Lung cancer

H&E stained samples from lung biopsies: (Top-left) Normal bronchiole surrounded by alveoli, (top-right) adenocarcinoma with papillary (finger-like) growth, (bottom-left) alveoli filled with mucin suggesting adenocarcinoma nearby, (bottom-right) squamous-cell carcinoma, with alveoli full of keratin.

At diagnosis, lung cancer is classified based on the type of cells the tumor is derived from; tumors derived from different cells progress and respond to treatment differently. There are two main types of lung cancer, categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: small cell lung cancer (SCLC; 15% of cases) and non-small-cell lung cancer (NSCLC; 85% of cases).[17] SCLC tumors are often found near the center of the lungs, in the major airways.[18] Their cells appear small with ill-defined boundaries, not much cytoplasm, many mitochondria, and have distinctive nuclei with granular-looking chromatin and no visible nucleoli.[19] NSCLCs comprise a group of three cancer types: adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma.[19] Nearly 40% of lung cancers are adenocarcinomas.[20] Their cells grow in three-dimensional clumps, resemble glandular cells, and may produce mucin.[19] About 30% of lung cancers are squamous-cell carcinomas. They typically occur close to large airways.[20] The tumors consist of sheets of cells, with layers of keratin.[19] A hollow cavity and associated cell death are commonly found at the center of the tumor.[20] Less than 10% of lung cancers are large-cell carcinomas,[19] so named because the cells are large, with excess cytoplasm, large nuclei, and conspicuous nucleoli.[20] Around 10% of lung cancers are rarer types.[19] These include mixes of the above subtypes like adenosquamous carcinoma, and rare subtypes such as carcinoid tumors, and sarcomatoid carcinomas.[20]

Several lung cancer types are subclassified based on the growth characteristics of the cancer cells. Adenocarcinomas are classified as lepidic (growing along the surface of intact alveolar walls),[21] acinar and papillary, or micropapillary and solid pattern. Lepidic adenocarcinomas tend to be least aggressive, while micropapillary and solid pattern adenocarcinomas are most aggressive.[22]

In addition to examining cell morphology, biopsies are often stained by immunohistochemistry to confirm lung cancer classification. SCLCs bear the markers of neuroendocrine cells, such as chromogranin, synaptophysin, and CD56.[23] Adenocarcinomas tend to express Napsin-A and TTF-1; squamous cell carcinomas lack Napsin-A and TTF-1, but express p63 and its cancer-specific isoform p40.[19] CK7 and CK20 are also commonly used to differentiate lung cancers. CK20 is found in several cancers, but typically absent from lung cancer. CK7 is present in many lung cancers, but absent from squamous cell carcinomas.[24]

Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. It is one of the factors affecting both the prognosis and the treatment of lung cancer.[26]

SCLC is typically staged with a relatively simple system: limited stage or extensive stage. Around a third of people are diagnosed at the limited stage, meaning cancer is confined to one side of the chest, within the scope of a single radiotherapy field.[26] The other two thirds are diagnosed at the "extensive stage", with cancer spread to both sides of the chest, or to other parts of the body.[26]

NSCLC – and sometimes SCLC – is typically staged with the American Joint Committee on Cancer's Tumor, Node, Metastasis (TNM) staging system.[27] The size and extent of the tumor (T), spread to regional lymph nodes (N), and distant metastases (M) are scored individually, and combined to form stage groups.[28]

Relatively small tumors are designated T1, which are subdivided by size: tumors ≤ 1 centimeter (cm) across are T1a; 1–2 cm T1b; 2–3 cm T1c. Tumors up to 5 cm across, or those that have spread to the visceral pleura (tissue covering the lung) or main bronchi, are designated T2. T2a designates 3–4 cm tumors; T2b 4–5 cm tumors. T3 tumors are up to 7 cm across, have multiple nodules in the same lobe of the lung, or invade the chest wall, diaphragm (or the nerve that controls it), or area around the heart.[28][29] Tumors that are larger than 7 cm, have nodules spread in different lobes of a lung, or invade the mediastinum (center of the chest cavity), heart, largest blood vessels that supply the heart, trachea, esophagus, or spine are designated T4.[28][29] Lymph node staging depends on the extent of local spread: with the cancer metastasized to no lymph nodes (N0), pulmonary or hilar nodes (along the bronchi) on the same side as the tumor (N1), mediastinal or subcarinal lymph nodes (in the middle of the lungs, N2), or lymph nodes on the opposite side of the lung from the tumor (N3).[29] Metastases are staged as no metastases (M0), nearby metastases (M1a; the space around the lung or the heart, or the opposite lung), a single distant metastasis (M1b), or multiple metastases (M1c).[28]

