EPIDEMIOLOGY AND ETIOPATHOGENESIS OF LUNG CANCER Dr. Sunil Arora J unior Resident Deptt. of Pulmonary Medicine Govt. Medical College, Patiala. 1 1 1.

EPIDEMIOLOGY AND ETIOPATHOGENESIS

OF LUNG CANCER

Dr. Sunil Arora Junior Resident Deptt. of Pulmonary Medicine Govt. Medical College, Patiala.

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INTRODUCTION At the start of 20th centaury, lung cancer was considered a rare disease, but now it is the most common malignant neoplasm in the world and accounts for more cancer deaths than any other cancer. Tobacco smoking remains the most important risk factor and etiological agent, but there are other causes of lung cancer also,some of which are acting in concert with smoking to increase risk synergistically.

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EPIDEMIOLOGY

• It accounts for 12.7% of all new cancer cases & 18.2% of all cancer related deaths throughout the world. In India, it is the commonest and most lethal cancer among males accounting for 10.9% of all cancer cases& 13% of cancer related mortality.

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Squamous cell carcinoma • Papillary • Clear cell • Small cell • Basaloid Small cell carcinoma • Combined small cell carcinomaAdenocarcinoma • Adenocarcinoma, mixed subtype• Acinar adenocarcinoma• Papillary adenocarcinoma • Bronchioloalveolar carcinoma• Nonmucinous• Mucinous • Mixed nonmucinous and

mucinous or indeterminate • Solid adenocarcinoma with mucin

production • Fetal adenocarcinoma• Mucinous (“colloid”) carcinoma • Mucinous cystadenocarcinoma• Signet ring adenocarcinoma• Clear cell adenocarcinoma

Large cell carcinoma • Large cell neuroendocrine carcinoma • Combined large cell neuroendocrine

carcinoma • Basaloid carcinoma • Lymphoepithelioma-like carcinoma• Clear cell carcinoma • Large cell carcinoma with rhabdoid

phenotype Adenosquamous carcinoma Sarcomatoid carcinoma • Pleomorphic carcinoma Spindle • cell carcinoma • Giant cell carcinoma• Carcinosarcoma • Pulmonary blastoma Carcinoid tumour • Typical carcinoid• Atypical carcinoidSalivary gland tumours• Mucoepidermoid carcinoma • Adenoid cystic carcinoma • Epithelial-myoepithelial carcinoma

CLASSIFICATION

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For most pathologists, five major subgroups of lung cancer still predominate and account for 95% of cases :--

1. Squamous cell Ca

2. Adeno Ca

3. Small cell Ca

4. Large cell Ca

5.Carcinoid tumors

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• In western and most of the Asian countries adenocarcinoma has surpassed squamous cell type. Most of the older and some recent studies in India have described squamous cell type as the commonest type.But a recent study at AIIMS showed adenocarcinoma as the most common variety.

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• Incidence rates of squamous cell Ca declined by about 30% or more among males in North America and some European countries,while decline is less in small cell type.

• Among females, incidence rates of both squamous and small cell type showed increase in most regions and adenocarcinoma increase in both sexes. Worldwide, adenocarcinoma is the commonest type in females.

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LINK BETWEEN HISTOLOGY AND SMOKING

• Histological shift towards ADC type in the developed countries has been linked to change in smoking behavior i.e. use of filtered cigrettes,lower content of tar and nicotine,which resulted in tendency for their smoke to be inhaled more deeply leading to higher conc. of carcinogen in peripheral area where ADC tends to form.

• Higher levels of nitrates in the tobacco blends used in cigarette manufacturing have also been linked to the development of ADC.

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• One of the likely reason for lack of change in epidemiology of lung ca. in India is the fact that MC smoking product is bidi instead of cigarette.

• The ratio of bidi to cigarette smoking is 2.6 :1 overall and 6.5 :1 in rural areas.

• Quit rates for smoking continue to be less than 10% in India.

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• An imp.difference in the pathogenesis of various histological types in relation to their site and cell of origin is that conducting bronchial airways are the site of origin of almost all squamous,small cell and small proportion of ADC.Basal bronchial cells are believed to be the cell of origin.

• Majority of ADC have their origin from peripheral compartment primarily the terminal respiratory unit,respiratory bronchioles and alveoli.Here bronchioloalveoler cell is thought to be the cell of origin.

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RISK FACTORS Tobacco smoking (Active) Environmental tobacco smoke (ETS) exposure Pulmonary diseases COPD,IPF, Systemic sclerosis type interstitial lung disease,Pneumoconiosis. Systemic Diseases HIV Infection Air Pollutions (indoor and outdoor) Domestic cooking fuels Petroleum product combustion Environmental exposures Radon,Arsenic,Nickel,Chromium,Asbestosis Dietary Factors Alcohol consumption Intake of vitamines,fruits and vegetables Hormone Therapy Genetic Factors Familial Specific gene abnormalities 11

TOBACCO SMOKING• It is the leading cause, approximately in 80-

90% of lung Carcinoma.• Compared with never smokers,smokers have

20 fold increase risk.• Worldwide 5.4 million death occurs every

year from smoking related lung ca.• 85% of NSCLC & 98% of SCLC arise in

smokers.• Several carcinogens(>80) have been

identified in tobacco smoke including PAH,nicotine derived nitrosoaminoketone. These carcinogens are responsible for DNA mutations. 12

PACK YEARS• It is calculated by multiplying the number of

packs of cigarettes smoked per day by the number of years the person has smoked. For example, 1 pack year is equal to smoking 1 pack per day for 1 year, or 2 packs per day for half a year, and so on.

