Salivary Gland Adenoid Cystic Carcinoma Research Articles

Salivary gland adenoid cystic carcinoma in the U.S population: Importance of grade, site of metastases, and adjuvant radiation for survival

BackgroundAdenoid cystic carcinoma (AdCC) is a rare and relatively heterogenous salivary gland malignancy, for which there is debate regarding grading, and clinical prognostic factors, including the role of adjuvant radiotherapy. MethodsSurveillance, Epidemiology, and End Results (SEER) data were reviewed for AdCC cases from 2000 to 2018. ResultsA total of 1978 patients with AdCC were identified. Most patients were between 50 and 59 years of age (21.4 %), female (59.9 %), and Caucasian (76.8 %). Most tumors were localized at presentation (44.3 %), and moderately differentiated (or grade II) (43.7 %). Overall and DSS 5-year survival rates were 70.7 % (95 % CI, 69.9–78.8), and 78.6 % (95 % CI, 77.6–79.6). The best overall 5-year survival rate was observed for those treated with surgery plus radiation, 76.8 % (95 % CI, 75.5–78.1). Multivariate analysis revealed male sex, age > 65 (H.R. 2.659 (95 % CI,2.291–3.098), p < .001), grade III/IV (H.R.5.172 (95 % CI, 3.418–7.824), p < .001), nodal metastasis, distant metastasis (H.R. 2.400 (95 % CI, 2.178–2.645), p < .001), chemotherapy only, and combination therapy as negative prognostic factors, and receiving surgery plus radiation therapy (H.R.0.586 (95 % CI, 0.505–0.679), p < .001) as a positive prognostic factor. When limited just to the lungs, had much better survival than those patients with distant metastases to other sites such as the bones and liver (p < .001). ConclusionThis SEER study identifies grade, particularly III and IV, to be the strongest single predictor of worse survival. Patients did best when treated with surgery and postoperative radiotherapy. These results can inform future management of patients with this challenging cancer type.

Omission of radiotherapy to lymph node level III in patients with cN0 adenoid cystic carcinoma of the major salivary gland: a single center experience.

Due to the rarity of adenoid cystic carcinoma (ACC) of the major salivary gland, there is no consensus on the extent of prophylactic neck irradiation (PNI) for patients with clinically negative lymph nodes (cN0) disease. We conducted a retrospective analysis of all patients with ACC of the major salivary gland who received treatment at our center between January 2010 and April 2020. The primary endpoint was regional failure-free survival(RRFS). Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), and acute toxicity. A total of 139 patients were included in the analysis. For cN0 patients, the 5-year RRFS, OS, DMFS, and LRFS were 93.2%, 90.2%, 75.7%, and 91.4%, respectively. Multivariate analysis revealed that PORT was an independent prognostic factor for RRFS and LRFS. No statistically significant differences were observed between the Level III sparing PNI group and the Standard PNI group in terms of RRFS, OS, DMFS, and LRFS. The doses delivered to the larynx and thyroid in the Level III sparing PNI group were significantly lower than those in the Standard PNI group. In patients with cN0 ACC of the major salivary gland, PNI improves regional control, and the level III nodal region sparing radiotherapy does not increase the risk of level III recurrence, while potentially reducing toxicity.

Cell-type-specific tumour sensitivity identified with a bromodomain targeting PROTAC in adenoid cystic carcinoma.

Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy with limited treatment options. The development of novel therapies is hindered by a lack of preclinical models. We have generated ACC patient-derived xenograft (PDX) lines that retain the physical and genetic properties of the original tumours, including the presence of the common MYB::NFIB or MYBL1::NFIB translocations. We have developed the conditions for the generation of both 2D and 3D tumour organoid patient-derived ACC models that retain MYB expression and can be used for drug studies. Using these models, we show in vitro and in vivo sensitivity of ACC cells to the bromodomain degrader, dBET6. Molecular studies show a decrease in BRD4 and MYB protein levels and target gene expression with treatment. The most prominent effect of dBET6 on tumours in vivo was a change in the relative composition of ACC cell types expressing either myoepithelial or ductal markers. We show that dBET6 inhibits the progenitor function of ACC cells, particularly in the myoepithelial marker-expressing population, revealing a cell-type-specific sensitivity. These studies uncover a novel mechanistic effect of bromodomain inhibitors on tumours and highlight the need to impact both cell-type populations for more effective treatments in ACC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

909P TROP2 expression in salivary gland adenoid cystic carcinoma (ACC): A new potential therapeutic target for the non-solid subtype

909P TROP2 expression in salivary gland adenoid cystic carcinoma (ACC): A new potential therapeutic target for the non-solid subtype

Salivary glands adenoid cystic carcinoma: a molecular profile update and potential implications.

Adenoid cystic carcinoma (ACC) is an aggressive tumor with a high propensity for distant metastasis and perineural invasion. This tumor is more commonly found in regions of the head and neck, mainly the salivary glands. In general, the primary treatment modality for ACC is surgical resection and, in some cases, postoperative radiotherapy. However, no effective systemic treatment is available for patients with advanced disease. Furthermore, this tumor type is characterized by recurrent molecular alterations, especially rearrangements involving the MYB, MYBL1, and NFIB genes. In addition, they also reported copy number alterations (CNAs) that impact genes. One of them is C-KIT, mutations that affect signaling pathways such as NOTCH, PI3KCA, and PTEN, as well as alterations in chromatin remodeling genes. The identification of new molecular targets enables the development of specific therapies. Despite ongoing investigations into immunotherapy, tyrosine kinase inhibitors, and anti-angiogenics, no systemic therapy is approved by the FDA for ACC. In this review, we report the genetic and cytogenetic findings on head and neck ACC, highlighting possible targets for therapeutic interventions.

Identification of MicroRNA Expression Profiles Related to the Aggressiveness of Salivary Gland Adenoid Cystic Carcinomas.

Adenoid cystic carcinoma (ACC) has been reported as the second most common carcinoma of the salivary glands. Few studies have associated miRNA expression with ACC aggressiveness. In this study, we evaluated the miRNA profile of formalin-fixed, paraffin-embedded (FFPE) samples of salivary gland ACC patients using the NanoString platform. We studied the miRNA expression levels associated with the solid growth pattern, the more aggressive histologic feature of ACCs, compared with the tubular and cribriform growth patterns. Moreover, the perineural invasion status, a common clinicopathological feature of the disease that is frequently associated with the clinical progression of ACC, was investigated. The miRNAs showing significant differences between the study groups were selected for target prediction and functional enrichment, which included associations with the disease according to dedicated databases. We observed decreased expression of miR-181d, miR-23b, miR-455, miR-154-5p, and miR-409 in the solid growth pattern compared with tubular and cribriform growth patterns. In contrast, miR-29c, miR-140, miR-195, miR-24, miR-143, and miR-21 were overexpressed in patients with perineural invasion. Several target genes of the miRNAs identified have been associated with molecular processes involved in cell proliferation, apoptosis, and tumor progression. Together, these findings allowed the characterization of miRNAs potentially associated with aggressiveness in salivary gland adenoid cystic carcinoma. Our results highlight important new miRNA expression profiles involved in ACC carcinogenesis that could be associated with the aggressive behavior of this tumor type.

Adenoid Cystic Carcinoma of Salivary Glands: A Ten-Year Review and an Assessment of the Current Management, Surgery, Radiotherapy, and Chemotherapy.

