Specialty Guide · Path-iQ Global Pathology Review
Lung cancer is the leading cause of cancer death worldwide, killing more people annually than breast, prostate, and colorectal cancer combined. Lung pathology demands accurate histological subtyping on small biopsies, optimal specimen management to preserve molecular testing material, and fluency with an ever-expanding biomarker landscape where each positive drives a different targeted therapy or immunotherapy eligibility.
| Tumour | Frequency | Histology | IHC Profile | Key Molecular Targets |
|---|---|---|---|---|
| Adenocarcinoma | ~40% of lung cancers | Lepidic, acinar, papillary, micropapillary, solid patterns; mucin production; Clara cell / type II pneumocyte differentiation | TTF-1+, Napsin A+, CK7+; p40− | EGFR (exon 19 del, exon 21 L858R), KRAS G12C, ALK, ROS1, NTRK1/2/3, MET exon 14, BRAF V600E, RET; PD-L1 TPS |
| Squamous cell carcinoma | ~25–30% | Keratinisation, intercellular bridges; solid/nested growth; central/hilar; rarely peripheral | p40+++, CK5/6+, TTF-1−, Napsin A− | FGFR1 amplification; CDKN2A del; limited targeted options; PD-L1 TPS important for pembrolizumab |
| Small cell lung carcinoma (SCLC) | ~15% | Small cells with scant cytoplasm, nuclear moulding, "salt-and-pepper" chromatin; high mitotic rate; necrosis; crush artefact in biopsy | Synaptophysin+, Chromogranin A+, CD56+, TTF-1+ (~70%); p40−; CK7 weak/focal; TdT− | TP53+RB1 co-inactivation nearly universal; SCLC-A (ASCL1), -N (NEUROD1), -P (POU2F3), -I (YAP1) molecular subtypes; atezolizumab (IMpower133) added to first-line chemo |
| Large cell carcinoma | ~5–10% (decreasing with IHC) | Large polygonal cells; no squamous, glandular, or NE differentiation; diagnosis of exclusion after IHC | No lineage IHC markers; TTF-1−, p40−, Syn−, CgA− | Molecular profiling still recommended; some harbor KRAS, TP53, STK11 mutations |
| Large cell NE carcinoma (LCNEC) | ~3% | Large cells with NE morphology (palisading, rosettes) AND high mitotic count (>10/10HPF) AND NE IHC; overlaps with SCLC in biology | Syn+ and/or CgA+; TTF-1 variable; p40−; Ki-67 high (>40%) | Two major genomic subsets: SCLC-like (RB1 loss) and NSCLC-like (KRAS mut, no RB1 loss); managed as SCLC or NSCLC depending on genomic profile |
| Adenosquamous carcinoma | ~1–4% | Both adenocarcinoma AND squamous cell carcinoma components (>10% each) in same tumour; worst prognosis of NSCLC | Both TTF-1+ and p40+ areas; requires sampling both components | EGFR mutations can occur; molecular testing indicated despite mixed histology |
| Carcinoid / Typical carcinoid | ~1–2% | Organoid, trabecular nests; minimal mitoses (<2/10 HPF); no necrosis; uniform cells | Syn+++, CgA+++, CD56+; Ki-67 <5%; TTF-1 negative (helps distinguish from atypical carcinoid) | MEN1 mutations in familial cases; DOTATATE PET positive; somatostatin analogues; everolimus for progressive disease |
Over 70% of lung cancer patients present at an advanced stage, making small biopsies (bronchoscopic biopsy, CT-guided core needle biopsy) or cytology (EBUS-FNA, pleural effusion) the primary diagnostic material. The pathologist must balance accurate subtyping with tissue conservation for molecular testing.
Minimal IHC approach for NSCLC subtyping on small biopsy:
All guidelines (CAP/IASLC/AMP, ESMO, NCCN) recommend comprehensive molecular testing for all advanced non-squamous NSCLC at diagnosis. Squamous cell carcinoma patients who are never/light smokers or have atypical clinical features should also receive molecular testing. Testing modality: broad-panel NGS is preferred over sequential single-gene testing to conserve tissue, reduce turnaround time, and detect rare actionable alterations.