• There is a strong dose–response relation between the number of pack years smoked and the risk of lung cancer. Pack year smoking histories are important for quantification of tobacco exposure

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The quantitative risk among smokers increases more with duration of smoking than the amount.e.g.Tripling the no.of cigarettes smoked estimated to triple the risk,whearas tripling the duration increases to about 100 fold.

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SMOKING CESSATION

• Smoker of any age can benefit from quitting smoking.

• However even for period of abstinence of over 40 yrs,the risk of lung ca. remains elevated compared to never smokers.

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THE CHANGING CIGARETTE• Use of filtered cigarette, with ventilation holes

added to the filter esp. in western countries.• The early studies showed somewhat decrease

risk,but now newer studies have shown that it has not shown any benefits.

• E-cigarette-The electronic cigarette is an emerging phenomenon that is becoming increasingly popular with smokers worldwide. Users report buying them to help quit smoking, to reduce cigarette consumption, to relieve tobacco withdrawal symptoms due to workplace smoking restrictions and to continue to have a 'smoking' experience but with reduced health risks.

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PASSIVE SMOKING• It increases risk for lung carcinoma but

weakly associated as compared to active smoking.(3400 lung ca. deaths have been recorded in US)

• Marriage to a smoker is associated with abt 20% increase risk and exposure in the workplace is associated with between 24% to two fold increase.

• A strong association have been observed between childhood exposure and lung ca.

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LUNG CARCINOMA IN NEVER SMOKERS

• An estimated 10-15% of lung cancer related mortality is related to factors other than active smoking.

• More in peripheral compartment in contrast to smokers (central compartment).

• Environmental tobacco smoke (ETS) exposure, outdoor& indoor air pollution can be responsible but clear etiological agents have not been identified.

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AIR POLLUTIONIndoor Air Pollution

• Due to domestic cooking fuels esp.among women in developing countries

• Among non-smokers,the risk of developing lung ca. was highest from biomass fuel exposure.

• It has been demonstrated that wood smoke exposure can produce similar molecular effects as p53 tumor suppresser agent as tobacco,thus imp.risk factor in never smokers.

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Atmosphere Air Pollution

• An adult inhales abt 10000 L of air/day.So even carcinogen at low conc. are of concerned risk factors for lung Ca.

• Carcinogens generated by combustion of fossil fuels include PAH & metals such as arsenic,nickel,chromium.

• Estimated that 1-2% of lung Ca. related to air pollution.

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Minerals and Metals

• Arsenic has been identified as lung carcinogen in human.A significant dose-response trend was observed between level of arsenic in drinking water and lung ca.

• A synergistic effect of smoking and arsenic is also seen.

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Asbestosis• Well established occupational carcinogen.• In UK--seen 10 fold rise in lung ca. incidence

after 30-35 yrs of the initial exposure to asbestos before regulations were implemented to lower asbestos dust in factories.

• There are 2 hypothesis 1)Lung ca. as a consequence of asbestosis. 2)Lung ca. risk is dependent on cumulative

dose of asbestos,regardless of presence of asbestosis

Asbestosis and smoking are both independent cause for lung ca.,but in combination they act synergistically.

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Radiation High LET radiation(Neutrons and Radon)• Radon-It is an inert gas produced naturally from radium in

the decay series of uranium.It emits alpha-particles and cause damage to DNA of cells of respiratory epithelium.

• Seen among miners working underground.• An estimated 15000-20000 lung cancer deaths in US per

year by radon.• Synergistic with smoking. Low LET radiation –(includes X-rays& gamma rays)-

Epidemiological data is from 3 principal populations: the atomic bomb survivors in Japan, patients who receive multiple radiation treatment and occupational groups in professions exposed to radiation.

• More biological damage is produced by High-LET than low-LET radiation.

• From NASA, available data suggest that lung cancer is the largest potential cancer risk from space travel for both men and women. In space, the radiation risk is from high energy and charge (HZE) nuclei (such as Fe) and high-energy protons from solar flares and not from gamma radiation.

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Socioeconomic Profile and Diet• Overall increase risk among low SE people• Studies have shown that individuals with high dietary

intake of fruits or vegetables have low risk of lung ca. e.g.tomatoes and cruciferous vegetables have shown to decrease risk.

• Fruits and vegetables are the major source of antioxidant micronutrients which may protect oxidative damage of DNA e.g. beta-carotene,folate,selenium.

• Non alcoholic and heavy alcoholics are at greater risk than very low drinkers.

• Persons with low BMI have have increased risk as per some studies.

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Hormone Use

• Studies in women could not find any strong association with lung cancer but have shown that risk increases after the age of 55.

