Lung cancer

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. The main types of lung cancer are small cell lung carcinoma (SCLC), also called oat cell cancer, and non-small cell lung carcinoma (NSCLC). The most common cause of lung cancer is long-term exposure to tobacco smoke.Nonsmokers account for 15% of lung cancer cases, and these cases are often attributed to a combination of genetic factors,radon gas, asbestos and air pollution including secondhand smoke.
The most common symptoms are coughing (including coughing up blood), weight loss and shortness of breath. Lung cancer may be seen on chest radiograph and computed tomography (CT scan). The diagnosis is confirmed with a biopsy. This is usually performed by bronchoscopy 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 radiotherapy.Survival depends on stage, overall health, and other factors. Overall, 15% of people in the United States diagnosed with lung cancer survive five years after the diagnosis. Worldwide, lung cancer is the most common cause of cancer-related death in men and women, and is responsible for 1.38 million deaths annually, as of 2008.

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. Lung carcinomas are categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope. The two broad classes are non-small cell and small cell lung carcinoma.

Non-small cell lung carcinoma

 There are three main sub-types: adenocarcinoma, squamous cell lung carcinoma, and large cell lung carcinoma.Nearly 40% of lung cancers are adenocarcinoma. This type of cancer usually originates in peripheral lung tissue.Most cases of adenocarcinoma are associated with smoking; however, among people who have smoked fewer than 100 cigarettes in their lifetimes ("never-smokers"), adenocarcinoma is the most common form of lung cancer. A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have different responses to treatment.Squamous cell carcinoma accounts for about 30% of lung cancers. They typically occur close to large airways. A hollow cavity and associated necrosis are commonly found at the center of the tumor.About 9% of lung cancers are large cell carcinoma. These are so named because the cancer cells are large, with a lot of cytoplasm, large nuclei and conspicuous nucleoli.

Small cell lung carcinoma

In small-cell lung carcinoma (SCLC), the cells contain dense neurosecretory granules (vesicles containing neuroendocrine hormones), which give this tumor an endocrine/paraneoplastic syndrome association. Most cases arise in the larger airways (primary and secondary bronchi).These cancers grow quickly and spread early in the course of the disease. 60–70% have metastatic disease at presentation. This type of lung cancer is strongly associated with smoking .

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

Metastasis

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 metastatic breast cancer. Metastases often have a characteristic round appearance on chest radiograph.

Primary lung cancers themselves most commonly metastasize to the brain, bones, liver, and adrenal glands.Immunostaining of a biopsy is often helpful to determine the original source.

Signs and symptoms

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.

Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease. 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, may invade the local part of the sympathetic nervous system, leading to Horner's syndrome as well as damage to the brachial plexus.

Many of the symptoms of lung cancer (poor appetite, weight loss, fever, fatigue) are nonspecific.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.About 10% of people with lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest radiograph.

Causes

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

Smoking

Smoking, particularly of cigarettes, is by far the main contributor to lung cancer.Cigarette smoke contains over 60 known carcinogens, including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue. Across the developed world, 91% of lung cancer deaths in men during the year 2000 were attributed to smoking (71% for women). In the United States, smoking accounts for 80–90% of lung cancer cases.

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.,Europe, the UK, and Australia have consistently shown a significantly increased risk among those exposed to passive smoke.Those who live with someone who smokes have a 20–30% increase in risk while those while those who work in an environment with second hand smoke have a 16–19% increase in risk. Investigations of sidestream smoke suggests that it is more dangerous than direct smoke. Passive smoking causes about 3,400 deaths from lung cancer each year in the USA.

Radon gas

Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the Earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon is the second most common cause of lung cancer in the USA, after smoking. The risk increases 8–16% for every 100 Bq/m³ increase in the radon concentration .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).

Asbestos

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. Asbestos can also cause cancer of the pleura, called mesothelioma (which is different from lung cancer).

Air pollution

Outdoor air pollution has a small effect on increasing the risk of lung cancer. Fine particulates (PM2.5) and sulfate aerosols, which may be released in traffic exhaust fumes, are associated with slightly increased risk.For nitrogen dioxide, an incremental increase of 10 parts per billion increases the risk of lung cancer by 14%.Outdoor air pollution is estimated to account for 1–2% of lung cancers.

Genetics

There is a genetic predisposition to lung cancer. In relatives of people with lung cancer, the risk is increased 2.4 times. This may be due to genetic polymorphisms

Pathogenesis

Main article: Carcinogenesis

Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.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. Mutations in the K-ras proto-oncogene are responsible for 10–30% of lung adenocarcinomas. The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion. 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.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. Other genes that are often mutated or amplified are c-MET, NKX2-1, LKB1, PIK3CA, and BRAF.

Diagnosis

Prevention

See also: Smoking ban

Prevention is the most cost-effective means of mitigating lung cancer development. While in most countries industrial and domestic carcinogens have been identified and banned, tobacco smoking is still widespread. Eliminating tobacco smoking is a primary goal in the prevention of lung cancer, and smoking cessation is an important preventive tool in this process.

Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries.Bhutan has had a complete smoking ban since 2005 . India introduced a ban on smoking in public in October 2008.

The World Health Organization has called for governments to institute a total ban on tobacco advertising to prevent young people from taking up smoking. They assess that such bans have reduced tobacco consumption by 16% where instituted.

