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Recent Advances in Investigation and Management of Salivary Gland Disease
Synthesised from Cummings Otolaryngology, K.J. Lee's Essential Otolaryngology, Goldman-Cecil Medicine, and current PubMed literature (2023–2026)
I. ADVANCES IN INVESTIGATION
1. Imaging
A. Ultrasound — Salivary Gland Elastography (Novel)
Standard B-mode ultrasound has been used for years, but ultrasound elastography (USE) is now an established advancement:
- Measures tissue stiffness by assessing shear wave velocity or strain — fibrotic/inflamed salivary glands (as in Sjögren syndrome) are stiffer than normal
- Two main techniques: strain elastography and shear wave elastography (SWE)
- A 2024 systematic review and meta-analysis (Dai et al., Eur Radiol, PMID 37658892) across 15 studies (816 pSS patients) showed:
- Pooled sensitivity: 80% | Pooled specificity: 87% for primary Sjögren syndrome (pSS)
- Better performance in patients aged ≤51 years
- SWE technique and measurement location are key determinants of performance
- A non-invasive, cost-effective technique that can differentiate pSS from healthy/disease controls without minor salivary gland biopsy
- A separate 2024 systematic review (Kise et al., Oral Radiol, PMID 38308723) also confirmed a role for USE in pSS diagnosis
- Point-of-care ultrasound (POCUS) is increasingly being integrated into rheumatology and ENT clinics for real-time salivary gland assessment
B. MRI with Advanced Sequences
The 2024 REFCOR (French Network of Rare Head and Neck Tumors) consensus guidelines (Varoquaux et al., Eur Ann Otorhinolaryngol, PMID 38036312) now recommend:
- MRI is the primary modality for characterising salivary gland tumours
- Required sequences include:
- Diffusion-weighted imaging (DWI) — apparent diffusion coefficient (ADC) maps help differentiate benign from malignant lesions; malignant lesions have restricted diffusion (low ADC)
- Dynamic contrast-enhanced (DCE) MRI — perfusion curves distinguish Warthin tumour (type III washout) from pleomorphic adenoma and malignancies
- MR Sialography — heavily T2-weighted; non-invasive ductal mapping; validated for Sjögren syndrome, ductal stenosis, and post-radiation xerostomia
- For malignancy: CT neck + chest for lymph node and metastasis assessment
- FDG-PET — not currently recommended in routine salivary gland tumour management (high false-positive rate from parotitis)
C. Cone Beam CT (CBCT) Sialography
- CBCT sialography provides 3D reconstruction of the ductal system with lower radiation than conventional CT
- Comparable to MR sialography for detecting sialoceles and sialoliths
- Allows virtual salivary endoscopy from 3D reconstructions in complex cases
D. Endosonography
- Emerging application of intraductal ultrasound during sialendoscopy — the endoscopic probe provides high-resolution intraluminal sonographic assessment of duct walls and periluminal structures (Brandt et al., Ultraschall Med, 2025, PMID 39706218)
2. Tissue Sampling — Core Needle Biopsy vs. FNA
Core needle biopsy (CNB) has emerged as the preferred biopsy modality over FNA in most clinical settings:
A 2026 meta-analysis (Kassem et al., Eur J Radiol, PMID 41264980) across 15 studies (3,669 patients):
| Parameter | FNA | Core Needle Biopsy |
|---|
| Sensitivity | ~68% | ~99% |
| Specificity | High (both similar) | High |
| Non-diagnostic rate | Higher | Lower |
| Repeat procedures needed | More | Fewer |
| Complications | Rare | Slightly higher hematoma risk |
| Operator dependency | Significant | Less |
- CNB shortens time-to-diagnosis, reduces repeat visits, and improves surgical planning
- Performed under ultrasound guidance with 18–22G needles
- Early meta-analyses had suggested increased risk of facial nerve damage and tumour seeding — but no major complications (nerve injury, tumour seeding) have been confirmed in current meta-analyses
3. Molecular Profiling and Biomarkers
Next-generation sequencing (NGS) / molecular tumour profiling is now central to the investigation of salivary gland malignancies (Rached et al., Cancer Treat Rev, 2024, PMID 38401478):
-
International guidelines (ESMO, NCCN) now urge routine testing of:
- Androgen receptor (AR) — in salivary duct carcinoma
- HER2 (ERBB2) — by IHC/FISH, particularly in salivary duct carcinoma
- NTRK gene fusions — in all non-adenoid cystic SGC eligible for systemic therapy