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HIV• Lung cancer risk is substantially elevated in

HIV-infected individuals as compared to general population.esp.NSCLC

• HIV-positive individuals are diagnosed with lung cancer at a median age of 45 yrs or younger(younger than normal).

• Explanation to it could be:- 1)HIV acting as a viral carcinogen 2)Defective immune system 3)Recurrent opportunistic infection and parenchymal inflammation leading to inflammatory foci and scar carcinomas

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Lung Diseases• Idiopathic Pulmonary Fibrosis – In a

retrospective longitudinal cohort analysis 20.4% patients developed lung cancer.The cumulative incidence rates were 3.3%,15.4%,54.7% at 1,5 and 10 years respectively.

• COPD• Old scars of Pulmonary TB• Systemic Sclerosis• Pneumoconiosis

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Genetic Factors• Genetic predisposition is seen in both

smokers as well as non smokers.Studies found an association between risk and a history of lung cancer in first degree relatives.

• More important in younger ages(40-59 yrs).

• It has been suggested that genetic factors are the independent risk factors for lung cancer.

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Molecular Mechanisms of Pathogenesis of Lung Cancer

Abnormalities in growth-stimulatory signaling pathways• EGFR deregulation• Mutations in other EGFR signaling pathway genes- ---KRAS• Anaplastic lymphoma kinase (ALK) fusion protiens• Thyroid transcription factor 1 (TTF-1)• Myc family Abnormalities in tumor suppressor gene pathways• p53 pathway• p16INK4/cyclin D1/Rb pathway• Serine/threonine kinase 11 gene Evasion of apoptosis• Altered regulation of mitochondrial apoptosis(Bax/Bcl2 imbalance)• Deregulation of death receptor (Fas-FasL) pathway• Inappropriate telomerase activity. Epigenetic changes• DNA methylation and hyper methylation• Epigenetic modifications(change in acetylation and/or methylation status) of

histones• Somatic mitochondrial DNA (mtDNA) mutations• MicroRNAs-dysregulation and/or specific expression patterns

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EGFR Expression• On activation of ligand,these receptor signal

through the RAS-RAF-mitogen activated protein kinase and phosphatidylinosetol 3-kinase pathway and play a key role in regulating cell proliferation and survival.

• Mutation or hyperexpressiom of these responsible in lung cancer for their oncogenic activation,favouring proliferation, differentiation and angiogenesis.

• MC EGFR mutation observed are exon 19 deletion and exon 21 L858R point mutation

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KRAS Mutations

• The RAS genes encode a family of membrane bound 21-kd GTP binding proteins and are involved in the regulation of cell growth,differentiation and apoptosis.

• Occurs in 20-30% of NSCLC.• These mutation lead to impaired GTPase

activity,which is located downstream of EGFR and consequently constitutive activation of RAS signaling.

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Comparison of EGFR and KRAS Genes Mutation

• EGFR mutations are more common in never smokers in contrast to KRAS mutations(Seen in Smokers).

• These mutations determine sensitivity to drugs like gefitinib and erlotinib(used in the treatment of NSCLC) that target EGFR signaling pathways.EGFR receptor blockade leads to inhibitory effects on tumor cell survival and proliferation.

• In presence of KRAS mutations,KRAS mediated effects are permanently turned on and downstream signals occur despite EGFR blockade and allowing tumor cell to survive and proliferate,so there is lack of responsiveness to anti-EGFR drugs

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Fragile Histidine Triade Gene

• FHIT gene plays an important role in the pathogenesis of lung cancer.

• Alterations in FHIT like loss of heterozygosity and complete/partial gene methylation have been observed.

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Angiogenesis and Role of Vascular Endothelial Growth Factor

• Angiogenesis is the regulated and determined by balance between pro-angiogenic and anti-angiogenic factors released by tumor cells and adjacent host cells.

• However,neovascularisation is charecterised by leaky capillaries,irregular and disorganized endothelial cells and abnormal basement membrane.

• VEGF family(includes four types A,B,C,D) are predominantly pro-angiogenic.

• Bevacizumab (a humanized monoclonal antibody directed against VEGF) has been shown to increase overall survival of patients in NSCLC.

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Evasion of Apoptosis• Bcl-2(anti-apoptotic) and Bax(pro-apoptotic) are the

key regulators of mitochondrial apoptosis.

• Bcl-2 overexpression has been observed in SCLC and a positive association of p53(tumor suppressor gene) with Bax expression has been demonstrated in sq.cell carcinoma lung.

• Another mechanisam is via death receptor pathway in which death receptor(Fas) activates a signaling pathway on binding to its ligand (FasL). Down-regulation is seen in majority of NSCLC.

• Telomerase gene over-expression is also observed in lung cancer.sputum telomerase activity has been shown to have sensitivity of 67.6% and specificity of 90%. 35

• Another finding in the last decade is new mode of gene regulation in the form of microRNAs, which are very short( appr.19-22 nucleotides) and single standard.

• Involved in the process of gene regulation by either causing induction of mRNA degradation or inhibition of translation.

• MicroRNAs can regulate several genes simultaneously and cellular processes like apoptosis,development,proliferation and differentiation.

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