Bronchogenic Carcinoma

Overview

Lung cancer from respiratory epithelium (bronchi/bronchioles/alveoli). Commonest primary malignancy in men, ~30% cancer deaths (developing countries). US: now exceeds breast cancer as female cancer-death cause. Peak 55-65yr.

Etiology

Smoking = dominant (~80% of cases). Active smoker 13x risk, passive 1.5x. >2 packs/day×20yr = 60-70x. Cessation lowers risk but never fully to baseline even at 10yr. Pipe/cigar = intermediate. Strongest link: squamous cell + small cell carcinoma. >90% smokers show squamous metaplasia→dysplasia→CIS sequence. Tar carcinogens: PAHs, nitrosamines; promoters: phenol derivatives.

Non-smoking causes (~15%, more in women): radiation (radon, thoracic RT), pollution (industrial cities, petrochemical proximity), occupational (asbestos, bis-ethers, nickel, beryllium, arsenic, iron oxide — asbestos+uranium mining = cocarcinogenic with smoking), dietary (vit A deficiency ↑risk; inverse socioeconomic correlation), chronic scarring (peripheral adenoCa near old TB/asbestosis/fibrosis/infarcts/scleroderma).

Molecular pathogenesis

1. Oncogene activation — K-RAS (dominant), EGFR-TK mutation (adenoCa in non-smokers), BRAF/PIK3CA/MYC, bcl-2 overexpression
2. Tumour-suppressor loss — 3p loss common, p53+Rb inactivation, p16/RASSF1A silencing
3. Autocrine signalling — nicotine = both initiator+promoter (unmasks nicotinic ACh receptors → proliferation, blocks apoptosis); paraneoplastic hormones via autocrine loops
4. Inherited predisposition (uncommon) — Li-Fraumeni (p53), retinoblastoma survivors (Rb), 1st-degree relatives (2-3x risk), P450 polymorphisms
5. Therapy targets — EGFR-TK inhibitors (~70% NSCC show EGFR overexpression/amplification), anti-VEGF monoclonal therapy

Morphology

Hilar (majority, more right-sided) vs Peripheral (mainly adenocarcinoma).

Hilar: main/segmental bronchus origin, small roughened mucosa→nodular/ulcerated→friable spherical mass (1-5cm), lumen narrowing. Necrosis/haemorrhage, sometimes cavitary. Secondary bronchopneumonia/abscess/bronchiectasis from obstruction.

Peripheral: small bronchiole origin (often indiscernible exact site), single/multiple nodules, pneumonia-like consolidation possible, grey mucoid cut surface.

5 histologic types

1. Squamous cell — historically commonest, men, smoking-linked. Large bronchus, necrosis+cavitation prone. Dx: intercellular bridges/keratinisation. Graded well/mod/poor. Spindle-cell variant = biphasic. Spreads faster than other NSCC. Adjacent mucosa: metaplasia→dysplasia→CIS.
2. Small cell — hilar/central, strong smoking link, highly malignant. Neuroendocrine (Kulchitsky cell) origin → ectopic hormones. “Oat cell”: small uniform lymphocyte-like cells, scanty cytoplasm, sheets/cords/pseudorosettes. EM: dense-core granules. +chromogranin/synaptophysin.
3. Adenocarcinoma — NOW COMMONEST overall (~half), rising while SCC declines. Subtypes: acinar/papillary/lepidic (old “bronchioloalveolar”)/solid/micropapillary predominant.
4. Large cell — undifferentiated; pleomorphic multinucleate or clear-cell variants.
5. Adenosquamous — small %, peripheral scar carcinomas, both keratinisation+glandular differentiation.

SCC vs NSCC (clinically decisive split)

Spread

Direct — bronchial wall→peribronchial tissue→opposite lung/pleura/pericardium/myocardium/great vessels. Apical tumour → brachial plexus+sympathetic chain = PANCOAST’S SYNDROME. Lymphatic — hilar→mediastinal/cervical/supraclavicular/para-aortic nodes; thoracic duct invasion→chylous ascites. Haematogenous — early/widespread: liver>adrenals>bones>pancreas>brain>opposite lung>kidneys>thyroid.

