Benign epithelial tumors
2025-04-14 Paola Dal Cin, PhD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
Classification
Definition
The majority (80%) of salivary neoplasms are benign. However, pleomorphic adenomas (PA) carry a considerable risk (5-15%) for malignant transformation, aswell as, basal cell adenomas and Warthin tumors but with much lesser degree, while the other eight types virtually never develop into malignancy. 1
Recurrent gene fusions are common in salivary gland tumors including benign tumors, such as pleomorphic adenoma, myoepithelioma and keratocystoma.
PLAG1 rearrangement in conjunction SOX10 and/or S100 protein immunopositivity in conjunction assisted in reclassification of a subset of oncocytomas as oncocytic variants of pleomorphic adenomas and myoepitheliomas, harboring recurrent ZBTB47-AS1::PLAG1 fusion.2,3The HMGA2::-WIF1 fusion, characterizing a specific PA with a canalicular adenoma -like pattern can also show malignancy and adverse outcome. 4
Mutations have emerged recently as potential drivers in several benign salivary gland entities including BRAF V600E mutations in sialdenoma papilliferum,AKT1mutations in intraductal papilloma/ papillary mucinous neoplasms, PIK3CA mutations in sclerosing polycystic adenoma, IDH2 mutations in striated duct adenoma and HRAS/CTNNB1 mutations in a subset of intercalated duct hyperplasia/adenoma and a subset of de novo proliferating Warthin tumors. 5
| Salivary gland tumors | |
|---|---|
| Benign epithelial tumors | Genetic event(s) |
| Pleomorphic adenoma (PA) | Involvement of PLAG1 at 8q12 (50% ) , or HMGA2 at 12q14.3 (10-20%) have been reported in most PA cases. 6PLAG1 and HMGA2 alterations can be confirmed either by FISH or immunohistochemistry. 7 t(3;8)(p21;q12) /PLAG1::CCNNB1 been the most frequent translocation in PA resulting in ectopic overexpression of a normal PLAG1 oncoprotein due to promoter swapping. Additional PLAG1 partners genes have been identified e.g., LIFR, TGFBR3, GEM, ACTA2, TMTC2,ND4,and some as cryptic rearrangements CHCHD7, TCEA1 , FGFR1. 8 In addition, to NFIB and FHIT, there are additional known fusion partner genes to HMGA2 in PA, including FTO, HELB, TMTC2, RPSAP52, WIF1 and more 8,9 Notably, the loss of the 3'-untranslated region of HMGA2 is a common denominator for the described rearrangements, possibly disrupting its negative regulation by small regulatory RNAs.10 |
| Some oncocytic PA variants are characterized by a recurrent ZBTB47-AS1::PLAG1 fusion. 2,3 A small group of PAs may contain only trisomy 8/8q , or and other random aberrations have bee described. Some PA with del(12) (q13q5), showed also dmin/hsr with HMGA2/ MDM2 amplification. 8 | |
| The HMGA2::-WIF1 fusion resulted from a cryptic paracentric inversion of 12q14-15 characterizes a PA with a characteristic canalicular adenoma -like pattern. 11 However, these tumours are not always benign, they can show malignancy and adverse outcome. 4 Interesiting, HMGA2::WIF1 fusion has been detected in 2 cases of mammary adenomyoepithelioma. 12 | |
| New clues studying Silver–Russel syndrome, with mutations in IGF2/HMGA2/PLAG1, identified IGF2 as a major oncogenic driver and therapeutic target in PA. 8 | |
| Basal cell adenoma (BCA) | CTNNB1 activating mutations, occur frequently in BCA , as well as, rarely, CYLD mutations, but occurring in differing domains than the basel cell adenocarcinoma . 13 |
| Warthin tumor (WT) | Absence of MAML2 rearrangement in any conventional or metaplastic WT to exclude mucoepidemoid carcinoma. 14,15 |
