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Recent Developments in Salivary Gland Pathology (Post-WHO 2024)

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BACKGROUND

• WHO 2024 (5th ed.) introduced new entities: mucinous adenocarcinoma, microsecretory adenocarcinoma, sclerosing microcystic adenocarcinoma (malignant); intercalated duct adenoma, striated duct adenoma, sclerosing polycystic adenoma (benign).
• Salivary gland tumor taxonomy continues to expand beyond WHO 2024, driven by molecular/genetic discoveries.

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A. NEWLY DESCRIBED (NON-WHO-LISTED) MALIGNANT ENTITIES

1. Palisading Adenocarcinoma (PaA)

• First described: Bishop et al. 2023 (9 cases)
• Demographics: Predominantly females; Asian ethnicity; median age 57 yrs
• Site: Sublingual gland (most common - rare site); also submandibular
• Morphology: Biphasic - polygonal cells in trabeculae + palisades/pseudorosettes around hyalinized stroma/vessels
• IHC: CD56+, pancytokeratin+, S100+, Androgen receptor+ | Chromogranin, Synaptophysin, INSM1 negative
• Molecular: No characteristic oncogenic driver mutation/fusion identified
• Prognosis: Favorable (no recurrence/metastasis in follow-up range 4-160 months)
• Key feature: Neuroendocrine-like morphology but neuroendocrine markers negative

2. Microcribriform Adenocarcinoma (MiA)

• First described: Weinreb et al. 2023 (4 cases); initially misclassified as MSA
• Distinguishing fusion: SS18::ZBTB7A (vs. MEF2C::SS18 in microsecretory adenocarcinoma)
• Site: Parotid, submandibular, minor glands (bronchial mucosa)
• Morphology: Cribriform, tubular, solid + multiple small "microcribriform" spaces; may show oncocytic change
• IHC: CK+, S100+, SOX10+ | p63/p40 absent (unlike MSA which is p63+)
• Prognosis: No recurrence in limited follow-up; too rare for reliable prognostic data

3. Fenestrating Adenocarcinoma (FAC)

• Fusion: EWSR1::BEND2 (highly specific)
• Site: Pharynx (base of tongue, pharyngeal wall, nasopharynx, trachea) - minor salivary glands
• Morphology: Unique fenestrated architecture; cribriform-like, dyscohesive sheets; eosinophilic/vacuolated cytoplasm; signet ring-like cells
• IHC: CK7+, BEND2+ | S100 negative; variable p63
• Key point: EWSR1::BEND2 fusion is absent in all other salivary neoplasms - diagnostic

4. Skin Analogue Poroid Carcinoma of Salivary Glands

• Fusions: YAP1/WWTR1::MAML2/NUTM1
• Site: Major and minor salivary glands
• Morphology: Monomorphic basaloid poroid cells + large eosinophilic cuticular cells; variable ductal component
• Key Differentials:
  • NUTM1-rearranged poroid vs. NUT carcinoma (both NUT immunoreactive, overlapping sites)
  • MAML2-fused poroid vs. high-grade MEC (both squamous phenotype + MAML2 rearrangement)
• IHC: p40+; loss of YAP1 C-terminus

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B. NEW SUBTYPES IN ESTABLISHED MALIGNANT ENTITIES

5. Mucoacinar Carcinoma (subtype of MEC)

• MAML2-fused (canonical MEC driver) - confirmed by FISH
• Morphology: MEC with simultaneous serous acinar differentiation (5-10% of tumor); clear cell change common
• IHC: SOX10+, DOG1+, NR4A3+ (focal, in acinar cells)
• Key trap: Can mimic Acinic Cell Carcinoma (AciCC) - molecular testing (MAML2 vs. NR4A3/MSANTD3 rearrangement) is essential
• Point to remember: Serous acinar differentiation does NOT automatically = AciCC

6. MEC Without Squamous Cell Differentiation

• Histology: No squamous cells on H&E; negative CK5/6, p63, p40 (classical squamous markers)
• Confirmed by MAML2 rearrangement (FISH/RNA-seq) - CRTC1::MAML2 (most common), CRTC3::MAML2, novel MAML2::CEP126
• Proposed updated MEC definition: "MEC = carcinoma with conventional features AND/OR MAML2 gene rearrangement"
• Subtypes recognized: Oncocytic, clear cell, spindle cell, combined

7. Metatypical Adenoid Cystic Carcinoma (AdCC)

• Morphology: Classic AdCC (cribriform) + squamous cell differentiation (keratin pearls); trabecular and macrocystic areas
• Fusions: MYB::NFIB (most common), MYBL1::NFIB; also non-canonical: EWSR1::DNM3, EWSR1::MYB, ACTN4::MYB
• Site predilection: Sinonasal tract, skull base
• Prognosis: Poor with NOTCH or BCOR mutations
• Differential: Must consider in head & neck tumors with squamous differentiation

8. AdCC with Striking Tubular Hypereosinophilia

• Series: 16 cases; exclusively from minor mucosal salivary glands
• Key morphology: Large ductal luminal cells with abundant eosinophilic cytoplasm resembling Paneth cells
• Growth patterns: Classical + glomeruloid, micropapillary, morular
• Novel fusions: EWSR1::MYB and FUS::MYB (absent in 102 classical AdCCs - diagnostic)
• Also: Can arise from/in association with respiratory epithelial adenomatoid hamartoma (REAH)

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C. NEW SUBTYPES IN ESTABLISHED BENIGN ENTITIES

9. Pleomorphic Adenoma (PA) with HMGA2::WIF1 Fusion - Canalicular/Trabecular Phenotype

• Morphology: Elongated cells in bilayered/multilayered branching trabeculae; resembles canalicular adenoma
• IHC: Nuclear HMGA2 immunopositivity
• Molecular driver: HMGA2::WIF1 fusion
• Site: Exclusively parotid gland (in the original series)
• Important: Carcinoma ex PA has been described in this phenotype

