View source for Lung cancer

{{Short description|Malignant tumor characterized by uncontrolled cell growth in lung tissue}}
{{About|lung carcinomas|other lung tumors|Lung tumor}}
{{Use dmy dates|date=October 2021}}
{{featured article}}
{{Infobox medical condition (new)
| name            = Lung cancer
| synonyms        = Lung carcinoma
| image           = LungCACXR.PNG
| caption         = A [[chest X-ray]] showing a tumor in the lung (marked by arrow)
| field           = [[Oncology]], [[pulmonology]]
| symptoms        = [[Coughing]] (including [[Hemoptysis|coughing up blood]]), [[weight loss]], [[dyspnea|shortness of breath]], [[chest pain]]s<ref name="Harrison"/>
| complications   =
| onset           = ~70 years<ref name="SEER"/>
| duration        =
| types           = [[Small-cell lung carcinoma]] (SCLC), [[non-small-cell lung carcinoma]] (NSCLC)<ref name="Holland-Frei84" />
| causes          =
| risks           = {{hlist|[[Tobacco smoking]]|[[genetics|genetic factors]]|[[radon]] gas|[[asbestos]]|[[air pollution]]<ref name="MurrayNadel52"/><ref name="Ramada"/>}}
| diagnosis       = [[Medical imaging]], [[tissue biopsy]]<ref name="Holland-Frei84"/>
| differential    =
| prevention      = Avoid smoking, [[radon gas]], [[asbestos]], [[second-hand smoke]], or other forms of [[air pollution]] exposure
| treatment       = [[Surgery]], [[chemotherapy]], [[radiation therapy|radiotherapy]]<ref name="Holland-Frei84"/>
| medication      =
| prognosis       = [[Five-year survival rate]]: 10 to 20% (most countries)<ref name="Sung2021"/>
| frequency       = 3.3&nbsp;million affected as of 2015<!-- prevalence --><ref name=GBD2015Pre>{{cite journal | vauthors = Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, etal | collaboration = GBD 2015 Disease and Injury Incidence and Prevalence Collaborators| title = Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015 | journal = Lancet | volume = 388 | issue = 10053 | pages = 1545–602 | date = October 2016 | pmid = 27733282 | pmc = 5055577 | doi = 10.1016/S0140-6736(16)31678-6 }}</ref>
| deaths          = 1.8&nbsp;million (2020)<ref name="Sung2021"/>
}}

'''Lung cancer''', also known as '''lung carcinoma'''<ref name="Kumar&Clark"/> (since about 98–99% of all lung cancers are [[carcinomas]]), is a malignant [[lung tumor]] characterized by uncontrolled [[cell growth]] in [[tissue (biology)|tissues]] of the [[lung]].<ref>{{cite web|title=Non-Small Cell Lung Cancer Treatment – Patient Version (PDQ®)|url=http://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq|website=NCI|access-date=5 March 2016|date=12 May 2015|url-status=live|archive-url=https://web.archive.org/web/20160229172247/http://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq|archive-date=29 February 2016}}</ref> Lung carcinomas derive from transformed, malignant cells that originate as epithelial cells, or from tissues composed of epithelial cells. Other lung cancers, such as the rare sarcomas of the lung, are generated by the malignant transformation of connective tissues (i.e. nerve, fat, muscle, bone), which arise from mesenchymal cells. Lymphomas and melanomas (from lymphoid and melanocyte cell lineages) can also rarely result in lung cancer.

In time, this uncontrolled [[neoplasm|growth]] can [[metastasis|metastasize]] (spreading beyond the lung) either by direct extension, by entering the lymphatic circulation, or via hematogenous, bloodborne spread – into nearby tissue or other, more distant parts of the body.<ref>{{cite book | vauthors=Falk S, Williams C | title=Lung Cancer – the facts | edition=3rd | chapter=Chapter 1 | pages=[https://archive.org/details/lungcancer0000falk/page/3 3–4] | publisher=Oxford University Press | year=2010 | isbn=978-0-19-956933-5 | chapter-url=https://archive.org/details/lungcancer0000falk | url=https://archive.org/details/lungcancer0000falk/page/3 }}</ref> Most [[cancer]]s that originate from within the lungs, known as primary lung cancers, are [[carcinomas]]. The two main types are [[small-cell lung carcinoma]] (SCLC) and [[non-small-cell lung carcinoma]] (NSCLC).<ref name="Holland-Frei84" /> The most common [[symptom]]s are coughing (including [[Hemoptysis|coughing up blood]]), weight loss, shortness of breath, and [[chest pain]]s.

The vast majority (85%) of cases of lung cancer are due to long-term [[tobacco smoking]].<ref name="MurrayNadel52"/> About 10–15% of cases occur in people who have never smoked.<ref name="Thun">{{cite journal | vauthors = Thun MJ, Hannan LM, Adams-Campbell LL, Boffetta P, Buring JE, Feskanich D, Flanders WD, Jee SH, Katanoda K, Kolonel LN, Lee IM, Marugame T, Palmer JR, Riboli E, Sobue T, Avila-Tang E, Wilkens LR, Samet JM | display-authors = 6 | title = Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies | journal = PLOS Medicine | volume = 5 | issue = 9 | pages = e185 | date = September 2008 | pmid = 18788891 | pmc = 2531137 | doi = 10.1371/journal.pmed.0050185 }}</ref> These cases are often caused by a combination of [[genetics|genetic factors]] and exposure to [[radon]] gas, [[asbestos]], [[passive smoking|second-hand smoke]], or other forms of [[air pollution]].<ref name="MurrayNadel52">{{cite book | vauthors = Alberg AJ, Brock MV, Samet JM | title=Murray & Nadel's Textbook of Respiratory Medicine | publisher=Saunders Elsevier | year=2016 | chapter=Chapter 52: Epidemiology of lung cancer | edition=6th | isbn=978-1-4557-3383-5 }}</ref><ref name="Ramada">{{cite journal |vauthors=Ramada Rodilla JM, Calvo Cerrada B, Serra Pujadas C, Delclos GL, Benavides FG |title=Fiber burden and asbestos-related diseases: an umbrella review |journal=Gaceta Sanitaria |date=June 2021 |volume=36 |issue=2 |pages=173–183 |pmid=34120777 |doi=10.1016/j.gaceta.2021.04.001|pmc=8882348 |doi-access=free }}</ref><ref name="AUTOREF">{{cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK44324/ | vauthors = Carmona RH |publisher=U.S. Department of Health and Human Services |title=The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General |date=27 June 2006 |quote=Secondhand smoke exposure causes disease and premature death in children and adults who do not smoke. |url-status=live |archive-url=https://web.archive.org/web/20170215064658/https://www.ncbi.nlm.nih.gov/books/NBK44324/ |archive-date=15 February 2017 | series = Publications and Reports of the Surgeon General | pmid = 20669524 }} Retrieved 2014-06-16</ref><ref name="AUTOREF1">{{Cite journal |url=http://monographs.iarc.fr/ENG/Monographs/vol83/mono83.pdf |publisher=WHO International Agency for Research on Cancer |title=Tobacco Smoke and Involuntary Smoking |journal=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans |volume=83 |year=2004 |quote=There is sufficient evidence that involuntary smoking (exposure to secondhand or 'environmental' tobacco smoke) causes lung cancer in humans.&nbsp;... Involuntary smoking (exposure to secondhand or 'environmental' tobacco smoke) is carcinogenic to humans (Group 1). |url-status=live |archive-url=https://web.archive.org/web/20150813204458/http://monographs.iarc.fr/ENG/Monographs/vol83/mono83.pdf |archive-date=13 August 2015 }}</ref> Lung cancer may be seen on [[chest radiograph]]s and [[computed tomography]] (CT) scans.<ref name="Merck"/> The [[medical diagnosis|diagnosis]] is confirmed by [[biopsy]], which is usually performed by [[bronchoscopy]] or [[Lung biopsy|CT-guidance.]]<ref name="Holland-Frei84">{{cite book | vauthors=Lu C, Onn A, Vaporciyan AA, etal | title=Holland-Frei Cancer Medicine | edition=9th | chapter=Chapter 84: Cancer of the Lung | publisher=Wiley Blackwell | year=2017 |isbn=9781119000846 }}</ref><ref name="Collins">{{cite journal | vauthors = Collins LG, Haines C, Perkel R, Enck RE | title = Lung cancer: diagnosis and management | journal = American Family Physician | volume = 75 | issue = 1 | pages = 56–63 | date = January 2007 | pmid = 17225705 | url = http://www.aafp.org/afp/20070101/56.html | url-status = live | archive-url = https://web.archive.org/web/20070929104510/http://www.aafp.org/afp/20070101/56.html | archive-date = 29 September 2007 }}</ref>

The major method of prevention is the avoidance of risk factors, including smoking and air pollution.<ref name=NCI2015Pre>{{cite web|title=Lung Cancer Prevention–Patient Version (PDQ®)|url=http://www.cancer.gov/types/lung/patient/lung-prevention-pdq#section/_12|website=NCI|access-date=5 March 2016|date=4 November 2015|url-status=live|archive-url=https://web.archive.org/web/20160309063009/http://www.cancer.gov/types/lung/patient/lung-prevention-pdq#section/_12|archive-date=9 March 2016}}</ref> Treatment and long-term outcomes depend on the type of cancer, the [[staging (pathology)|stage]] (degree of spread), and the person's overall health.<ref name="Merck"/> Most cases are not curable.<ref name="Holland-Frei84" /> Common treatments include [[surgery]], [[chemotherapy]], and [[radiation therapy|radiotherapy]].<ref name="Merck"/> NSCLC is sometimes treated with surgery, whereas SCLC usually responds better to chemotherapy and radiotherapy.<ref>{{cite book | vauthors = Chapman S, Robinson G, Stradling J, West S, Wrightson J | title=Oxford Handbook of Respiratory Medicine | edition=3rd | chapter=Chapter 31 | page=284 | publisher=Oxford University Press | year=2014 | isbn=978-0-19-870386-0 }}</ref>

Worldwide in 2020, lung cancer occurred in 2.2 million people and resulted in 1.8 million deaths.<ref name="Sung2021">{{cite journal | vauthors = Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F | title = Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries | journal = CA: A Cancer Journal for Clinicians | volume = 71 | issue = 3 | pages = 209–249 | date = May 2021 | pmid = 33538338 | doi = 10.3322/caac.21660 | doi-access = free }}</ref> It is the most common cause of cancer-related death in both men and women.<ref>{{cite journal | vauthors = de Groot PM, Wu CC, Carter BW, Munden RF | title = The epidemiology of lung cancer | journal = Translational Lung Cancer Research | volume = 7 | issue = 3 | pages = 220–233 | date = June 2018 | pmid = 30050761 | pmc = 6037963 | doi = 10.21037/tlcr.2018.05.06 }}</ref><ref>{{cite journal | vauthors = Romaszko AM, Doboszyńska A | title = Multiple primary lung cancer: A literature review | journal = Advances in Clinical and Experimental Medicine | volume = 27 | issue = 5 | pages = 725–730 | date = May 2018 | pmid = 29790681 | doi = 10.17219/acem/68631 | s2cid = 46897665 }}</ref> The most common age at diagnosis is 70 years.<ref name="SEER">{{cite web | title=Surveillance, Epidemiology and End Results Program | url=http://seer.cancer.gov/statfacts/html/lungb.html | website=National Cancer Institute | access-date=5 March 2016 | url-status=live | archive-url=https://web.archive.org/web/20160304031945/http://seer.cancer.gov/statfacts/html/lungb.html | archive-date=4 March 2016 }}</ref> In most countries the [[five-year survival rate]] is around 10 to 20%,<ref name="Sung2021"/> while in Japan it is 33%, in Israel 27%, and in the Republic of Korea 25%.<ref name="Sung2021"/> Outcomes typically are worse in the developing world.<ref name=Maj2009>{{cite book| vauthors = Majumder S |title=Stem cells and cancer|year=2009|publisher=Springer|location=New York|isbn=978-0-387-89611-3|page=193|url=https://books.google.com/books?id=HaErOupWnO0C&pg=PA193|edition=Online-Ausg.|url-status=live|archive-url=https://web.archive.org/web/20151018040051/https://books.google.com/books?id=HaErOupWnO0C&pg=PA193|archive-date=18 October 2015}}</ref>
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==Signs and symptoms==
Early lung cancer often has no symptoms. When symptoms do arise they are often [[Signs_and_symptoms#Nonspecific_symptoms|nonspecific]] respiratory problems – [[cough]]ing, [[shortness of breath]], and/or [[chest pain]] – that can differ from person to person.{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Presentation/Initital Evaluation"}} Those who experience coughing tend to report either a new cough, or an increase in the frequency or strength of a pre-existing cough.{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Presentation/Initital Evaluation"}} Around a quarter [[Hemoptysis|cough up blood]], ranging from small streaks in the [[sputum]] to large amounts.{{sfn|Nasim|Sabath|Eapen|2019|loc="Clinical Manifestations"}}{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Presentation/Initital Evaluation"}} Around half of those diagnosed with lung cancer experience shortness of breath, while 25–50% experience a dull, persistent [[chest pain]] that remains in the same location over time.{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Presentation/Initital Evaluation"}} In addition to respiratory symptoms, some experience [[systemic disease|systemic symptoms]] including [[anorexia (symptom)|loss of appetite]], [[weight loss]], general weakness, [[fever]], and [[night sweats]].{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Presentation/Initital Evaluation"}}{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}}

Some less common symptoms suggest tumors in particular locations. Tumors in the [[thorax]] can cause breathing problems by obstructing the [[trachea]] or disrupting the nerve to the [[thoracic diaphragm|diaphragm]], [[dysphagia|difficulty swallowing]] by compressing the [[esophagus]], [[hoarseness]] by disrupting the [[nerve]]s of the [[larynx]], and [[Horner's syndrome]] by disrupting the [[sympathetic nervous system]].{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Presentation/Initital Evaluation"}}{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}} Horner's syndrome is also common in tumors at the [[Apex of lung|top of the lung]], known as [[Pancoast tumor]]s, which also cause [[shoulder pain]] that radiates down the little finger-side of the arm<!--is this a clear enough synonym for "radiates in the ulnar distribution of the arm"?--> as well as destruction of the topmost [[rib]]s.{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}} [[Swollen]] [[lymph node]]s above the [[collarbone]] can indicate a tumor that has spread within the chest.{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Presentation/Initital Evaluation"}} Tumors obstructing bloodflow to the heart can cause [[superior vena cava syndrome]], while tumors infiltrating the area around the heart can cause [[cardiac tamponade|fluid buildup around the heart]], [[arrythmia]], and [[heart failure]].{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}}

