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 | |
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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
Citation
Paola Dal Cin
Benign epithelial tumors
Atlas Genet Cytogenet Oncol Haematol. 2025-04-14
Online version: http://atlasgeneticsoncology.org/solid-tumor/209322