Molecular Pathology in Oral Lesions
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Direct answer
The microscope now shares the diagnostic bench with the thermal cycler: immunohistochemistry reads proteins, fluorescent in-situ hybridisation and PCR detect the gene rearrangements and fusions that define tumours, and next-generation sequencing panels read dozens of genes from a single block of routine paraffin tissue. In the oral pathology of examinations, the payload is a map of named alterations: PTCH1 lost in the odontogenic keratocyst and germline-mutated in Gorlin syndrome; GNAS activating fibrous dysplasia and SH3BP2 mutated in cherubism; the fusion pairs CRTC1-MAML2, ETV6-NTRK3, MYB-NFIB and PLAG1/HMGA2 partitioning salivary tumours; immunoglobulin and T-cell receptor clonality separating neoplastic from reactive lymphoid infiltrates; and p16 immunohistochemistry standing in, with confirmation, for transcriptionally active HPV in oropharyngeal carcinoma.
What you must remember
- Technique-to-question mapping: immunohistochemistry (protein expression), FISH (amplifications and structural rearrangements via break-apart probes — the ETV6 assay is the example examiners quote), RT-PCR (fusion transcripts), NGS panels (many genes, small input), IgH/TCR clonality PCR (lymphoid clonality), and methylation profiling (emerging classifiers).
- Gorlin syndrome and PTCH1: germline mutation of the tumour suppressor at 9q22.3 in the Hedgehog pathway; multiple odontogenic keratocysts from the early teens, basal cell carcinomas, falx calcification, bifid ribs, palmoplantar pits, medulloblastoma risk — the jaw cysts are frequently the first sign, so the diagnosis is dental.
- Fibro-osseous genetics: GNAS activating mutations (mosaic, post-zygotic) in fibrous dysplasia; SH3BP2 mutation in cherubism — a reliable two-mark matching question.
- Salivary fusion map: CRTC1/3-MAML2 for mucoepidermoid carcinoma, ETV6-NTRK3 for secretory carcinoma (with TRK-inhibitor therapy implications), MYB/MYBL1-NFIB for adenoid cystic carcinoma, and PLAG1 or HMGA2 rearrangements in pleomorphic adenoma — with HMGA2 amplification accompanying progression to carcinoma ex pleomorphic adenoma.
- Clonality: PCR of immunoglobulin heavy chain and T-cell receptor rearrangements distinguishes monoclonal neoplasia from polyclonal reactive infiltrates — the molecular question behind every "atypical lymphoid aggregate".
- HPV surrogate: p16 immunohistochemistry overexpression in oropharyngeal carcinoma; positive staining is confirmed by E6/E7 in-situ hybridisation or PCR — surrogate and confirmatory test are separate marks.
- Odontogenic epithelium and beyond: BRAF V600E in ameloblastoma links to MAPK-targeted therapy; adamantinomatous craniopharyngioma shares CTNNB1 — developmental kinship worth a viva sentence.
- Pre-analytical limit: decalcified bone damages DNA and epitopes alike — formic acid or EDTA decalcification preserves testable material.
Where students slip
The technique-confusion pair: attributing chromosomal translocations to immunohistochemistry (protein-level, not DNA-level) or asking FISH to quantify expression — matching the platform to the question is exactly what the viva examines. The surrogate trap: calling a p16-positive oral cavity carcinoma "HPV-driven" — p16 is a functional surrogate validated in the oropharynx, and oral cavity tumours require confirmatory E6/E7 testing before any biological claim. And the integration error: offering molecular tests as the starting point rather than the finish of morphology; panels resolve selected differential questions, they do not replace the haematoxylin-eosin section that frames them — the phrase "molecular complements, never replaces, morphology" is the mark-winning sentence.
Frequently asked questions
Which gene is mutated in Gorlin syndrome?
PTCH1, a tumour suppressor on chromosome 9q22.3 of the Hedgehog pathway — germline mutations underlie the multiple keratocysts, basal cell carcinomas and skeletal signs.
Which technique detects the ETV6-NTRK3 fusion?
Break-apart FISH on tissue sections, or RT-PCR for the fusion transcript — both applicable to routine paraffin material.
What does clonality testing by PCR establish?
Monoclonal immunoglobulin or T-cell receptor gene rearrangement, separating a neoplastic lymphoid proliferation from a polyclonal reactive infiltrate.
Why is p16 called a surrogate marker?
Because HPV E7 disables retinoblastoma protein, the cell compensates with p16 overexpression; the stain marks the consequence, and confirmatory E6/E7 testing establishes HPV itself.
What mutations define fibrous dysplasia and cherubism?
GNAS activating mutations in fibrous dysplasia; SH3BP2 mutations in cherubism — both examined as fixed pairings.
Which genes are rearranged in pleomorphic adenoma?
PLAG1 and HMGA2, with HMGA2 amplification accompanying progression toward carcinoma ex pleomorphic adenoma.