Around a third of people diagnosed with lung cancer have symptoms caused by [[metastases]] in sites distant from the lung.{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}} Lung cancer can metastasize anywhere in the body, with different symptoms depending on the location. Brain metastases can cause [[headache]], [[nausea]], [[vomiting]], [[seizure]]s, and [[neurological deficit]]s. Bone metastases can cause pain, [[bone fracture]]s, and compression of the [[spinal cord]]. Metastasis into the [[bone marrow]] can [[cytopenia|deplete blood cells]] and cause [[leukoerythroblastosis]] (immature immune cells in the blood).{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}} Liver metastases can cause [[hepatomegaly|liver enlargement]], pain in the [[Quadrants and regions of abdomen|right upper quadrant of the abdomen]], fever, and weight loss.{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}}

Lung tumors also often cause the release of body-altering [[hormone]]s, which themselves cause unusual symptoms, called [[paraneoplastic syndrome|paraneoplastic syndrome]]s.{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}}<!--Loss of appetite, unexplained weight loss, fever, and immune suppression are all common, though it's not clear why these occur -- from Harrison's 21 -- need to reword, and should I move mention of these in paragraph 1 down here? Also note the Pastis, et al. chapter has much more detail on these, but I'm not sure how much I want to add to this section--> Inappropriate hormone release can cause dramatic shifts in concentrations of blood [[Mineral (nutrient)|minerals]]. Most common is [[hypercalcemia]] caused by over-production of [[parathyroid hormone-related protein]] or [[parathyroid hormone]]. Hypercalcemia can manifest as nausea, vomiting, abdominal pain, constipation, [[polydipsia|increased thirst]], [[polyuria|frequent urination]], and altered mental status.{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}} Those with lung cancer also commonly experience [[hypokalemia]] due to inappropriate secretion of [[adrenocorticotropic hormone]], as well as [[hyponatremia]] due to overproduction of [[antidiuretic hormone]] or [[atrial natriuretic peptide]].{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}} Around a third of people with lung cancer develop [[nail clubbing]], while up to one in ten experience [[hypertrophic primary osteoarthropathy]]<!--expand on what this is?-->. A variety of autoimmune disorders can arise as paraneoplastic syndromes in those with lung cancer, including [[Lambert–Eaton myasthenic syndrome]] (which causes muscle weakness), [[sensory neuropathies]], [[polymyositis|muscle inflammation]], [[encephalitis|brain swelling]], and autoimmune deterioration of [[cerebellum]], [[limbic system]], or [[brainstem]].{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}} Up to 1 in 12 people with lung cancer have paraneoplastic clotting issues, including [[migratory venous thrombophlebitis]], clots in the heart, and [[disseminated intravascular coagulation]].{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}} Paraneoplastic syndromes involving the skin and kidneys are rare, each occurring in up to 1% of those with lung cancer.{{sfn|Horn|Iams|2022|loc="Clinical Manifestations"}}

==Diagnosis==
[[File:Primary Pulmonary Sarcoma.jpg|right|thumb|Primary pulmonary [[sarcoma]] in an asymptomatic 72-year-old male]]
[[File:Thorax CT peripheres Brronchialcarcinom li OF.jpg|right|thumb|[[CT scan]] showing a cancerous tumor in the left lung]]

A person suspected of having lung cancer will first have various imaging tests done to evaluate the presence, extent, and location of tumors. First, many [[primary care provider]]s perform a [[chest X-ray]] to look for a mass inside the lung.<ref name=NHS>{{cite web|url=https://www.nhs.uk/conditions/lung-cancer/diagnosis/ |accessdate=30 November 2022 |title=Diagnosis – Lung Cancer |publisher=National Health Service |date=1 November 2022}}</ref> The x-ray may reveal an obvious mass, the widening of the [[mediastinum]] (suggestive of spread to [[lymph node]]s there), [[atelectasis]] (lung collapse), consolidation ([[pneumonia]]), or [[pleural effusion]];<ref name="Merck" /> however, some lung tumors are not visible by X-ray.{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Presentation/Initital Evaluation"}} Next, many undergo [[CT scan|computed tomography (CT) scanning]], which can reveal the sizes and locations of tumors.<!--and give some sense of its density? Need a source that explicitly mentions how tumor appearance on CT scan is predictive of outcomes--><ref name=NHS/>{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Noninvasive Staging"}} 

A definitive diagnosis of lung cancer requires a [[biopsy]] of the suspected tissue be [[histopathology|histologically]] examined for cancer cells.{{sfn|Horn|Iams|2022|loc="Diagnosing Lung Cancer"}} [[Bronchoscopy|Bronchoscopic]] or CT-guided [[biopsy]] is often used to sample the tumor for [[histopathology]].<ref name="Collins" /><!--Add more on biopsy methods, I know a saw a nice discussion somewhere--> Additionally, biopsy material of the original tumor or metastases are often tested for their molecular profile to determine eligibility for targeted therapies.<!--Add more details on how this is done--> Those who cannot undergo a more invasive biopsy procedure may instead have a [[liquid biopsy]] taken (i.e. a sample of some body fluid) which may contain [[circulating tumor DNA]] that can be used for molecular testing.{{sfn|Alexander|Kim|Cheng|2020|loc="Liquid Biopsy"}}

Imaging is also used to assess the extent of cancer spread. [[Positron emission tomography]] (PET) scanning or combined [[PET-CT]] scanning is often used to locate metastases in the body. Since PET scanning cannot be used in the brain, the [[National Comprehensive Cancer Network]] recommends [[magnetic resonance imaging]] (MRI) – or CT where MRI is unavailable – to scan the brain for metastases in those with NSCLC and large tumors, or tumors that have spread to the nearby lymph nodes.{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Suspected Metastatic Disease"}} When spread to lymph nodes or to a single site is suspected, the suspected metastasis is often biopsied using a minimally invasive needle biopsy technique – typically using [[endobronchial ultrasound]] to guide a [[bronchoscope]] equipped with [[transbronchial needle aspiration]].{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Minimally Invasive Staging"}} Primary lung cancers most commonly metastasize to the brain, bones, liver, and [[adrenal gland]]s.<ref name="Holland-Frei84" />

Lung cancer can often appear as a [[solitary pulmonary nodule]] on a chest radiograph. However, the [[differential diagnosis]] is wide and many other diseases can also give this appearance, including metastatic cancer, [[hamartoma]]s, and infectious [[granuloma]]s caused by [[tuberculosis]], [[histoplasmosis]], or [[coccidioidomycosis]].<ref>{{cite book | vauthors = Ost D | title=Fishman's Pulmonary Diseases and Disorders | publisher=McGraw-Hill | veditors = Grippi MA, Elias JA, Fishman JA, Kotloff RM, Pack AI, Senior RM | year=2015 | chapter=Chapter 110: Approach to the patient with pulmonary nodules | page=1685 | edition=5th | isbn=978-0-07-179672-9 }}</ref> Lung cancer can also be an [[incidentaloma|incidental finding]], as a solitary pulmonary nodule on a chest radiograph or CT scan done for an unrelated reason.<ref>{{cite journal | vauthors = Frank L, Quint LE | title = Chest CT incidentalomas: thyroid lesions, enlarged mediastinal lymph nodes, and lung nodules | journal = Cancer Imaging | volume = 12 | issue = 1 | pages = 41–48 | date = March 2012 | pmid = 22391408 | pmc = 3335330 | doi = 10.1102/1470-7330.2012.0006 }}</ref> [[Clinical practice guideline]]s recommend specific frequencies (suggested intervals of time between tests) for pulmonary nodule surveillance.<ref name="ACCPandATSfive">{{cite web |author1 = American College of Chest Physicians |author1-link = American College of Chest Physicians |author2 = American Thoracic Society |author2-link = American Thoracic Society |date = September 2013 |title = Five Things Physicians and Patients Should Question |publisher = American College of Chest Physicians and American Thoracic Society |work = [[Choosing Wisely]]: an initiative of the [[ABIM Foundation]] |url = http://www.choosingwisely.org/doctor-patient-lists/american-college-of-chest-physicians-and-american-thoracic-society/ |access-date = 6 January 2013 |url-status = live |archive-url = https://web.archive.org/web/20131103063427/http://www.choosingwisely.org/doctor-patient-lists/american-college-of-chest-physicians-and-american-thoracic-society/ |archive-date = 3 November 2013 }}</ref> CT imaging is not suggested to be used for longer or more frequently than indicated in the clinical guidelines, as any additional [[Disease surveillance|surveillance]] exposes people to increased radiation and is costly.<ref name="ACCPandATSfive"/><!--Rudin, et al. has a discussion of differential histopathological diagnoses for SCLC-->

===Classification===
{| class="wikitable floatright" style="text-align:center;font-size:90%;width:25%;margin-left:1em"
|+ style="background:#E5AFAA;"|'''Age-adjusted [[incidence (epidemiology)|incidence]] of lung cancer by histological type'''<ref name="MurrayNadel52" />
|- style="background: #E5AFAA;text-align:center;font-size:90%;"
! abbr="Type" | Histological type
! abbr="Frequency" | Incidence per 100,000 per year
|-
| All types
| 66.9
|-
| Adenocarcinoma
| 22.1
|-
| Squamous-cell carcinoma
| 14.4
|-
| Small-cell carcinoma
| 9.8
|}
[[File:Pie chart of lung cancers.svg|thumb|upright=1.2|Pie chart showing incidences of NSCLCs as compared to SCLCs shown at right, with fractions of smokers versus nonsmokers shown for each type<ref>Smokers defined as current or former smokers of more than 1 year of duration. See [[Commons:File:Pie chart of lung cancers.svg|image page in Commons]] for percentages in numbers. Reference: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044470/table/T2/ Table 2] {{webarchive|url=https://web.archive.org/web/20170910181827/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044470/table/T2/ |date=10 September 2017 }} in: {{cite journal | vauthors = Kenfield SA, Wei EK, Stampfer MJ, Rosner BA, Colditz GA | title = Comparison of aspects of smoking among the four histological types of lung cancer | journal = Tobacco Control | volume = 17 | issue = 3 | pages = 198–204 | date = June 2008 | pmid = 18390646 | pmc = 3044470 | doi = 10.1136/tc.2007.022582 }}</ref>]]

At diagnosis, lung cancers are 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 [[histopathology|histopathologist]] under a [[microscope]]: [[small cell lung cancer]] (SCLC; 15% of lung cancer diagnoses) and [[non-small-cell lung cancer]] (NSCLC; 85% of diagnoses).{{sfn|Thai|Solomon|Sequist|Gainor|2021|loc="Histology"}} In SCLC, cancerous cells appear small with ill-defined boundaries, not much [[cytoplasm]], many [[mitochondria]], and have distinctive [[cell nucleus|nuclei]] with granular-looking [[DNA]] and no visible [[nucleoli]].{{sfn|Horn|Iams|2022|loc="Pathology"}} Cells contain dense neurosecretory granules ([[vesicle (biology)|vesicles]] containing [[neuroendocrine]] [[hormone]]s), which give this tumor an endocrine or [[paraneoplastic syndrome]] association.<ref name="Rosti" /> Most cases arise in the larger airways (primary and secondary [[bronchus|bronchi]]).<ref name="Collins" /> NSCLCs comprise a group of three cancer types: [[adenocarcinoma of the lung|adenocarcinoma]],  [[squamous-cell lung carcinoma|squamous-cell carcinoma]], and [[large-cell lung carcinoma|large-cell carcinoma]].{{sfn|Horn|Iams|2022|loc="Pathology"}} Nearly 40% of lung cancers are adenocarcinomas, which usually come from peripheral lung tissue.<ref name="Holland-Frei84"/> Squamous-cell carcinoma causes about 30% of lung cancers. They typically occur close to large airways. A hollow cavity and associated [[necrosis|cell death]] are commonly found at the center of the tumor.<ref name="Holland-Frei84" /> Less than 10% of lung cancers are large-cell carcinomas,{{sfn|Horn|Iams|2022|loc="Pathology"}} so named because the cells are large, with excess [[cytoplasm]], large [[cell nucleus|nuclei]], and conspicuous [[nucleolus|nucleoli]].<ref name="Holland-Frei84" /><!--Add more about how the other subtypes are histologically differentiated-->

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 [[alveoli|alveolar]] walls),{{sfn|Jones|2013|loc="Conclusion"}} acinar and papillary, or micropapillary and solid pattern. Lepidic adenocarcinomas tend to be least aggressive; micropapillary and solid pattern adenocarcinomas most aggressive.{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Histology and Prognosis"}}

In addition to examining cell morphology, biopsies are also often stained with [[immunohistochemistry]] to confirm the diagnosis. SLCL is most often confirmed by the presence of [[chromogranin]], [[synaptophysin]], and [[CD56]].{{sfn|Rudin|Brambilla|Faivre-Finn|Sage|2021|loc="Immunohistochemistry"}} The presence of [[Napsin-A]], [[TTF-1]], [[CK7]], and [[CK20]] help confirm the subtype of lung carcinoma.<ref name="Harrison" /> 

Around 10% of lung cancers are rarer types.{{sfn|Horn|Iams|2022|loc="Pathology"}} These include mixes of the above subtypes like [[adenosquamous carcinoma]].<ref name="Holland-Frei84" /> Rare subtypes include [[lung carcinoid|carcinoid tumors]], bronchial gland carcinomas, and [[Sarcomatoid carcinoma of the lung|sarcomatoid carcinomas]].<ref name="Holland-Frei84" /> A subtype of adenocarcinoma, the [[bronchioloalveolar carcinoma]], is more common in females who have not smoked tobacco.<ref name="Raz"/>