Clinical features

1. Local — cough, chest pain, dyspnoea, haemoptysis
2. Obstructive — bronchopneumonia/abscess/bronchiectasis distal to block; fever, productive cough, effusion, weight loss
3. Metastatic (sometimes presenting feature) — SVC syndrome, painful bony lesions, recurrent laryngeal nerve palsy, brain met neuro deficits
4. Paraneoplastic (esp. SMALL CELL): ACTH→Cushing’s, ADH→hyponatraemia, PTH→hypercalcaemia, calcitonin→hypocalcaemia, gonadotropins→gynaecomastia, serotonin→carcinoid syndrome. Also: neuromuscular (polymyositis, myopathy, subacute cerebellar degeneration), skeletal (clubbing, hypertrophic osteoarthropathy), cutaneous (acanthosis nigricans, dermatomyositis), CV (Trousseau’s syndrome, NBTE), haematologic (coagulopathy, leukaemoid reaction)

Staging (TNM)

Occult (cells in secretions, no demonstrable primary) → Stage I (<3cm ± ipsilateral nodes) → Stage II (>3cm + ipsilateral hilar nodes) → Stage III (any size + adjacent invasion) → further stages = distant metastasis.

Clinical relevance

SCC vs NSCC split = most clinically consequential distinction — determines surgical candidacy (NSCC resectable, SCC not — diffuse presentation, chemo/radio only) — drives real treatment decisions more than the full 5-type classification. Small cell’s neuroendocrine origin directly explains its paraneoplastic hormone burden — tumour retains secretory machinery of cell of origin, why ACTH/ADH/calcitonin syndromes cluster here specifically. Pancoast’s syndrome = tumour LOCATION determining presentation independent of histologic type. Adenocarcinoma’s rising incidence vs SCC/small cell = real epidemiologic shift (lower-tar cigarettes, deeper inhalation → more peripheral carcinogen deposition) — not a fixed timeless proportion.

Overview

“Bronchogenic carcinoma” denotes cancer of the lung arising from the respiratory epithelium lining bronchi, bronchioles, and alveoli. It is the most common primary malignant tumour in men, and accounts for ~30% of all cancer deaths in both sexes in developing countries; in the US, lung cancer incidence in women has already surpassed breast cancer as a cause of death. Peak incidence 55–65 years. Male lung cancer deaths have declined slightly in the West with smoking cessation, but the global picture remains grim.

Etiology

Smoking is the dominant factor — ~80% of lung cancer occurs in active smokers, with strong dose-response evidence:

• Active smokers: 13× risk; passive smokers: 1.5× risk, versus non-smokers.

• 2 packs/day for 20 years: 60–70× risk.

• Cessation gradually lowers risk, but even after 10 years abstinence, risk never returns fully to non-smoker baseline.
• Pipe/cigar smokers: intermediate risk (higher than non-smokers, lower than cigarette smokers).
• Association is strongest for squamous cell and small cell carcinoma; >90% of smokers show a sequential epithelial change — squamous metaplasia → dysplasia → carcinoma in situ.
• Tar contains known carcinogens (polycyclic aromatic hydrocarbons, nitrosamines) and tumour promoters (phenol derivatives), though the exact human mechanism remains incompletely understood (animal skin-painting models induce cancer but don’t reproduce the human respiratory pattern).

Non-smoking causes (~15% of cases, more often in women, possibly hormone-related):

• Radiation — radon exposure, thoracic radiotherapy.
• Atmospheric pollution — higher risk in industrialised/smoky cities, near petrochemical industries.
• Occupational exposure — asbestos, bis-ethers, nickel, beryllium, arsenic, iron/iron oxide; asbestos and uranium mining show cocarcinogenic synergy with smoking.
• Dietary — vitamin A deficiency increases susceptibility; risk inversely correlates with socioeconomic status (via diet).
• Chronic scarring — peripheral adenocarcinomas arise more often in areas of chronic inflammatory scarring (old TB, asbestosis, chronic interstitial fibrosis, old infarcts, scleroderma).

