Pathology of lung ca

Presenter Dr Delelegn(GSR1)
Moderator Dr Sasibew( Assistant
Professor and Cardiothoracic surgeon)
 Course outline
• Introduction
• Classifications and subtypes
• Clinical features
 Introduction
• Most common cause of cancer mortality
• 2.1 M new cases and 1.8M deaths annually with overall 5
year survival rate being 15%
• Often occur b/n age 55 to 84, only 2% occur at age <40
• The second most common next to prostate in male and
breast in female
• Twice as common in male than female

• Most but not all lung ca are associated with cigarete smoking
• Broadly classified as SCLC and NSCLC
 Risks
• Tobacco smoking
• 80% lung cancer occur in smokers
• 10 -15 % of smokers develop cancer; 60x risks
relative to non smokers
• Women are more susceptible to carcinogens
than men
• Cessation decreases risk of acquiring disease yet
no return to nonsmokers level
• Electronic vaping effect is under study
• Second hand smoke kills yearly around 3000
• Mutagenic effect of carcinogens are affected by
genetics(CYP450)
• Linear correlation b/n intensity of cigarette smoking in pack
year and lung ca
• Most patients are diagnosed at an advanced stage of
disease, so therapy is rarely curative
• Over 4800 chemicals have been identified in tobacco
smoke, but the main chemical carcinogens are polycyclic
aromatic hydrocarbons,nitrogen cyanide,co,
• Tar is the major carcinogens
• Industrial hazards: asbestos(occur after latent
period of 10-30 years; 5x in nonsmoker's and
55x in smoker), Arsenic, chromium, Uranium(4x
in non smokers and 10x in smoker miners),
Nickel, vinyl Chloride, Mustard
• Air pollution: can cause chronic inflammation
leading to cancer formation
• Radiation
• Diet
• Acquired mutations,
• The relationship b/n molecular, genomic and
environmental factors in tumorogenisis remains
complex
• Epithelial cancer occur after initiation,
promotion and propagation phases.
• TP53(tumor suppressor) mutation
• TP53 Stabilized due to response to genotoxic
stress and oncogene activation
• Both pathways result in cell apoptosis, cell senescence,
DNA repair
• Approximately 75% mutation are missense mutation
• Present in 90% of SCLCs and >50% NSCLCs
• CDKN2A-RB1 pathway:
• RB1 negatively regulate cell cycle progression at G1
phase,
• Mutations of such is found commonly in heavier
smokers and squamous cell ca.
• 90% RB1 mutation in SCLC 15% to 30% in NSCLCs.
• Ras Family mutation:
• Myc Family mutation:
• Epidermal Growth Factor Receptor
overexpression

• Angiogenesis: it is required for tumor to grew

beyond 1mm3 size and for metastases.
• Regulated by VEGF, basic fibroblast factor,
MMP-9
• Bcl2 Family:
• Nuclear factor YB
• Genomics and proteomics:
• Aids in classification categories and subsets,
prognostic association of gene expression,
Identification of genes or proteins targets for
diagnosis or therapy
• Epigenetics;
• Methlation events: global hypomethylation,
dysregulation of methyltransferases which
maintain methylation patterns, regional
hyermethylation in CpG islands
• Adenocarcinoma (50%)
• Squamous cell carcinoma (20%)
• Small cell carcinoma (15%)
• Large cell carcinoma (2%)

• Mixtures of histologic features may also

coexist
• Non endocrine pulmonary carcinomas
• Squamous cell ca:
• Highly asscociated with tobacco smoking
• deletion of chr in tumor suppresson foci
• Mutations in TP53(early event in even
histologically normal respiratory mucosal
cells), p53(can be seen in
immunohistochemical staining)
• Has propensity to arise in large central airways
proximal to subsegmental bronchi.
• Frequently accompained by obstsructive pneuomnia