{| class="wikitable floatright" style="text-align:center;font-size:90%;width:25%;margin-left:1em"
|+ style="background:#E5AFAA;"|'''Typical [[Napsin-A]] and [[TTF-1]] [[immunostaining]] in primary lung carcinoma'''<ref name="Harrison" />
|- style="background: #E5AFAA;text-align:center;font-size:90%;"
! abbr="Type" | Histological type
! abbr="Nap=A" | Napsin-A
! TTF-1
|-
| Squamous-cell carcinoma
| Negative
| Negative
|-
| Adenocarcinoma
| Positive
| Positive
|-
| Small-cell carcinoma
| Negative
| Positive
|}

===Staging===
{{see also|Lung cancer staging}}

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 potential treatment of lung cancer.<ref name=ACS-SCLC-Stage>{{cite web|url=https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/staging-sclc.html |accessdate=2 December 2022 |title=Small Cell Lung Cancer Stages |publisher=American Cancer Society |date=1 October 2019}}</ref> 

SCLC is typically staged with a relatively simple system; cancers are scored as either "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 tolerable [[radiotherapy]] field.<ref name=ACS-SCLC-Stage/> 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.<ref name=ACS-SCLC-Stage/> 

NSCLC – and sometimes SCLC – is typically staged with the [[American Joint Committee on Cancer]]'s [[TNM staging system|Tumor, Node, Metastasis (TNM) staging system]].<ref name=ACS-NSCLC-Stage>{{cite web|url=https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/staging-nsclc.html |accessdate=2 December 2022 |title=Small Cell Lung Cancer Stages |publisher=American Cancer Society |date=1 October 2019}}</ref> 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".{{sfn|Horn|Iams|2022|loc="Staging System for Non-Small-Cell Lung Cancer"}} 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 [[Pulmonary pleurae|visceral pleura]] (tissue covering the lung) or [[main bronchi]], are desginated 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 [[Lung#Lobes|lobe]] of the lung, or invade the [[chest wall]], diaphragm (or the [[phrenic nerve|nerve that controls it]]), or area around the heart.{{sfn|Horn|Iams|2022|loc="Staging System for Non-Small-Cell Lung Cancer"}}{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Eight Edition Lung Cancer Stage Classification"}} 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, [[great vessels|largest blood vessels]] that supply the heart, [[trachea]], [[esophagus]], or [[Vertebral column|spine]] are designated T4.{{sfn|Horn|Iams|2022|loc="Staging System for Non-Small-Cell Lung Cancer"}}{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Eight Edition Lung Cancer Stage Classification"}} 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).{{sfn|Pastis|Gonzalez|Silvestri|2022|loc="Eight Edition Lung Cancer Stage Classification"}} 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).{{sfn|Horn|Iams|2022|loc="Staging System for Non-Small-Cell Lung Cancer"}} These T, N, and M scores are combined to designate a "stage grouping" for the cancer. Cancers limited to smaller tumors are designated stage I. Those with larger tumors or spread to the nearest lymph nodes are stage II. Those with the largest tumors or extensive lymph node spread are stage III. Cancers that have metastasized are stage IV. Each stage is further subdivided based on the combination of T, N, and M scores.{{sfn|Horn|Iams|2022|loc="Table 78–6 TNM Stage Groupings, Eight Edition"}} Around 40% of those diagnosed with NSCLC have stage IV disease at the time of diagnosis.{{sfn|Horn|Iams|2022|loc="Management of Metastatic NSCLC"}}

{| class="wikitable" style="text-align:center;font-size:90%;margin-left:1em;background:#E5AFAA;"
|+ TNM classification in lung cancer<ref>{{cite web | title=8th edition lung cancer TNM staging summary | publisher=International Association for the Study of Lung Cancer | url=https://www.iaslc.org/sites/default/files/wysiwyg-assets/iaslc_8th_posters_24x36_2018_final_version_1.pdf | access-date=30 May 2018 | archive-url=https://web.archive.org/web/20180617220133/https://www.iaslc.org/sites/default/files/wysiwyg-assets/iaslc_8th_posters_24x36_2018_final_version_1.pdf | archive-date=17 June 2018 | url-status=dead }}</ref><ref>{{cite journal | vauthors = Van Schil PE, Rami-Porta R, Asamura H | title = 8th TNM edition for lung cancer: a critical analysis | journal = Annals of Translational Medicine | volume = 6 | issue = 5 | pages = 87 | date = March 2018 | pmid = 29666810 | pmc = 5890051 | doi = 10.21037/atm.2017.06.45 }}</ref>

|-
|
{| class="wikitable"
|-
! colspan="3" | T: Primary tumor
|-
| T0
| colspan="2" | No primary tumor
|-
| Tis
| colspan="2" | [[Carcinoma in situ]]
|-
| T1
| colspan="2" | Tumor ≤ 3&nbsp;cm across, surrounded by lung or visceral pleura
|-
| rowspan="4" |
| T1mi
| Minimally invasive adenocarcinoma
|-
| T1a
| Tumor ≤ 1&nbsp;cm across
|-
| T1b
| Tumor > 1&nbsp;cm but ≤ 2&nbsp;cm across
|-
| T1c
| Tumor > 2&nbsp;cm but ≤ 3&nbsp;cm across
|-
| rowspan="4" | T2
| rowspan="4" | Any of:
| Tumor size > 3&nbsp;cm but ≤ 5&nbsp;cm across
|-
| Involvement of the main bronchus but not the carina
|-
| Invasion of visceral pleura
|-
| Atelectasis/[[obstructive pneumonitis]] extending to the [[Hilum (anatomy)|hilum]]
|-
| rowspan="2" |
| T2a
| Tumor > 3&nbsp;cm but ≤ 4&nbsp;cm across
|-
| T2b
| Tumor > 4&nbsp;cm but ≤ 5&nbsp;cm across
|-
| rowspan="3" | T3
| rowspan="3" | Any of:
| Tumor size > 5&nbsp;cm but ≤ 7&nbsp;cm across
|-
| Invasion into the chest wall, [[phrenic nerve]], or parietal [[pericardium]]
|-
| Separate tumor nodule in the same lobe
|-
| rowspan="3" | T4
| rowspan="3" | Any of:
| Tumor size > 7&nbsp;cm
|-
| Invasion of the diaphragm, mediastinum, heart, [[great vessels]], [[trachea]], [[Carina of trachea|carina]], [[recurrent laryngeal nerve]], [[esophagus]], or [[vertebral body]]
|-
| Separate tumor nodule in a different lobe of the same lung
|}
| style="vertical-align:top;" |
{| class="wikitable"
|-
! colspan="3" | N: Lymph nodes
|-
| N0
| colspan="2" | No lymph node metastasis
|-
| N1
| colspan="2" | Metastasis to [[ipsilateral]] peribronchial and/or hilar lymph nodes
|-
| N2
| colspan="2" | Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes
|-
| rowspan="2" | N3
| rowspan="2" | Any of:
| Metastasis to scalene or supraclavicular lymph nodes
|-
| Metastasis to contralateral hilar or mediastinal lymph nodes
|}
| style="vertical-align:top;" |
{| class="wikitable"
|-
! colspan="3" | M: Metastasis
|-
| M0
| colspan="2" | No distant metastasis
|-
| rowspan="3" | M1a
| rowspan="3" | Any of:
| Separate tumor nodule in the other lung
|-
| Tumor with pleural or pericardial nodules
|-
| Malignant [[Pleural effusion|pleural]] or [[pericardial effusion]]
|-
| M1b
| colspan="2" | A single metastasis outside the chest
|-
| M1c
| colspan="2" | Two or more metastases outside the chest
|}
|}

{| class="wikitable floatright" style="text-align:right;font-size:90%;margin-left:1em;background:#E5AFAA;"
|+ Stage group according to TNM classification in lung cancer<ref name="Harrison" />
|-
! TNM
! Stage group
|-
| T1a–T1b N0 M0
| IA
|-
| T2a N0 M0
| IB
|-
| T1a–T2a N1 M0
| rowspan="2" | IIA
|-
| T2b N0 M0
|-
| T2b N1 M0
| rowspan="2" | IIB
|-
| T3 N0 M0
|-
| T1a–T3 N2 M0
| rowspan="3" | IIIA
|-
| T3 N1 M0
|-
| T4 N0–N1 M0
|-
| N3 M0
| rowspan="2" | IIIB
|-
| T4 N2 M0
|-
| M1
| IV
|}

For both NSCLC and SCLC, the two general types of staging evaluations are clinical staging and surgical staging. Clinical staging is performed before definitive surgery. It is based on the results of imaging studies (such as CT scans and [[positron emission tomography|PET scans]]) and biopsy results. Surgical staging is evaluated either during or after the operation. It is based on the combined results of surgical and clinical findings, including surgical sampling of thoracic lymph nodes.<ref name="Holland-Frei84" />

<gallery widths="200px" heights="200px" perrow="4" caption="Diagrams of main features of staging">
Diagram showing stage 1A and 1B lung cancer CRUK 197.svg|Stage IA and IB lung cancer
Diagram showing stage 2A lung cancer CRUK 213.svg|Stage IIA lung cancer
Diagram showing one option for stage 2Ba lung cancer CRUK 176.svg|Stage IIB lung cancer
Diagram showing one option for stage 2Bb lung cancer CRUK 177.svg|One option for stage IIB lung cancer, with T2b; but if tumor is within 2&nbsp;cm of the [[Carina of trachea|carina]], this is stage 3
Diagram 1 of 3 showing stage 3A lung cancer CRUK 008.svg|Stage IIIA lung cancer
Diagram 2 of 3 showing stage 3A lung cancer CRUK 014.svg|Stage IIIA lung cancer, if there is one feature from the list on each side
Diagram 3 of 3 showing stage 3A lung cancer CRUK 017.svg|Stage IIIA lung cancer
Diagram 1 of 2 showing stage 3B lung cancer CRUK 005.svg|Stage IIIB lung cancer
Diagram 2 of 2 showing stage 3B lung cancer CRUK 011.svg|Stage IIIB lung cancer
Diagram showing stage 4 lung cancer CRUK 232.svg|Stage IV lung cancer
</gallery>

==Treatment==
{{main|Treatment of lung cancer}}
Treatment for lung cancer depends on the cancer's specific cell type, how far it has [[cancer staging|spread]], and the person's [[performance status]]. Common treatments for early stage cancers include [[Segmental resection|surgical removal]] of the tumor, [[chemotherapy]], and [[radiation therapy]].<ref name="Harrison" /> For later stage cancers, chemotherapy and radiation therapy are combined with newer targeted molecular therapies and [[immune checkpoint inhibitor]]s. All lung cancer treatment regimens are combined with lifestyle changes and [[palliative care]] to improve quality of life.<!--may have to tweak this wording based on sources-->

===Small-cell lung cancer===
Limited-stage SCLC is typically treated with a combination of chemotherapy and radiotherapy.{{sfn|Horn|Iams|2022|loc="Treatment – Small-Cell Lung Cancer"}} For chemotherapy, the [[National Comprehensive Cancer Network]] and [[American College of Chest Physicians]] guidelines recommend four to six cycles of a [[Platinum-based antineoplastic|platinum-based chemotherapeutic]] – [[cisplatin]] or [[carboplatin]] – combined with either [[etoposide]] or [[irinotecan]].{{sfn|Rivera|Mody|Weiner|2022|loc="Treatment of Small Cell Lung Cancer"}} This is typically combined with thoracic radiation therapy – 45 [[Gray (unit)|Gray]] (Gy) twice-daily – alongside the first two chemotherapy cycles.{{sfn|Horn|Iams|2022|loc="Treatment – Small-Cell Lung Cancer"}} 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.{{sfn|Horn|Iams|2022|loc="Treatment – Small-Cell Lung Cancer"}} [[Irinotecan]], [[paclitaxel]], [[docetaxel]], [[vinorelbine]], etoposide, and [[gemcitabine]] are also sometimes used, and are similarly efficacious.{{sfn|Horn|Iams|2022|loc="Treatment – Small-Cell Lung Cancer"}} [[Prophylactic cranial irradiation]] can also reduce the risk of brain metastases and improve survival in those with limited-stage disease.{{sfn|Rudin|Brambilla|Faivre-Finn|Sage|2021|loc="Locally advanced SCLC"}}{{sfn|Horn|Iams|2022|loc="Treatment – Small-Cell Lung Cancer"}}

Similarly, 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.{{sfn|Rudin|Brambilla|Faivre-Finn|Sage|2021|loc="Metastatic Disease"}} 

===Non-small-cell lung cancer===
[[File:Lung cancer.jpg|thumb|[[Pneumonectomy]] specimen containing a [[squamous-cell carcinoma]], seen as a white area near the bronchi]]
<!--Add something about wait-and-see for certain small nodules. A bit in Harrison's-->For stage I and stage II NSCLC the first line of treatment is often surgical removal of the affected lobe of the lung.{{sfn|Horn|Iams|2022|loc="Management of Stages I and II NSCLC"}} For those not well enough to tolerate full lobe removal<!--expand on this?-->, a smaller chunk of lung tissue can be removed by [[wedge resection]] or [[segmentectomy]] surgery.{{sfn|Horn|Iams|2022|loc="Management of Stages I and II NSCLC"}} Those with centrally located tumors and otherwise-healthy respiratory systems may have more extreme surgery to remove an entire lung ([[pneumonectomy]]).{{sfn|Horn|Iams|2022|loc="Management of Stages I and II NSCLC"}} Experienced [[thoracic surgeon]]s, and a high-volume surgery clinic improve chances of survival.{{sfn|Horn|Iams|2022|loc="Management of Stages I and II NSCLC"}} Those who are unable or unwilling to undergo surgery can instead receive radiation therapy. <!--Would be nice to have a clinical recommendation statement here-->[[Stereotactic body radiation therapy]] is best practice, typically administered several times over 1–2 weeks.{{sfn|Horn|Iams|2022|loc="Management of Stages I and II NSCLC"}} 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]].{{sfn|Horn|Iams|2022|loc="Management of Stages I and II NSCLC"}}

[[File:Diagram showing how you have internal radiotherapy for lung cancer CRUK 160.svg|thumb|right|[[Brachytherapy]] (internal radiotherapy) for lung cancer given via the airway]]

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]].{{sfn|Horn|Iams|2022|loc="Management of Stage III NSCLC"}} Combined chemotherapy and radiation enhances survival compared to chemotherapy followed by radiation, though the combination therapy comes with harsher side effects.{{sfn|Horn|Iams|2022|loc="Management of Stage III NSCLC"}}