The long-term use of supplemental vitamin A, vitamin C, vitamin D or vitamin Edoes not reduce the risk of lung cancer. Some studies suggest that people who eat diets with a higher proportion of vegetables and fruit tend have a lower risk. However this is likely due to confounding. More rigorous studies have not demonstrated a clear association.

Screening

Main article: Lung cancer screening

Screening refers to the use of medical tests to detect disease in asymptomatic people. Possible screening tests for lung cancer include sputum cytology, chest radiograph, and computed tomography (CT). Screening programs using CXR or cytology have not demonstrated any benefit. Screening those at high risk (i.e. age 55 to 79 who have smoked more than 30 pack years or those who have had previous lung cancer) annually with low does CT scans may reduce the chance of death from lung cancer by an absolute amount of 0.3% (relative amount of 20%).The potential risks of screening however are not well known.

Surgery

If investigations confirm non-small cell lung cancer, the stage must be re-assessed 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. CT scan and positron emission tomography (PET) are used. If mediastinal lymph node involvement is suspected, mediastinoscopy may be used to sample the nodes and assist staging.Blood tests and pulmonary function testing are also necessary to assess whether the patient is well enough to be operated on.If pulmonary function tests reveal poor respiratory reserve, surgery may be contraindicated.In most cases of early stage non-small cell lung cancer, removal of a lobe of lung (lobectomy) is the surgical treatment of choice. In patients who are unfit for a full lobectomy, a smaller sublobar excision (wedge resection) may be performed. However wedge resection has a higher risk of recurrent disease than lobectomy.Radioactive iodine brachytherapy at the margins of wedge excision may reduce the risk of recurrence.Rarely, removal of a whole lung (pneumonectomy) is performed.Video-assisted thoracoscopic surgery and VATS lobectomy use a minimally invasive approach to lung cancer surgery. VATS lobectomy is equally effective compared to conventional open lobectomy, and with less post-operative illness.

In small-cell lung carcinoma (SCLC), chemotherapy and/or radiotherapy is typically used.However the role of surgery in SCLC is being reconsidered. Surgery might improve outcomes when added to chemotherapy and radiation in early stage SCLC.

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.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.Post-operative thoracic radiotherapy generally should not be used after curative intent surgery for non-small cell lung carcinoma.Some patients with mediastinal N2 lymph node involvement might benefit from post-operative radiotherapy.For small cell lung carcinoma cases that are potentially curable, chest radiotherapy is often recommended in addition to chemotherapy.If cancer growth blocks a short section of bronchus, brachytherapy (localized radiotherapy) may be given directly inside the airway to open the passage.Compared to external beam radiotherapy, brachytherapy allows a reduction in treatment time and reduced radiation exposure to healthcare staff.Prophylactic cranial irradiation (PCI) is a type of radiotherapy to the brain, used to reduce the risk of metastasis. PCI is most useful in small cell lung carcinoma. In limited stage disease, PCI increases three-year survival from 15% to 20%; in extensive disease, one-year survival increases from 13% to 27%.Recent improvements in targeting and imaging have led to the development of stereotactic radiation in the treatment of early-stage lung cancer. In this form of radiotherapy, high doses are delivered in a small number of sessions using stereotactic targeting techniques. Its use is primarily in patients who are not surgical candidates due to medical comorbidities.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) .                                               

Non-small cell lung carcinoma

In advanced non-small cell lung carcinoma, chemotherapy improves survival and is used as first-line treatment, provided the patient is well enough for the treatment.Typically, two drugs are used, of which one is often platinum-based (either cisplatin or carboplatin). Other commonly used drugs are gemcitabine, paclitaxel and docetaxel.Advanced non-small cell lung carcinoma is often treated with cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide, or vinorelbine. Recently, pemetrexed has become available.

Adjuvant chemotherapy

Adjuvant chemotherapy refers to the use of chemotherapy after apparently curative surgery to improve the outcome. In non-small cell lung carcinoma, samples are taken of nearby lymph nodes during surgery to assist staging. If stage II or III disease is confirmed, adjuvant chemotherapy improves survival by 5% at 5 years.The combination of vinorelbine and cisplatin is more effective than older regimens.

Adjuvant chemotherapy for patients with stage IB cancer is controversial, as clinical trials have not clearly demonstrated a survival benefit. Trials of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable non-small-cell lung carcinoma have been inconclusive .

History

Lung cancer was uncommon before the advent of cigarette smoking; it was not even recognized as a distinct disease until 1761. Different aspects of lung cancer were described further in 1810.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. Case reports in the medical literature numbered only 374 worldwide in 1912, but a review of autopsies showed that the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952. In Germany in 1929, physician Fritz Lickint recognized the link between smoking and lung cancer, which led to an aggressive antismoking campaign.The British Doctors Study, published in the 1950s, was the first solid epidemiological evidence of the link between lung cancer and smoking. As a result, in 1964 the Surgeon General of the United States recommended that smokers should stop smoking.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.Despite this discovery, mining continued into the 1950s, due to the USSR's demand for uranium. Radon was confirmed as a cause of lung cancer in the 1960s.The first successful pneumonectomy for lung cancer was performed in 1933. Palliative radiotherapy has been used since the 1940s.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.In 1997, continuous hyperfractionated accelerated radiotherapy (CHART) was seen as an improvement over conventional radical radiotherapy.With small cell lung carcinoma, initial attempts in the 1960s at surgical resection and radical radiotherapy were unsuccessful. In the 1970s, successful chemotherapy regimens were developed.