- MYB/MYBL1 rearrangements — pathognomonic for adenoid cystic carcinoma (AdCC)
- CRTC1/3::MAML2 fusion — diagnostic for mucoepidermoid carcinoma (MEC)
-
Advanced panels (NGS) also identify actionable mutations: NOTCH1/2, PI3KCA, BRAF, EGFR, FGFR
Saliva metabolomics and liquid biopsy are emerging as non-invasive investigation tools:
- Saliva is rich in proteins, metabolites, RNA, and cell-free DNA
- Salivary metabolomics may detect oral and systemic disease biomarkers (Garcia et al., Clin Oral Investig, 2024, PMID 39377832)
- Circulating tumour DNA (ctDNA) in saliva holds promise for early malignancy detection
Updated Immunohistochemistry (Swid et al., Arch Pathol Lab Med, 2023, PMID 37074867):
- Novel IHC markers now used diagnostically: NR4A3 (nuclear receptor — acinic cell carcinoma), p63/p40, SOX10, GATA3, INSM1, PLAG1 (pleomorphic adenoma)
- These improve classification in diagnostically challenging cases
II. ADVANCES IN MANAGEMENT
1. Sialendoscopy — Expanded Role and Evidence Base
Sialendoscopy is now the established gold-standard for gland-preserving management of obstructive and inflammatory salivary gland disease:
A landmark 2024 systematic review and meta-analysis (Beumer et al., Oral Dis, PMID 37486613) — 91 studies, 8,218 patients, 9,043 procedures:
| Indication | Weighted Pooled Success Rate |
|---|
| Sialolithiasis (all) | 89.6% |
| Submandibular gland | 88.3% |
| Parotid gland | 81.2% |
| Ductal stenosis | 56.3% |
| Juvenile recurrent parotitis (JRP) | 67.0% |
| Radioiodine-induced sialadenitis (RAIS) | 45.8% |
| Combined endoscope + transoral | 86.3% |
Key advances within sialendoscopy:
- Intraductal pneumatic lithotripsy — newer addition alongside Holmium laser for fragmentation of hard/large stones
- Holmium laser lithotripsy — now used safely for most stones regardless of size
- Balloon dilation + stenting — for ductal stenosis; stents kept 4 weeks to prevent re-stenosis
- Steroid irrigation — A 2026 systematic review (Teng et al., Clin Otolaryngol, PMID 41501981) found symptomatic relief irrespective of steroid type/dose; however, evidence is insufficient to determine whether benefit is from steroid or mechanical flushing alone
Sialendoscopy for JRP: A 2023 systematic review (Soriano-Martín et al., PMID 37598195) confirmed sialendoscopy as an effective intervention in JRP with saline washout + steroid instillation.
Paediatric sialendoscopy: A 2023 meta-analysis (Skalias et al., Eur Arch Otorhinolaryngol, PMID 36781439) confirmed sialendoscopy is safe and effective for sialolithiasis in children.
2. Transoral Robotic Surgery (TORS) for Salivary Gland Disease
- TORS has been applied to submandibular sialolithiasis and parapharyngeal space tumours
- A 2025 systematic review and meta-analysis (Lazzeroni et al., Am J Otolaryngol, PMID 40311492) — 23 studies, 2,520 patients:
- TORS success rate: 95.7% vs conventional transoral: 92.6%
- Transient lingual nerve neuropraxia: more common with TORS (15.8% vs 8.1%)
- No permanent lingual nerve injuries in either group
- Conclusion: TORS is a valid option; high cost mandates strict patient selection
3. Targeted Molecular Therapy — Salivary Gland Malignancies
This is the most rapidly evolving area (Steuer et al., CA Cancer J Clin, 2023, PMID 37490348; Rached et al., 2024):
| Target | Drug | Histotype | Evidence |
|---|
| NTRK fusion | Larotrectinib (TRK inhibitor) | Any SGC with NTRK fusion | ~75% response rate; FDA-approved tissue-agnostic |
| NTRK fusion | Entrectinib | Any SGC with NTRK fusion | FDA-approved |
| HER2 | Trastuzumab ± pertuzumab | Salivary duct carcinoma | Phase II trials; responses seen |
| HER2 | Trastuzumab deruxtecan (T-DXd) | HER2-positive SGC | Promising phase II data |
| Androgen receptor | Androgen deprivation therapy (ADT) | Salivary duct carcinoma (AR+) | Used in clinical practice |
| NOTCH1/2 | NOTCH inhibitors (investigational) | Adenoid cystic carcinoma | Clinical trials |
| PI3K/AKT/mTOR | Investigational | Multiple histotypes | Trials ongoing |
| BRAF V600E | Vemurafenib/dabrafenib | BRAF-mutated SGC | Case reports/small series |
| MYB/MYBL1 | No approved target yet | AdCC | Active research |
From Goldman-Cecil Medicine: "The TRK inhibitor larotrectinib can yield a response rate of 75% for tumors that harbor an NTRK gene fusion, including salivary gland cancers." This represents a paradigm shift toward histotype-agnostic, biomarker-driven therapy.