Those with stage IV disease are treated with combinations of pain medication, radiotherapy, immunotherapy, and chemotherapy.{{sfn|Horn|Iams|2022|loc="Management of Metastatic NSCLC"}} 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 ''[[Epidermal growth factor receptor|EGFR]]'' gene that result in an overactive EGFR protein;{{sfn|Alexander|Kim|Cheng|2020|loc="Basis of Molecularly Targeted Therapy in Lung Cancer"}} 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.{{sfn|Horn|Iams|2022|loc="Management of Metastatic NSCLC"}} Up to 7% of those with NSCLC harbor mutations that result in hyperactive [[anaplastic lymphoma kinase|ALK]] protein, which can be treated with [[ALK inhibitor]]s [[crizotinib]], or its successors [[alectinib]], [[brigatinib]], and [[ceritinib]].{{sfn|Horn|Iams|2022|loc="Management of Metastatic NSCLC"}} Those treated with ALK inhibitors who relapse can then be treated with the third-generation ALK inhibitor [[lorlatinib]].{{sfn|Horn|Iams|2022|loc="Management of Metastatic NSCLC"}} Up to 5% with NSCLC have overactive [[C-Met|MET]], which can be inhibited with [[c-Met inhibitor|MET inhibitors]] [[capmatinib]] or [[tepotinib]].{{sfn|Horn|Iams|2022|loc="Management of Metastatic NSCLC"}} Targeted therapies are also available for some cancers with rare mutations. Cancers with hyperactive [[BRAF (gene)|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 proto-oncogene|RET]] (around 1% of NSCLC) by [[selpercatinib]].{{sfn|Horn|Iams|2022|loc="Management of Metastatic NSCLC"}}

People whose NSCLC is not targetable by current molecular targeted therapies instead can be treated with combination chemotherapy plus [[immune checkpoint inhibitor]]s, which prevent cancer cells from inactivating immune [[T cell]]s. 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.{{sfn|Horn|Iams|2022|loc="Cytotoxic Chemotherapy for Metastatic or Recurrent NSCLC"}} Immune checkpoint inhibitors are most effective against cancers that express the protein [[PD-L1]], but are sometimes effective in those that do not.{{sfn|Horn|Iams|2022|loc="Immunotherapy"}} Treatment with [[pembrolizumab]], [[atezolizumab]], or combination [[nivolumab]] plus [[ipilimumab]] are all superior to chemotherapy alone against tumors expressing PD-L1.{{sfn|Horn|Iams|2022|loc="Immunotherapy"}} Those who relapse on the above are treated with second-line chemotherapeutics [[docetaxel]] and [[ramucirumab]].{{sfn|Horn|Iams|2022|loc="Second-Line Therapy and Beyond"}}

[[File:Monoclonal antibodies used in the treatment of non small cell lung cancer and their mechanism of action.webp|alt=https://doi.org/10.3390/ph13110373|thumb|Monoclonal antibodies used in the treatment of NSCLC and their mechanism of action https://doi.org/10.3390/ph13110373]]
[[File:Pharmaceuticals-13-00373-g002-550.jpg|alt=https://doi.org/10.3390/ph13110373|thumb|The main treatment arms of phase 3 clinical trials providing immunotherapy in the first line for patients with NSCLC https://doi.org/10.3390/ph13110373]]

Several treatments can be provided via bronchoscopy for the management of airway obstruction or bleeding. If an airway becomes obstructed by cancer growth, options include rigid bronchoscopy, balloon bronchoplasty, stenting, and microdebridement.<ref>{{cite book | vauthors = Lazarus DR, Eapen GA | title=Lung Cancer | publisher=Wiley-Blackwell | veditors = Roth JA, Hong WK, Komaki RU | year=2014 | chapter=Chapter 16: Bronchoscopic interventions for lung cancer | edition=4th | isbn=978-1-118-46874-6 }}</ref> Laser photosection involves the delivery of laser light inside the airway via a bronchoscope to remove the obstructing tumor.<ref>{{cite journal | vauthors = Khemasuwan D, Mehta AC, Wang KP | title = Past, present, and future of endobronchial laser photoresection | journal = Journal of Thoracic Disease | volume = 7 | issue = Suppl 4 | pages = S380–88 | date = December 2015 | pmid = 26807285 | pmc = 4700383 | doi = 10.3978/j.issn.2072-1439.2015.12.55 }}</ref>

===Palliative care===
Integrating palliative care (i.e. 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.{{sfn|Aragon|2020|loc="Integrating palliative care into lung cancer care"}} For both NSCLC and SCLC patients, smaller doses of radiation to the chest may be used for symptom control ([[palliative care|palliative]] radiotherapy).<ref>{{cite journal | vauthors = Fairchild A, Harris K, Barnes E, Wong R, Lutz S, Bezjak A, Cheung P, Chow E | display-authors = 6 | title = Palliative thoracic radiotherapy for lung cancer: a systematic review | journal = Journal of Clinical Oncology | volume = 26 | issue = 24 | pages = 4001–11 | date = August 2008 | pmid = 18711191 | doi = 10.1200/JCO.2007.15.3312 }}</ref><ref name=":5">{{cite journal | vauthors = Stevens R, Macbeth F, Toy E, Coles B, Lester JF | title = Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD002143 | date = January 2015 | issue = 1 | pmid = 25586198 | doi = 10.1002/14651858.CD002143.pub4 | pmc = 7017846 | veditors = Stevens R }}</ref> With adequate [[Performance status|physical fitness]] maintaining chemotherapy during lung cancer palliation offers 1.5 to 3 months of prolongation of survival, symptomatic relief, and an improvement in quality of life, with better results seen with modern agents.<ref name="pmid11441939">{{cite journal | vauthors = Sörenson S, Glimelius B, Nygren P | title = A systematic overview of chemotherapy effects in non-small cell lung cancer | journal = Acta Oncologica | volume = 40 | issue = 2–3 | pages = 327–39 | year = 2001 | pmid = 11441939 | doi = 10.1080/02841860151116402 }}</ref><ref name="pmid12065068">{{cite journal | vauthors = Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N | title = A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer | journal = Health Technology Assessment | volume = 5 | issue = 32 | pages = 1–195 | year = 2001 | pmid = 12065068 | doi = 10.3310/hta5320 | url = http://wrap.warwick.ac.uk/52130/ | url-status = live | archive-url = https://web.archive.org/web/20170830234842/http://wrap.warwick.ac.uk/52130/ | archive-date = 30 August 2017 | doi-access = free }}</ref>

Palliative care when added to usual cancer care benefits people even when they are still receiving chemotherapy.<ref>{{cite journal | vauthors = Parikh RB, Kirch RA, Smith TJ, Temel JS | title = Early specialty palliative care – translating data in oncology into practice | journal = The New England Journal of Medicine | volume = 369 | issue = 24 | pages = 2347–51 | date = December 2013 | pmid = 24328469 | pmc = 3991113 | doi = 10.1056/nejmsb1305469 }}</ref> These approaches allow additional discussion of treatment options and provide opportunities to arrive at well-considered decisions.<ref name="pmid20818881">{{cite journal | vauthors = Kelley AS, Meier DE | title = Palliative care – a shifting paradigm | journal = The New England Journal of Medicine | volume = 363 | issue = 8 | pages = 781–82 | date = August 2010 | pmid = 20818881 | doi = 10.1056/NEJMe1004139 }}</ref><ref name="pmid19856592">{{cite journal | vauthors = Prince-Paul M | title = When hospice is the best option: an opportunity to redefine goals | journal = Oncology | volume = 23 | issue = 4 Suppl Nurse Ed | pages = 13–17 | date = April 2009 | pmid = 19856592 }}</ref> Palliative care may avoid unhelpful but expensive care not only at the end of life, but also throughout the course of the illness. For individuals who have more advanced disease, [[hospice care]] may also be appropriate.<ref name="Collins" /><ref name="pmid19856592" />

=== Noninvasive interventions ===

The most effective intervention for avoiding death from lung cancer is to stop smoking; even people who already have lung cancer are encouraged to stop smoking.<ref name=":1">{{cite journal|vauthors=Zeng L, Yu X, Yu T, Xiao J, Huang Y|date=June 2019|title=Interventions for smoking cessation in people diagnosed with lung cancer|journal=The Cochrane Database of Systematic Reviews|volume=6|issue=6 |pages=CD011751|doi=10.1002/14651858.CD011751.pub3|pmc=6554694|pmid=31173336}}</ref> There is no clear evidence which [[smoking cessation]] program is most effective for people who have been diagnosed with lung cancer.<ref name=":1" />

Some weak evidence suggests that certain supportive care interventions ([[noninvasive]]) that focus on well-being for people with lung cancer may improve quality of life.<ref name=":4">{{cite journal | vauthors = Rueda JR, Solà I, Pascual A, Subirana Casacuberta M | title = Non-invasive interventions for improving well-being and quality of life in patients with lung cancer | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD004282 | date = September 2011 | volume = 2011 | pmid = 21901689 | doi = 10.1002/14651858.CD004282.pub3 | pmc = 7197367 }}</ref> Interventions such as nurse follow-ups, [[psychotherapy]], [[psychosocial]] therapy, and educational programs may be beneficial, however, the evidence is not strong (further research is needed).<ref name=":4" /> [[Counseling psychology|Counseling]] may help people cope with emotional symptoms related to lung cancer.<ref name=":4" /> [[Reflexology]] may be effective in the short-term, however more research is needed.<ref name=":4" /> No evidence has been found to suggest that nutritional interventions or exercise programs for a person with lung cancer result in an improvement in the quality of life that are relevant or last very long.<ref name=":4" />

Exercise training may benefit people with NSCLC who are recovering from lung surgery.<ref>{{cite journal|vauthors=Cavalheri V, Burtin C, Formico VR, Nonoyama ML, Jenkins S, Spruit MA, Hill K|date=June 2019|title=Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer|journal=The Cochrane Database of Systematic Reviews|volume=2019|issue=6|pages=CD009955|doi=10.1002/14651858.CD009955.pub3|pmc=6571512|pmid=31204439}}</ref> In addition, exercise training may benefit people with NSCLC who have received radiotherapy, chemotherapy, chemoradiotherapy, or palliative care.<ref name="Driessen 63–76">{{cite journal|vauthors=Driessen EJ, Peeters ME, Bongers BC, Maas HA, Bootsma GP, van Meeteren NL, Janssen-Heijnen ML|date=June 2017|title=Effects of prehabilitation and rehabilitation including a home-based component on physical fitness, adherence, treatment tolerance, and recovery in patients with non-small cell lung cancer: A systematic review|url=https://cris.maastrichtuniversity.nl/ws/files/53426593/Bongers_2017_Effects_of_prehabilitation_and_rehabilitation.pdf|journal=Critical Reviews in Oncology/Hematology|volume=114|pages=63–76|doi=10.1016/j.critrevonc.2017.03.031|pmid=28477748|s2cid=207023145 }}</ref> Exercise training before lung cancer surgery may also improve outcomes.<ref name=":8">{{cite journal|vauthors=Sebio Garcia R, Yáñez Brage MI, Giménez Moolhuyzen E, Granger CL, Denehy L|date=September 2016|title=Functional and postoperative outcomes after preoperative exercise training in patients with lung cancer: a systematic review and meta-analysis|journal=Interactive Cardiovascular and Thoracic Surgery|volume=23|issue=3|pages=486–97|doi=10.1093/icvts/ivw152|pmid=27226400|doi-access=free}}</ref> It is unclear if exercise training or exercise programs are beneficial for people who have advanced lung cancer.<ref>{{cite journal|vauthors=Peddle-McIntyre CJ, Singh F, Thomas R, Newton RU, Galvão DA, Cavalheri V|date=February 2019|title=Exercise training for advanced lung cancer|journal=The Cochrane Database of Systematic Reviews|volume=2|issue=2 |pages=CD012685|doi=10.1002/14651858.CD012685.pub2|pmc=6371641|pmid=30741408}}</ref><ref name=":4" /> A home-based component in a personalized [[Physical medicine and rehabilitation|physical rehabilitation]] program may be useful for recovery.<ref name="Driessen 63–76" /> It is unclear if home-based prehabilitation (before surgery) leads to less adverse events or hospitalization time.<ref name="Driessen 63–76" /> Physical rehabilitation with a home-based component may improve recovery after treatment and overall lung health.<ref name="Driessen 63–76" />

==Prognosis==
{| class="wikitable floatright" style="text-align:center;font-size:90%;width:35%;margin-left:1em"
|+ style="background:#E5AFAA;"|'''Outcomes in lung cancer according to clinical stage'''<ref name="Rami-Porta">{{cite journal | vauthors = Rami-Porta R, Crowley JJ, Goldstraw P | title = The revised TNM staging system for lung cancer | journal = Annals of Thoracic and Cardiovascular Surgery | volume = 15 | issue = 1 | pages = 4–9 | date = February 2009 | pmid = 19262443 | url = http://www.atcs.jp/pdf/2009_15_1/4.pdf | url-status = live | archive-url = https://web.archive.org/web/20120509223416/http://www.atcs.jp/pdf/2009_15_1/4.pdf | archive-date = 9 May 2012 }}</ref>
|- style="background: #E5AFAA;text-align:center;font-size:90%;"
! abbr="Type" rowspan="2" | Clinical stage
! abbr="5-year" colspan="2" | Five-year survival (%)
|- style="background: #E5AFAA;text-align:center;font-size:90%;"
! abbr="NSCLC" | Non-small-cell lung carcinoma
! abbr="SCLC" | Small-cell lung carcinoma
|-
| IA
| 50
| 38
|-
| IB
| 47
| 21
|-
| IIA
| 36
| 38
|-
| IIB
| 26
| 18
|-
| IIIA
| 19
| 13
|-
| IIIB
| 7
| 9
|-
| IV
| 2
| 1
|}