• It has irregular, friable, gray-white cut surface witwh

lare area of central necrosis with or withour cavitation
• Resemble stratified squamous epithelium of upper
airway with disorder architecture.
• Anucleate keratin and squamous pearls(in well
differentiated)
• Adenocarcinoma: currently the most common
form of lung ca,
• Predominantly peripheral lesions
• Show irregular lobulated configuration with
gray-white cut surface
• Sometimes it be difficult to differentiate
primary from secondary pathologically
• most common in non smokers, and least one to be
associated with smoking(1/4 of lung ca are in non
smokers)
• Has oncogenic gain of function mutation involving growth
factor receptor signaling pathways( defferent receptor
thyrosine kinase: EGFR, ALK, ROS1,MET, RET,
• gain-of-function mutations in serine/throsine kinases
BRAF,, and PI3K or in the KRAS gene(never in non
smokers) (roughly 30% of tumors), all of which encode
signaling molecules that lie downstream of receptor
tyrosine kinases in growth factor signaling pathways
• Bronchioloalveolar carcinoma:
• More common in older age,
• Three discrete subsets 1, px with Rx and clinical
suggestion of pneumonia, 2, with solitary peripheral
mass lesion, 3, with multiple rounded densities
throughout one or both lung fields( donut shape
with central cavitation) imitate metastasis.
• Histologically devided as
mucinous(pseudopheumonic, aggressive) an non
mucinous(solitary mass),
• Chx by lepidic growth comforming preexisting
ari spaces by single layer or limite strate and
micropapillae of only atypical cuboidal or
columnar epithelial cessl with /out
intra/extracellular mucin production,
• Difficult to distinguish from extrpulmonay ACA
• Should be differentiated from IFP, organizing
pulmonary infarcts, AAAH, papillay alveolar
adenoma
• Reactive lesions include multiple type cells,
interstitial scarring extends beyond areas of
alveolar cell atypia.
• BAC have uniformly atypical nuclei, large
lesional size and complex growth wth budding
of tumor cells in alveolar spaces, and nuclear
area >4omcro m2 and lesional diameter of
>5mm
• Adenocarcinoma associated with scars,
• There is no reason to suspect that fibrosing
conditions in the lung are preneoplastic.
• Presence of scar indicate worse prognosis
• Adenosquamous carcinoma
• <5% of lung ca
• Chx clinical,Rx and path pure ACA
• Propensity peripheral rather than large airways as in
HG mucoepidermoid ca of salivary glandular type.
• Large cell undifferentiated carcinoma:
• 15% of lung ca.
• > 5cm resembling fish flesh with internal
necrosis
• Shows a composition of large polygonal cells
with vesicular chromatin prominent nucleoli
discernible cytoplasmic border and lack of
glandular differentiation.
• Has Subtypes of giant cell carcinoma(extremely
pleomorphic large tumor cells which are
multinucleated) and clear cell carcinoma of the lungs
• Sarcomatoid carcinomas(carcinosaarcoma,blastoma)
• Neoplasm of lung with feature of fusiform and
pleomorphic cells.
• M:F = 2:1 ; mean age of 65 and virtually all are
smolers
• Rx; shows irregularly marginated with dimesion b/n
1.5-12cm
• Monodifferentiated spindle cell and
pleomorphic lesion
• Neuroendocrine neoplasms of lungs
• All of them potontially malignant tumor
• Classic carcinoid: grow as polypoid
intraluminal masses with intact overlying
epithelium of squamous metaplasia.
• 5 year survival of 90%-95%
• Atypical carcinoid: chx with>=2 of mitotic rate
>5/10hpf, moderate nucledar pleomorphisim,
spontanous necrosis, loss of organoid growth
pattern associated with low grade
neuroendocrine ca. of lung.
• Is larger than the typidal relatives >3cm and
25% remote metastasis
• Small cell carcicnoma,
• 20% of lung ca.
• Most occur in central airways
• Morphologically small hyperchromatic, ;molded
cells with barely visible cytoplasm, inconspicuous
or absesnt nucleoli, single cell necrosis and
relative abssence of stromal desmoplasia,
• Small cell nature may not be obvious in limited
biopsy material.
• virtually always smoking related,
• Inactivation of TP52 and RB; and also there is
unusual transformation of non small cell lung ca.
to small cell ca..
• Precursor lesions:
• 1,atypical adenomatous hyperplasia, 2,
adenocarcinoma in situ, 3, squamous dysplasia
and carcinoma in situ, and 4, diffuse idiopathic
pulmonary neuroendocrine cell hyperplasia
• Large cell neuroendocrine carcinoma:
• Most are located in peripheral lung
parenchyma and almost always in heavy
smokers
• Aggressive behaviour of it cannot be
overstated; only 10% are alive after 2 years.
• Early detection and screening of lung cancer;
• Area of debate and inconclusive conclusions
• Diagnosis and stsaging of lung ca.
• this involves clinical, radiological and
pathologic information
• Important for prognosis, extent
determination, therapy selection
• Clinical features:
• Pulmonary: cougn, dyspnea, wheeze, stridor,
hemoptysis and pneumonic symptoms
• Extrapulmonay symptoms: chest wall pain,
pancoast tumor,
• Phrenic and recurrent laryngeal nerve invasion
• Superior vena caval syndrome.
• Extrathoracic symptoms:
• Paraneoplastic syndromes: parathyroid like
hormone, hypertrophic pulmonay
osteoarthropathy, neurologic manifestations
• endocrine manifestions( SIADH,ectopic ACTH
and parathyroid like hormone secretion,
lambert eaton myasthenic syndrome)
• Solitary pulmonary
nodule:
• Size <3cm
• 70% found tomalignant
at follow up,
• Of benign 80% are
infectious granuloma
and 10% are
hemartoma,
• Benign • Malignant
• Smooth margin • Lobulated to spiculatd
• Homegenous attenuation margin
• Thin wall <4mm
• Thick wall >16mm
• Calcification(central, diffuse
solid and laminated-loci of • Pseudocavitation(BAV
prior infections; popcorn ca)
calcification-hamartoma • Part solid lesion
• Stable size >2year
• Intranodular fat(hamartoma)
 staging
• Cxr • Video assisted
• CT thoracoscopic surgery
• PET • Thoracotomy;
• Sputum cytology • Metastatic scanning
• Bronchoscopy • Molecular biologic
• Transthoracic Needle staging
Aspiration
• Mediastinoscopy/
mediastinotomy
• Endoscopic U/s(FNA)
• References
• G. Alexander patterson and others(2008)
(Pearson’s Thoracic and Esophageal
sursgery(3rd ed), Churchill living stone
• Viny kumar(2021)Robbins and cotran
pathology pasis of diseases(10th ed) Elsevier