Adenoid cystic carcinoma (ACC) is a rare cancer that arises from the salivary glands and other sites in the body, such as the lung and breast. Although the tumor accounts for 10% of all salivary gland malignancies, it only accounts for 1% of head and neck malignancies. It can affect both major and minor salivary glands; here, it is called salivary gland adenoid cystic carcinoma or SACC, with a slight predilection to the latter, and commonly manifests between the 6th and 7th decades of life. The disease also shows a slight female predilection, with a reported female to male ratio of 3 : 2. Lesions of SACC are often insidious and slow-growing, and symptoms such as pain and altered sensation are frequently associated with advanced stages of the disease. Salivary adenoid cystic carcinoma is characterized by perineural invasion (PNI), a distinctive feature that potentially plays a significant role in the tumor's relapse and recurrence, which is approximately 50%. The disease is not prevalent, and its etiopathogenesis is poorly understood, although several genetic patterns and biomarkers have been linked to its initiation and/or progression. The discovery of these mutations and biomarkers has encouraged several clinical studies to use therapeutic agents to target the specific receptors on the cancer cells to potentially prevent further proliferation of the tumor cells and metastasis of the disease. Diagnosis of SACC is often challenging and frequently requires a combination of clinical examination, imaging, and histopathology. Management of SACC is primarily surgical excision, while radiotherapy has shown to be effective in improving local control in cases with microscopic residual disease. However, treatment of recurrent or metastatic tumors by radiotherapy with or without chemotherapy has so far shown limited success. The aim of this thesis is to provide an update of literature on SACC with a particular focus on the latest management approaches and future trends.

Immunoexpression of Autophagy-Related Proteins in Salivary Gland Tumors: An Exploratory Study.

Autophagy is a cellular survival mechanism involved in several human diseases, but its participation in the development of salivary gland tumors is not fully understood. This study investigated the immunoexpression of autophagy-related proteins (autophagy-related 7 [Atg7], microtubule-associated protein 1 light chain 3A [LC3A], microtubule-associated protein 1 light chain 3B [LC3B], protein p62 [p62], and phosphorylated mammalian target of rapamycin [p-mTOR]) in pleomorphic adenoma (PA), polymorphous adenocarcinoma (PAC), mucoepidermoid carcinoma (MEC), and adenoid cystic carcinoma (ACC) of salivary glands. Twenty PAs, 20 PACs, 20 MECs, and 14 ACCs were selected. The percentages of cytoplasmic and nuclear positivity for autophagy-related proteins in neoplastic cells were assessed and correlated with histopathological parameters. Cytoplasmic immunoexpression of Atg7 was observed in all groups, with high median percentages of positivity. Regarding LC3A and LC3B, cytoplasmic immunoexpression was found in most PACs (95%) and in all cases of PA, MEC and ACC, with the highest percentages of positivity in PACs and PAs (p < 0.005). ACCs exhibited lower cytoplasmic immunoexpression of p-mTOR (p < 0.005) and lower nuclear expression of p62 (p < 0.05) when compared to PAs, PACs and MECs. Low nuclear immunoexpression of Atg7, LC3A and p-mTOR and absence of nuclear staining for LC3B were observed in all groups. Regarding histopathological parameters of PAs, MECs and ACCs, there were no significant differences in the expression of autophagy-related proteins. In all groups, positive correlations were observed between the immunoexpression of some autophagy-related proteins (p < 0.05). The results suggest the participation of autophagy in the pathogenesis of PA, PAC, MEC, and ACC of salivary glands. Upregulation of autophagy and reduced nuclear translocation of p62 may contribute to the aggressive biological behavior of salivary gland ACC.

