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PA25.6 | Tumours of the Lung & Pleura — SDL Guide (Part 2)

NSCLC Type 1 — Squamous Cell Carcinoma

Squamous Cell Carcinoma of Lung

Panel A: Central grey-white tumour, lobar bronchus, segmental bronchus, bronchial epithelium, hilar region, narrowed bronchial lumen, distal atelectasis, post-obstructive pneumonia, haemoptysis, heavy smoking association. Panel B: Normal bronchial epithelium, squamous metaplasia, dysplasia, carcinoma in situ, invasive squamous cell carcinoma. Panel C: Firm central grey-white mass, cavitary necrosis, bronchial communication, lung parenchyma, central location. Panel D: Malignant squamous cell nests, keratin pearl, intercellular bridges, pleomorphic nuclei, CK5/6 positive, p63 positive, p40 positive, TTF-1 negative, PTHrP secretion, hypercalcaemia.

Squamous cell carcinoma (SCC) of the lung accounts for ~25–30% of all lung cancers and has the strongest association with heavy smoking among NSCLC subtypes.

Location: Central — arises from bronchial epithelium (preceded by squamous metaplasia → dysplasia → carcinoma in situ) in segmental or lobar bronchi. May cavitate.

Gross: Grey-white, firm, central mass. Cavitation (central necrosis) in up to 10–15%.

Microscopy:
• Keratin pearls (whorled concentrically layered squamous cells with central keratinisation) — pathognomonic.
• Intercellular bridges (desmosomes) between tumour cells.
• Well to poorly differentiated; poorly differentiated SCC may lack pearls.

IHC: CK5/6, p63, p40 positive; TTF-1 negative.

Key molecular: TP53, CDKN2A (p16) deletion; FGFR1 amplification.

Paraneoplastic: Hypercalcaemia via PTHrP (parathyroid hormone-related peptide) secretion — the most characteristic paraneoplastic of SCC.

Clinical note: Central location causes endobronchial obstruction → post-obstructive pneumonia, haemoptysis, atelectasis.

NSCLC Type 2 — Adenocarcinoma

Medical diagram showing peripheral lung adenocarcinoma with pleural puckering, lepidic and glandular histology, IHC markers, and targetable mutations. — **Panel A:** Peripheral subpleural adenocarcinoma nodule in lung; pleural puckering; terminal bronchiole/alveolar lining origin; type II pneumocyte / Clara cell origin.. **Panel B:** Gross peripheral grey-white tumour nodule with desmoplastic reaction and pleural puckering.. **Panel C:** Lepidic growth along intact alveolar walls; adenocarcinoma in situ; glandular/acinar architecture; mucin production, PAS-positive.. **Panel D:** IHC profile: TTF-1 positive, Napsin A positive, p40 negative, CK5 negative; molecular testing by NGS/IHC; EGFR, ALK, ROS1, RET, MET, and KRAS targetable alterations..

Adenocarcinoma is now the single commonest subtype of lung cancer overall (~40%) and is the predominant type in non-smokers, women, and younger patients.

Location: Peripheral — arises from terminal bronchioles or alveolar lining (type II pneumocytes / Clara cells). Often subpleural.

Gross: Peripheral grey-white nodule, frequently with pleural puckering (desmoplastic reaction). The lepidic pattern grows along alveolar walls without destruction — this is the non-invasive precursor lesion (adenocarcinoma in situ, formerly BAC).

Microscopy:
• Glandular/tubular/papillary/acinar architecture.
• Mucin production (PAS-positive).
• Lepidic pattern — tumour cells line alveolar walls like wallpaper; purely lepidic = adenocarcinoma in situ (AIS).

IHC: TTF-1 positive (most important marker), Napsin A positive; p40/CK5 negative.