These T, N, and M scores are combined to designate a stage grouping for the cancer. Cancer limited to smaller tumors is designated stage I. Disease with larger tumors or spread to the nearest lymph nodes is stage II. Cancer with the largest tumors or extensive lymph node spread is stage III. Cancer that has metastasized is stage IV. Each stage is further subdivided based on the combination of T, N, and M scores.[30]

Some countries recommend that people who are at a high risk of developing lung cancer be screened at different intervals using low-dose CT lung scans. Screening programs may result in early detection of lung tumors in people who are not yet experiencing symptoms of lung cancer, ideally, early enough that the tumors can be successfully treated and result in decreased mortality.[32] There is evidence that regular low-dose CT scans in people at high risk of developing lung cancer reduces total lung cancer deaths by as much as 20%.[15] Despite evidence of benefit in these populations, potential harms of screening include the potential for a person to have a 'false positive' screening result that may lead to unnecessary testing, invasive procedures, and distress.[33] Although rare, there is also a risk of radiation-induced cancer.[33] The United States Preventive Services Task Force recommends yearly screening using low-dose CT in people between 55 and 80 who have a smoking history of at least 30 pack-years.[34] The European Commission recommends that cancer screening programs across the European Union be extended to include low-dose CT lung scans for current or previous smokers.[35] Similarly, The Canadian Task Force for Preventative Health recommends that people who are current or former smokers (smoking history of more than 30 pack years) and who are between the ages of 55–74 years be screened for lung cancer.[36]

Setup for radiation therapy. The person lies flat while a radiation beam is focused on the tumor site

Limited-stage SCLC is typically treated with a combination of chemotherapy and radiotherapy.[38] For chemotherapy, the National Comprehensive Cancer Network and American College of Chest Physicians guidelines recommend four to six cycles of a platinum-based chemotherapeutic – cisplatin or carboplatin – combined with either etoposide or irinotecan.[39] This is typically combined with thoracic radiation therapy – 45 Gray (Gy) twice-daily – alongside the first two chemotherapy cycles.[38] First-line therapy causes remission in up to 80% of those who receive it; however most people relapse with chemotherapy-resistant disease. Those who relapse are given second-line chemotherapies. Topotecan and lurbinectedin are approved by the US FDA for this purpose.[38] Irinotecan, paclitaxel, docetaxel, vinorelbine, etoposide, and gemcitabine are also sometimes used, and are similarly efficacious.[38] Prophylactic cranial irradiation can reduce the risk of brain metastases and improve survival in those with limited-stage disease.[40][38]

Extensive-stage SCLC is treated first with etoposide along with either cisplatin or carboplatin. Radiotherapy is used only to shrink tumors that are causing particularly severe symptoms. Combining standard chemotherapy with an immune checkpoint inhibitor can improve survival for a minority of those affected, extending the average person's lifespan by around 2 months.[41]

The extent of common surgeries to remove a lung tumor (shown in black). Areas that are surgically removed along with the tumor are shown in blue.

For stage I and stage II NSCLC the first line of treatment is often surgical removal of the affected lobe of the lung.[42] For those not well enough to tolerate full lobe removal, a smaller chunk of lung tissue can be removed by wedge resection or segmentectomy surgery.[42] Those with centrally located tumors and otherwise-healthy respiratory systems may have more extreme surgery to remove an entire lung (pneumonectomy).[42] Experienced thoracic surgeons, and a high-volume surgery clinic improve chances of survival.[42] Those who are unable or unwilling to undergo surgery can instead receive radiation therapy. Stereotactic body radiation therapy is best practice, typically administered several times over 1–2 weeks.[42] Chemotherapy has little effect in those with stage I NSCLC, and may worsen disease outcomes in those with the earliest disease. In those with stage II disease, chemotherapy is usually initiated six to twelve weeks after surgery, with up to four cycles of cisplatin – or carboplatin in those with kidney problems, neuropathy, or hearing impairment – combined with vinorelbine, pemetrexed, gemcitabine, or docetaxel.[42]

Treatment for those with stage III NSCLC depends on the nature of their disease. Those with more limited spread may undergo surgery to have the tumor and affected lymph nodes removed, followed by chemotherapy and potentially radiotherapy. Those with particularly large tumors (T4) and those for whom surgery is impractical are treated with combination chemotherapy and radiotherapy along with the immunotherapy durvalumab.[43] Combined chemotherapy and radiation enhances survival compared to chemotherapy followed by radiation, though the combination therapy comes with harsher side effects.[43]

