Salivary Gland Tumour Genetics: Fusions, Mutations, IHC Surrogates (WHO 5th Edition), Virtual Slides and MCQs

Chromosomes and a fusion gene illustrating salivary gland tumour genetics

Subtitle: The fusions and mutations that define salivary gland tumours in the WHO 5th edition, their immunohistochemical surrogates and how they help in practice, with virtual slides and 10 MCQs.

Author: PathologyMCQ Editorial Board

Category: Head and Neck Pathology

Last Updated: October 2026

Read Time: 9 minutes

At-a-Glance

Many salivary tumours have a defining fusion or mutation; molecular testing helps when morphology overlaps.
Key pairs: secretory carcinoma–ETV6::NTRK3, mucoepidermoid–CRTC1::MAML2, adenoid cystic–MYB::NFIB, hyalinizing clear cell–EWSR1::ATF1, pleomorphic adenoma–PLAG1/HMGA2.
Several have IHC surrogates: pan-TRK, MYB, PLAG1, HMGA2, NR4A3.
Some alterations are treatment targets: NTRK (TRK inhibitors), HER2 and AR (salivary duct carcinoma).

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Master Table

Salivary gland tumours: defining alterations

Tumour	Alteration	IHC clues
Pleomorphic adenoma	PLAG1 (8q12) or HMGA2 (12q14-15) rearrangement	PLAG1, HMGA2
Carcinoma ex pleomorphic adenoma	PLAG1/HMGA2 plus TP53, HER2 and others	Depends on carcinoma type
Mucoepidermoid carcinoma	CRTC1::MAML2 t(11;19); CRTC3::MAML2	p63/p40 in epidermoid cells; mucicarmine
Adenoid cystic carcinoma	MYB::NFIB t(6;9); MYBL1::NFIB	CD117 luminal, p63 abluminal, MYB
Secretory carcinoma	ETV6::NTRK3 t(12;15); rarely ETV6::RET, ETV6::MET	S100, mammaglobin, SOX10, pan-TRK (nuclear)
Acinic cell carcinoma	t(4;9) enhancer hijacking upregulates NR4A3	DOG1, SOX10, NR4A3 (nuclear)
Hyalinizing clear cell carcinoma	EWSR1::ATF1 t(12;22)	p63/p40 positive; myoepithelial markers negative
Polymorphous adenocarcinoma	PRKD1 E710D (classic); PRKD1/2/3 fusions (cribriform subtype)	S100, SOX10; p63 positive, p40 negative
Salivary duct carcinoma	HER2 amplification, TP53, PIK3CA, HRAS	AR, GATA3, HER2
Epithelial-myoepithelial carcinoma	HRAS Q61 mutation	Bilayered: CK7 luminal, p63/SMA abluminal
Intraductal carcinoma	NCOA4::RET (intercalated duct type)	S100, SOX10; intact myoepithelial rim
Microsecretory adenocarcinoma	MEF2C::SS18	S100, SOX10, p63 positive; p40 negative
Salivary mucinous adenocarcinoma	AKT1 E17K	—

Tumour by Tumour

1. Secretory Carcinoma

Alteration: ETV6::NTRK3 from t(12;15)(p13;q25); alternative ETV6 partners in a minority.
Morphology: microcystic and follicular spaces with eosinophilic, bubbly secretions; low-grade nuclei.
IHC: S100, mammaglobin, SOX10, GATA3; nuclear pan-TRK; DOG1 usually negative.
Why it matters: usually indolent, and NTRK fusions can be targeted with TRK inhibitors.

Secretory carcinoma histology — Image: hisham.h.alshuaibi

2. Hyalinizing Clear Cell Carcinoma

Alteration: EWSR1::ATF1 from t(12;22)(q13;q12).
Morphology: cords and nests of clear to pale cells in hyalinised stroma, usually in minor glands.
IHC: p63/p40 positive; myoepithelial markers (SMA, calponin) negative.
Pitfall: EWSR1::ATF1 also occurs in clear cell sarcoma and angiomatoid fibrous histiocytoma.

Hyalinizing clear cell carcinoma histology — Image: hisham.h.alshuaibi

3. Mucoepidermoid Carcinoma

Alteration: CRTC1::MAML2 from t(11;19)(q21;p13); CRTC3::MAML2 less often.
Morphology: mucous, epidermoid and intermediate cells; cystic spaces and mucin pools.
IHC: p63 and p40 in epidermoid and intermediate cells; mucicarmine highlights mucocytes.
Why it matters: fusion is commonest in low and intermediate grade tumours and supports the diagnosis in unusual variants.

