WHO Classification of Salivary Gland Tumours
The current standard for classifying salivary gland tumors is the 5th edition of the WHO Classification of Head and Neck Tumours (2022), which has significantly expanded to include new molecular-defined entities and refined existing categories based on recurrent gene fusions and molecular alterations 1.
Key Structural Framework
The WHO classification organizes salivary gland tumors into:
- Benign neoplasms
- Malignant neoplasms
- Salivary carcinoma not otherwise specified (NOS) and emerging entities
The classification emphasizes histological grading (low grade vs high grade), which is universally recognized as critical for treatment decision-making 2.
Major Updates in the 5th Edition (2022)
New Benign Entities Added:
- Sclerosing polycystic adenoma (upgraded from adenosis to neoplasm) 1, 3
- Keratocystoma 1, 3
- Intercalated duct adenoma 1
- Striated duct adenoma (now has dedicated chapter) 1, 3
- Canalicular adenoma-like variant of pleomorphic adenoma 3
New Malignant Entities Added:
- Microsecretory adenocarcinoma (defined by SS18::MEF2C fusion) 4, 1, 3
- Sclerosing microcystic adenocarcinoma (similar to skin adnexal tumors) 4, 1, 3
- Mucinous adenocarcinoma (characterized by AKT1 E17K mutations, subdivided into papillary, colloid, signet ring, and mixed subtypes) 1, 3
Entities Removed or Reclassified:
- Hemangioma, lipoma, nodular fasciitis, and hematolymphoid tumors were omitted as they don't occur exclusively in salivary glands 1
- Oncocytic carcinoma has been downgraded to "emerging entities" due to doubts about its existence as a distinct entity 3
Molecular Integration
The 5th edition heavily incorporates molecular alterations into diagnostic definitions, particularly recurrent gene fusions that are tumor-type specific 1. Key molecular features now included in entity definitions:
- Mucoepidermoid carcinoma: CRTC1-MAML2 or CRTC3-MAML2 fusions
- Adenoid cystic carcinoma: MYB-NFIB or MYBL1-NFIB fusions
- Secretory carcinoma: ETV6-NTRK3 fusion (theranostic target) 5, 1
- Polymorphous adenocarcinoma: PRKD1/2/3 alterations
- Hyalinizing clear cell carcinoma: EWSR1-ATF1 fusion
- Microsecretory adenocarcinoma: SS18-MEF2C fusion
- Mucinous adenocarcinoma: AKT1 E17K mutations
Important Conceptual Changes
Polymorphous Adenocarcinoma (PAC):
Cribriform adenocarcinoma of salivary gland origin (CASG) is now classified as a distinctive subtype of PAC 1. PAC is defined as clinically, histologically, and molecularly heterogeneous, though controversy remains about whether CASG should be separate or a variant.
Cytopathology Reporting:
For preoperative diagnosis, pathologists should use the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) 6, which includes categories:
- Non-diagnostic
- Non-neoplastic
- Atypia of undetermined significance
- Neoplasm (subdivided into benign and salivary gland neoplasm of uncertain malignant potential)
- Suspicious for malignancy
- Malignant (subdivided into low grade and high grade)
Clinical Application
For staging, the TNM AJCC/UICC classification remains the standard 2. The histological grade (low vs high) directly determines treatment intensity:
- High-grade tumors: Surgery plus postoperative radiotherapy is standard for stages II-IV 2
- Low-grade tumors: Surgery plus radiotherapy for stages III-IV only 2
Critical Pitfalls to Avoid
- Don't rely solely on morphology: Many entities now require molecular confirmation for definitive diagnosis 5, 1
- Frozen section limitations: While 99% sensitive for identifying neoplastic lesions, accuracy drops to 59% for specific malignant tumor typing 6
- Avoid major irreversible decisions (like facial nerve resection) based on indeterminate intraoperative diagnoses alone 6
The molecular revolution in salivary gland tumor classification continues to accelerate, with therapeutic implications emerging particularly for secretory carcinoma (NTRK inhibitors) and adenoid cystic carcinoma 5.