ETIOPATHOGENESIS OF LUNG CARCINOMA

ETIOPATHOGENESIS OF LUNG CARCINOMA

• Most common cause of cancer mortality worldwide

• Age : 40-70 yrs with peak incidence in 50s and 60s

• 2% of cases appear before the age of 40 years

• Sex: Males>Females

ETIOLOGIC FACTORS

• Tobacco smoking

  • 87 % of lung cancers occur in active smokers

  • Linear correlation between – Amount of daily smoking and duration of the smoking habit

  • Average smokers – 10 fold­ risk of developing malignancy

  • Heavy smokers (2 packs/ day)– 60 fold ­ risk of developing cancer

  • Most common carcinomas associated are  Squamous & Small cell Ca >98%

  • Cessation of smoking decreases the risk of cancer but never returns to base line

  • Passive smoking increases the risk for lung cancer – twice that of non- cancer

  • Women have higher susceptibility to tobacco carcinogens than men

  • Smoking by cigars and pipes also increases the risk but less than that of cigarette smoking

  • Smokeless tobacco is not safe substitute for cigarette smoking, as they spare lungs but cause oral cancers and lead to nicotine addiction

  • More than 1200 substances are present in cigarette smoke, many of which are potential carcinogens

    • Initiators : Polycyclic aromatic hydrocarbons (Benzopyrene)

    • Promotors : Phenol derivatives, Radio active elements (Carbon-14, pot.40), Arsenic, nickel, molds etc.

• Industrial hazards

  • Industrial exposures such as asbestos, arsenic, chromium, uranium, nickle, vinyl chloride and mustard gas increases risk of lung cancer

  • High-dose ionizing radiation is carcinogenic

  • Uranium coupled with smoking – 10 increased risk of developing carcinomas

  • Asbestos coupled with smoking – 50 times increased risk of developing malignancy

  • Asbestos workers with out smoking – 5 folds increased risk

• Air pollution

  • Adds to risk who smoke or non smokers exposed to second hand smoke

  • Chronic exposure to air particulates in smog causes lung irritation, chronic inflammation and repair which increases risk for cancers

  • Radon-a ubiquitous radioactive gas  attach to environmental aerosols and enters lung by inhalation & Bronchial deposition leads to risk of developing malignancy

• Dietary factors:

  • Vitamin-A deficiency if associated with smoking ­ increases risk of developing carcinomas

• Chronic scarring :

  • Adeno Carcinoma occurs in areas of chronic scarring

  •   Eg: Old TB, Chronic interstitial fibrosis, Asbestosis, old infarcts, Scleroderma

• All the smokers do not develop lung cancer due to modified mutagenic effect of carcinogens in smoke by genetic variants (11% of heavy smokers develop lung cancers)

• For example – many chemical carcinogens are converted to active carcinogens via activation through highly polymorphic p-450 monooxygenase enzyme system.

• Specific p-450 polymorphisms have an increased capacity to activate procarcinogens in cigarette smoke, and smokers with this genetic variant have increased risk

• MOLECULAR GENETICS

  • 10 to 20 genetic mutations occur by the time tumor is clinically apparent

  • Dominant oncogenes : C-Myc, K-RAS

  • Commonly deleted / inactivated tumor suppressor genes : p53, RB, p16 ch.3p

  • p53 mutations : Both small & non-small cell carcinomas

• CYTOGENETIC ABNORMALITIES IN SPECIFIC TUMORS 

• Squamous cell carcinoma

  • ASSOCIATED WITH SMOKING

  • CHROMOSOMAL DELETION – 3p, 9p (site of CDKN2A gene) and 17p (Site of TP53 gene)

  • LOSS OF EXPRESSION of Rb tumor suppressor gene

  • AMPLIFICATION of FGFR1

  • INACTIVATION of cyclin dependent kinase inhibitor gene – p16 protein lost

• Adenocarcinoma

  • GAIN OF FUNCTION MUTATIONS involving multiple genes encoding tyrosine kinase receptors – EGFR, ALK, ROS, MET and RET

  • MUTATIONS in the KRAS gene in tumors without tyrosine kinase gene

• Small cell carcinoma

  • STRONGLY ASSOCIATED WITH SMOKING

  • LOSS OF FUNCTION ABERRATIONS involving TP53 and Rb gene

  • Chromosome 3p deletions

  • AMPLIFICATION of genes of Myc family

• Lung cancer in non-smokers

  • More common in females and are adenocarcinomas

  • Common mutations – EGFR 

  • TP 53 mutations – not uncommon

• Inherited predisposition

  • Rare – found in Li-Fraumeni syndrome who inherit p53 mutations

  • First degree relatives – 2-3 folds increased risk

References

Vinay kumar, Abul K.Abbas, Nelson Fausto, Jon C. Aster. Robbins and Cotran Pathologic basis of disease. 9th edition