| Salivary oncocytoma | Oncocytoma negative for S100 protein and SOX10 by immuno histochemistry were FISH negative for PLAG1 rearrangement. 2 Interestingly, salivary oncocytomas appear to be a unique tumor related to Birt-Hogg-Dube syndrome, belongs to the family of so-called “hereditary hamartoma syndromes”.16 |
| Salivary gland myoepithelioma | SOX10 and/or S100 protein immunopositivity in conjunction with PLAG1 rearrangement will help in reclassification of a subset of oncocytomas as oncocytic variants of salivary myoepithelioma (ME). Althoguth several PLAG1 partner genes have been reported , a molecularly distinct subset of oncocytic salivary myoepithelioma harbored a recurrent ZBTB47-AS1::PLAG1 gene fusion. 2,3 EWSR1 rearrangement was present in a subset of cases with variable morphological features ,and therfore not helpful to distinguish malignant from benign myoepithelial tumors of salivary glands. 17 |
| Canalicular adenoma | Negative for IDH2 mutation.18 |
| Cystadenoma of salivary gland | No genetic markers so far |
| Ductal papillomas | A single case of inverted with HRAS mutation was reported. 19 |
| Intraductal papilloma represents the least common variant of ductal papilloma, affecting maily mainly the oral minor salivary glands, rarely the major salivary glands. Amplicon-based massive parallel sequencing revealed identical AKT1 p.Glu17Lys mutation, but absence of concurring mutations in other genes of the RAS or PI3K pathways. 20 | |
| Sialadenoma papilliferum (SP) | Classic SP subtypes are SOX10-positive and harbor BRAF V600E mutations , whereas the oncocytic SP subtypes are SOX10-negative with BRAF wild-type. Rarely HRAS muation was reported.21 |
| Lymphadenoma (LAD) | Absence of MAML2 rearrangement.22 |
| Sebaceous adenoma | No genetic markers so far |
| Intercalated duct adenoma and hyperplasia | A subset of intercalated duct lesions harbors CTNNB1 mutation mainly in hyperpastic lesion and HRAS mutation in adenomas .23 |
| Striated duct adenoma (SDA) | Recurrent IDH2 R172X mutations observed by either molecular testing or immunohistochemistry 18,24 The same muataions have been also reported in tall-cell carcinoma with reversed polarity (TCCRP) of the breast.25 |
| Sclerosing polycystic adenoma (SPA) | Recurrent genetic alterations are reported in the PI3k/Akt pathway, including PIK3CA, AKT1,HRAS ,PTEN. 26 A single case show a TFG::PIK3CA fusion. 27 |
| Keratocystoma | RUNX2 rearrangements were detected , mainly as IRF2BP2::RUNX2.28 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 3120970 | 1987 | An outline of formal logic and its applications in medicine--II. | Slaney JK et al |
| 2 | 32673681 | 2020 | What is hiding behind S100 protein and SOX10 positive oncocytomas? Oncocytic pleomorphic adenoma and myoepithelioma with novel gene fusions in a subset of cases. | Baněčková M et al |
| 3 | 38497430 | 2024 | Characterization of a Molecularly Distinct Subset of Oncocytic Pleomorphic Adenomas/Myoepitheliomas Harboring Recurrent ZBTB47-AS1::PLAG1 Gene Fusion. | Alsugair Z et al |
| 4 | 37849332 | 2024 | Expanding the histological spectrum of salivary gland neoplasms with HMGA2::WIF1 fusion emphasising their malignant potential: a report of eight cases. | Katabi N et al |
| 5 | 35312980 | 2022 | Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Salivary Glands. | Skálová A et al |
| 6 | 39812386 | 2025 | The Transcriptomic and Gene Fusion Landscape of Pleomorphic Salivary Gland Adenomas. | Afshari MK et al |