Molecular Pathogenesis

A multistep process combining oncogene activation and tumour-suppressor loss:

1. Oncogene activation — K-RAS mutation is the dominant change; EGFR tyrosine-kinase-domain mutation characterises adenocarcinoma in non-smokers; also BRAF, PIK3CA, MYC mutations, bcl-2 overexpression (anti-apoptotic).
2. Tumour-suppressor inactivation — chromosome 3p loss is common; p53 and Rb inactivation; p16, RASSF1A promoter silencing.
3. Autocrine growth signalling — nicotine acts as both initiator and promoter, unmasking nicotinic acetylcholine receptors that activate proliferative signalling and block apoptosis; some paraneoplastic hormones act via autocrine loops.
4. Inherited predisposition (uncommon) — Li-Fraumeni syndrome (inherited p53 mutation), retinoblastoma survivors (Rb mutation), first-degree relatives of lung cancer patients (2–3× risk), cytochrome P450 polymorphisms affecting carcinogen metabolism.
5. Molecular therapy targets — EGFR-TK inhibitors (~70% of NSCC show EGFR overexpression/amplification); anti-VEGF monoclonal therapy against tumour angiogenesis.

Morphology

Occurs most often in the hilum, less often peripherally.

Hilar type (majority) — arises in the main bronchus or a segmental branch, more often right-sided; begins as a small roughened mucosal area at a bifurcation, thickens into a nodular/ulcerated mass, coalesces into a friable spherical mass (1–5 cm) that narrows/occludes the lumen. Cut surface yellowish-white with necrosis/haemorrhage, sometimes cavitary. Secondary bronchopneumonia, abscess, and bronchiectasis commonly follow from obstruction.

Peripheral type (mainly adenocarcinomas, including the lepidic-pattern subtype) — arises from a small peripheral bronchiole, exact origin often indiscernible; single or multiple nodules, sometimes producing pneumonia-like consolidation; cut surface greyish, mucoid.

The Five Histologic Types

1. Squamous cell (epidermoid) carcinoma — historically the commonest subtype, more common in men, strongly smoking-linked. Arises in a large bronchus, prone to massive necrosis and cavitation. Diagnosed by intercellular bridges or keratinisation; graded well/moderately/poorly-differentiated. A spindle-cell variant shows biphasic squamous-plus-sarcoma-like growth. Spreads faster than other NSCC types; adjoining bronchial mucosa often shows the metaplasia-dysplasia-CIS sequence.
2. Small cell carcinoma — frequently hilar/central, strongly smoking-linked, highly malignant. Cells resemble bronchial neuroendocrine (Kulchitsky/argentaffin) cells and frequently produce ectopic hormones. Classic “oat cell” appearance: small, uniform, lymphocyte-like cells with scanty cytoplasm, arranged in sheets/cords/pseudorosettes; EM shows dense-core neurosecretory granules; positive for chromogranin/synaptophysin.
3. Adenocarcinoma — now the most frequent subtype overall (~half of all lung cancers), incidence rising while small cell carcinoma declines. Subtypes: acinar-, papillary-, lepidic- (formerly “bronchioloalveolar”), solid-, and micropapillary-predominant.
4. Large cell carcinoma — undifferentiated, including highly pleomorphic multinucleate-cell and clear-cell variants (clear/foamy cytoplasm, no mucin).
5. Adenosquamous carcinoma — a small proportion of peripheral scar carcinomas showing both keratinisation and glandular differentiation.