| Biomarker | Alteration Type | Frequency in Adeno | Approved Therapy | Testing Method |
|---|---|---|---|---|
| EGFR | Point mutation / small indel; exon 19 del, exon 21 L858R (classic); exon 20 ins (resistance to classic TKIs) | ~15% (Western); ~40–50% (East Asian) | Osimertinib (1st line); erlotinib, gefitinib, afatinib (older); amivantamab + lazertinib (exon 20 ins) | DNA NGS; PCR; allele-specific PCR; liquid biopsy ctDNA for T790M resistance monitoring |
| KRAS G12C | Point mutation (G12C specifically targetable) | ~13% (Western); ~5% East Asian | Sotorasib (Lumakras); adagrasib (Krazati) | DNA NGS; PCR; cobas KRAS Mutation Test (CDx for sotorasib) |
| ALK | Gene rearrangement / fusion (EML4-ALK most common) | ~3–5% | Alectinib, brigatinib, lorlatinib (2nd/3rd gen); crizotinib (older) | IHC (D5F3 clone, Ventana CDx) as screening; FISH or RNA NGS for confirmation; RNA fusion testing preferred |
| ROS1 | Gene rearrangement / fusion (CD74-ROS1 most common) | ~1–2% | Crizotinib; entrectinib; lorlatinib | FISH; RNA NGS; ROS1 IHC (D4D6 clone) for screening in experienced labs |
| MET exon 14 skipping | Splice site mutations causing exon 14 skipping → MET activation | ~3% | Capmatinib (Tabrecta); tepotinib (Tepmetko) | DNA NGS (splice site variants); RNA NGS preferred to detect exon skipping directly; IHC unreliable |
| BRAF V600E | Point mutation | ~2% | Dabrafenib + trametinib | DNA NGS; PCR; IHC (VE1 clone) for screening in some protocols |
| RET | Gene rearrangement / fusion (KIF5B-RET most common) | ~1–2% | Selpercatinib (Retevmo); pralsetinib (Gavreto) | RNA NGS preferred; FISH; RET-specific IHC not available clinically |
| NTRK1/2/3 | Gene fusion (rare but highly actionable) | <1% | Larotrectinib (Vitrakvi); entrectinib (Rozlytrek) | IHC (pan-TRK, clone A7H6R) for screening; RNA NGS for confirmation and partner identification |
| PD-L1 | Protein expression (TPS — tumour proportion score) | All NSCLC | Pembrolizumab (TPS ≥50% 1st line; ≥1% with chemo); atezolizumab; cemiplimab | IHC — 22C3 (Dako) CDx for pembrolizumab; 28-8 for nivolumab; SP142 for atezolizumab; not interchangeable |
| STK11 / KEAP1 | Loss-of-function mutations | ~10–20% (STK11), ~10% (KEAP1) | Negative predictors — STK11/KEAP1 mutation associated with reduced immunotherapy benefit even in PD-L1-high KRAS-mutant NSCLC | DNA NGS; IHC (STK11 loss useful for STK11-inactivating mutations; KEAP1 IHC less reliable) |
The tumour proportion score (TPS) counts the percentage of viable tumour cells with any partial or complete membranous PD-L1 staining at the 1+ intensity threshold. TPS is the scoring method for NSCLC. The combined positive score (CPS) — used in gastric, urothelial, cervical, and other tumour types — includes tumour cells plus immune cells and stromal cells as the numerator. For NSCLC:
World's foremost authority on lung tumour pathology. Chair of the WHO/IASLC/AMP multidisciplinary expert panel that produced the 2011 and 2015 IASLC/ATS/ERS lung adenocarcinoma classifications and co-edited the WHO 2021 Thoracic Tumours Blue Book (5th edition).
International authority on molecular testing in lung cancer pathology, EGFR/ALK/ROS1/PD-L1 biomarker testing standardisation, and CAP/IASLC/AMP molecular testing guidelines. Expert on early-stage lung cancer pathology and prognostic biomarkers.
Japan's leading lung pathologist; key contributor to WHO 2021 lung classification. Pioneer in integrated molecular-morphological classification of lung adenocarcinoma in the Asia-Pacific context; expert on EGFR mutation testing in East Asian populations.
Europe's leading lung pathologist; past president of the European Society of Pathology. International authority on PD-L1 IHC testing standardisation, the Blueprint Project (comparing PD-L1 assay comparability), and NSCLC biomarker reporting for clinical trials.
Expert in lung cytopathology and the use of cytological specimens (EBUS-FNA, effusion) for molecular testing in NSCLC. Pioneer in liquid biopsy and cell-free DNA approaches for lung cancer biomarker monitoring in Europe.
Past president of the German Society of Pathology; leading lung pathologist in Germany. Expert in neuroendocrine tumours of the lung, molecular subtyping of SCLC, and quality assurance in lung cancer molecular diagnostics.