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http://www.pathophys.

org/lung-cancer/ Lung cancer
Ke Wu, Eric Wong and Sultan Chaudhry

Editors: Eric Wong and Sultan Chaudhry

Contents
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Overview Etiology Pathogenesis Classification of invasive lung cancer Pathophysiology and clinical features Treatment

Overview
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Clin Chest Med. 2011 Dec;32(4):605-44. Canadian Cancer Society: Canadian Cancer Statistics 2012 Lung cancer is the leading cause of cancer-related death in Canada and worldwide (about 27% of cancer deaths in Canada). Overall incidence of lung cancer is: o Higher in men than women o Declining for men since 1980s o Declining for women since mid-2000s (reversal of increasing trend since 1980s) o Second highest cancer incidence in both sexes after prostate (males) and breast (females) cancers. Lung cancer has a poor prognosis, which means incidence closely matches mortality. The five-year relative survival rate of lung cancer is 16% in Canada. Small-cell lung carcinoma (SCLC, 15% of all lung cancer) and non-small-cell lung carcinoma (NSCLC, 85%) are the two major forms of lung cancer. Non-small-cell lung cancer is further classified into squamous-cell carcinoma, adenocarcinoma, and largecell carcinoma. Smoking is the single most important risk factor for lung cancer, which can cause all types of lung cancer but is more strongly linked with SCLC and squamous-cell carcinoma.

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Etiology

Surg Oncol Clin N Am. 2011 Oct;20(4):605-18.

J Natl Cancer Inst. increasing the addictiveness of cigarettes. which are located on both sympathetic and parasympathetic postganglionic neurons. smoking stimulates both sympathetic (increased heart rate. intensity and depth of smoke inhalation. and cause angiogenesis in lung tumours. mediating reward and addiction o Carcinogen: nicotine does not initiate carcinogenesis. Never smokers   Defined as people who smoked fewer than 100 cigarettes in their lifetime. The endogenous ligand for this receptor is acetylcholine (nicotine is not naturally found in humans). releasing a whole range of hormones and neurotransmitters into the circulation.96(2):99-106. Distribution of carcinogens: Cigar and pipe tobacco smoking produces relatively large particles that only reach the upper airways.  Clin Chest Med. Accounts for 25% of lung cancers worldwide and is seen as a distinct lung cancer type. but is less strongly associated compared to active smoking. Risk for lung cancer increases with the duration. which produces fine particles that reaches the distal airways.32(4):605-44. several of which are potent animal carcinogens. Cigarette smoking       Cigarette smoking is the leading cause of lung cancer. but it does promote initiated cells by nicotinic cholinergic receptor signalling in the lungs. Biochem Pharmacol. o Sympathetic/parasympathetic activation: nicotine binds to and activates nicotinic cholinergic receptors. accounting for about 85% of lung cancers. Smoking cessation: smokers at all ages can benefit from the cessation of smoking.g. G to T transversion within the p53 gene is a molecular signature of lung tumours caused by tobacco mutagens.82(8):1015-21. 2004 Jan 21. unlike cigarette smoking. o Polycyclic aromatic hydrocarbons (PAH) such as benzo[α]pyrene produce mutations in the p53 gene. 2011 Dec. Second-hand (passive) smoking also causes lung cancer. o Addiction: nicotine causes dopamine release from the nucleus accumbens. menthol) to cigarettes allows deeper inhalation and a more rapid rise in serum nicotine levels. o N-nitroso compounds are a major group of chemicals found in tobacco smoke. cancer risk is lower with cigar and pipe smoking. Therefore. Cigarettes contain multiple carcinogens (more than 60) that have been shown to induce cancers in laboratory settings. The addition of anti-irritants (e. however. blood pressure) and parasympathetic (intestinal motility. . proliferate cells. Thus. the risk still remains elevated compared to never smokers. Nicotine has been shown to inhibit apoptosis. Nicotine: causes addiction to cigarette smoking and is also a promoter for carcinogenesis. relaxation) systems. 2011 Oct 15.

