Pleomorphic adenoma (PA), the most prevalent salivary gland tumor, exhibits a diverse histological spectrum characterized by epithelial, myoepithelial, and mesenchymal patterns, and secretory products. However, a subset of PAs presents microscopic features suggestive of malignancy, leading to challenging and potentially significant diagnostic pitfalls. A comprehensive retrospective analysis was conducted on the Salivary Gland Tumor Registry, compiled by the authors. A total of 104 cases diagnosed between 1960 and 2023 were retrieved. Clinical findings, pathological features, and molecular genetic results were analyzed. In the study of 104 PA cases, 23 (22.1%) presented features suggestive of pseudoinvasion, with satellite nodules being the most common (43.5%) along with capsular penetration, irregular growth, pseudopodia, lipomatous changes, and vascular permeation. Features of pseudomalignant cytomorphology were found in 97 cases (93.3%), characterized by increased cellularity, cellular atypia, heightened proliferative activity, oncocytic metaplasia, and necrosis. Additionally, 30 cases (28.8%) displayed features resembling other defined malignant salivary gland tumors, particularly myoepithelial carcinoma, adenoid cystic carcinoma, and polymorphous adenocarcinoma. Despite PA's generally straightforward diagnosis, cases with these features may be mistakenly interpreted as malignant tumors. The shared morphocytological features underscore the complexity of an accurate diagnosis, emphasizing the need for meticulous examination and a comprehensive assessment, incorporating morphological, molecular, and immunohistochemical analyses to differentiate between benign and malignant salivary gland tumors, in selected cases.

• Keywords
• Atypical, Mimic of malignancy, Pitfall, Pleomorphic adenoma, Salivary gland neoplasms,
• MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor analysis   genetics   MeSH
• Salivary Gland Neoplasms * pathology   diagnosis   genetics   MeSH
• Adenoma, Pleomorphic * pathology   genetics   diagnosis   MeSH
• Registries MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers, Tumor MeSH

Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs in all major and minor salivary gland and seromucous gland sites. AdCCs of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost consistent presence of fusion genes MYB::NFIB , or less commonly MYBL1::NFIB. We collected a cohort of 95 cases of AdCC, which were largely characterized by canonical fusions MYB::NFIB (49 cases) or MYBL1::NFIB (9 cases). In additional 11 cases of AdCC, rearrangements in MYB or NFIB genes were detected by FISH. In addition, NGS revealed novel noncanonical fusion transcripts EWSR1::MYB ; ACTB::MYB; ESRRG::DNM3, MYB::TULP4 , and ACTN4::MYB , each of them in 1 case. The tumors that showed noncanonical fusions had features of metatypical AdCC with a diverse architecture, lobulated multinodular growth pattern, and hypercellular peripheral palisading of nuclei (2 cases), tubular hypereosinophilia (2 cases), and pale eosinophilic to vacuolated (bubbly) cytoplasm (3 cases). Our study documented 3 cases of AdCC of salivary glands harboring novel gene fusions TULP4::MYB , ACTN4::MYB , and ACTB::MYB , in 1 case each, which have not been described before. A rare EWSR1::MYB fusion was detected in 1 case. Moreover, 1 case of sinonasal metatypical AdCC showed EWSR1 rearrangement detected by FISH. Also, 1 case with an ESRRG::DNM3 fusion of unknown significance is described in this study. These discoveries illustrate how broad molecular profiling will expand understanding of changes in known entities.

• Keywords
• adenoid cystic carcinoma, salivary gland neoplasm, sinonasal,
• MeSH
• Carcinoma, Adenoid Cystic * genetics   pathology   MeSH
• Adult MeSH
• Gene Fusion MeSH
• Oncogene Proteins, Fusion * genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Gene Rearrangement MeSH
• In Situ Hybridization, Fluorescence MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Biomarkers, Tumor * genetics   MeSH
• Salivary Gland Neoplasms * genetics   pathology   MeSH
• RNA-Binding Protein EWS * genetics   MeSH
• Proto-Oncogene Proteins c-myb genetics   MeSH
• Proto-Oncogene Proteins MeSH
• Aged MeSH
• Trans-Activators genetics   MeSH
• NFI Transcription Factors genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• EWSR1 protein, human MeSH Browser
• Oncogene Proteins, Fusion * MeSH
• MYB protein, human MeSH Browser
• MYBL1 protein, human MeSH Browser
• Biomarkers, Tumor * MeSH
• NFIB protein, human MeSH Browser
• RNA-Binding Protein EWS * MeSH
• Proto-Oncogene Proteins c-myb MeSH
• Proto-Oncogene Proteins MeSH
• Trans-Activators MeSH
• NFI Transcription Factors MeSH

Salivary gland tumors are a heterogeneous group of tumors originating from the major and minor salivary glands. The pleomorphic adenoma (PA), which is the most common subtype, is a benign lesion showing a remarkable morphologic diversity and that, upon recurrence or malignant transformation, can cause significant clinical problems. Cytogenetic studies of >500 PAs have revealed a complex and recurrent pattern of chromosome rearrangements. In this review, we discuss the specificity and frequency of these rearrangements and their molecular/clinical consequences. The genomic hallmark of PA is translocations with breakpoints in 8q12 and 12q13-15 resulting in gene fusions involving the transcription factor genes PLAG1 and HMGA2. Until recently, the association between these two oncogenic drivers was obscure. Studies of the Silver−Russel syndrome, a growth retardation condition infrequently caused by mutations in IGF2/HMGA2/PLAG1, have provided new clues to the understanding of the molecular pathogenesis of PA. These studies have demonstrated that HMGA2 is an upstream regulator of PLAG1 and that HMGA2 regulates the expression of IGF2 via PLAG1. This provides a novel explanation for the 8q12/12q13-15 aberrations in PA and identifies IGF2 as a major oncogenic driver and therapeutic target in PA. These studies have important diagnostic and therapeutic implications for patients with PA.

• Keywords
• HMGA2, IGF2, PLAG1, chromosome 12q13-15, chromosome 8q12, chromosome translocation, diagnostic biomarker, gene fusion, pleomorphic adenoma, therapeutic target,
• Publication type
• Journal Article MeSH
• Review MeSH