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.

Bioptic Laboratory Ltd Plzen Czech Republic

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Department of Pathology Faculty of Medicine Sikl's Charles University E Benese 13 305 99 Plzen Czech Republic

Institute of Biomedicine Pathology Department of Pathology University of Turkuand Turku University Hospital Turku Finland

Molecular and Genetic Laboratory Bioptic Laboratory Ltd Plzen Czech Republic

Pathology Unit IRCCS Azienda Ospedaliero Universitaria Di Bologna Bologna Italy

The Fingerland Department of Pathology Faculty of Medicine Charles University Hradec Kralove and University Hospital Hradec Kralove Hradec Kralove Czech Republic

See more in PubMed

WHO Classification of Tumours Editorial Board. Head and neck tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2023 [cited 2025/01/11]. (WHO classification of tumours series, 5th ed.; vol. 9). Available from: https://tumourclassification.iarc.who.int/chapters/52 .

Dardick I, Daley TD, van Nostrand AW (1986) Basal cell adenoma with myoepithelial cell-derived “stroma”: a new major salivary gland tumor entity. Head Neck Surg 8:257–267 PubMed DOI

Hernandez-Prera JC, Skalova A, Franchi A et al (2021) Pleomorphic adenoma: the great mimicker of malignancy. Histopathology 79:279–290 PubMed DOI

Lopez-Janeiro A, Blasco-Santana L, Perez-Perez M et al (2023) Diagnostic role of DOG-1, GFAP and B-catenin in basal cell adenoma and cellular pleomorphic adenoma of the salivary gland. Head Neck Pathol 17:339–346 PubMed DOI

Seethala RR (2017) Basaloid/blue salivary gland tumors. Mod Pathol 30:S84–S95 PubMed DOI

Skalova A, Bradova M, Michal M Jr et al (2024) Molecular pathology in diagnosis and prognostication of head and neck tumors. Virchows Arch 484:215–231 PubMed DOI PMC

Skalova A, Stenman G, Simpson RHW et al (2018) The role of molecular testing in the differential diagnosis of salivary gland carcinomas. Am J Surg Pathol 42:e11–e27 PubMed DOI

Katabi N, Xu B, Jungbluth AA et al (2018) PLAG1 immunohistochemistry is a sensitive marker for pleomorphic adenoma: a comparative study with PLAG1 genetic abnormalities. Histopathology 72:285–293 PubMed DOI

Agaimy A, Ihrler S, Baneckova M et al (2022) HMGA2-WIF1 rearrangements characterize a distinctive subset of salivary pleomorphic adenomas with prominent trabecular (canalicular adenoma-like) morphology. Am J Surg Pathol 46:190–199 PubMed DOI

Mito JK, Jo VY, Chiosea SI et al (2017) HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex-pleomorphic adenoma. Histopathology 71:511–521 PubMed DOI

Capper D, Jones DTW, Sill M et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474 PubMed DOI PMC

Koelsche C, Schrimpf D, Stichel D et al (2021) Sarcoma classification by DNA methylation profiling. Nat Commun 12:498 PubMed DOI PMC

Jurmeister P, Leitheiser M, Arnold A et al (2024) DNA methylation profiling of salivary gland tumors supports and expands conventional classification. Mod Pathol 37 PubMed DOI

Landrum MJ, Lee JM, Benson M et al (2018) ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 46:D1062–D1067 PubMed DOI

Steiner P, Andreasen S, Grossmann P et al (2018) Prognostic significance of 1p36 locus deletion in adenoid cystic carcinoma of the salivary glands. Virchows Arch 473:471–480 PubMed DOI

Kawahara A, Harada H, Abe H et al (2011) Nuclear beta-catenin expression in basal cell adenomas of salivary gland. J Oral Pathol Med 40:460–466 PubMed DOI

Sato M, Yamamoto H, Hatanaka Y et al (2018) Wnt/beta-catenin signal alteration and its diagnostic utility in basal cell adenoma and histologically similar tumors of the salivary gland. Pathol Res Pract 214:586–592 PubMed DOI

Jo VY, Sholl LM, Krane JF (2016) Distinctive patterns of CTNNB1 (beta-catenin) alterations in salivary gland basal cell adenoma and basal cell adenocarcinoma. Am J Surg Pathol 40:1143–1150 PubMed DOI

Al-Fageeh M, Li Q, Dashwood WM et al (2004) Phosphorylation and ubiquitination of oncogenic mutants of beta-catenin containing substitutions at Asp32. Oncogene 23:4839–4846 PubMed DOI PMC

Bonnet C, Brahmbhatt A, Deng SX et al (2021) Wnt signaling activation: targets and therapeutic opportunities for stem cell therapy and regenerative medicine. RSC Chem Biol 2:1144–1157 PubMed DOI PMC

Suriano G, Vrcelj N, Senz J et al (2005) Beta-catenin (CTNNB1) gene amplification: a new mechanism of protein overexpression in cancer. Genes Chromosomes Cancer 42:238–246 PubMed DOI

Groenewald W, Lund AH, Gay DM. The role of WNT pathway mutations in cancer development and an overview of therapeutic options. Cells. 2023;12.