| 7 | 35265254 | 2022 | HMGA2 Immunoexpression is frequent in salivary gland pleomorphic adenoma: immunohistochemical and molecular analyses of PLAG1 and HMGA2 in 25 cases. | Owosho AA et al |
| 8 | 36009517 | 2022 | Chromosome Translocations, Gene Fusions, and Their Molecular Consequences in Pleomorphic Salivary Gland Adenomas. | Stenman G et al |
| 9 | 39089476 | 2024 | Beneath HMGA2 alterations in pleomorphic adenomas: Pathological, immunohistochemical, and molecular insights. | Alsugair Z et al |
| 10 | 17322030 | 2007 | Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. | Mayr C et al |
| 11 | 34324456 | 2022 | HMGA2-WIF1 Rearrangements Characterize a Distinctive Subset of Salivary Pleomorphic Adenomas With Prominent Trabecular (Canalicular Adenoma-like) Morphology. | Agaimy A et al |
| 12 | 32550265 | 2020 | Pleomorphic adenomas and mucoepidermoid carcinomas of the breast are underpinned by fusion genes. | Pareja F et al |
| 13 | 33526221 | 2021 | Basal Cell Adenoma and Basal Cell Adenocarcinoma. | Robinson RA et al |
| 14 | 24121173 | 2013 | CRTC1-MAML2 and CRTC3-MAML2 fusions were not detected in metaplastic Warthin tumor and metaplastic pleomorphic adenoma of salivary glands. | Skálová A et al |
| 15 | 32222825 | 2020 | MAML2 rearrangement as a useful diagnostic marker discriminating between Warthin tumour and Warthin-like mucoepidermoid carcinoma. | Bieńkowski M et al |
| 16 | 39614964 | 2024 | Salivary Gland Oncocytomas. A Systematic Review. | Alberto PL et al |
| 17 | 28648935 | 2017 | EWSR1 rearrangement is present in a subset of myoepithelial tumors of salivary glands with variable morphology and does not correlate with clinical behavior. | Ni H et al |
| 18 | 36510691 | 2023 | Recurrent IDH2 Mutations in Salivary Gland Striated Duct Adenoma Define an Expanded Histologic Spectrum Distinct From Canalicular Adenoma. | Rooper LM et al |
| 19 | 34547823 | 2021 | Activating HRAS mutation in a case of inverted ductal papilloma of the salivary gland. | Ide F et al |
| 20 | 29738361 | 2018 | Intraductal Papillary Mucinous Neoplasms of Minor Salivary Glands With AKT1 p.Glu17Lys Mutation. | Agaimy A et al |
| 21 | 33526222 | 2021 | Sialadenoma Papilliferum. | Hsieh MS et al |
| 22 | 32960941 | 2021 | Reevaluation of Salivary Lymphadenoma: A Subgroup Identified as Warthin-like Mucoepidermoid Carcinoma Following Molecular Investigation for MAML2 Rearrangement. | Zhang C et al |
| 23 | 36480093 | 2023 | A Subset of Salivary Intercalated Duct Lesions Harbors Recurrent CTNNB1 and HRAS Mutations: A Molecular Link to Basal Cell Adenoma and Epithelial-Myoepithelial Carcinoma? | McLean AC et al |
| 24 | 39347880 | 2024 | Striated Duct Adenoma: A Case Report and a Scoping Review. | Martins-Chaves RR et al |
| 25 | 27913435 | 2016 | IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity. | Chiang S et al |
| 26 | 35447367 | 2022 | Sclerosing polycystic adenoma - A review. | Petersson F et al |
| 27 | 34410594 | 2022 | Sclerosing Polycystic Adenoma: Conclusive Clinical and Molecular Evidence of Its Neoplastic Nature. | Hernandez-Prera JC et al |
| 28 | 38084005 | 2024 | Keratocystoma: A Distinctive Salivary Gland Neoplasm Characterized by RUNX2 Rearrangements. | Bishop JA et al |
Citation
Paola Dal Cin, PhD
Benign epithelial tumors
Atlas Genet Cytogenet Oncol Haematol. 2025-04-14
Online version: http://atlasgeneticsoncology.org/solid-tumor/209322/benign-epithelial-tumors
