2. LUNG TUMORS
Out of many benign and malignant tumors in the lung the vast
majority are –
90 – 95% - Carcinomas
5% - Bronchial carcinoids
2 – 5 % - Mesenchymal & other neoplasms
3. CARCINOMA - LUNG
• 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
• Males > Females
• Since 1990 lung cancer mortality in men has reduced but in women it has
not changed because of lagging behind in changing patterns of smoking
• Due to which cancer mortality in women is more due to lung cancer than
breast cancer.
4. CARCINOMA LUNG - ETIOPATHOGENESIS
Tobacco smoking
• 87 % of lung cancers occur in active smokers
• Linear correlation between - Amount of daily smoking
• Duration of the smoking habit
• Average smokers – 10 fold risk
• Heavy smokers (2 packs/ day)– 60 fold risk
• Most common: Squamous & Small cell Ca >98%
5. CARCINOMA LUNG - ETIOPATHOGENESIS
Tobacco smoking
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
6. CARCINOMA LUNG - ETIOPATHOGENESIS
Tobacco smoking
• 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
7. CARCINOMA LUNG - ETIOPATHOGENESIS
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 times
Asbestos coupled with smoking – 50 times
Asbestos workers with out smoking – 5 folds increased risk
8. CARCINOMA LUNG - ETIOPATHOGENESIS
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 inhalation & Bronchial deposition
9. CARCINOMA LUNG - ETIOPATHOGENESIS
Dietary factors:
Vit-A deficiency if associated with smoking risk
Chronic scarring :
Adeno Carcinoma occurs in areas of chronic scarring
Eg: Old TB, Chronic interstitial fibrosis, Asbestosis, old infarcts,
Scleroderma
10. CARCINOMA LUNG - ETIOPATHOGENESIS
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
11. CARCINOMA LUNG –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
12. MOLECULAR PATHOGENESIS OF LUNG
CANCER
SQUAMOUS CELL CARCINOMA SMALL CELL CARCINOMA
ADENOCARCINOMA
LUNG CANCER IN NON-SMOKERS
•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
•STRONGLY ASSOCIATED WITH SMOKING
•LOSS OF FUNCTION ABERRATIONS involving
TP53 and Rb gene
•Chromosome 3p deletions
•AMPLIFICATION of genes of Myc family
•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
•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
13. ETIOLOGICAL FACTORS
TOBACCO SMOKING
INDUSTRIAL HAZARDS
• ASBESTOS
• ARSENIC
• CHROMIUM
• URANIUM
• NICKLE
• VINYL CHLORIDE
• MUSTARD GAS
AIR POLLUTION
• AIR PARTICULATES
• RADON
DIETARY FACTORS
VIT A DEFICIENCY
CHRONIC SCARRING
• OLD TB, CHRONIC INTERSTITIAL
FIBROSIS, OLD INFARCT
• ADENOCARCINOMA
MOLECULAR GENETIC
ABERRATIONS
14. CARCINOMA LUNG
Etiopathogenesis
• Arises by stepwise accumulation of genetic abnormalities
• Bronchial epithelium Neoplastic tissue
• Normal mucosa Basal cell Hyperplasia squamous
Metaplasia Dysplasia Ca. insitu Invasive carcinoma
20. SQUAMOUS CELL CARCINOMA
Most common in men
Strongest relationship with smoking
Initially starts as squamous metaplasia or dysplasia in bronchial
epithelium transforming into carcinoma in-situ
During this phase dysplastic epithelial cells are seen in sputum
or bronchial washings though not visible radiologically
21. SQUAMOUS CELL CARCINOMA
Squamous cell Ca. begins as thickening of bronchial mucosa warty
excrescence Fungate into bronchial lumen intra luminal mass
Penetrate the wall of bronchus infiltrate the peribronchial tissue
(Carina/ mediastinum) Cauliflower like intraparenchymal mass
Bronchial obstruction later leads to distal atelectasis and infection
Grossly – tumor is gray-white, firm to hard with areas of necrosis and
hemorrhage
28. ADENOCARCINOMA
Most common in women & non smokers (>75 % found in smokers)
More peripherally located & smaller lesions
Morphological types
Atypical adenomatous hyperplasia – precursor lesion
Adenocarcinoma in-situ – precursor lesion
Microinvasive adenocarcinoma
Adenocarcinoma
29. ATYPICAL ADENOMATOUS HYPERPLASIA
Small lesion – less than or equal to 5mm
Characterised by dysplastic pneumocytes lining alveolar walls
that are widely fibrotic
Can be single or multiple and can be in lung adjacent to invasive
tumor
32. ADENOCARCINOMA IN-SITU
Formerly called as Bronchioloalveolar carcinoma
Lesion less than 3cm
Composed of dysplastic cells growing along pre-existing alveolar
septae
Cells are more dysplastic than atypical adenomatous
hyperplasia and may or may not have intracellular mucin
(Mucinous or non-mucinous respectively)
35. MICROINVASIVE ADENOCARCINOMA
Tumors with less than 3cms with a small invasive component
(less than 5mm) and peripheral lepidic growth pattern i,e.
tumor cells crawl along the normal alveolar septae
This has far better prognosis when compared to invasive
carcinomas of size larger
36. ADENOCARCINOMA
Invasive malignant epithelial tumor with glandular differentiation or
mucin production by tumor cells
Lesions are peripherally located and are smaller
Present as solitary or multiple nodules
Various histological patterns include – acinar, lepidic, papillary,
micropapillary and solid with mucin formation
At the periphery of the lesion tumor shows lepidic pattern of spread
37. ADENOCARCINOMA
Non mucinous : cuboidal / low colummar
Mucinous : Tall, Columnar cells with cytoplasmic & intra-
alveolar mucin, growing along alveolar septa
Tumor cells express Thyroid transcription factor – 1 (normally
identified in thyroid cells) and is required for normal lung
development
43. SMALL CELL CARCINOMA
Strongest association with smoking
Highly malignant tumor
Localization – either in central bronchi or in periphery
There is no preinvasive phase
More aggressive widely metastasize and always prove fatal
44. SMALL CELL CARCINOMA
Microscopy
Small cells with scant cytoplasm, finely granular nuclear chromatin (salt
& pepper pattern), ill defined cell borders and absent or inconspicuous
nucleoli
Cells are round to oval showing nuclear moulding
Size of the cell – smaller than 3 times the diameter of small lymphocytes
Cells grow in clusters without glandular and squamous differentiation
Azzopardi effect – basophilic staining of vessel wall due to encrustation
by DNA of necrotic tumor cells
Necrosis is common
Electron Microscopy: Dense-core neurosecretory granules
45. SCC - Arising centrally in this lung and spreading extensively
49. LARGE CELL CARCINOMA
Undifferentiated malignant epithelial tumor lacking cytologic features
of both squamous or adenocarcinoma
Common in men / smokers
Large nuclei, prominent nucleoli
Variant – large cell neuroendocrine carcinoma
It is a diagnosis of exclusion as it neither expresses markers of
adenocarcinoma (TTF-1, napsin A) and squamous cell carcinoma (p63,
p40)
