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Lung Carcinoma - NEET PG / INICET High-Yield Notes

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1. Epidemiology & Risk Factors

• Most common cause of cancer death worldwide in both sexes
• Smoking is the #1 risk factor for ALL types - risk is 60x higher with heavy smoking (2 packs/day x 20 years) vs. nonsmokers
• ~90% of lung cancers occur in current or recent smokers
• Women are more susceptible to tobacco carcinogens than men
• Other risk factors: asbestos, radon, arsenic, nickel, chromium, air pollution, radiation
• Asbestos + smoking = synergistic (multiplicative) risk

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2. WHO Classification (2021)

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3. Histologic Types - Key Features (MOST TESTED)

A. Adenocarcinoma

• Most common type overall (including in nonsmokers, women)
• Peripheral location (subpleural)
• Arises from: atypical adenomatous hyperplasia → adenocarcinoma in situ (AIS) (formerly bronchioloalveolar carcinoma)
• Lepidic growth pattern = growth along pre-existing alveolar walls without stromal invasion (AIS = pure lepidic, ≤3 cm)
• Key mutations: EGFR (~20%, nonsmokers/women), KRAS (~30%), ALK fusions (4-6%, nonsmokers, signet ring morphology), ROS1, HER2, MET
• EGFR and KRAS mutations are mutually exclusive
• ALK fusions: often have signet ring morphology; treated with crizotinib/alectinib
• Targetable with TKIs (gefitinib, erlotinib for EGFR; crizotinib for ALK)

B. Squamous Cell Carcinoma (SCC)

• Central/hilar location (arises from bronchial epithelium)
• Arises from: squamous dysplasia → squamous CIS (via squamous metaplasia)
• Histology: keratin pearls, intercellular bridges
• Strongly associated with smoking
• Paraneoplastic: PTHrP → hypercalcemia (most classic association)
• Key mutation: p16/CDKN2A (~50%)
• Cavitation common

C. Small Cell Carcinoma (SCLC)

• Central location, near major bronchi
• Neuroendocrine origin (Kulchitsky cells)
• Oat-cell appearance: scant cytoplasm, hyperchromatic nuclei, fine chromatin ("salt and pepper"), indistinct nucleoli
• IHC markers: chromogranin A, synaptophysin, CD56, NSE
• Dense core granules on electron microscopy
• Paraneoplastic syndromes (most common of all types):
  • SIADH → hyponatremia (ADH secretion)
  • Cushing syndrome → ACTH secretion
  • Lambert-Eaton myasthenic syndrome (anti-VGCC antibodies)
  • Anti-Hu antibody → encephalomyelitis/sensory neuropathy
• Key mutations: TP53 (~90%), RB (~90%), 3p deletion (~90%)
• Virtually always metastatic at diagnosis → NOT surgical → chemotherapy + radiotherapy
• Responds to chemo initially but invariably recurs
• Median survival with treatment: ~1 year; 5-year survival: only 5%
• Less responsive to immune checkpoint inhibitors than NSCLC

D. Large Cell Carcinoma

• Peripheral location
• Diagnosis of exclusion (no squamous, glandular, or neuroendocrine differentiation)
• Poorly differentiated; abundant cytoplasm, prominent nucleoli
• Large cell neuroendocrine carcinoma (LCNEC) is a subset

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4. Comparison Table: SCLC vs. NSCLC (MUST MEMORIZE)

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5. Paraneoplastic Syndromes (HIGH YIELD)

Key rule: SCLC predominantly produces ACTH and ADH; SCC predominantly produces PTHrP (hypercalcemia). Any histologic type may occasionally produce any hormone.