Targetable mutations — clinically critical:
• EGFR mutation (~15% Western, ~40–50% Asian; exon 19 deletion or L858R point mutation) → targeted by erlotinib, gefitinib, osimertinib.
• ALK rearrangement (~5%; EML4-ALK fusion) → targeted by crizotinib, alectinib.
• ROS1, RET, MET alterations — rarer but targetable.
• KRAS mutation — commonest driver (~30%); historically untargetable, now targeted by sotorasib (KRAS G12C).

Note: Presence of targetable mutations mandates molecular testing (NGS/IHC) on all non-squamous NSCLC — this is now standard of care.

NSCLC Type 3 — Large Cell Carcinoma and Other Subtypes

A multi-panel lung carcinoma comparison diagram showing SCLC, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, LCNEC features, IHC markers, and central versus peripheral clinical clues. — **Panel A:** Four microscopy comparison columns: SCLC oat cells with nuclear moulding, SCC with keratin pearl and intercellular bridges, adenocarcinoma with lepidic/glandular pattern, and LCC with undifferentiated large cells, vesicular nuclei, prominent nucleoli, no glands, no keratin pearls.. **Panel B:** Large cell carcinoma diagnosis of exclusion: negative CK5/6, TTF-1, napsin A, synaptophysin/chromogranin; no squamous, glandular, or neuroendocrine differentiation.. **Panel C:** Large cell neuroendocrine carcinoma: large cells in nests, rosettes, peripheral palisading, positive synaptophysin and chromogranin staining.. **Bottom strip:** Clinical localization clues: central mass suggests SCLC or SCC, SCC hypercalcaemia via PTHrP, peripheral nodule in non-smoker suggests adenocarcinoma with EGFR/ALK testing, LCC may be peripheral or central..

Large cell carcinoma (LCC) is a diagnosis of exclusion (~10% of lung cancers): undifferentiated NSCLC lacking squamous, glandular, or neuroendocrine differentiation on H&E and IHC.

Microscopy: Large cells with vesicular nuclei and prominent nucleoli; no keratin pearls, no glands. IHC negative for CK5/6, TTF-1, napsin A, neuroendocrine markers.

Behaviour: Peripheral or central; poor prognosis; no targetable mutations by definition.

Large cell neuroendocrine carcinoma (LCNEC): A distinct variant — large cells with neuroendocrine architecture (nesting, rosettes, peripheral palisading) and IHC expression of synaptophysin/chromogranin. Aggressive, treated similarly to SCLC.

A 2×2 histology comparison of small cell, squamous cell, adenocarcinoma, and large cell lung carcinoma with diagnostic labels and a clinical pearl ribbon summarizing central versus peripheral tumour clues. — **Panel A:** Small cell lung carcinoma: oat cells, nuclear moulding, scant cytoplasm, hyperchromatic nuclei, necrosis, crush artefact.. **Panel B:** Squamous cell carcinoma: keratin pearl, intercellular bridges, polygonal squamous tumour cells, central bronchial association.. **Panel C:** Adenocarcinoma: lepidic growth along preserved alveolar septa, gland-forming tumour cells, mucin, peripheral nodule association.. **Panel D:** Large cell carcinoma: large undifferentiated pleomorphic cells, prominent nucleoli, abundant cytoplasm, no gland formation, no keratinization.. **Panel E:** Clinical pearl ribbon: central mass suggests SCLC or SCC; SCC hypercalcaemia via PTHrP; peripheral nodule suggests adenocarcinoma with EGFR/ALK testing; peripheral cavitation favours SCC..

CLINICAL PEARL

The periphery–centre rule for quick subtyping at the bedside:

Central mass + smoker + SVC syndrome/haemoptysis → think SCLC or SCC.
Central mass + SCC + hypercalcaemia → PTHrP is the mechanism (not bony metastases — confirm with normal bone scan).
Peripheral nodule + non-smoker or Asian woman → adenocarcinoma; send EGFR/ALK regardless of clinical features.
Peripheral cavitating mass → more likely SCC than adenocarcinoma (though abscess and fungal must be excluded).

This rule guides the initial management while awaiting the full pathology report.