Benign epithelial tumors

2025-04-14   Paola Dal Cin, PhD 

1.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 tumorsGenetic 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 oncocytomaOncocytoma 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 myoepitheliomaSOX10 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 adenomaNegative for IDH2 mutation.18
Cystadenoma of salivary glandNo genetic markers so far
Ductal papillomasA 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 adenomaNo genetic markers so far
Intercalated duct adenoma and hyperplasiaA 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
KeratocystomaRUNX2 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