Mucoepidermoid carcinoma histology — Image: hisham.h.alshuaibi

4. Adenoid Cystic Carcinoma

Alteration: MYB::NFIB from t(6;9)(q22-23;p23-24); MYBL1 rearrangement in some.
Morphology: tubular, cribriform and solid patterns; frequent perineural invasion.
IHC: luminal CK7 and CD117; abluminal p63, SMA and S100; MYB overexpression.
Why it matters: relentless course with late distant metastasis; a predominantly solid pattern is associated with worse outcome.

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5. Polymorphous Adenocarcinoma

Alteration: PRKD1 E710D hotspot mutation (classic); PRKD1/2/3 fusions in the cribriform subtype.
Morphology: uniform cells with varied architecture (targetoid, trabecular, papillary, cribriform), mostly in the palate.
IHC: S100, SOX10, CK7; p63 positive but p40 negative.
Why it matters: the p63+/p40− profile helps separate it from adenoid cystic carcinoma, which has a p40-positive abluminal layer, and from mucoepidermoid carcinoma.

Polymorphous adenocarcinoma histology — Image: hisham.h.alshuaibi

6. Salivary Duct Carcinoma

Alteration: HER2 amplification in a subset; TP53, PIK3CA, HRAS mutations.
Morphology: resembles high-grade breast ductal carcinoma, with comedonecrosis and apocrine cells.
IHC: AR, GATA3, GCDFP-15; HER2 in a subset.
Why it matters: aggressive; HER2-directed and androgen-deprivation therapies are options.

7. Pleomorphic Adenoma and Carcinoma ex Pleomorphic Adenoma

Alteration: PLAG1 (8q12) or HMGA2 (12q14-15) rearrangement.
Morphology: ducts, myoepithelial cells and chondromyxoid stroma.
IHC: PLAG1 and HMGA2 immunostains support the diagnosis.
Carcinoma ex PA: carcinoma arising in PA, with added TP53 or HER2 alterations; extent of invasion predicts behaviour.

Pleomorphic adenoma histology — Image: hisham.h.alshuaibi

8. Salivary Mucinous Adenocarcinoma

Alteration: AKT1 E17K.
Morphology: rare carcinoma with abundant extracellular mucin and papillary or cystic epithelium.

9. Microsecretory Adenocarcinoma

Alteration: MEF2C::SS18.
Morphology: microcysts and tubules lined by attenuated intercalated duct-like cells with basophilic secretions (secretory carcinoma has eosinophilic secretions).
IHC: S100, SOX10, p63 positive; p40 negative.

Microsecretory adenocarcinoma overview — Microsecretory adenocarcinoma.

Microsecretory adenocarcinoma with basophilic secretions — Microsecretory adenocarcinoma with numerous basophilic secretions.

10. Acinic Cell Carcinoma

Alteration: t(4;9)(q13;q31) places active secretory gene enhancers next to NR4A3 (enhancer hijacking), so NR4A3 is upregulated; there is no fusion protein.
Morphology: serous acinar cells with basophilic, zymogen-rich cytoplasm in solid, microcystic, follicular or papillary-cystic patterns.
IHC: DOG1, SOX10 and strong nuclear NR4A3; mammaglobin negative (helps exclude secretory carcinoma).
Behaviour: usually low grade, but high-grade transformation can occur.

Acinic cell carcinoma histology — Image: hisham.h.alshuaibi

Virtual Slides

Compare four tumours with defining alterations. Tap an annotated region to zoom to it.

Virtual slides · real casesSalivary gland tumours

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What to look for

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Summary Infographics

Summary of genetic alterations in salivary gland tumours — Summary: genetic alterations in salivary gland tumours.

Salivary tumour genetics summary table — Image: Brian Cox, MD, MAS

Salivary tumour genetics summary table, continued — Image: Brian Cox, MD, MAS

Test Yourself: 10 MCQs

Salivary gland tumour genetics: 10 MCQs

Fusions, mutations and IHC surrogates, with instant explanations.

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More practice: the salivary gland histology and IHC →

Exam Pearls

ETV6::NTRK3: secretory carcinoma (also infantile fibrosarcoma, secretory breast carcinoma).
CRTC1::MAML2: mucoepidermoid carcinoma.
MYB::NFIB: adenoid cystic carcinoma.
EWSR1::ATF1: hyalinizing clear cell carcinoma.
PRKD1: polymorphous adenocarcinoma.
PLAG1 or HMGA2: pleomorphic adenoma.
NR4A3: acinic cell carcinoma.
MEF2C::SS18: microsecretory adenocarcinoma; AKT1 E17K: mucinous adenocarcinoma.
HRAS: epithelial-myoepithelial carcinoma; NCOA4::RET: intraductal carcinoma.

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