The molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood. The secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 encodes structurally related phosphoproteins of which some are specifically expressed at high levels in the salivary glands and constitute major components of saliva. Here we report on recurrent rearrangements [t(4;9)(q13;q31)] in AciCC that translocate active enhancer regions from the SCPP gene cluster to the region upstream of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) at 9q31. We show that NR4A3 is specifically upregulated in AciCCs, and that active chromatin regions and gene expression signatures in AciCCs are highly correlated with the NR4A3 transcription factor binding motif. Overexpression of NR4A3 in mouse salivary gland cells increases expression of known NR4A3 target genes and has a stimulatory functional effect on cell proliferation. We conclude that NR4A3 is upregulated through enhancer hijacking and has important oncogenic functions in AciCC.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson’s disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies.

Recently, we discovered the recurrent genomic rearrangement [t(4;9)(q13;q31)] enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in “zymogen granule”-poor examples within the differential diagnostic spectrum of AciCC and MASC.

Treatment for sialolithiasis has undergone significant changes since the 1990s. Following the development of new minimally invasive and gland-preserving treatment modalities, a 40–50% rate of gland resection was reduced to less than 5%. Extracorporeal shock-wave lithotripsy (ESWL), refinement and extension of methods of transoral duct surgery (TDS), and in particular diagnostic and interventional sialendoscopy (intSE) are substantial parts of the new treatment regimen. It has also become evident that combining the different treatment modalities further increases the effectiveness of therapy, as has been especially evident with the combined endoscopic–transcutaneous approach. In the wake of these remarkable developments, a treatment algorithm was published in 2009 including all the known relevant therapeutic tools. However, new developments have also taken place during the last 10 years. Intraductal shock-wave lithotripsy (ISWL) has led to remarkable improvements thanks to the introduction of new devices, instruments, materials, and techniques, after earlier applications had not been sufficiently effective. Techniques involving combined approaches have been refined and modified. TDS methods have been modified through the introduction of sialendoscopy-assisted TDS in submandibular stones and a retropapillary approach for distal parotid sialolithiasis. Recent trends have revealed a potential for significant changes in therapeutic strategies for both major salivary glands. For the submandibular gland, ISWL has replaced ESWL and TDS to some extent. For parotid stones, ISWL and modifications of TDS have led to reduced use of ESWL and the combined transcutaneous–sialendoscopic approach. To illustrate these changes, we are here providing an updated treatment algorithm, including tried and tested techniques as well as promising new treatment modalities. Prognostic factors (e.g., the size or location of the stones), which are well recognized as having a strong impact on the prognosis, are taken into account and supplemented by additional factors associated with the new applications (e.g., the visibility or accessibility of the stones relative to the anatomy of the duct system).

Surgical resection remains the first line treatment for salivary gland cancer (SGC). In the case of locally advanced disease, surgery is followed by adjuvant radiotherapy. Surgical resection should be favored in resectable locoregional recurrent disease as well, and even the complete resection of all distant oligometastases has clinical benefit for the patients. For inoperable and disseminated metastatic disease, a multitude of systemic therapies including chemotherapy, targeted therapy, and immunotherapy are available. In this review, the current therapeutic options for inoperable recurrent or metastatic SGCs are summarized. Systemic treatment can achieve prolonged progression-free and overall survival, while the overall prognosis remains poor. Current clinical trials include only a limited number of patients and mostly combine different histologic subtypes. Additionally, no randomized controlled trial comparing different therapeutic options has been performed. In the future, further studies with a larger patient cohort and ideally only one histologic subtype are needed in order to improve the outcome for SGC patients. However, this may be difficult to accomplish due to the rarity and diversity of the disease. Additionally, molecular analyses need to be performed routinely in order to individualize treatment and to go one step further towards precision medicine.