Lung Carcinoma

Lung cancer (bronchogenic carcinoma) is the leading cause of cancer mortality worldwide and a perennial NEET PG favourite. The examiner loves the histology–location–paraneoplastic triad, plus the molecular markers (EGFR/ALK) that now define modern targeted therapy. Master the small-cell vs non-small-cell split and the paraneoplastic syndromes — they generate a disproportionate number of MCQs.

Definition & broad classification

Lung carcinoma arises from the bronchial/bronchiolar/alveolar epithelium. The single most important clinical division is small cell lung carcinoma (SCLC) versus non-small cell lung carcinoma (NSCLC), because it dictates staging philosophy and treatment.

• NSCLC (~85%) — adenocarcinoma, squamous cell carcinoma (SCC), large cell carcinoma.
• SCLC (~15%) — oat cell carcinoma; neuroendocrine origin, highly aggressive.

Adenocarcinoma is now the most common lung cancer overall and the most common in non-smokers, women, and Asians. Squamous cell carcinoma is the type most strongly associated with smoking along with SCLC.

High-yield: Adenocarcinoma = commonest lung cancer overall and in non-smokers. SCC and SCLC have the strongest smoking link. SCLC is the most aggressive and most strongly associated with paraneoplastic syndromes.

Type	Frequency	Location	Smoking link	Key feature
Adenocarcinoma	Most common (~40%)	Peripheral	Weakest (non-smokers)	Glands/mucin; arises in scars; EGFR/ALK
Squamous cell	~25–30%	Central	Strong	Keratin pearls, intercellular bridges; cavitation; hypercalcaemia
Small cell (oat)	~15%	Central	Strongest	Neuroendocrine; paraneoplastic; early metastasis
Large cell	~5–10%	Peripheral	Strong	Undifferentiated, poor prognosis

Etiology & risk factors

• Cigarette smoking — the dominant cause; risk proportional to pack-years. Strongest for SCC and SCLC.
• Radon — second commonest cause overall and the leading cause in non-smokers.
• Asbestos — synergistic (multiplicative) risk with smoking; causes both bronchogenic carcinoma and mesothelioma.
• Other occupational: arsenic, nickel, chromium, beryllium, vinyl chloride, radiation, polycyclic aromatic hydrocarbons.
• Pre-existing lung scarring (TB scar, fibrosis) → scar carcinoma (usually adenocarcinoma).

High-yield: Asbestos + smoking = multiplicative (not merely additive) risk. Radon is the top cause of lung cancer in non-smokers.

Pathophysiology & molecular biology

Carcinogens cause a stepwise accumulation of mutations. Key oncogenes and tumour suppressors are type-specific and very high-yield:

Gene/marker	Association
EGFR mutation	Adenocarcinoma, non-smokers, Asian women → targetable
ALK rearrangement	Younger non-smokers, adenocarcinoma
KRAS	Adenocarcinoma, smokers; poor response to EGFR TKI
ROS1, BRAF, MET, RET	Adenocarcinoma subsets
p53, RB, MYC	SCLC (RB and p53 almost universally lost)
PD-L1	Predicts immunotherapy response

Immunohistochemistry helps subtype: TTF-1 and Napsin A mark adenocarcinoma; p40/p63 and CK5/6 mark squamous; chromogranin, synaptophysin, CD56, NSE mark neuroendocrine (SCLC/carcinoid).

High-yield: TTF-1 (+) → adenocarcinoma or SCLC. p40/p63 (+) → squamous. Synaptophysin/chromogranin/CD56 → small cell/neuroendocrine.

Histology of each subtype

Adenocarcinoma — glandular differentiation, mucin production, often peripheral, may grow along intact alveolar septa (lepidic pattern, formerly bronchioloalveolar carcinoma → now adenocarcinoma in situ). Spectrum: atypical adenomatous hyperplasia → adenocarcinoma in situ → minimally invasive → invasive.

Squamous cell carcinoma — keratin pearls and intercellular bridges; arises centrally from squamous metaplasia → dysplasia → carcinoma in situ → invasive. Tends to cavitate. Produces PTHrP → hypercalcaemia.

Small cell carcinoma — small dark cells, scant cytoplasm, finely granular "salt-and-pepper" chromatin, nuclear moulding, abundant mitoses and necrosis, Azzopardi effect (DNA encrustation of vessel walls). Neuroendocrine granules. Central, early widespread metastasis; usually inoperable at diagnosis.

Large cell carcinoma — undifferentiated, large cells, no glandular/squamous/neuroendocrine features by light microscopy; diagnosis of exclusion; poor prognosis.