 Associated with: female cases. have been posed as a significant risk factor for lung cancer. beginning with carcinogen-induced initiation events. Environmental exposure     A number of environmental risk factors have been identified. Currently there are 3 types of recognized precursor lesions: o Squamous dysplasia and carcinoma: precursor lesion for squamous-cell carcinoma. family history. Precursor lesions    Precursor lesions are of increasing interest due to implication in lung cancer screening. Air pollution has also been linked to increased risk of lung cancer. Candidate gene studies have identified several enzymes in the cytochrome P-450 system as risk factors for lung cancer. tar. such that risk is multiplicative instead of additive. which codes for aryl hydrocarbon hydroxylase.g. Precursor lesion for SCLC is unknown. 2011 Dec. asbestos). 2004 Jul. followed by a long period of promotion and progression in a multistep . Pathogenesis    N Engl J Med. a form of adenocarcinoma. Am J Respir Cell Mol Biol.87(1):68-74. adenocarcinoma type. chromium. most of which relates to occupational exposures such as asbestos. Clin Chest Med. 2005 Sep. and a number of metals such as arsenic. EGFR mutations. Genetics   There is an increased risk of lung cancer among first-degree relatives. o Adenomatous hyperplasia: precursor lesion for bronchioalveolar carcinoma. and better prognosis (23% 5-year survival vs 16% for smokers). The pathogenesis of lung cancer is like other cancers. soot. a radioactive gas that percolates up soil and becomes concentrated inside buildings.33(3):216-23. Certain alleles of CYP1A1 are thought to increase the risk of lung cancer through increased metabolic activation of procarcinogens derived from cigarette smoke. East Asian populations. 2008 Sep 25. and nickel.359(13):1367-80. indicating a genetic susceptibility. Health Phys. Smoking potentiates the effect of a number of occupational lung carcinogens (e. Indoor radon-222. One such gene is CYP1A1.32(4):703-40. o Idiopathic pulmonary neuroendocrine cell hyperplasia: precursor for pulmonary carcinoids.

CD44. requiring 20-25 years for cancer formation. providing a large population of initiated cells and increasing the chance of transformation. The time delay between smoking onset and cancer onset is typically long.g. 2002 Mar. and RB.g. phenol. 2011 Jul. Continued smoke exposure allows additional mutations to accumulate due to promotion by chronic irritation and promoters in cigarette smoke (e. nicotine.23(1):65-81. KRAS. viii. Clin Chest Med. while NSCLC often has mutations in EGFR. and (iii) accumulate different genetic mutations. The initiation event happens early on. but existing initiated cells may progress if another carcinogen carries on the process. SCLC often harbours mutations in MYC. (ii) undergo different pathogenesis processes. Smoking thus causes a “field effect” on the lung epithelium. The pathological types are divided into SCLC and NSCLC. See Cancer genetics and Cancer biology chapters for a description of how mutations like these can cause cancer. BCL2.46(3):178-86.process. 3p deletion. Lung cancer diagnosis is established by biopsy of tumours found on imaging (chest X-ray or CT). p53 mutations). NSCLC is further divided into the types below: Lung cancer Location in the lung type Adenocarcinoma Peripheral (38%) Features      Most common type of lung cancer in nonsmokers and morecommon in women Arises from small airway epithelial and type II alveolar cells Should test for EGFR mutation for possible targeted therapy Sometimes appear at site of scarring Tend to form glands and secrete mucin Strongly associated with cigarette smoking Arises from large (proximal) airway epithelial cells Tend to create obstruction and cause distal atelectasis Intrathoracic spread rather than distant Squamous cell ⅔ central carcinoma (20%) ⅓ peripheral     . Cigarette smoke both initiates and promotes carcinogenesis. SCLC and NSCLC are treated differently because they (i) originate from different cells. c-KIT. and p16. Cancer risk decreases after smoking cessation. as evidenced by similar genetic mutations between current and former smokers (e. formaldehyde). Classification of invasive lung cancer   Semin Roentgenol. These are all either tumour suppressor genes or oncogenes. p53.