Those with stage IV disease are treated with combinations of pain medication, radiotherapy, immunotherapy, and chemotherapy.[44] Many cases of advanced disease can be treated with targeted therapies depending on the genetic makeup of the cancerous cells. Up to 30% of tumors have mutations in the EGFR gene that result in an overactive EGFR protein;[45] these can be treated with EGFR inhibitors osimertinib, erlotinib, gefitinib, afatinib, or dacomitinib – with osimertinib known to be superior to erlotinib and gefitinib, and all superior to chemotherapy alone.[44] Up to 7% of those with NSCLC harbor mutations that result in hyperactive ALK protein, which can be treated with ALK inhibitors crizotinib, or its successors alectinib, brigatinib, and ceritinib.[44] Those treated with ALK inhibitors who relapse can then be treated with the third-generation ALK inhibitor lorlatinib.[44] Up to 5% with NSCLC have overactive MET, which can be inhibited with MET inhibitors capmatinib or tepotinib.[44] Targeted therapies are also available for some cancers with rare mutations. Cancers with hyperactive BRAF (around 2% of NSCLC) can be treated by dabrafenib combined with the MEK inhibitor trametinib; those with activated ROS1 (around 1% of NSCLC) can be inhibited by crizotinib, lorlatinib, or entrectinib; overactive NTRK (<1% of NSCLC) by entrectinib or larotrectinib; active RET (around 1% of NSCLC) by selpercatinib.[44]

People whose NSCLC is not targetable by current molecular therapies instead can be treated with combination chemotherapy plus immune checkpoint inhibitors, which prevent cancer cells from inactivating immune T cells. The chemotherapeutic agent of choice depends on the NSCLC subtype: cisplatin plus gemcitabine for squamous cell carcinoma, cisplatin plus pemetrexed for non-squamous cell carcinoma.[46] Immune checkpoint inhibitors are most effective against tumors that express the protein PD-L1, but are sometimes effective in those that do not.[47] Treatment with pembrolizumab, atezolizumab, or combination nivolumab plus ipilimumab are all superior to chemotherapy alone against tumors expressing PD-L1.[47] Those who relapse on the above are treated with second-line chemotherapeutics docetaxel and ramucirumab.[48]

Brachytherapy (internal radiotherapy) for lung cancer given via the airway

Integrating palliative care (medical care focused on improving symptoms and lessening discomfort) into lung cancer treatment from the time of diagnosis improves the survival time and quality of life of those with lung cancer.[49] Particularly common symptoms of lung cancer are shortness of breath and pain. Supplemental oxygen, improved airflow, re-orienting an affected person in bed, and low-dose morphine can all improve shortness of breath.[50] In around 20 to 30% of those with lung cancer – particularly those with late-stage disease – growth of the tumor can narrow or block the airway, causing coughing and difficulty breathing.[51] Obstructing tumors can be surgically removed where possible, though typically those with airway obstruction are not well enough for surgery. In such cases the American College of Chest Physicians recommends opening the airway by inserting a stent, attempting to shrink the tumor with localized radiation (brachytherapy), or physically removing the blocking tissue by bronchoscopy, sometimes aided by thermal or laser ablation.[52] Other causes of lung cancer-associated shortness of breath can be treated directly, such as antibiotics for a lung infection, diuretics for pulmonary edema, benzodiazepines for anxiety, and steroids for airway obstruction.[50]

Up to 92% of those with lung cancer report pain, either from tissue damage at the tumor site(s) or nerve damage.[53] The World Health Organization (WHO) has developed a three-tiered system for managing cancer pain. For those with mild pain (tier one), the WHO recommends acetominophen or a nonsteroidal anti-inflammatory drug.[53] Around a third of people experience moderate (tier two) or severe (tier three) pain, for which the WHO recommends opioid painkillers.[53] Opioids are typically effective at easing nociceptive pain (pain caused by damage to various body tissues). Opioids are occasionally effective at easing neuropathic pain (pain cauesd by nerve damage). Neuropathic agents such as anticonvulsants, tricyclic antidepressants, and serotonin–norepinephrine reuptake inhibitors, are often used to ease neuropathic pain, either alone or in combination with opioids.[53] In many cases, targeted radiotherapy can be used to shrink tumors, reducing pain and other symptoms caused by tumor growth.[54]

