Basal cell adenoma (BCA) is a benign salivary neoplasm that exhibits a divergent spectrum of growth patterns, including cribriform, tubular, trabecular, membranous, and solid. A subset of BCAs is characterized by the presence of abundant S100 protein-positive stroma, which makes this variant unique and potentially represents a hybrid lesion or an entity intermediate between BCA and pleomorphic adenoma (PA). From the authors' registry, we selected 17 cases of BCA with abundant S100 protein-positive stromal components and compared them with 7 cases of BCA without S100 protein-positive stroma, and 6 cases of myoepithelial cell-rich PAs. All cases were analyzed by immunohistochemistry (IHC) using antibodies to S100 protein, SOX10, PLAG1, HMGA2, p63/p40, cytokeratins, EMA, LEF1, and/or β-catenin. Next-generation sequencing (NGS), fluorescence in situ hybridization (FISH) for the rearrangement of PLAG1, and methylation analysis were performed. The BCA S100 protein stromal cell-rich group consisted of 7 males and 10 females with an average age of 62 years. Their tumors showed typical S100 protein-positive stroma, which was also positive for SOX10 in all cases. The stromal and/or epithelial components showed expression of LEF1 and β-catenin in 17 and 15 cases, respectively. HMGA2 IHC showed nuclear expression in one case while PLAG1 was negative in all cases. In 11 cases, one or more mutations were present, including CTNNB1 mutation (n = 11). The first control cohort of BCA without S100 protein-positive stroma consisted of 1 male and 6 females with an average age of 50 years. This group showed LEF1 and nuclear β-catenin expression in 1 and 2 cases, respectively. The second control group of PA (including 4 spindle-shaped cellular and 2 oncocytic PAs) was devoid of CTNNB1 mutations. Two cases presented with gene fusions, including MEG3::PLAG1 and ACTA2::PLAG1, and an additional two cases showed PLAG1 break. It has been proposed earlier that BCA is related to PA based on a shared biphasic nature and a divergent spectrum of growth patterns. Our findings suggest that BCAs with abundant S100 protein-positive stroma are tumors that morphologically display tricellular differentiation into inner (luminal) ductal epithelial cells, outer (abluminal) basaloid myoepithelial cells, and spindle-shaped stromal S100-positive cells (stromal abluminal). According to our investigation, BCAs with S100 protein-positive stroma represent a distinctive triphasic subset of BCA, which is substantially different from PA, both in immunoprofile and molecular underpinnings.

• Keywords
• Basal cell adenoma, Methylation analysis, Molecular diagnostics, Next-generation sequencing, S100 protein–positive stroma, Salivary gland,
• Publication type
• Journal Article MeSH

Canalicular tumors of the salivary glands have recently emerged as an entity characterized by distinct morphology and recurrent HMGA2 gene rearrangement. In this study, we analyzed 40 cases intending to elucidate their features further. The monophasic or biphasic tumors exhibited a growth pattern of interconnected anastomosing trabeculae and canaliculi, accompanied by a classical pleomorphic adenoma in one-third of the cases. Invasive growth into surrounding adipose tissue was revealed in one case which was, therefore, diagnosed as epithelial-myoepithelial carcinoma. Although the tumor cells uniformly expressed HMGA2 protein in all cases, cytokeratin 7, S100 protein, and SOX10 displayed either diffuse positivity or highlighted the luminal and abluminal cell populations, respectively. Areas with morphological oncocytoid change and AR-immunopositivity of luminal cells were seen in 13/14 (93%) of tested biphasic cases. HMGA2 rearrangement was detected by RNA-sequencing in 30 cases. The most common alteration was an HMGA1::WIF1 fusion, but several novel or rare fusion partners were identified, including ARID2 , FHIT , MSRB3 and its antisense variant MSRB3-AS1 , IFNG-AS1 , and the long intergenic region LINC02389 . In addition, FISH revealed HGMA2 break-apart in the remaining 10 cases where targeted sequencing failed to detect any alteration or where RNA sequencing could not be performed. Notably, the loss of the 3'-untranslated region of HMGA2 emerges as the common denominator for the described rearrangements, possibly disrupting its negative regulation by small regulatory RNAs. Awareness of this lesion ensures appropriate diagnosis and clinical management, especially with regard to the possibility of malignant transformation described in this and previous studies.

• Keywords
• apocrine transformation, canalicular adenoma-like subtype of pleomorphic adenoma, epithelial-myoepithelial carcinoma, salivary glands,
• MeSH
• Adult MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Gene Rearrangement * MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor * genetics   analysis   MeSH
• Salivary Gland Neoplasms * genetics   pathology   chemistry   MeSH
• Adenoma, Pleomorphic * genetics   pathology   chemistry   MeSH
• HMGA2 Protein * genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• 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
• HMGA2 protein, human MeSH Browser
• Biomarkers, Tumor * MeSH
• HMGA2 Protein * 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