New Entities and Concepts in Salivary Gland Tumor Pathology

Ninth Princeton Integrated Pathology Symposium: Ear, Nose, and Throat Pathology

Special Section Overview

  • Topic: Salivary Gland Tumor Pathology, focusing on new entities and concepts.

  • Presenter: Raja R. Seethala, MD.

  • Focus: Molecular alterations in salivary gland tumors leading to an expansion and reclassification of tumor categories.

Context

  • Salivary gland tumors are relatively rare with evolving molecular understandings.

  • The 5th edition of the World Health Organization (WHO) Classification reflects these changes but carries complexities needing clarification.

Objectives

  • To explore how molecular alterations reclassify, justify, and define new entities in salivary gland pathology.

  • To summarize newer theranostic applications based on molecular phenotypes.

Data Sources

  • WHO classification editions (3rd to 5th).

  • Literature reviews and personal experiences noted in tumor pathology.

Conclusions

  • Molecular alterations facilitate the reclassification and defining of salivary gland tumor entities.

  • Key emerging entities include:

    • Sclerosing polycystic adenoma.

    • Microsecretory adenocarcinoma.

    • Mucinous adenocarcinoma.

  • These alterations enable targeted therapies for specific types, such as secretory carcinoma and adenoid cystic carcinoma.

Key Themes in Salivary Gland Tumor Pathology

Reclassification of Entities

  • Sclerosing Polycystic Adenoma (SPA): Formerly considered nonneoplastic; now recognized as a benign neoplasm due to PI3K pathway alterations and clonal evidence.

    • SPA has also shown local recurrence that questions its original classification.

    • Suggested connection to neoplasms due to documented cases of progression to invasive carcinoma.

Justification of Entity Placement

  • Sialadenoma Papilliferum (SP): Retained as a benign neoplasm, delineated from other papillomas.

    • SP shows a unique morphology and molecular profile differing from other ductal papillomas like inverted ductal and intraductal papillomas.

    • BRAF p.V600E mutations correlate with its classification, though its benign nature is maintained despite a higher recurrence rate compared to other papillomas.

Definition of New Entities

  • Microsecretory Adenocarcinoma (MSA): A new type of low-grade malignancy arising predominantly in minor salivary glands, recognized for characteristic MEF2C::SS18 fusions.

    • Morphology includes ductal components with distinct myxoid stroma.

    • Differential diagnosis should involve secretory carcinoma, which has distinctly different cellular characteristics and immunohistochemical profiles.

Reinstate Previous Entities

  • Mucinous Adenocarcinoma (MAdC): Previously collapsed into generalized adenocarcinoma categories, reinstated due to molecular and morphological distinctions now recognized.

    • Characterized by AKT1 mutations and, in some cases, TP53 mutations, differentiating it from the less aggressive SG-IPMN variant.

Expansion of Subtype Spectrum

  • Mucoepidermoid Carcinoma (MEC): Recognized as the most common salivary malignancy in North America, showing an increased morphological spectrum validated by CRTC1::MAML2 fusions.

    • Subtypes identified include oncocytic and clear cell variants, often confused with benign lesions.

Formation of Continuity Across Entities

  • Intraductal Carcinoma (IDC): Undergoes ongoing classification changes, marking connections between various salivary ductal lesions.

    • Recognized subtypes include intercalated duct, oncocytic IDC, and apocrine IDC.

    • Each subtype displays a distinctly overlapping yet defining molecular profile, complicating diagnosis and management.

Therapeutic Relevance

  • Molecular characteristics of tumors beyond salivary duct carcinoma (e.g., SC and ACC) demonstrate burgeoning theranostic significance.

    • Secretory Carcinoma (SC): Identified with NTRK fusions, particularly relevant with recent FDA-approved therapies targeting these alterations.

    • Adenoid Cystic Carcinoma (ACC): Demonstrates MYB activation and various targetable pathways for ongoing treatment evaluation.

Future Directions

  • Continued evolution of molecular alterations necessitates careful classification approaches.

    • Strategies may evolve with advances in data science and machine learning to refine tumor entity discernment.

    • The growing understanding of tumor immune microenvironments and epigenetic factors will be critical for future diagnostics and therapeutics.

Summary of WHO 5th Edition Findings

  • The 5th edition integrates molecular features into the classification of salivary gland tumors, enhancing traditional methods and improving therapeutic strategies.