Clinical features

A flow of how patients present:

Cough/haemoptysis → recurrent same-site pneumonia (post-obstructive) → weight loss → local invasion syndromes → paraneoplastic/metastatic features.

• Local: cough, haemoptysis, dyspnoea, wheeze, post-obstructive pneumonia.
• Pancoast (superior sulcus) tumour — apical tumour invading the brachial plexus (C8–T1 → arm/shoulder pain, wasting of small muscles of hand) and the sympathetic chain → Horner syndrome (ptosis, miosis, anhidrosis, enophthalmos). Usually NSCLC (SCC).
• SVC obstruction — facial/arm swelling, distended neck veins, plethora; most often by SCLC (central, bulky).
• Hoarseness — left recurrent laryngeal nerve palsy.
• Diaphragm paralysis — phrenic nerve involvement.
• Malignant pleural/pericardial effusion, dysphagia (oesophageal compression).

High-yield: Pancoast tumour → Horner syndrome + lower brachial plexopathy. SVC syndrome is most commonly caused by SCLC. Hoarseness = left recurrent laryngeal nerve (passes around the aortic arch).

Paraneoplastic syndromes (very high-yield)

Syndrome	Mediator	Tumour type
SIADH (hyponatraemia)	ADH	SCLC
Cushing (ectopic ACTH)	ACTH	SCLC
Lambert-Eaton myasthenic syndrome	Anti-VGCC antibody	SCLC
Hypercalcaemia	PTHrP	Squamous cell
Hypertrophic pulmonary osteoarthropathy / clubbing	—	Adenocarcinoma (NSCLC)
Carcinoid syndrome (rare)	Serotonin	Carcinoid
Migratory thrombophlebitis (Trousseau)	Hypercoagulable	Adenocarcinoma
Cerebellar degeneration (anti-Yo/Hu)	Autoantibody	SCLC
Acanthosis nigricans, dermatomyositis	—	Various

High-yield: SIADH, ectopic ACTH (Cushing), and Lambert-Eaton are the classic SCLC triad. Hypercalcaemia (PTHrP) = squamous cell. This is the single most-tested paraneoplastic distinction in the exam.

Lambert-Eaton vs Myasthenia gravis (favourite MCQ): LEMS improves with repeated use/exercise (incremental response on repetitive nerve stimulation), affects proximal muscles, spares ocular/bulbar relatively, autonomic features present, anti-VGCC (P/Q type calcium channel) antibodies. MG worsens with use (decremental response), prominent ocular/bulbar involvement, anti-AChR antibodies.

Mnemonic for SCLC paraneoplastic: "SCLC = Several Cancer-Linked Crises" → SIADH, Cushing, Lambert-eaton, Cerebellar/neurologic.

Diagnosis & investigation of choice

Stepwise approach:

1. Chest X-ray — initial; mass, hilar enlargement, effusion, collapse, cavitation.
2. Contrast CT chest (+ upper abdomen) — investigation of choice for delineating and staging the tumour locally; assesses nodes, liver, adrenals.
3. Tissue diagnosis — bronchoscopy + biopsy/brushing for central lesions; CT-guided percutaneous transthoracic biopsy for peripheral lesions; sputum cytology (low sensitivity).
4. PET-CT — best for distant metastases and mediastinal nodal staging; guides operability.
5. EBUS / mediastinoscopy — mediastinal lymph node sampling.
6. MRI brain — for SCLC staging and suspected brain metastasis.
7. Molecular testing — EGFR, ALK, ROS1, PD-L1 on adenocarcinoma/NSCLC samples (mandatory before targeted therapy).

High-yield: Contrast CT chest is the investigation of choice for staging the primary; PET-CT is best for detecting distant/nodal metastasis. Bronchoscopy for central tumours, percutaneous biopsy for peripheral ones.

Staging

• NSCLC → TNM staging (8th edition). Determines surgical resectability; stages I–II and selected IIIA are surgical.
• SCLC → traditionally limited stage (confined to one hemithorax, encompassable in a single radiation field) vs extensive stage (beyond), though TNM is now also applied.

Management / drug of choice

NSCLC:

• Early stage (I–II, selected IIIA): surgical resection (lobectomy + mediastinal lymph node dissection) ± adjuvant chemo.
• Locally advanced (III): concurrent chemoradiation.
• Advanced/metastatic (IV): driven by molecular profile —
  • EGFR mutation → EGFR tyrosine kinase inhibitors (osimertinib preferred; also gefitinib, erlotinib).
  • ALK rearrangement → ALK inhibitors (alectinib, crizotinib).
  • ROS1 → crizotinib/entrectinib.
  • High PD-L1 / no driver mutation → immunotherapy (pembrolizumab, nivolumab) ± platinum-doublet chemo (cisplatin/carboplatin + pemetrexed for non-squamous).