Around 19% of people diagnosed with lung cancer survive [[Five-year survival rate|five years from diagnosis]].{{sfn|Rivera|Mody|Weiner|2022|loc="Introduction"}} Five-year survival is higher in women (22%) than men (16%);{{sfn|Rivera|Mody|Weiner|2022|loc="Introduction"}} women tend to be diagnosed with less-advanced disease, and have better outcomes than men diagnosed at the same stage.{{sfn|Rivera|Mody|Weiner|2022|loc="Prognostic and Predictive Factors in Lung Cancer"}}  In England and Wales, between 2013 and 2017, overall [[Five-year survival rate|five-year survival]] for lung cancer was estimated at 13.8%.<ref>{{cite web | title=Lung cancer survival statistics | publisher=Cancer Research UK |url=https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/survival#heading-Zero| date=2 April 2020 }}</ref> Outcomes are generally worse in the [[developing world]].<ref name="Maj2009"/> In the US, people with [[Health insurance|medical insurance]] are more likely to have a better outcome.<ref>{{cite journal | vauthors = Slatore CG, Au DH, Gould MK | title = An official American Thoracic Society systematic review: insurance status and disparities in lung cancer practices and outcomes | journal = American Journal of Respiratory and Critical Care Medicine | volume = 182 | issue = 9 | pages = 1195–205 | date = November 2010 | pmid = 21041563 | doi = 10.1164/rccm.2009-038ST }}</ref>

Survival for lung cancer falls as the stage at diagnosis becomes more advanced; the English data suggest that around 70% of patients survive at least a year when diagnosed at the earliest stage, but this falls to just 14% for those diagnosed with the most advanced disease (stage IV).<ref>{{cite web|url=http://www.cancerresearchuk.org/cancer-info/cancerstats/types/lung/survival/#stage|title=Lung cancer survival statistics|access-date=28 October 2014|url-status=live|archive-url=https://web.archive.org/web/20141009015127/http://www.cancerresearchuk.org/cancer-info/cancerstats/types/lung/survival/#stage|archive-date=9 October 2014}}</ref>

SCLC is particularly aggressive. Most people treated for SCLC relapse and eventually develop chemotherapy-resistant cancer. The average person diagnosed with SCLC at the limited stage survives 12–20 months from diagnosis; the average person diagnosed at the extensive stage survives around 12 months.{{sfn|Horn|Iams|2022|loc="Treatment – Small-Cell Lung Cancer"}} 10–15% of people with SCLC survive 5 years after diagnosis.{{sfn|Horn|Iams|2022|loc="Treatment – Small-Cell Lung Cancer"}} Those with limited stage SCLC that goes into complete remission after chemotherapy and radiotherapy have a 50% chance of brain metastases developing within the next two years – a chance reduced by prophylactic cranial irradiation.{{sfn|Rivera|Mody|Weiner|2022|loc="Treatment of Small Cell Lung Cancer"}}

For NSCLC, the best prognosis is achieved with complete surgical resection of stage-IA disease, with up to 70% five-year survival.<ref name="OTM">{{Cite book | vauthors = Spiro SG | title=Oxford Textbook Medicine | publisher=OUP Oxford | year=2010 | chapter=18.19.1 | edition=5th | isbn=978-0-19-920485-4 }}</ref>  The prognosis of patients with NSCLC improved significantly in the last years with the introduction of immunotherapy.<ref name="Nasser_2020">{{cite journal | vauthors = Nasser NJ, Gorenberg M, Agbarya A | title = First line Immunotherapy for Non-Small Cell Lung Cancer | journal = Pharmaceuticals | volume = 13 | issue = 11 | pages = 373 | date = November 2020 | pmid = 33171686 | pmc = 7695295 | doi = 10.3390/ph13110373 | doi-access = free }}</ref> 68–92% of those diagnosed with stage I NSCLC survive at least 5 years after diagnosis, as do 53–60% of those diagnosed with stage II NSCLC.{{sfn|Horn|Iams|2022|loc="Management of Stages I and II NSCLC"}}

Several personal and disease factors are associated with improved outcomes. Those diagnosed at an earlier disease stage tend to have better prognoses, as do those diagnosed at a younger age. Those who smoke or experience weight loss as a symptom tend to have worse outcomes. Large/active metastases (by PET scan) and tumor mutations in ''KRAS'' are associated with reduced survival.{{sfn|Rivera|Mody|Weiner|2022|loc="Prognostic and Predictive Factors in Lung Cancer"}}

[[File:Overall survival in non-small lung cancer patients treated with modern immunotherapy in the first line for advanced or metastatic disease.jpg|thumb|Overall survival in NSCLC patients treated with protocols incorporating immunotherapy in the first line for advanced or metastatic disease. Nasser NJ, Gorenberg M, Agbarya A. ''Pharmaceuticals'' 2020, ''13''(11), 373; <nowiki>https://doi.org/10.3390/ph13110373</nowiki>]]

==Causes==
[[File:Lung Cancer Incidece vers Cigarette Consumption.svg|thumb|upright=1.3|Relationship between cigarette consumption per person (blue) and male lung cancer rates (dark yellow) in the US over the century]]
[[File:Cumulative risk of death from lung cancer 1990.svg|thumb|upright=1.3|Risk of death from lung cancer is strongly correlated with smoking.]]
Cancer develops after [[genetic damage]] to [[DNA]] and [[Epigenetics|epigenetic]] changes. Those changes affect the [[Cell biology|cell's normal functions]], including [[cell proliferation]], programmed cell death ([[apoptosis]]), and [[DNA repair]]. As more damage accumulates, the risk for cancer increases.<ref name="Holland-Frei8">{{Cite book  |vauthors=Brown KM, Keats JJ, Sekulic A, et al. | title=Holland-Frei Cancer Medicine | publisher=People's Medical Publishing House | year=2010 | chapter=Chapter 8 | edition=8th | isbn=978-1-60795-014-1 }}</ref>

===Smoking===
[[Tobacco smoking]] is by far the major contributor to lung cancer, causing 80% to 90% of cases.{{sfn|Schabath|Cote|2019|loc="Introduction"}} Across the developed world, 90% of lung cancer deaths in men and 70% of those in women during 2000 were attributed to smoking.<ref name="Peto" /> [[Tobacco smoke|Cigarette smoke]] contains at least [[list of cigarette smoke carcinogens|73 known carcinogens]],<ref name="Hecht">{{cite journal | vauthors = Hecht SS | title = Lung carcinogenesis by tobacco smoke | journal = International Journal of Cancer | volume = 131 | issue = 12 | pages = 2724–32 | date = December 2012 | pmid = 22945513 | pmc = 3479369 | doi = 10.1002/ijc.27816 }}</ref> including [[benzo(a)pyrene|benzo[''a'']pyrene]],<ref>{{cite book | vauthors = Kumar V, Abbas AK, Aster JC | year=2013 | title=Robbins Basic Pathology |edition=9th | publisher=Elsevier Saunders | page=199 | chapter=Chapter 5 | isbn=978-1-4377-1781-5 }}</ref> [[NNK]], [[1,3-butadiene]], and a [[radioisotope|radioactive isotope]] of polonium – [[polonium-210]].<ref name="Hecht" />   [[electronic cigarette|Vaping]] may be a risk factor for lung cancer, but less than that of cigarettes, and further research is necessary due to the length of time it can take for lung cancer to develop following an exposure to carcinogens.<ref name=NansseuBigna2016>{{cite journal | vauthors = Nansseu JR, Bigna JJ | title = Electronic Cigarettes for Curbing the Tobacco-Induced Burden of Noncommunicable Diseases: Evidence Revisited with Emphasis on Challenges in Sub-Saharan Africa | journal = Pulmonary Medicine | volume = 2016 | pages = 4894352 | year = 2016 | pmid = 28116156 | pmc = 5220510 | doi = 10.1155/2016/4894352 | doi-access = free }}{{CC-notice|cc=by4|url=https://www.hindawi.com/journals/pm/2016/4894352/|author(s)= Nansseu JR, Bigna JJ}}</ref><ref name="Bracken-ClarkeKapoor2021">{{cite journal | vauthors = Bracken-Clarke D, Kapoor D, Baird AM, Buchanan PJ, Gately K, Cuffe S, Finn SP | title = Vaping and lung cancer – A review of current data and recommendations | journal = Lung Cancer | volume = 153 | pages = 11–20 | date = March 2021 | pmid = 33429159 | doi = 10.1016/j.lungcan.2020.12.030 | doi-access = free }}</ref>
<!--Just a note, the Christiani Epidemiology chapter has a long section on molecular connections of cigarette smoking and lung cancer-->

Being around tobacoo smoke – called [[passive smoking]] – can also cause lung cancer. Living with a tobacco smoker increaes 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.{{sfn|Bade|Dela Cruz|2020|loc="Environmental Tobacco Smoke"}}

[[Cannabis smoking|Cannabis smoke]] contains many of the same [[carcinogen]]s as those found in tobacco smoke,<ref>{{cite journal | vauthors = Greydanus DE, Hawver EK, Greydanus MM, Merrick J | title = Marijuana: current concepts(†) | journal = Frontiers in Public Health | volume = 1 | issue = 42 | pages = 42 | date = October 2013 | pmid = 24350211 | pmc = 3859982 | doi = 10.3389/fpubh.2013.00042 | doi-access = free }}</ref> but the effect of smoking [[cannabis]] on lung cancer risk is not clear.<ref>{{cite journal | vauthors = Owen KP, Sutter ME, Albertson TE | title = Marijuana: respiratory tract effects | journal = Clinical Reviews in Allergy & Immunology | volume = 46 | issue = 1 | pages = 65–81 | date = February 2014 | pmid = 23715638 | doi = 10.1007/s12016-013-8374-y | s2cid = 23823391 }}</ref><ref>{{cite journal | vauthors = Joshi M, Joshi A, Bartter T | title = Marijuana and lung diseases | journal = Current Opinion in Pulmonary Medicine | volume = 20 | issue = 2 | pages = 173–79 | date = March 2014 | pmid = 24384575 | doi = 10.1097/mcp.0000000000000026 | s2cid = 8010781 }}</ref>

===Other exposures===
Exposure to a variety of other toxic chemicals – typically encountered in certain occupations – are associated with an increased risk of lung cancer.{{sfn|Christiani|Amos|2022|loc="Occupational Exposures"}} In all, occupational exposures to carcinogens are estimated to cause 9–15% of lung cancers.{{sfn|Christiani|Amos|2022|loc="Occupational Exposures"}} A prominent example is [[asbestos]], which causes lung cancer either directly or indirectly by inflamming the lung.{{sfn|Christiani|Amos|2022|loc="Occupational Exposures"}} Exposure to all commercially available forms of asbestos increase cancer risk, and cancer risk increases with time of exposure.{{sfn|Christiani|Amos|2022|loc="Occupational Exposures"}} Asbestos and cigarette smoking increase risk synergestically – i.e. 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.{{sfn|Christiani|Amos|2022|loc="Occupational Exposures"}} Similarly, exposure to [[radon]], a naturally occurring breakdown product of the Earth's [[uranium]], is associated with increased lung cancer risk. This is particularly true in underground miners, who have the greatest exposure; but also in indoor air in residential spaces. Like asbestos, cigarette smoking and radon exposure increase risk synergistically.{{sfn|Christiani|Amos|2022|loc="Occupational Exposures"}} Radon exposure is responsible for between 3% and 14% of lung cancer cases.{{sfn|Schabath|Cote|2019|loc="Radon"}}

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 [[jeweler]]s, [[ceramic]]s workers, missile technicians, and [[nuclear reactor]] workers; [[chromium]] in [[stainless steel]] production, [[welding]], and [[Tanning (leather)|hide tanning]]; [[nickel]] in [[electroplate]]rs, glass workers, metal workers, welders, and those who make batteries, ceramics, and jewelry; and [[diesel exhaust]] encountered by miners.{{sfn|Christiani|Amos|2022|loc="Occupational Exposures"}} 

[[Air pollution|Outdoor air pollutants]], especially chemicals released from the burning of [[fossil fuel]]s, increase the risk of lung cancer.<ref name="MurrayNadel52"/> Fine [[Atmospheric particulate matter|particulates]] (PM<sub>2.5</sub>) and [[stratospheric sulfur aerosols|sulfate aerosols]], which may be released in traffic [[Exhaust gas|exhaust fumes]], are associated with a slightly increased risk.<ref name="MurrayNadel52" /><ref>{{cite journal | vauthors = Chen H, Goldberg MS, Villeneuve PJ | title = A systematic review of the relation between long-term exposure to ambient air pollution and chronic diseases | journal = Reviews on Environmental Health | volume = 23 | issue = 4 | pages = 243–97 | date = Oct–Dec 2008 | pmid = 19235364 | doi = 10.1515/reveh.2008.23.4.243 | s2cid = 24481623 }}</ref> For [[nitrogen dioxide]], an incremental increase of 10 [[parts per billion]] increases the risk of lung cancer by 14%.<ref>{{cite journal | vauthors = Clapp RW, Jacobs MM, Loechler EL | title = Environmental and occupational causes of cancer: new evidence 2005–2007 | journal = Reviews on Environmental Health | volume = 23 | issue = 1 | pages = 1–37 | date = Jan–Mar 2008 | pmid = 18557596 | pmc = 2791455 | doi = 10.1515/REVEH.2008.23.1.1 }}</ref> Outdoor air pollution is estimated to cause 1–2% of lung cancers.<ref name="MurrayNadel52" />