10. Triphasic Basal Cell Adenoma (BCA) with S100-Positive "Stroma" and CTNNB1 Mutation

• Key concept: Classic BCA is biphasic; this subtype is triphasic - luminal cells + abluminal cells + neoplastic S100+ spindle-shaped stromal cells
• Mutation: CTNNB1 (beta-catenin) - identical mutations in both stromal AND epithelial components (proves neoplastic nature)
• IHC: Nuclear beta-catenin+, LEF1+ in all cell types; S100+ stroma
• DNA methylation: Forms distinct cluster separate from classic BCA and PA

11. Proliferating (Metaplastic) Warthin Tumor with KRAS Mutation

• Traditional concept: "Metaplastic WT" = squamous metaplasia after FNA-induced infarction
• New finding: WTs with prominent mucoepidermoid-like/solid proliferations WITHOUT prior injury/FNA show KRAS codon 12 mutations (27% of such tumors)
• Conventional WTs: KRAS negative
• Proposed new term: "De novo proliferating Warthin tumor" - supports neoplastic (not reactive) nature

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D. EMERGING / PROPOSED ENTITIES

12. Sialadenopapillary Ductal Tumor (Unifying Concept)

• Unifies: Sialadenoma papilliferum (SP) + SP-like intraductal papillary tumor (SP-IPT) + tubulopapillary hidradenoma-like tumor
• Shared molecular driver: BRAF p.V600E mutation (SP and SP-IPT)
• Morphology resembles cutaneous adnexal tumors (syringocystadenoma papilliferum, tubular adenoma)
• Low malignant potential with risk of local aggressive growth/regional metastasis
• Proposed unifying term due to indistinguishable features

13. Thymus-like Phenotype in Non-Sebaceous Lymphadenoma (NSLA)

• Study: 20 cases; 13M:7F; median 61 yrs; all in parotid gland
• Key molecular feature: Inactivating CYLD mutations (57% of cases)
• IHC: p63/p40+, CK5/CK14+; CD5+ (65%), CD117+ (79%)
• Morphology: Large squamoid cells in anastomosing aggregates within lymphoid stroma with Hassall corpuscle-like structures
• Possible inclusion in next WHO classification under consideration

14. Biphasic Myoepithelial Carcinoma with 5p/5q Loss

• Identified by: DNA methylation profiling (forms distinct cluster)
• Demographics: Striking female predominance
• Molecular: Highly recurrent chromosome 5p/5q loss + frequent MDM2 amplification (12q)
• Morphology: Biphasic-tubular + monophasic myoepithelial areas; low atypia; minimal proliferation
• Behavior: Frequently invasive; occasional lymph node metastasis → classified as low-grade carcinoma
• IHC: MDM2 positivity helpful; DNA methylation/copy number analysis confirmatory

15. Salivary Carcinosarcoma - Reclassification

• New evidence: These are sarcomatoid carcinoma ex PA (not true biphasic neoplasms)
• Clonal origin confirmed - sarcomatoid pattern with or without heterologous mesenchymal elements (osteosarcoma, chondrosarcoma)
• Proposed preferred term: "Sarcomatoid carcinoma (with or without heterologous mesenchymal elements)"

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E. NEW GRADING SYSTEMS

Grading of Acinic Cell Carcinoma (AciCC)

• Xu et al. 2022 (117 cases, all parotid)
• Parameters (4): Mitotic activity, necrosis, tumor margin (well-defined vs. infiltrative), peripheral fibrosis
• High-grade criteria: ≥5 mitoses/10 HPF and/or necrosis
• Survival: Low/intermediate-grade: 5-yr OS ~100%; High-grade: 5-yr OS ~50%
• High-grade = independent adverse prognostic factor (p=0.025)

Grading of Secretory Carcinoma (SC)

• Bradová et al. 2023 (215 cases; 74% parotid)
• Parameters (6): Architecture, pleomorphism, mitotic/Ki-67 activity, necrosis, lymphovascular invasion, perineural spread
• High-grade criteria: Solid architecture, marked hyalinization, infiltrative invasion, nuclear pleomorphism, LVI/PNI, Ki-67 >30%
• Distribution: Grade 1: 45%, Grade 2: 42%, Grade 3: 13%
• 5-yr OS: Grade 1: 98%, Grade 2: 83%, Grade 3: 63% (p=0.0001)

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KEY EXAM SUMMARY TABLE

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KEY EXAM POINTS / MNEMONICS

1. "CAMP" fusions in AdCC: Canonical = MYB::NFIB or MYBL1::NFIB; Novel in tubular hypereosinophilia = EWSR1::MYB / FUS::MYB
2. Palisading adenocarcinoma: CD56+ but synaptophysin/chromogranin/INSM1 negative - do not call it neuroendocrine carcinoma
3. MiA vs. MSA: Same site, similar look, but MiA is p63/p40 absent; MSA is p63+ - differentiated by SS18::ZBTB7A vs. MEF2C::SS18
4. Mucoacinar carcinoma trap: MAML2 rearranged (MEC) but also DOG1/NR4A3 positive (AciCC-like) - always do molecular testing
5. KRAS in Warthin: Only in "de novo proliferating" type (no prior FNA/infarction) - not conventional WT
6. Grading memory: AciCC - 4 parameters (necrosis + mitosis = high-grade); SC - 6 parameters (Ki-67 >30% + solid = high-grade)
7. Fenestrating adenocarcinoma: Pharynx + EWSR1::BEND2 = unique combination, no other salivary tumor has this fusion