Individuals who have advanced disease and are approaching end-of-life can benefit from dedicated end-of-life care to manage symptoms and ease suffering. As in earlier disease, pain and difficulty breathing are common, and can be managed with opioid pain medications, transitioning from oral medication to injected medication if the affected individual loses the ability to swallow.[55][56] Coughing is also common, and can be managed with opioids or cough suppressants. Some experience terminal delirium – confused behavior, unexplained movements, or a reversal of the sleep-wake cycle – which can be managed by antipsychotic drugs, low-dose sedatives, and investigating other causes of discomfort such as low blood sugar, constipation, and sepsis.[55] In the last few days of life, many develop terminal secretions – pooled fluid in the airways that can cause a rattling sound while breathing. This is thought not to cause respiratory problems, but can distress family members and caregivers. Terminal secretions can be reduced by anticholinergic medications.[55] Even those who are non-communicative or have reduced consciousness may be able to experience cancer-related pain, so pain medications are typically continued until the time of death.[55]

The uncertainty of lung cancer prognosis often causes stress, and makes future planning difficult, for those with lung cancer and their families.[60] Those whose cancer goes into remission often experience fear of their cancer returning or progressing, associated with poor quality of life, negative mood, and functional impairment. This fear is exacerbated by frequent or prolonged surveillance imaging, and other reminders of cancer risks.[60]

Relationship between cigarette consumption per person (blue) and male lung cancer rates (dark yellow) in the US

Tobacco smoking is by far the major contributor to lung cancer, causing 80% to 90% of cases.[64] Lung cancer risk increases with quantity of cigarettes consumed.[65] Tobacco smoking's carcinogenic effect is due to various chemicals in tobacco smoke that cause DNA mutations, increasing the chance of cells becoming cancerous.[66] The International Agency for Research on Cancer identifies at least 50 chemicals in tobacco smoke as carcinogenic, and the most potent is tobacco-specific nitrosamines.[65] Exposure to these chemicals causes several kinds of DNA damage: DNA adducts, oxidative stress, and breaks in the DNA strands.[67] Being around tobacco smoke – called passive smoking – can also cause lung cancer. Living with a tobacco smoker increases one's risk of developing lung cancer by 24%. An estimated 17% of lung cancer cases in those who do not smoke are caused by high levels of environmental tobacco smoke.[68]

Vaping may be a risk factor for lung cancer, but less than that of cigarettes, and further research as of 2021 is necessary due to the length of time it can take for lung cancer to develop following an exposure to carcinogens.[69]

The smoking of non-tobacco products is not known to be associated with lung cancer development. Marijuana smoking does not seem to independently cause lung cancer – despite the relatively high levels of tar and known carcinogens in marijuana smoke. The relationship between smoking cocaine and developing lung cancer has not been studied as of 2020.[70]

Sign warning of potential for asbestos exposure, typically used during demolition/renovation of asbestos-containing buildings

Exposure to a variety of other toxic chemicals – typically encountered in certain occupations – is associated with an increased risk of lung cancer.[71] Occupational exposures to carcinogens cause 9–15% of lung cancer.[71] A prominent example is asbestos, which causes lung cancer either directly or indirectly by inflaming the lung.[71] Exposure to all commercially available forms of asbestos increases cancer risk, and cancer risk increases with time of exposure.[71] Asbestos and cigarette smoking increase risk synergistically – that is, the risk of someone who smokes and has asbestos exposure dying from lung cancer is much higher than would be expected from adding the two risks together.[71] Similarly, exposure to radon, a naturally occurring breakdown product of the Earth's radioactive elements, is associated with increased lung cancer risk. Radon levels vary with geography.[72] Underground miners have the greatest exposure; however even the lower levels of radon that seep into residential spaces can increase occupants' risk of lung cancer. Like asbestos, cigarette smoking and radon exposure increase risk synergistically.[71] Radon exposure is responsible for between 3% and 14% of lung cancer cases.[72]

Several other chemicals encountered in various occupations are also associated with increased lung cancer risk including arsenic used in wood preservation, pesticide application, and some ore smelting; ionizing radiation encountered during uranium mining; vinyl chloride in papermaking; beryllium in jewelers, ceramics workers, missile technicians, and nuclear reactor workers; chromium in stainless steel production, welding, and hide tanning; nickel in electroplaters, glass workers, metal workers, welders, and those who make batteries, ceramics, and jewelry; and diesel exhaust encountered by miners.[71]

Exposure to air pollution, especially particulate matter released by motor vehicle exhaust and fossil fuel-burning power plants, increases the risk of lung cancer.[73][74] Indoor air pollution from burning wood, charcoal, or crop residue for cooking and heating has also been linked to an increased risk of developing lung cancer.[75] The International Agency for Research on Cancer has classified emission from household burning of coal and biomass as "carcinogenic" and "probably carcinogenic" respectively.[75]