Small Cell vs Non-Small Cell Carcinoma — the Clinically Decisive Split

Spread

• Direct — invades through the bronchial wall, destroys peribronchial tissue, extends to the opposite bronchus/lung, pleura, pericardium, myocardium, great vessels. Apical tumours extending into the thoracic cage can invade the brachial plexus and sympathetic chain, producing Pancoast’s syndrome (pain, sensory disturbance).
• Lymphatic — hilar nodes first, then mediastinal, cervical, supraclavicular, para-aortic; thoracic duct invasion can cause chylous ascites.
• Haematogenous — early and widespread; descending frequency: liver, adrenals, bones, pancreas, brain, opposite lung, kidneys, thyroid.

Clinical Features

1. Local symptoms — cough, chest pain, dyspnoea, haemoptysis.
2. Bronchial obstructive symptoms — bronchopneumonia, abscess, bronchiectasis distal to obstruction, with fever, productive cough, effusion, weight loss.
3. Metastatic symptoms — sometimes the presenting feature: superior vena caval syndrome, painful bony lesions, recurrent laryngeal nerve palsy, neurologic deficits from brain metastases.
4. Paraneoplastic syndromes (see Paraneoplastic Syndromes) — particularly associated with small cell carcinoma’s ectopic hormone production:
   • ACTH → Cushing’s syndrome; ADH → hyponatraemia; parathormone → hypercalcaemia; calcitonin → hypocalcaemia; gonadotropins → gynaecomastia; serotonin → carcinoid syndrome.
   • Neuromuscular (polymyositis, myopathy, peripheral neuropathy, subacute cerebellar degeneration), skeletal (clubbing, hypertrophic osteoarthropathy), cutaneous (acanthosis nigricans, dermatomyositis), cardiovascular (migratory thrombophlebitis/Trousseau’s syndrome, non-bacterial thrombotic endocarditis), haematologic (coagulation abnormalities, leukaemoid reaction).

Staging

TNM-based clinical staging: Occult (malignant cells in secretions, no demonstrable primary/metastasis) → Stage I (<3 cm, ± ipsilateral nodes, no distant metastasis) → Stage II (>3 cm, ipsilateral hilar nodes, no distant metastasis) → Stage III (any size, adjacent structure invasion) → (further stages incorporate distant metastasis).

Clinical Relevance

• The small-cell-versus-non-small-cell split is the single most clinically consequential distinction in this topic, since it determines whether surgery is even an option — NSCC can potentially be resected, SCC essentially cannot (it presents diffusely and is treated with chemo-/radiotherapy), which is why this binary split, not the full five-type histologic classification, drives real-world treatment decisions.
• Small cell carcinoma’s neuroendocrine origin (Kulchitsky/argentaffin cell derivation) is the direct mechanistic explanation for its outsized paraneoplastic hormone burden — the tumour cells retain the secretory machinery of their cell of origin, which is why ectopic ACTH, ADH, and calcitonin syndromes cluster specifically with this histologic type rather than being randomly distributed across lung cancer types.
• Pancoast’s syndrome is a clean example of tumour location determining clinical presentation independent of histologic type — an apical tumour’s local anatomic relationships (brachial plexus, sympathetic chain) produce a recognisable symptom complex regardless of which of the five histologic types is actually present.
• The rising incidence of adenocarcinoma relative to squamous/small cell carcinoma over recent decades is a real epidemiologic shift worth understanding as smoking-pattern-dependent (lower-tar cigarettes and reduced/deep inhalation patterns shifting carcinogen deposition more peripherally) rather than a fixed, timeless proportion — the histologic-type “commonest” answer has genuinely changed over the study period the source data reflects.

• Hilar vs peripheral gross patterns and their typical histologic types
• Small cell vs non-small cell carcinoma: morphology, markers, genetics, and treatment compared
• Three spread routes (direct/lymphatic/haematogenous) with their characteristic destinations
• Paraneoplastic hormone syndromes mapped to small cell carcinoma’s neuroendocrine origin

Multiple Choice Questions (1)