and hemoptysis. bone). The symptoms produced by the primary tumour depend on its location (i. wheezing. Symptoms Primary lung lesion symptoms Cough (50-70%) Mechanism and pathophysiology    Presence of a mass irritates the cough receptors in the airway More common in squamous cell carcinoma andSCLC (more commonly found in the central airways) Obstruction from central airway could also lead to post-obstructive pneumonia and distal atelectasis Cancer induced lipolysis and proteolysis leads to loss of adipose and skeletal muscle. atelectasis.14(5):338-51. postobstructive pneumonia. in addition to causing cough and dyspnea.e. best prognosis Small-cell lung carcinoma (SCLC) (14%) Central (endobronchial)    Neuroendocrine cells are located at bifurcation of small airways   Strongest smoking association Arises from pulmonary neuroendocrine cells. Weight loss (46%)  . 2007 Sep.56(8):2107-11. dyspnea. which are responsible for making neurotransmitters. and vasoactive substances Causes paraneoplastic syndrome: commonly secrete ADH (SIADH) or ACTH (ectopic Cushing syndrome) Rapid growth and early distant metastasis (brain. therefore.132(3 Suppl):149S-160S. 2002 Oct. liver. Chest. growth factors. can lead to pleural effusion and severe pain as a result of infiltration of parietal pleura and the chest wall.. Clin Oncol (R Coll Radiol). leading to the worst prognosis Behave similar to adenocarcinomas but the lesions formed tend to be somewhat larger Large cell carcinoma (35%) Peripheral  Pathophysiology and clinical features    Cancer. peripheral tumours. central vs peripheral). Central tumours generally produce symptoms of cough.metastasis. Protein synthesis is also reduced via a number of mechanisms. whereas. 1985 Oct 15.

13(4):220-32. numbness of ipsilateral hand . 1997 Apr. or atelectasis Malignant pleural effusion occurs when malignant cells are present in pleural fluid Enlargement of the subcarinal lymph nodes compressing on the middle third of the esophagus Tumour originates in the apical portion of the lung Occurs in 5% of non-small cell lung cancer Invasion of brachial plexus causes pain and muscle wasting of arm and hand Invasion of superior cervical sympathetic ganglion leads to Horner syndrome: Pericardial effusion   Pleural effusion    Chest pain Dyspnea  Dysphagia  Pancoast tumour (superior sulcus tumour)       Shoulder or arm pain Weakness. 2010 Mar.Symptoms Mechanism and pathophysiology Curr Opin Gastroenterol. See also Mediastinal involvement Tumour involving pleural surface causing pleuritic chest pain See also Mediastinal involvement Dyspnea (25%)    Chest pain (20%)   Mediastinal involvement Superior vena cava syndrome     Obstruction of superior vena cava by the tumour More common in SCLC (central tumour) 2-4% of lung cancer patients develop it at some point See Oncologic emergencies chapter Tumours can at times infiltrate into the pericardium or press on the heart causing pericardial effusion See Oncologic emergencies chapter Benign pleural effusion may be due to lymphatic obstruction.26(2):146-51. predisposing them to easy rupture and causing hemoptysis Extrinsic or intraluminal airway obstruction Activation of mechanoreceptors and chemoreceptors in lungs due to cachexia or hypoxemia/acidosis J Pain Symptom Manage. post-obstructive pneumonitis. atrophy.   Hemoptysis (25-50%) Tumour in the central airway Blood vessels resulting from tumour-induced angiogenesis are leaky and tortuous.

wrists and elbows.Symptoms  Horner syndrome o Ptosis o Miosis o Anhidrosis N Engl J Med. Mechanism and pathophysiology o Loss of sympathetic control of Muller muscle that elevates the upper eyelid leads to partial ptosis o Loss of sympathetic drive of iris dilator muscle leads to miosis (excessive constriction of the pupil) o Anhidrosis (lack of sweating) caused by impingement of sweat gland fibres arising from cervical sympathetic ganglion   Phrenic nerve involvement can lead to unilateral diaphragm paralysis Recurrent pharyngeal nerve involvement can lead to voice hoarseness Paraneoplastic syndromes: symptoms in cancer patients not attributable to tumour compression or invasion Mayo Clin Proc. hypokalemia. especially the adenocarcinoma type Periosteal proliferation of the tubular bones characterized by (i) painful symmetrical arthritis of the ankles. respiratory depression. severe symptoms include altered mental status. knees. especially SCLC Ectopic secretion of ADH → retain free water in collecting ducts Euvolemic hyponatremia and concentrated urine Mild symptoms include headache and weakness. Ectopic Cushing syndrome   See Adrenal cortex chapter in Endocrinology  Ectopic secretion of adrenocorticotrophic hormone (ACTH) → adrenal cortisol secretion → weight gain. 2010 Sep. muscle weakness Most common form of ectopic secretion in lung cancer.85(9):838-54. 1997 Nov 6. and (ii) digital Syndrome of inappropriate antidiuretic hormone production (SIADH)     See Hyponatremia in Nephrology for details  Hypercalcemia    Hypertrophic osteoarthropathy and digital clubbing   . seizures. hypertension. and death Common in SCLC Increased secretion of PTHrP → acts like parathyroid hormone to increase bone resorption and renal calcium reabsorption → hypercalcemia Associated with squamous cell carcinoma See Oncologic emergencies chapter Associated with NSCLC.337(19):1370-6.

