, as well as treatment selection and monitoring of disease. A recent study has found an abnormal structure of micro RNA (miRNA) to be present in lung cancer patients. The study also found this biomarker to be present in patients before CT scans were able to detect lung nodules in the patients.

Disease progression

Lung cancer will always originate in the lung, and can remain localized without any symptoms presenting. The most common disease progression is as follows:

·      local tumor(s) exists in the lung

·      invasion of airways and blood vessels by tumor(s)

·      primary symptoms may appear

·      malignancy spreads to the lymph nodes

·      lung cancer metastasizes throughout the body (most often to the liver, adrenal glands, bones and brain)

·      advanced symptoms may appear

Staging

Staging is an attempt to define the true extent of a cancer in each patient based on the extent of the primary tumor and the presence or absence of lymphatic involvement or distant metastases. Treatment and prognosis rely on accurate staging for effectiveness
and accuracy.

Staging SCLC: There are two classifications in the staging of SCLC: limited and extensive. A staging classification of limited stage (LS) signifies that disease is confined to the chest, with involvement of only one lung and one nearby lymph node. Any further progression of disease (the disease has spread to other organs) is classified as extensive stage (ES).

Staging NSCLC: NSCLC is staged using roman numerals I-IV, as well as a Stage 0, each having a specific definition indicating the progression of the disease and anatomy involved. 0 indicates local cancer (cancer is in situ) while IV indicates cancer outside of the chest. The
chart below outlines the different stages of NSCLC and survival rates associated with each.

Treatment regimes

Which treatment or combination of treatments is used is determined by the stage of
the cancer, as well as the patient’s overall health. In earlier stages of lung cancer, surgery may be successful in removal of the malignancy. When the lung cancer has metastasized to a more advanced stage, surgery may no longer be an option.

NSCLC stages 0 – I are usually treated with surgery, while stage II cancers will oftentimes
be treated with surgery followed by chemotherapy or radiation therapy. NSCLC stages III and IV will usually use a combination of chemotherapy and radiation therapy, as the disease is too widespread to surgically remove the malignancy with positive results.

SCLC in limited stage may be treatable with surgery, although it is extremely rare for
SCLC to be diagnosed at that stage. Chemotherapy is the most commonly the main
treatment for SCLC, while it can be combined with other treatments as well.  

Surgery: Surgery is used to remove malignancies that are confined to a defined area of the lung anatomy. In most cases, surgery is performed to remove a malignancy before it can metastasize throughout the body. Often times lymph nodes surrounding the area of the malignancy are also removed as a precautionary measure, or if a biopsy has shown lymph node involvement. Surgery may not be an option for certain patients who are not healthy enough to undergo the physical demands of such an intensive mediastinal procedure.

Segmentectemoy/wedge resection: removal of small segments or wedges of the lung

Lobectomy: removal of a lobe of the lung

Pneumonectomy: removal of a lung

Lymph node removal: removal of lymph nodes surrounding the malignancy

Chemotherapy: Chemotherapy is the use of cytotoxic, or cell-killing, drugs to kill cancerous cells in the body, or to decrease their activity. Chemotherapy differs from surgery and radiation therapy in that it is a systemic treatment, targeting cancer cells throughout the entire body. Chemotherapy is often times used in conjunction with surgery and/or radiation therapy, in the case that the malignancy has spread to undetectable locations in the body. Because chemotherapy is most commonly used in addition to other treatments, it can be referred to as an adjuvant therapy. Chemotherapy may also be used to shrink tumor size before surgery (neo-adjuvant therapy), or to shrink tumor size to decrease tumor effects (such as a large tumor obstructing an airway). Chemotherapy may also be used in late-stage lung cancer to prolong life.

In lung cancer, chemotherapy is used as an adjuvant therapy, before and/or after
surgery, and is sometimes combined with radiation therapy. Lung cancer treatment with chemotherapy usually uses a combination of 2 or more drugs, and is given in cycles of 3-4 weeks, usually 4-6 times. Chemotherapy agents can be given orally or intravenously. Cisplatin and carboplatin are two commonly used chemotherapy drugs to treat lung cancer. These platinum-containing agents will bind to DNA and trigger apoptosis (cell
death). It is common for patients to develop a resistance to these agents over
time.

Radiation therapy: Radiation therapy, also called radiotherapy, uses high-energy radiation targeted in specific areas of malignancy to kill or shrink tumors. The radiation will damage the DNA of the cells and lead to cell death. Radiation therapy is often combined with chemotherapy and/or surgery to treat SCLC and NSCLC. Two types of commonly used radiation therapy are external beam radiation therapy and internal radiation therapy
(brachytherapy). Research into other brachytherapy protocols, such as the implantation of radioactive seeds next to malignancies in the lung (which has been successful in prostate cancer treatment), is currently underway.

External beam radiation therapy: a machine emits high-energy radiation targeted towards the area of treatment.

Internal radiation (brachytherapy) therapy: in lung cancer, brachytherapy can be administered by passing radioactive material through a plastic tube inserted into the lung where the malignancy to be treated is (this is done via bronchoscopy).  

Prognosis and outcome

Of all diagnosed cases of lung cancer, 10% are ultimately cured. If a patient cannot be cured by surgery at the time of diagnosis there exists a 50% chance of survival for one year. 85% of all lung cancers diagnosed are in stage II or higher (NSCLC), or in extensive stage (SCLC).

One-year survival rate is 41% for lung cancers diagnosed in this stage (stage II or higher or ES), and the five-year survival rate is approximately 15% (compared to approximately 65% for colon cancer and approximately 90% for breast cancer). If lung cancer is diagnosed before it has spread to the lymph nodes, the five-year survival rate increases to about 42%, although less than 20% of all lung cancers are diagnosed at this early of a stage. Most noticeable symptoms of lung cancer do not present themselves until after metastasis has occurred.

References consulted

Hansen, H. (Ed.). (2008). Textbook of Lung Cancer (2^nd Edition), London, Informa Healthcare.

American Cancer Society

U.S. National Library of Medicine (NIH), Medline Plus

World Health Organization, International Agency for Research on Cancer

Journal of the American Medical Association, Lung Cancer Facts

Proceedings of the National Academy of Sciences, MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer, Mattia Boeri, CarlaVerri, Davide Conte, Luca Roz, Piergiorgio Modena, Federica Facchinetti, Elisa Calabro, Carlo M. Croce, Ugo Pastorino, and Gabriella Sozzi, 2011.

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