Several other diseases that cause inflammation of the lung increase one's risk of lung cancer. This association is strongest for chronic obstructive pulmonary disorder – the risk is highest in those with the most inflammation, and reduced in those whose inflammation is treated with inhaled corticosteroids.[76] Other inflammatory lung and immune system diseases such as alpha-1 antitrypsin deficiency, interstitial fibrosis, scleroderma, Chlamydia pneumoniae infection, tuberculosis, and HIV infection are associated with increased risk of developing lung cancer.[76] Epstein–Barr virus is associated with the development of the rare lung cancer lymphoepithelioma-like carcinoma in people from Asia, but not in people from Western nations.[77] A role for several other infectious agents – namely human papillomaviruses, BK virus, JC virus, human cytomegalovirus, SV40, measles virus, and Torque teno virus – in lung cancer development has been studied but remains inconclusive as of 2020.[77]

Particular gene combinations may make some people more susceptible to lung cancer. Close family members of those with lung cancer have around twice the risk of developing lung cancer as an average person, even after controlling for occupational exposure and smoking habits.[78] Genome-wide association studies have identified many gene variants associated with lung cancer risk, each of which contributes a small risk increase.[79] Many of these genes participate in pathways known to be involved in carcinogenesis, namely DNA repair, inflammation, the cell division cycle, cellular stress responses, and chromatin remodeling.[79] Some rare genetic disorders that increase the risk of various cancers also increase the risk of lung cancer, namely retinoblastoma and Li–Fraumeni syndrome.[80]

Those who smoke can reduce their lung cancer risk by quitting smoking – the risk reduction is greater the longer a person goes without smoking.[83] Self-help programs tend to have little influence on success of smoking cessation, whereas combined counseling and pharmacotherapy improve cessation rates.[83] The US FDA has approved antidepressant therapies and the nicotine replacement varenicline as first-line therapies to aid in smoking cessation. Clonidine and nortriptyline are recommended second-line therapies.[83] The majority of those diagnosed with lung cancer attempt to quit smoking; around half succeed.[84] Even after lung cancer diagnosis, smoking cessation improves treatment outcomes, reducing cancer treatment toxicity and failure rates, and lengthening survival time.[85]

No smoking sign at a train station in Colorado

Graphic cigarette packaging in Belgium labelled "open wound following lung surgery"

At a societal level, smoking cessation can be promoted by tobacco control policies that make tobacco products more difficult to obtain or use. Many such policies are mandated or recommended by the WHO Framework Convention on Tobacco Control, ratified by 182 countries, representing over 90% of the world's population.[86] The WHO groups these policies into six intervention categories, each of which has been shown to be effective in reducing the cost of tobacco-induced disease burden on a population:

1. increasing the price of tobacco by raising taxes;
2. banning tobacco use in public places to reduce exposure;
3. banning tobacco advertisements;
4. publicizing the dangers of tobacco products;
5. instituting help programs for those attempting to quit smoking; and
6. monitoring population-level tobacco use and the effectiveness of tobacco control policies.[87]

Policies implementing each intervention are associated with decreases in tobacco smoking prevalence. The more policies implemented, the greater the reduction.[88] Reducing access to tobacco for adolescents is particularly effective at decreasing uptake of habitual smoking, and adolescent demand for tobacco products is particularly sensitive to increases in cost.[89]

Several foods and dietary supplements have been associated with lung cancer risk. High consumption of some animal products – red meat (but not other meats or fish), saturated fats, as well as nitrosamines and nitrites (found in salted and smoked meats) – is associated with an increased risk of developing lung cancer.[90] In contrast, high consumption of fruits and vegetables is associated with a reduced risk of lung cancer, particularly consumption of cruciferous vegetables and raw fruits and vegetables.[90] Based on the beneficial effects of fruits and vegetables, supplementation of several individual vitamins have been studied. Supplementation with vitamin A or beta-carotene had no effect on lung cancer, and instead slightly increased mortality.[90] Dietary supplementation with vitamin E or retinoids similarly had no effect.[91] Consumption of polyunsaturated fats, tea, alcoholic beverages, and coffee are all associated with reduced risk of developing lung cancer.[90]

Along with diet, body weight and exercise habits are also associated with lung cancer risk. Being overweight is associated with a lower risk of developing lung cancer, possibly due to the tendency of those who smoke cigarettes to have a lower body weight.[92] However, being underweight is also associated with a reduced lung cancer risk.[92] Some studies have shown those who exercise regularly or have better cardiovascular fitness to have a lower risk of developing lung cancer.[92]