2007 Jan 24. liver and adrenal glands   Frequently asymptomatic however 33% of patient presents with symptoms relating to distal metastasis See Oncological emergencies and Metastasis chapters for details. First line of choice for NSCLC who are medically fit to undergo surgery. PDGF.4:CD006103. II. Cochrane Database Syst Rev. and III describe various sizes of primary tumour and lymph node involvement without distant metastasis. and prostaglandin E2. all forms increases rate of quitting by 5070%. II. . Cochrane Database Syst Rev. 2012 Apr 18. o Nicotine receptor partial agonist: varenicline is more effective than bupropion and NRT. Distant metastasis Metastatic sites include brain. Surgery   Surgical resection of the tumour and some normal tissue around it. Treatment Lung Cancer: the diagnosis and treatment of lung cancer (National Institute for Health and Clinical Excellence. Cochrane Database Syst Rev. 2011) Smoking cessation   Smoking increases the risk of pulmonary complications after surgery Three main interventions exist in addition to counselling and support: o Nicotine replacement therapy (NRT): can be purchased in many forms including gum and transdermal patch. o In lung cancer. Radiation therapy  Indicated for patients with stage I. o Antidepressants: bupropion and nortriptyline are as effective as NRT. 2008 Jan 23. other antidepressants such as selective serotonin reuptake inhibitors (SSRI) are not effective.(1):CD000146. stages I.  Mechanism is due to secretion of various factors including VEGF.Symptoms Mechanism and pathophysiology clubbing. Any distant metastasis is automatically stage IV.(1):CD000031. III NSCLC. bone. o See Introduction to neoplasia for definition of TMN staging.

but relapse often occurs due to accumulation of other mutations. Given the poor prognosis. unnecessary treatment. o Epidermal growth factor receptor (EGFR): epidermal growth factor (EGF) stimulates cell proliferation by binding the EGFR and causing tyrosine kinase activation of effectors. First line therapy for NSCLC with EGFR mutations involves targeted therapies. NSCLC often harbour EGFR mutations that make the receptor more active.363(8):733-42. Two classes of drugs target this particular aberrant protein: EGFR tyrosine kinase inhibitors (erlotinib and gefitinib) and monoclonal antibody targeted at EGFR (cetuximab). the goals of lung cancer therapy may be switched from curative to palliative. Palliative care aims to improve the quality of life and reduce suffering for patients rather than to prolong life. Studies have shown that early palliative care actually prolongs life in lung cancer patients (by 2. 2010 Aug 19. and impart greater patient and family satisfaction. signalling downstream effectors to increase cell proliferation.7 months in a study with metastatic NSCLC patients). Also indicated for patients with more advanced stage of NSCLC (to improve survival. Contents       Overview Etiology Pathogenesis Classification of invasive lung cancer Pathophysiology and clinical features Treatment . which are often disseminated upon clinical presentation. healthcare costs. Chemotherapy    First line of treatment for SCLC. It also reduces patient suffering. N Engl J Med.o Also used in combination with surgery for NSCLC and with chemotherapy for SCLC. Palliative care   Advanced disease may be present at the diagnosis. Both classes of drugs are usually effective initially in tumours with EGFR mutations. disease control or for palliative care).