[[Indoor air pollution]] from burning [[Wood fuel|wood]], [[Charcoal-burning|charcoal]], or crop residue for cooking and heating has also been linked to an increased risk of developing lung cancer.{{sfn|Bade|Dela Cruz|2020|loc="Biomass Burning"}} The [[International Agency for Research on Cancer]] has classified emission from household burning of coal and biomass as "carcinogenic" and "probably carcinogenic" respectively.{{sfn|Bade|Dela Cruz|2020|loc="Biomass Burning"}} This risk affects about 2.4&nbsp;billion people worldwide,<ref name=Lim2012>{{cite journal | vauthors = Lim WY, Seow A | title = Biomass fuels and lung cancer | journal = Respirology | volume = 17 | issue = 1 | pages = 20–31 | date = January 2012 | pmid = 22008241 | doi = 10.1111/j.1440-1843.2011.02088.x | doi-access = free }}</ref> and it is believed to result in 1.5% of lung cancer deaths.<ref name=Sood2012>{{cite journal | vauthors = Sood A | title = Indoor fuel exposure and the lung in both developing and developed countries: an update | journal = Clinics in Chest Medicine | volume = 33 | issue = 4 | pages = 649–65 | date = December 2012 | pmid = 23153607 | pmc = 3500516 | doi = 10.1016/j.ccm.2012.08.003 }}</ref>
<!--Maybe merge the two air pollution paragraphs and have a third paragraph with other causes, including HIV?-->
===Genetics===
About 8% of lung cancer cases are caused by [[heredity|inherited]] (genetic) factors.<ref>{{cite journal | vauthors = Yang IA, Holloway JW, Fong KM | title = Genetic susceptibility to lung cancer and co-morbidities | journal = Journal of Thoracic Disease | volume = 5 | issue = Suppl. 5 | pages = S454–62 | date = October 2013 | pmid = 24163739 | pmc = 3804872 | doi = 10.3978/j.issn.2072-1439.2013.08.06 }}</ref> In relatives of people who are diagnosed with lung cancer, the risk is doubled, likely due to a [[polygenic disorder|combination of genes]].<ref>{{Cite book | vauthors = Dela Cruz CS, Tanoue LT, Matthay RA | title=Fishman's Pulmonary Diseases and Disorders | publisher=McGraw-Hill | veditors = Grippi MA, Elias JA, Fishman JA, Kotloff RM, Pack AI, Senior RM | year=2015 | chapter=Chapter 109: Epidemiology of lung cancer | page=1673 | edition=5th | isbn=978-0-07-179672-9 }}</ref> [[Genetic polymorphism|Polymorphisms]] on [[chromosome]]s 5, 6, and 15 have been identified and are associated with an increased risk of lung cancer.<ref name=":0">{{cite journal | vauthors = Larsen JE, Minna JD | title = Molecular biology of lung cancer: clinical implications | journal = Clinics in Chest Medicine | volume = 32 | issue = 4 | pages = 703–40 | date = December 2011 | pmid = 22054881 | pmc = 3367865 | doi = 10.1016/j.ccm.2011.08.003 }}</ref> [[Single-nucleotide polymorphism]]s <!-- (SNPs) --> of the genes encoding the [[nicotinic acetylcholine receptor]] (nAChR) – ''[[CHRNA5]]'', ''[[CHRNA3]]'', and ''[[CHRNB4]]'' – are of those associated with an increased risk of lung cancer, as well as ''[[RGS17]]'' – a gene regulating [[G protein#Signaling|G-protein signaling]].<ref name=":0" /> Newer genetic studies, have identified 18 susceptibility loci achieving genome-wide significance. These loci highlight a heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, again identifying the cholinergic nicotinic receptors, e.g. CHRNA2.<ref name="pmid28604730">{{cite journal | vauthors = McKay JD, Hung RJ, Han Y, Zong X, Carreras-Torres R, Christiani DC, etal | title = Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes | journal = Nature Genetics | volume = 49 | issue = 7 | pages = 1126–1132 | date = July 2017 | pmid = 28604730 | pmc = 5510465 | doi = 10.1038/ng.3892 }}</ref>

==Pathogenesis==
{{See also|Carcinogenesis}}

Similar to many other cancers, lung cancer is initiated by either the activation of [[oncogene]]s or the inactivation of [[tumor suppressor gene]]s.<ref>{{cite journal | vauthors = Cooper WA, Lam DC, O'Toole SA, Minna JD | title = Molecular biology of lung cancer | journal = Journal of Thoracic Disease | volume = 5 | issue = Suppl. 5 | pages = S479–90 | date = October 2013 | pmid = 24163741 | pmc = 3804875 | doi = 10.3978/j.issn.2072-1439.2013.08.03 }}</ref> Carcinogens cause mutations in these genes that induce the development of cancer.<ref>{{Cite book | vauthors = Tobias J, Hochhauser D | title=Cancer and its Management | publisher=Wiley-Blackwell | year=2010 | page=200 | chapter=Chapter 12 | edition=6th | isbn=978-1-4051-7015-4 }}</ref>

[[Mutation]]s in the ''[[Ras (protein)|K-ras]]'' proto-oncogene contribute to roughly 10–30% of lung [[adenocarcinoma]]s.<ref name="NEJM-molecular" /><ref name="Aviel-Ronen" /> Nearly 4% of non-small-cell lung carcinomas involve an [[EML4-ALK positive lung cancer|EML4-ALK]] [[tyrosine kinase]] [[fusion gene]].<ref>{{cite book | vauthors = Kumar V, Abbas AK, Aster JC | year=2013 | title=Robbins Basic Pathology |edition=9th | publisher=Elsevier Saunders | page=212 | chapter=Chapter 5 | isbn=978-1-4377-1781-5 }}</ref> The [[epidermal growth factor receptor]] (EGFR) regulates cell proliferation, [[apoptosis]], [[angiogenesis]], and tumor invasion.<ref name="NEJM-molecular" /> Mutations and [[Amplification of DNA|amplification]] of EGFR are common in NSCLC, and they provide the basis for treatment with EGFR inhibitors. ''[[Her2/neu]]'' is affected less frequently.<ref name="NEJM-molecular" /> Other genes that are often mutated or amplified include ''[[c-MET]]'', ''[[NKX2-1]]'', ''[[LKB1]]'', ''[[PIK3CA]]'', and ''[[BRAF (gene)|BRAF]]''.<ref name="NEJM-molecular" /> 

Importantly, cancer cells develop resistance to [[oxidative stress]], which enables them to withstand and exacerbate [[Inflammation|inflammatory]] conditions that inhibit the activity of the [[immune system]] against the tumor.<ref>{{cite journal | vauthors = Takahashi N, Chen HY, Harris IS, Stover DG, Selfors LM, Bronson RT, Deraedt T, Cichowski K, Welm AL, Mori Y, Mills GB, Brugge JS | display-authors = 6 | title = Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance | journal = Cancer Cell | volume = 33 | issue = 6 | pages = 985–1003.e7 | date = June 2018 | pmid = 29805077 | pmc = 6100788 | doi = 10.1016/j.ccell.2018.05.001 }}</ref><ref>{{cite journal | vauthors = Vlahopoulos S, Adamaki M, Khoury N, Zoumpourlis V, Boldogh I | title = Roles of DNA repair enzyme OGG1 in innate immunity and its significance for lung cancer | journal = Pharmacology & Therapeutics | volume = 194 | pages = 59–72 | date = February 2019 | pmid = 30240635 | pmc = 6504182 | doi = 10.1016/j.pharmthera.2018.09.004 }}</ref>

The [[Cell lineage|cell lines]] of origin are not fully understood.<ref name="Harrison">{{cite book | vauthors = Horn L, Lovly CM | title=Harrison's Principles of Internal Medicine | publisher=McGraw-Hill | veditors=Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J | year=2018 | chapter=Chapter 74: Neoplasms of the lung | edition=20th | isbn=978-1259644030 }}</ref> The mechanism may involve the abnormal activation of [[stem cell]]s. In the proximal airways, stem cells that express [[keratin 5]] are more likely to be affected, typically leading to [[Squamous cell lung carcinoma|squamous-cell lung carcinoma]]. In the middle airways, implicated stem cells include [[club cell]]s and [[neuroepithelial cell]]s that express [[uteroglobin|club-cell secretory protein]]. SCLC may originate from these cell lines<ref name="Mulvihill" /> or [[neuroendocrine cell]]s,<ref name="Harrison" /> and it may express [[CD44]].<ref name="Mulvihill">{{cite journal | vauthors = Mulvihill MS, Kratz JR, Pham P, Jablons DM, He B | title = The role of stem cells in airway repair: implications for the origins of lung cancer | journal = Chinese Journal of Cancer | volume = 32 | issue = 2 | pages = 71–74 | date = February 2013 | pmid = 23114089 | pmc = 3845611 | doi = 10.5732/cjc.012.10097 }}</ref> [[Metastasis]] of lung cancer requires [[Epithelial–mesenchymal transition|transition]] from [[Epithelium|epithelial]] to [[mesenchyme|mesenchymal]] cell type. This may occur through the activation of signaling pathways such as [[Protein kinase B|Akt]]/[[GSK3B]]eta, [[MAPK/ERK pathway|MEK-ERK]], [[Fas receptor|Fas]], and Par6.<ref name = "Powell_2013">{{cite journal | vauthors = Powell CA, Halmos B, Nana-Sinkam SP | title = Update in lung cancer and mesothelioma 2012 | journal = American Journal of Respiratory and Critical Care Medicine | volume = 188 | issue = 2 | pages = 157–66 | date = July 2013 | pmid = 23855692 | pmc = 3778761 | doi = 10.1164/rccm.201304-0716UP }}</ref>

The overwhelming majority of SCLCs have mutations that inactivate the [[tumor suppressor]]s [[p53]] and [[RB]].{{sfn|Rudin|Brambilla|Faivre-Finn|Sage|2021|loc="Mechanisms/Pathophysiology"}}

==Prevention==
[[File:cancerous lung.jpg|thumb|Cross section of a human lung: The white area in the upper lobe is cancer; the black areas are discoloration due to [[Tobacco smoking|smoking]].]]
[[Smoking prevention]] and [[smoking cessation]] are effective ways of reducing the risk of lung cancer.

===Smoking cessation===
Those who smoke can reduce their lung cancer risk by quitting smoking – the risk reduction is greater the longer a person goes without smoking.{{sfn|Horn|Iams|2022|loc="Risk Factors"}} Self-help programs tend to have little influence on success of smoking cessation, whereas combined counseling and pharmacotherapy improve cessation rates.{{sfn|Horn|Iams|2022|loc="Risk Factors"}} The U.S. 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<!--recommended by whom?-->.{{sfn|Horn|Iams|2022|loc="Risk Factors"}}

===Tobacco control===
{{see also|Tobacco control}}
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.<ref name="Dela_Cruz_2011">{{cite journal | vauthors = Dela Cruz CS, Tanoue LT, Matthay RA | title = Lung cancer: epidemiology, etiology, and prevention | journal = Clinics in Chest Medicine | volume = 32 | issue = 4 | pages = 605–44 | date = December 2011 | pmid = 22054876 | pmc = 3864624 | doi = 10.1016/j.ccm.2011.09.001 }}</ref>

Policy interventions to decrease [[passive smoking]] in public areas such as restaurants and workplaces have become more common in many [[Western world|Western countries]].<ref>{{cite journal | vauthors = McNabola A, Gill LW | title = The control of environmental tobacco smoke: a policy review | journal = International Journal of Environmental Research and Public Health | volume = 6 | issue = 2 | pages = 741–58 | date = February 2009 | pmid = 19440413 | pmc = 2672352 | doi = 10.3390/ijerph6020741 | doi-access = free }}</ref> [[Bhutan]] has had a complete [[smoking ban]] since 2005<ref name="Bhutan" /> while India introduced a ban on smoking in public in October 2008.<ref>{{cite news | vauthors = Pandey G | title=Indian ban on smoking in public | url=http://news.bbc.co.uk/1/hi/world/south_asia/7645868.stm | publisher=[[BBC]] | date=2 October 2008 | access-date=25 April 2012 | url-status=live | archive-url=https://web.archive.org/web/20090115143617/http://news.bbc.co.uk/1/hi/world/south_asia/7645868.stm | archive-date=15 January 2009 }}</ref> The [[World Health Organization]] has called for governments to institute a total ban on [[tobacco advertising]] to prevent young people from taking up smoking.<ref name="AUTOREF10" /> They assess that such bans have reduced tobacco consumption by 16% where instituted.<ref name="AUTOREF10">{{Cite press release |title=UN health agency calls for total ban on tobacco advertising to protect young |url=https://www.un.org/apps/news/story.asp?NewsID=26857 |publisher=[[United Nations]] News service |date=30 May 2008 |url-status=live |archive-url=https://web.archive.org/web/20160304201703/http://www.un.org/apps/news/story.asp?NewsID=26857 |archive-date=4 March 2016 }}</ref>

===Screening===
{{main|Lung cancer screening}}

Some forms of population screening can allow for earlier detection and treatment of lung cancer cases, reducing deaths from lung cancer. In some trials, screening programs providing low-dose CT scans of individuals at high risk for lung cancer (i.e. people who smoke tobacco and are aged 55 to 74) reduced overall lung cancer mortality.{{sfn|Schabath|Cote|2019|loc="Screening and Early Detection"}} The [[United States Preventive Services Task Force]] recommends yearly screening using low-dose CT in those who have a total smoking history of at least 30 [[pack-year]]s and are between 55 and 80 years old.{{sfn|Alexander|Kim|Cheng|2020|loc="Lung Cancer Screening"}} <!--Schabath and Cote suggests several pro-screening studies had recently been released in Europe. Perhaps there's some update since that 2019 review-->

===Other prevention strategies===

The long-term use of supplemental [[vitamin A]], [[B vitamins]], [[vitamin D]] or [[vitamin E]] does not reduce the risk of lung cancer.<ref name="Alsharairi">{{cite journal | vauthors=Alsharairi NA | title=The effects of dietary supplements on asthma and lung cancer risk in smokers and non-smokers: a review of the literature | journal=Nutrients | volume=11 | issue=4 | page=725 | date=March 2019 | pmid=30925812 | pmc=6521315 | doi=10.3390/nu11040725 | doi-access=free }}</ref> [[Vitamin C]] supplementation might reduce the risk of lung cancer.<ref>{{cite journal | vauthors=Luo J, Shen L, Zheng D | title=Association between vitamin C intake and lung cancer: a dose-response meta-analysis | journal=Scientific Reports | volume=4 | issue=6161 | date=August 2014 | page=6161 | pmid=25145261 | pmc=5381428 | doi=10.1038/srep06161 | bibcode=2014NatSR...4E6161L }}</ref><ref>{{cite journal | vauthors=Shareck M, Rousseau MC, Koushik A, Siemiatycki J, Parent ME | title=Inverse association between dietary intake of selected carotenoids and vitamin C and risk of lung cancer | journal=Frontiers in Oncology | volume=7 | issue=23 | page= 23| date=February 2017 | pmid=28293540 | pmc=5328985 | doi=10.3389/fonc.2017.00023 | doi-access=free }}</ref> Some studies have found vitamins A, B, and E may increase the risk of lung cancer in those who have a history of smoking.<ref name="Alsharairi" />