SCLC:

• Chemotherapy is the mainstay — platinum (cisplatin/carboplatin) + etoposide; now combined with immunotherapy (atezolizumab/durvalumab) in extensive stage.
• Limited stage → concurrent chemoradiation.
• Prophylactic cranial irradiation (PCI) in responders — reduces brain metastasis.
• Generally not a surgical disease (early dissemination).

High-yield: Osimertinib = preferred first-line for EGFR-mutant NSCLC. SCLC is chemo-sensitive (platinum-etoposide) but rapidly relapses; PCI is given in responders.

Complications

• Post-obstructive pneumonia, lung abscess (especially cavitating SCC).
• Massive haemoptysis.
• Malignant pleural effusion, pericardial tamponade.
• SVC obstruction, recurrent laryngeal/phrenic palsy.
• Metastases — brain, bone, liver, adrenal are the classic sites.
• Paraneoplastic crises (hyponatraemia from SIADH, hypercalcaemia).
• Cachexia, venous thromboembolism.

Key differentials

• Pulmonary tuberculoma / TB — cavitating lesion, common in India; sputum AFB/GeneXpert.
• Pneumonia / lung abscess — but recurrent same-site pneumonia raises cancer suspicion.
• Pulmonary hamartoma — benign, "popcorn" calcification, peripheral coin lesion.
• Carcinoid tumour — low-grade neuroendocrine, central, "cherry-red" vascular endobronchial lesion, carcinoid syndrome rare.
• Metastasis to lung (cannonball — renal, choriocarcinoma; lymphangitis carcinomatosa from breast/stomach).
• Mesothelioma — pleural-based, asbestos-related (calretinin/WT-1 positive, TTF-1 negative).
• Solitary pulmonary nodule — benign vs malignant features (size, margins, calcification pattern, growth rate).

Benign vs malignant solitary pulmonary nodule:

Feature	Benign	Malignant
Margin	Smooth, well-defined	Spiculated, irregular
Calcification	Central, popcorn, laminated	Eccentric / none
Size	< 1 cm	> 2 cm more concerning
Growth	Stable > 2 yr	Rapid growth
Age	Younger	Older smoker

Recently asked / exam angle

• "Oat cell carcinoma" paraneoplastic matching — SIADH/Cushing/Lambert-Eaton all map to SCLC; hypercalcaemia (PTHrP) maps to squamous. This is the single most repeated stem.
• Histology image identification: keratin pearls/intercellular bridges = SCC; salt-and-pepper chromatin, nuclear moulding = SCLC; gland/mucin = adenocarcinoma.
• IHC markers: TTF-1 & Napsin A (adeno), p40 (squamous), synaptophysin/chromogranin/CD56 (neuroendocrine).
• Central vs peripheral location one-liners (SCC & SCLC central; adeno & large cell peripheral).
• EGFR/ALK → targeted therapy; osimertinib/alectinib drug-of-choice questions.
• Pancoast tumour → Horner syndrome; SVC obstruction → SCLC.
• Investigation of choice: CT for staging primary, PET-CT for metastasis.
• Asbestos → mesothelioma vs bronchogenic carcinoma; multiplicative risk with smoking.

Rapid revision

1. Adenocarcinoma = commonest lung cancer overall and in non-smokers/women; peripheral; TTF-1 + Napsin A positive.
2. Squamous cell carcinoma = central, cavitates, keratin pearls + intercellular bridges, PTHrP → hypercalcaemia, p40/CK5-6 positive.
3. Small cell (oat cell) = central, neuroendocrine, salt-and-pepper chromatin, most aggressive, chemo-sensitive but relapses; synaptophysin/chromogranin/CD56 positive.
4. SCLC paraneoplastic triad = SIADH, ectopic ACTH (Cushing), Lambert-Eaton; also cerebellar degeneration.
5. Lambert-Eaton = anti-VGCC, improves with use; Myasthenia gravis = anti-AChR, worsens with use.
6. Pancoast tumour → Horner syndrome + lower brachial plexus wasting.
7. SVC obstruction most commonly caused by SCLC; hoarseness = left recurrent laryngeal nerve.
8. Radon = top cause in non-smokers; asbestos + smoking = multiplicative risk.
9. EGFR mutation → osimertinib; ALK rearrangement → alectinib; high PD-L1/no driver → immunotherapy.
10. Investigation of choice: contrast CT for staging primary, PET-CT for distant metastasis; central → bronchoscopy, peripheral → percutaneous biopsy.
11. SCLC = limited vs extensive stage; PCI given in responders; rarely operable.
12. Common metastatic sites: brain, bone, liver, adrenal.