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6. Molecular Pathogenesis

• 3p deletion - earliest molecular event (even in histologically normal smoker bronchial epithelium = "field effect")
• TP53 mutations - relatively late event
• KRAS mutations - relatively late event (adenocarcinoma)
• Sequence for SCC: Normal epithelium → Squamous metaplasia → Squamous dysplasia → CIS → Invasive SCC
• Sequence for adeno: Normal → Atypical adenomatous hyperplasia → AIS → Minimally invasive → Invasive adenocarcinoma

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7. Clinical Features

• Cough, hemoptysis, dyspnea, wheezing (central tumors cause obstruction)
• SVC syndrome - SCLC (most common cause) compresses SVC
• Horner syndrome - Pancoast tumor (superior sulcus) compresses cervical sympathetic chain → ptosis, miosis, anhidrosis
• Pancoast tumor (superior sulcus tumor): shoulder/arm pain, Horner syndrome, rib erosion
• Recurrent laryngeal nerve palsy - hoarseness
• Phrenic nerve palsy - elevated hemidiaphragm
• Pleural effusion, pericardial involvement

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8. Diagnosis

• Chest X-ray / CT scan for detection and staging
• Sputum cytology - positive in central tumors (SCC, SCLC)
• Bronchoscopy + biopsy (central tumors)
• CT-guided needle biopsy (peripheral lesions)
• PET-CT for staging
• Mediastinoscopy for N2 nodal staging
• Molecular testing mandatory: EGFR, ALK, KRAS, ROS1, PD-L1 for NSCLC

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9. Treatment Summary

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10. Quick One-Liners for MCQs

• Most common lung cancer overall = Adenocarcinoma
• Most common in smokers = Adenocarcinoma (also most common in nonsmokers)
• Most central tumor = SCLC or SCC
• Most peripheral = Adenocarcinoma or Large cell
• Cavitation most common in = SCC (also large cell)
• "Oat cells" = SCLC
• "Keratin pearls" = SCC
• Best treated with surgery = NSCLC (early)
• Never surgical = SCLC (usually)
• PTHrP hypercalcemia = SCC
• SIADH + Cushing = SCLC
• Lambert-Eaton = SCLC
• Lepidic growth / AIS = Adenocarcinoma
• EGFR mutation + female + nonsmoker = Adenocarcinoma
• ALK fusion + signet ring = Adenocarcinoma
• 3p deletion earliest molecular change = All lung cancers
• RB mutation 90% = SCLC
• p16/CDKN2A mutation 50% = NSCLC (SCC)
• Finger clubbing + periostitis = Hypertrophic pulmonary osteoarthropathy
• Pancoast tumor location = Apex of lung (superior sulcus)
• Pancoast tumor = SCC most commonly

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Lung Carcinoma - Images from Robbins Pathology

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IMAGE 1: Pathology of Lung Carcinomas - Complete Panel (Robbins Basic Pathology)

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IMAGE 2: Pathology of Lung Carcinomas - Robbins, Cotran & Kumar (Pathologic Basis of Disease)

NEET MCQ tip: TTF-1 positivity = adenocarcinoma (also positive in small cell carcinoma). p40/p63 positivity = squamous cell carcinoma.

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IMAGE 3: Precursor Lesions of Lung Cancer (Robbins, Cotran & Kumar)

Sequence to memorize: Normal → AAH → AIS (lepidic, ≤3cm, no invasion) → Minimally invasive → Invasive adenocarcinoma Normal → Metaplasia → Dysplasia → CIS → Invasive SCC

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IMAGE 4: Sputum Cytology - Squamous Cell Carcinoma

• Large arrow: Orange-staining, keratinized squamous carcinoma cell with hyperchromatic nucleus - the diagnostic cell in sputum
• Small arrow: Normal neutrophils for size comparison
• The tumor cell is dramatically larger with a markedly abnormal nucleus
• Orange staining = keratin (Papanicolaou stain)

NEET tip: Sputum cytology is most useful for central tumors (SCC, SCLC) - cells shed into the bronchial lumen. Peripheral adenocarcinoma = CT-guided biopsy preferred.

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Key Histologic Identifiers - Quick Reference