Some studies suggest that people who eat food with a higher proportion of vegetables and fruit tend to have a lower risk,<ref name="Alberg">{{cite journal | vauthors = Alberg AJ, Ford JG, Samet JM | title = Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition) | journal = Chest | volume = 132 | issue = 3 Suppl | pages = 29S–55S | date = September 2007 | pmid = 17873159 | doi = 10.1378/chest.07-1347}}</ref><ref name="Key">{{cite journal | vauthors = Key TJ | title = Fruit and vegetables and cancer risk | journal = British Journal of Cancer | volume = 104 | issue = 1 | pages = 6–11 | date = January 2011 | pmid = 21119663 | pmc = 3039795 | doi = 10.1038/sj.bjc.6606032 }}</ref> but this may be due to [[confounding]]{{snd}}with the lower risk actually due to the association of a high fruit and vegetables diet with less smoking.<ref>{{cite journal | vauthors = Bradbury KE, Appleby PN, Key TJ | title = Fruit, vegetable, and fiber intake in relation to cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC) | journal = The American Journal of Clinical Nutrition | volume = 100 | issue = Suppl. 1 | pages = 394S–98S | date = July 2014 | pmid = 24920034 | doi = 10.3945/ajcn.113.071357 | doi-access = free }}</ref> Several rigorous studies have not demonstrated a clear association between diet and lung cancer risk,<ref name="Harrison" /><ref name="Key" /> although meta-analysis that accounts for smoking status may show benefit from a healthy diet.<ref>{{cite journal | vauthors = Sun Y, Li Z, Li J, Li Z, Han J | title = A Healthy Dietary Pattern Reduces Lung Cancer Risk: A Systematic Review and Meta-Analysis | journal = Nutrients | volume = 8 | issue = 3 | pages = 134 | date = March 2016 | pmid = 26959051 | pmc = 4808863 | doi = 10.3390/nu8030134 | doi-access = free }}</ref>

==Epidemiology==
[[File:Trachea, bronchus, lung cancers world map-Deaths per million persons-WHO2012.svg|upright=1.3|thumb|Trachea, bronchus, and lung cancers deaths per million persons in 2012
{{refbegin|2}}{{legend|#ffff20|0–7}}{{legend|#ffe820|8–12}}{{legend|#ffd820|13–32}}{{legend|#ffc020|33–53}}{{legend|#ffa020|54–81}}{{legend|#ff9a20|82–125}}{{legend|#f08015|126–286}}{{legend|#e06815|287–398}}{{legend|#d85010|399–527}}{{legend|#d02010|528–889}}{{refend}}
]]
[[File:Lung cancer, incidence, mortality and survival, England 1971 - 2011.png|thumb|right|Lung cancer, incidence, mortality, and survival, England 1971–2011]]
Worldwide, lung cancer is the most diagnosed type of cancer, and the leading cause of cancer death.{{sfn|Schabath|Cote|2019|loc="Descriptive Epidemiology"}}{{sfn|Christiani|Amos|2022|loc="Introduction"}} In 2020, 2.2&nbsp;million new cases were diagnosed, and 1.8&nbsp;million people died from lung cancer, representing 18% of all cancer deaths.<ref name="Sung2021"/> Lung cancer deaths are expected to rise globally to nearly 3 million annual deaths by 2035, due to high rates of tobacco use and aging populations.{{sfn|Christiani|Amos|2022|loc="Introduction"}} Lung cancer is rare in those younger than 40; from there cancer rates increase with age, stabilizing around age 80.{{sfn|Horn|Iams|2022|loc="Epidemiology"}} The median age of a person diagnosed with lung cancer is 70; the median age of death is 72.{{sfn|Bade|Dela Cruz|2020|loc="Age"}}

Lung cancer incidence varies dramatically by geography and sex, with the highest rates in Micronesia, Polynesia, Europe, Asia, and North America; and lowest rates in Africa and Central America.<ref name="Sung2021"/> Globally, around 8% of men and 6% of women develop lung cancer in their lifetimes.{{sfn|Horn|Iams|2022|loc="Epidemiology"}} However, the ratio of lung cancer cases in men to women varies dramatically by geography, as high as nearly 12:1 in Belarus, to 1:1 in Brazil, likely due to differences in smoking patterns.{{sfn|Christiani|Amos|2022|loc="Geographic, Gender, and Ethnic Variability"}} In the United States, lung cancer remains the most common cause of cancer deaths, despite a nearly 50% decrease in the death rate from its peak in 1990.{{sfn|Christiani|Amos|2022|loc="Introduction"}} Lung cancer is the third-most common cancer in the UK (47,968 people were diagnosed with the disease in 2017),<ref>{{cite web | title=Cancer incidence statistics | url=http://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence#heading-One | website=Cancer Research UK | date=13 May 2015 | access-date=23 July 2021 }}</ref> and it is the most common cause of cancer-related death (around 34,600 people died in 2018).<ref>{{cite web | title=Lung cancer statistics | url=http://www.cancerresearchuk.org/cancer-info/cancerstats/types/lung/ | website=Cancer Research UK | date=14 May 2015 | access-date=23 July 2021 }}</ref> 

In the US, lung cancer rates also vary by racial and ethnic group, with the highest rates in [[African American]]s, and the lowest rates in [[Hispanic]]s, [[Native American in the United States|Native American]]s and [[Asian American]]s.{{sfn|Horn|Iams|2022|loc="Epidemiology"}}  Also in the US, military veterans have a 25–50% higher rate of lung cancer primarily due to higher rates of smoking.<ref>{{cite web |title=Honoring veterans with good health | work =  Gibbs Cancer Center & Research Institute |url=http://gibbscancercenter.org/news/honoring-veterans-good-health/|access-date=1 December 2015|date=7 November 2014|url-status=dead|archive-url=https://web.archive.org/web/20151128063005/http://gibbscancercenter.org/news/honoring-veterans-good-health/|archive-date=28 November 2015}}</ref> During World War II and the [[Korean War]], asbestos also played a role, and [[Agent Orange]] may have caused some problems during the [[Vietnam War]].<ref>{{cite web|title=Lung Cancer As It Affects Veterans And Military | work = Lung Cancer Alliance |url=http://www.lungcanceralliance.org/special-features/special-focus-on-veterans-and-lung-cancer/lung-cancer-and-wartime-exposure.html|access-date=1 December 2015|url-status=dead|archive-url=https://web.archive.org/web/20151208170738/http://www.lungcanceralliance.org/special-features/special-focus-on-veterans-and-lung-cancer/lung-cancer-and-wartime-exposure.html|archive-date=8 December 2015}}</ref>

Lung cancer risk is dramatically influenced by environmental exposure, namely cigarette smoking, as well as occupational risks in mining, shipbuilding, petroleum refining, and occupations that involve asbestos exposure.{{sfn|Christiani|Amos|2022|loc="Geographic, Gender, and Ethnic Variability"}} 85–90% of lung cancer cases are in people who have smoked cigarettes, and 15% of smokers develop lung cancer.{{sfn|Christiani|Amos|2022|loc="Geographic, Gender, and Ethnic Variability"}} People who have a long history of smoking have the highest risk of developing lung cancer, with the risk increasing with duration of smoking. The incidence in men rose until the mid-1980s, and has declined since then. In women, the incidence rose until the late 1990s, and has since been stable.<ref name="Holland-Frei84" /> Non-smokers' risk of developing lung cancer is also influenced by tobacco smoking; [[secondhand smoke]] (i.e. being around tobacco smoke) increases risk of developing lung cancer around 30%, with risk correlated to duration of exposure.{{sfn|Christiani|Amos|2022|loc="Geographic, Gender, and Ethnic Variability"}}

For every 3–4&nbsp;million cigarettes smoked, one lung cancer death can occur.<ref>{{cite journal | vauthors = Proctor RN | title = The history of the discovery of the cigarette-lung cancer link: evidentiary traditions, corporate denial, global toll | journal = Tobacco Control | volume = 21 | issue = 2 | pages = 87–91 | date = March 2012 | pmid = 22345227 | doi = 10.1136/tobaccocontrol-2011-050338 | doi-access = free }}</ref> The influence of "[[Big Tobacco]]" plays a significant role in smoking.<ref name="Lum" /> Young nonsmokers who see [[Nicotine marketing|tobacco advertisements]] are more likely to smoke.<ref>{{cite journal | vauthors = Lovato C, Watts A, Stead LF | title = Impact of tobacco advertising and promotion on increasing adolescent smoking behaviours | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD003439 | date = October 2011 | volume = 2011 | pmid = 21975739 | doi = 10.1002/14651858.CD003439.pub2 | pmc = 7173757 }}</ref> The role of passive smoking is increasingly being recognized as a risk factor for lung cancer,<ref name=renamed_from_32848276_on_20210721203832>{{cite journal |vauthors=Dubin S, Griffin D |title=Lung Cancer in Non-Smokers |journal=Missouri Medicine |volume=117 |issue=4 |pages=375–379 |date=2020 |pmid=32848276 |pmc=7431055 }}</ref> resulting in policy interventions to decrease the undesired exposure of nonsmokers to others' tobacco smoke.<ref>{{cite journal | vauthors = Kemp FB | title = Smoke free policies in Europe. An overview | journal = Pneumologia | volume = 58 | issue = 3 | pages = 155–58 | date = Jul–Sep 2009 | pmid = 19817310 }}</ref>

From the 1960s, the rates of lung adenocarcinoma started to rise in relation to other kinds of lung cancer, partially 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.<ref name="Charloux" /> Rates of lung adenocarcinoma continues to rise.<ref>{{cite journal | vauthors = Kadara H, Kabbout M, Wistuba II | title = Pulmonary adenocarcinoma: a renewed entity in 2011 | journal = Respirology | volume = 17 | issue = 1 | pages = 50–65 | date = January 2012 | pmid = 22040022 | pmc = 3911779 | doi = 10.1111/j.1440-1843.2011.02095.x }}</ref>

==History==
Lung cancer was uncommon before the advent of cigarette smoking; it was not even recognized as a distinct disease until 1761.<ref name="AUTOREF27" /> Different aspects of lung cancer were described further in 1810.<ref name="AUTOREF28" /> 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.<ref name="Witschi" /> Case reports in the medical literature numbered only 374 worldwide in 1912,<ref name="AUTOREF29" /> but a review of autopsies showed the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952.<ref name="Grannis" /> In [[Germany]] in 1929, physician [[Fritz Lickint]] recognized the link between smoking and lung cancer,<ref name="Witschi" /> which led to an aggressive [[Anti-tobacco movement in Nazi Germany|antismoking campaign]].<ref name="Proctor" /> The [[British Doctors Study|British Doctors' Study]], published in the 1950s, was the first solid [[epidemiology|epidemiological]] evidence of the link between lung cancer and smoking.<ref name="Doll" /> As a result, in 1964, the [[Surgeon General of the United States]] recommended smokers should stop smoking.<ref name="AUTOREF30" />

The connection with [[radon]] gas was first recognized among miners in the [[Ore Mountains (Germany)|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.<ref name="Greaves" /> Miners developed a disproportionate amount of lung disease, eventually recognized as lung cancer in the 1870s.<ref>{{cite journal | vauthors = Greenberg M, Selikoff IJ | title = Lung cancer in the Schneeberg mines: a reappraisal of the data reported by Harting and Hesse in 1879 | journal = The Annals of Occupational Hygiene | volume = 37 | issue = 1 | pages = 5–14 | date = February 1993 | pmid = 8460878 | doi = 10.1093/annhyg/37.1.5 }}</ref> Despite this discovery, mining continued into the 1950s, due to the [[USSR]]'s demand for uranium.<ref name="Greaves" /> Radon was confirmed as a cause of lung cancer in the 1960s.<ref>{{cite journal | vauthors = Samet JM | title = Radiation and cancer risk: a continuing challenge for epidemiologists | journal = Environmental Health | volume = 10 | issue = Suppl. 1 | pages = S4 | date = April 2011 | pmid = 21489214 | pmc = 3073196 | doi = 10.1186/1476-069X-10-S1-S4 }}</ref>

The first successful [[pneumonectomy]] for lung cancer was performed in 1933.<ref name="AUTOREF32" /> Palliative radiotherapy has been used since the 1940s.<ref name="Edwards" /> 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.<ref name="AUTOREF33" /> In 1997, CHART was seen as an improvement over conventional radical radiotherapy.<ref name="Saunders" /> With SCLC, initial attempts in the 1960s at surgical resection<ref name="AUTOREF34" /> and radical radiotherapy<ref name="AUTOREF35" /> were unsuccessful. In the 1970s, successful chemotherapy regimens were developed.<ref name="AUTOREF36" />

==Research directions==
{{update-section|date=June 2022}}
The search for new treatment options continues. Many clinical trials involving radiotherapy, surgery, EGFR inhibitors, microtubule inhibitors and immunotherapy are currently underway.<ref name="Batra" >{{cite journal | vauthors=Batra H, Pawar S, Bahl D | title=Current clinical trials and patent update on lung cancer: a retrospective review | journal=Lung Cancer Management | volume=10 | issue=5 | pages=LMT45 | date=February 2021 | pmid=34084211 | pmc=8162165 | doi=10.2217/lmt-2020-0029 }}</ref>

Research directions for lung cancer treatment include [[immunotherapy]],<ref name="Brahmer" >{{cite journal | vauthors = Brahmer JR | title = Immune checkpoint blockade: the hope for immunotherapy as a treatment of lung cancer? | journal = Seminars in Oncology | volume = 41 | issue = 1 | pages = 126–32 | date = February 2014 | pmid = 24565586 | pmc = 4732704 | doi = 10.1053/j.seminoncol.2013.12.014 }}</ref><ref name=Syn2017>{{cite journal | vauthors = Syn NL, Teng MW, Mok TS, Soo RA | title = De-novo and acquired resistance to immune checkpoint targeting | journal = The Lancet. Oncology | volume = 18 | issue = 12 | pages = e731–41 | date = December 2017 | pmid = 29208439 | doi = 10.1016/s1470-2045(17)30607-1 }}</ref> which encourages the body's immune system to attack the tumor cells, epigenetics, and new combinations of chemotherapy and radiotherapy, both on their own and together.  Many of these new treatments work through [[immune checkpoint blockade]], disrupting cancer's ability to evade the [[immune system]].<ref name="Brahmer" /><ref name=Syn2017 />