4. Adenoid Cystic Carcinoma (AdCC) — New Molecular Insights
A 2025 review (Almeida et al., Arch Oral Biol, PMID 40499274) highlights:
- MYB::NFIB and MYBL1::NFIB fusions — present in ~60–80% of AdCC; ongoing therapeutic targeting
- NOTCH1 mutations — present in high-grade transformation cases; NOTCH inhibitors under trial
- Epigenetic modifications (DNMT3A, KDM6A) — potential therapeutic targets
- AdCC is characterised by indolent but relentless progression; targeted therapy offers hope for unresectable/metastatic disease (Zupancic et al., Anticancer Res, 2024, PMID 38537991)
5. Management of Cancer Therapy-Related Salivary Dysfunction
Radiation-induced xerostomia management advances (Paz et al., J Clin Invest, 2024, PMID 39225092):
| Approach | Details |
|---|
| IMRT / proton therapy | Parotid-sparing techniques; reduces xerostomia incidence |
| Amifostine | Radioprotector; reduces radiation-induced dry mouth (modest effect) |
| Pilocarpine / cevimeline | Muscarinic agonists; current standard sialogogues |
| Botulinum toxin (novel use) | Intra-glandular injection to manage sialocele and drooling; reduces Frey syndrome |
| Acupuncture | Growing evidence for XRT-induced xerostomia |
| Stem cell therapy (emerging) | Salivary gland stem/progenitor cell transplantation post-radiation; early-phase trials |
| Gene therapy (emerging) | AQP1 (aquaporin-1) gene transfer to restore secretory function — Phase I trial (NIH) showed promising results |
| Cellular organoids (emerging) | Salivary gland organoids under development for gland regeneration after radiation damage (Wu et al., Int J Oral Sci, 2024, PMID 39482304) |
6. Radioiodine-Induced Sialadenitis (RAIS)
- Sialendoscopy (washout, mucus plug removal, dilation, stenting) has success rates of 50–100%
- Amifostine and vitamin E have been explored as protective agents with limited evidence
- Botulinum toxin injection into the parotid pre-radioiodine therapy has been studied as a protective measure (reduces salivary gland uptake)
- Intensity-modulated proton therapy — avoidance of salivary glands in thyroid cancer treatment planning
7. Sjögren Syndrome — Advances in Management
- Rituximab (anti-CD20, B-cell depletion) — used for systemic manifestations; TRACTISS and TEARS trials showed limited benefit for glandular symptoms; role still debated
- Belimumab and abatacept — under active clinical investigation
- Sialendoscopy with steroid irrigation for recurrent sialadenitis episodes (multidisciplinary salivary endoscopist + rheumatologist model)
- Salivary gland ultrasonography (B-mode + elastography) is now being integrated into 2022 ACR/EULAR classification criteria revisions and monitoring protocols
8. Surgical Advances
- Partial (extracapsular) parotidectomy — growing evidence that partial superficial parotidectomy for benign tumours has lower rates of facial nerve dysfunction and Frey syndrome compared to complete superficial parotidectomy, with no higher recurrence rates (K.J. Lee)
- Facelift (retrotragal) incision — adopted for improved cosmesis in benign disease
- Intraoperative nerve monitoring (EMG) — now standard in many centres, especially revision surgery and malignancy
- 3D virtual planning and surgical navigation for complex deep-lobe and parapharyngeal tumours
Summary of Key Recent Evidence
| Area | Advance | Level | PMID |
|---|
| Investigation | Ultrasound elastography for pSS (Se 80%, Sp 87%) | Meta-analysis | 37658892 |
| Investigation | Core needle biopsy superior to FNA (Se ~99% vs ~68%) | Meta-analysis | 41264980 |
| Investigation | MRI (DWI + DCE) as primary imaging for tumours (REFCOR guidelines) | Consensus | 38036312 |
| Management | Sialendoscopy overall success rate 80.9% (stones 89.6%) | Meta-analysis | 37486613 |
| Management | Intraductal steroids in sialendoscopy — symptomatic benefit but insufficient quantitative data | Systematic Review | 41501981 |
| Management | TORS for submandibular stones: 95.7% success | Meta-analysis | 40311492 |
| Management | Personalised molecular therapy (NTRK/HER2/AR) in SGC | Review | 38401478 |
| Management | Cancer therapy-related xerostomia: stem cell/gene therapy emerging | Review | 39225092 |
| Emerging | Salivary gland organoids for regenerative medicine | Review | 39482304 |
| Evolving landscape | AdCC: NOTCH/MYB targets; salivary duct carcinoma: HER2/AR | Review | 37490348 |