[[Ipilimumab]] blocks [[Signal transduction|signaling]] through a [[Receptor (biochemistry)|receptor]] on [[T cells]] known as [[CTLA-4]], which dampens down the immune system. It has been approved by the US [[U.S. Food and Drug Administration|Food and Drug Administration]] <!-- (FDA) --> for treatment of [[melanoma]], and is undergoing clinical trials for both NSCLC and SCLC.<ref name="Brahmer" />

Other immunotherapy treatments interfere with the binding of [[programmed cell death 1]] (PD-1) protein with its [[ligand]] [[programmed cell death 1 ligand 1|PD-1 ligand 1]] (PD-L1), and have been approved as first- and subsequent-line treatments for various subsets of lung cancers.<ref name=Syn2017 /> Signaling through PD-1 inactivates T cells. Some cancer cells appear to exploit this by expressing PD-L1 in order to switch off T cells that might recognise them as a threat. Monoclonal antibodies targeting both PD-1 and PD-L1, such as [[pembrolizumab]], [[nivolumab]],<ref name = "Powell_2013" /> [[atezolizumab]], and [[durvalumab]]<ref name=Syn2017 /> are currently in clinical trials for treatment for lung cancer.<ref name="Brahmer" /><ref name=Syn2017 />

Epigenetics is the study of small molecular modifications{{snd}}or "tags"{{snd}}that bind to DNA and modify [[gene expression]] levels. Targeting these tags with drugs can kill cancer cells. Early-stage research in NSCLC using drugs aimed at epigenetic modifications shows that blocking more than one of these tags can kill cancer cells with fewer side effects.<ref name="Epi" >{{cite journal | vauthors = Forde PM, Brahmer JR, Kelly RJ | title = New strategies in lung cancer: epigenetic therapy for non-small cell lung cancer | journal = Clinical Cancer Research | volume = 20 | issue = 9 | pages = 2244–48 | date = May 2014 | pmid = 24644000 | pmc = 4325981 | doi = 10.1158/1078-0432.ccr-13-2088 }}</ref> Studies also show that giving people these drugs before standard treatment can improve its effectiveness. Clinical trials are underway to evaluate how well these drugs kill lung cancer cells in humans.<ref name="Epi" /> Several drugs that target epigenetic mechanisms are in development. [[Histone deacetylase inhibitor]]s in development include [[valproic acid]], [[vorinostat]], [[belinostat]], [[panobinostat]], [[entinostat]], and [[romidepsin]]. [[DNA methyltransferase]] inhibitors in development include [[decitabine]], [[azacitidine|azacytidine]], and [[hydralazine]].<ref name="Jakopovic">{{cite journal | vauthors = Jakopovic M, Thomas A, Balasubramaniam S, Schrump D, Giaccone G, Bates SE | title = Targeting the epigenome in lung cancer: expanding approaches to epigenetic therapy | journal = Frontiers in Oncology | volume = 3 | issue = 261 | pages = 261 | date = October 2013 | pmid = 24130964 | pmc = 3793201 | doi = 10.3389/fonc.2013.00261 | doi-access = free }}</ref>

The TRACERx project is looking at how NSCLC develops and evolves, and how these tumors become resistant to treatment.<ref name="Tracer" >{{cite journal | vauthors = Jamal-Hanjani M, Hackshaw A, Ngai Y, Shaw J, Dive C, Quezada S, Middleton G, de Bruin E, Le Quesne J, Shafi S, Falzon M, Horswell S, Blackhall F, Khan I, Janes S, Nicolson M, Lawrence D, Forster M, Fennell D, Lee SM, Lester J, Kerr K, Muller S, Iles N, Smith S, Murugaesu N, Mitter R, Salm M, Stuart A, Matthews N, Adams H, Ahmad T, Attanoos R, Bennett J, Birkbak NJ, Booton R, Brady G, Buchan K, Capitano A, Chetty M, Cobbold M, Crosbie P, Davies H, Denison A, Djearman M, Goldman J, Haswell T, Joseph L, Kornaszewska M, Krebs M, Langman G, MacKenzie M, Millar J, Morgan B, Naidu B, Nonaka D, Peggs K, Pritchard C, Remmen H, Rowan A, Shah R, Smith E, Summers Y, Taylor M, Veeriah S, Waller D, Wilcox B, Wilcox M, Woolhouse I, McGranahan N, Swanton C | display-authors = 6 | title = Tracking genomic cancer evolution for precision medicine: the lung TRACERx study | journal = PLOS Biology | volume = 12 | issue = 7 | pages = e1001906 | date = July 2014 | pmid = 25003521 | pmc = 4086714 | doi = 10.1371/journal.pbio.1001906 }}</ref> The project will look at tumor samples from 850 people with NSCLC at various stages including diagnosis, after first treatment, post-treatment, and relapse.<ref>[http://scienceblog.cancerresearchuk.org/2013/07/18/a-new-era-in-lung-cancer-research-the-tracerx-study/ TRACERx project, Cancer Research UK science blog] {{webarchive|url=https://web.archive.org/web/20141129023515/http://scienceblog.cancerresearchuk.org/2013/07/18/a-new-era-in-lung-cancer-research-the-tracerx-study/ |date=29 November 2014 }}</ref> By studying samples at different points of tumor development, the researchers hope to identify the changes that drive tumor growth and resistance to treatment. The results of this project will help scientists and doctors gain a better understanding of NSCLC and potentially lead to the development of new treatments for the disease.<ref name="Tracer" />

For lung cancer cases that develop resistance to epidermal growth factor receptor (EGFR) and [[anaplastic lymphoma kinase]] (ALK) [[Kinase tyrosine-based inhibitory motif|tyrosine kinase inhibitors]], new drugs are in development. EGFR inhibitors include [[erlotinib]], [[gefitinib]], [[afatinib]] and [[icotinib]] (the last one is only available in China).<ref name=":3">{{cite journal|vauthors=Greenhalgh J, Boland A, Bates V, Vecchio F, Dundar Y, Chaplin M, Green JA|date=18 March 2021|title=First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer|journal=The Cochrane Database of Systematic Reviews|volume=2021|issue=3|pages=CD010383|doi=10.1002/14651858.CD010383.pub3|pmid=33734432|pmc=8092455}}</ref> An alternative signaling pathway, [[c-Met]], can be inhibited by [[tivantinib]] and [[onartuzumab]]. New ALK inhibitors include [[crizotinib]] and [[ceritinib]].<ref>{{cite journal | vauthors = Spaans JN, Goss GD | title = Trials to Overcome Drug Resistance to EGFR and ALK Targeted Therapies – Past, Present, and Future | journal = Frontiers in Oncology | volume = 4 | issue = 233 | pages = 233 | date = August 2014 | pmid = 25221748 | pmc = 4145253 | doi = 10.3389/fonc.2014.00233 | doi-access = free }}</ref> If the [[MAPK/ERK pathway]] is involved, the [[BRAF (gene)|BRAF]] kinase inhibitor [[dabrafenib]] and the MAPK/MEK inhibitor [[trametinib]] may be beneficial.<ref>{{cite journal | vauthors = Weart TC, Miller KD, Simone CB | title = Spotlight on dabrafenib/trametinib in the treatment of non-small-cell lung cancer: place in therapy | journal = Cancer Management and Research | volume = 10 | pages = 647–52 | date = April 2018 | pmid = 29662327 | pmc = 5892608 | doi = 10.2147/CMAR.S142269 }}</ref>

The [[PI3K/AKT/mTOR pathway|PI3K pathway]] has been investigated as a target for lung cancer therapy. The most promising strategies for targeting this pathway seem to be selective inhibition of one or more members of the [[Class I PI 3-kinases|class I PI3Ks]], and co-targeted inhibition of this pathway with others such as MEK.<ref>{{cite journal | vauthors = Heavey S, O'Byrne KJ, Gately K | title = Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC | journal = Cancer Treatment Reviews | volume = 40 | issue = 3 | pages = 445–56 | date = April 2014 | pmid = 24055012 | doi = 10.1016/j.ctrv.2013.08.006 }}</ref>

Lung [[cancer stem cell]]s are often resistant to conventional chemotherapy and radiotherapy. This may lead to relapse after treatment. New approaches target [[protein]] or [[glycoprotein]] markers that are specific to the stem cells. Such markers include [[CD133]], [[CD90]], [[ALDH1A1]], [[CD44]], and [[ABCG2]]. [[Cell signaling|Signaling pathways]] such as [[Hedgehog signaling pathway|Hedgehog]], [[Wnt signaling pathway|Wnt]], and [[Notch signaling pathway|Notch]] are often implicated in the self-renewal of stem cell lines. Thus, treatments targeting these pathways may help to prevent relapse.<ref>{{cite journal | vauthors = Prabavathy D, Swarnalatha Y, Ramadoss N | title = Lung cancer stem cells-origin, characteristics and therapy | journal = Stem Cell Investigation | volume = 5 | issue = 6 | pages = 6 | date = March 2018 | pmid = 29682513 | pmc = 5897668 | doi = 10.21037/sci.2018.02.01 }}</ref>

== See also ==

* [[Cancer recurrence#Lung cancer|Recurrence of lung cancer]]

== References ==
{{Clear}}
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<ref name="Merck">{{cite web | title=Lung Carcinoma: Tumors of the Lungs | publisher=Merck Manual Professional Edition, Online edition |url=http://www.merck.com/mmpe/sec05/ch062/ch062b.html#sec05-ch062-ch062b-1405 | access-date=21 July 2021 |date=July 2020 }}</ref>

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}}

===Cited===
*{{cite journal |vauthors=Alexander M, Kim SY, Cheng H |title=Update 2020: Management of Non-Small Cell Lung Cancer |journal=Lung |volume=198 |issue=6 |pages=897–907 |date=December 2020 |pmid=33175991 |pmc=7656891 |doi=10.1007/s00408-020-00407-5 }}
*{{cite journal |vauthors=Aragon KN |title=Palliative Care in Lung Cancer |journal=Clin Chest Med |volume=41 |issue=2 |pages=281–293 |date=June 2020 |pmid=32402363 |doi=10.1016/j.ccm.2020.02.005 }}
*{{cite journal |vauthors=Bade BC, Dela Cruz CS |title=Lung Cancer 2020: Epidemiology, Etiology, and Prevention |journal=Clin Chest Med |volume=41 |issue=1 |pages=1–24 |date=March 2020 |pmid=32008623 |doi=10.1016/j.ccm.2019.10.001|s2cid=211015015 }}
*{{cite book|vauthors=Christiani DC, Amos CI |chapter=Lung Cancer: Epidemiology |title=Murray & Nadel's Textbook of Respiratory Medicine |edition=7 |date=2022 |publisher=Elsevier |pages=1018–1028}}
*{{cite book|vauthors=Horn L, Iams WT |chapter=78: Neoplasms of the Lung |title=[[Harrison's Principles of Internal Medicine]] |edition=21 |publisher=McGraw Hill |date=2022}}
*{{cite journal |vauthors=Jones KD |title=Whence lepidic?: the history of a Canadian neologism |journal=Arch Pathol Lab Med |volume=137 |issue=12 |pages=1822–4 |date=December 2013 |pmid=23937575 |doi=10.5858/arpa.2013-0144-HP }}
*{{cite journal |vauthors=Nasim F, Sabath BF, Eapen GA |title=Lung Cancer |journal=Med Clin North Am |volume=103 |issue=3 |pages=463–473 |date=May 2019 |pmid=30955514 |doi=10.1016/j.mcna.2018.12.006|s2cid=102349766 }}
*{{cite book|vauthors=Pastis NJ, Gonzalez AV, Silvestri GA |chapter=Lung Cancer: Diagnosis and Staging |title=Murray & Nadel's Textbook of Respiratory Medicine |edition=7 |date=2022 |publisher=Elsevier |pages=1039–1051}}
*{{cite book|vauthors=Rivera P, Mody GN, Weiner AA |chapter=Lung Cancer: Treatment |title=Murray & Nadel's Textbook of Respiratory Medicine |edition=7 |date=2022 |publisher=Elsevier |pages=1052–1065}}
*{{cite journal |vauthors=Rudin CM, Brambilla E, Faivre-Finn C, Sage J |title=Small-cell lung cancer |journal=Nat Rev Dis Primers |volume=7 |issue=1 |pages=3 |date=January 2021 |pmid=33446664 |pmc=8177722 |doi=10.1038/s41572-020-00235-0 }}
*{{cite journal |vauthors=Schabath MB, Cote ML |title=Cancer Progress and Priorities: Lung Cancer |journal=Cancer Epidemiol Biomarkers Prev |volume=28 |issue=10 |pages=1563–1579 |date=October 2019 |pmid=31575553 |pmc=6777859 |doi=10.1158/1055-9965.EPI-19-0221 }}
*{{cite journal |vauthors=Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS |title=Lung cancer |journal=Lancet |volume=398 |issue=10299 |pages=535–554 |date=August 2021 |pmid=34273294 |doi=10.1016/S0140-6736(21)00312-3|s2cid=236034814 }}

== External links ==
{{commons category|Cancers of bronchus and lung}}
{{wikiquote}}

{{Medical resources
|DiseasesDB = 7616
|ICD11 = {{ICD11|2C24}}–{{ICD11|2C25}}
|ICD10 = {{ICD10|C|33||c|30}}–{{ICD10|C|34||c|30}}
|ICD9 = {{ICD9|162}}
|ICDO =
|OMIM =211980
|MedlinePlus = 007194
|eMedicineSubj = med
|eMedicineTopic = 1333
|eMedicine_mult = {{eMedicine2|med|1336}} {{eMedicine2|emerg|335}} {{eMedicine2|radio|807}} {{eMedicine2|radio|405}} {{eMedicine2|radio|406}}
|MeshID = D002283
}}
{{Respiratory tract neoplasia}}
{{Authority control}}

{{DEFAULTSORT:Lung cancer}}
[[Category:Lung cancer| ]]
[[Category:Causes of death]]
[[Category:Types of cancer]]
[[Category:Health effects of tobacco]]