Increased retinoic acid signaling decreases lung metastasis in salivary adenoid cystic carcinoma by inhibiting the noncanonical Notch1 pathway

MYB-NFIB fusion and NOTCH1 mutation are common hallmark genetic events in salivary gland adenoid cystic carcinoma (SACC). However, abnormal expression of MYB and NOTCH1 is also observed in patients without MYB-NFIB fusion and NOTCH1 mutation. Here, we explore in-depth the molecular mechanisms of lung metastasis through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near-normal to cancer-based on the abundance of each cell cluster in normal tissue. In this context, we identified the Notch signaling pathway enrichment in almost all cancer cells; RNA velocity, trajectory, and sub-clustering analyses were performed to deeply investigate cancer progenitor-like cell clusters in primary tumor-associated lung metastases, and signature genes of progenitor-like cells were enriched in the “MYC_TARGETS_V2” gene set. In vitro, we detected the NICD1-MYB-MYC complex by co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) as an endogenous antagonist of genes in the “MYC_TARGETS_V2” gene set. Following this, we confirmed that all-trans retinoic acid (ATRA) suppresses the lung metastasis of SACC by correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic, RNA-seq, and immunohistochemical (IHC) analyses of primary tissues and metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of the RA system in diagnosis and treatment.

Dominant Gene Expression Profiles Define Adenoid Cystic Carcinoma (ACC) from Different Tissues: Validation of a Gene Signature Classifier for Poor Survival in Salivary Gland ACC.

Adenoid cystic carcinoma (ACC) is an aggressive malignancy that most often arises in salivary or lacrimal glands but can also occur in other tissues. We used optimized RNA-sequencing to analyze the transcriptomes of 113 ACC tumor samples from salivary gland, lacrimal gland, breast or skin. ACC tumors from different organs displayed remarkedly similar transcription profiles, and most harbored translocations in the MYB or MYBL1 genes, which encode oncogenic transcription factors that may induce dramatic genetic and epigenetic changes leading to a dominant 'ACC phenotype'. Further analysis of the 56 salivary gland ACC tumors led to the identification of three distinct groups of patients, based on gene expression profiles, including one group with worse survival. We tested whether this new cohort could be used to validate a biomarker developed previously with a different set of 68 ACC tumor samples. Indeed, a 49-gene classifier developed with the earlier cohort correctly identified 98% of the poor survival patients from the new set, and a 14-gene classifier was almost as accurate. These validated biomarkers form a platform to identify and stratify high-risk ACC patients into clinical trials of targeted therapies for sustained clinical response.

Analysis of Cytological Misdiagnosis and Oversight of Adenoid Cystic Carcinoma of Salivary Gland.

In this article on adenoid cystic carcinoma (ACC) of salivary gland, we intend to summarize the causes of misdiagnosis and oversight of ACC hoping to improve cytological diagnostic accuracy, clinical management and patient treatment. The study retrospectively reviewed 32 patients with ACC of salivary gland, registered at the Affiliated Hospital of Southwest Medical University from July 2014 to June 2021. These cases were diagnosed by FNA and surgical excision biopsy. All cytopathological results were retrospectively categorized according to Milan system for reporting salivary gland cytopathology (MSRSGC). The accuracy of FNA was verified by surgical excision biopsy. Of these 32 patients, 16 (50.0%) cases were male, and 16 (50.0%) were female. Their age ranged from 21 to 79 years, with an average age of 50.32 years. The highest incidence (15/32, 46.9%) of ACC was observed in patients between 41 and 50 years of age. 10 cases (31.3%) occurred in the parotid gland, 9 cases (28.1%) in the submandibular gland, 9 cases (28.1%) in the sublingual gland, 3 cases (9.4%) in the palate, and 1 case (3.1%) in the lip. Among the 32 cases of ACC, 23 cases (71.9%) were classified to VI, 4 cases (12.5%) to IVa, and 5 cases (15.6%) to II by MSRSGC. A comparison of the FNA results with biopsy showed that the accuracy of FNA in ACC of salivary gland is 71.9%. Being able to identify the cytomorphological features is the key factor for accurate diagnosis of ACC of the salivary gland. Our results confirm that FNA is an important initial screening in the diagnosis of ACC of salivary gland. Increased study of the cytomorphology of ACC is beneficial for more accurate diagnosis of ACC, to reduce misdiagnosis and oversight.

Erratum: Salivary Gland Adenoid Cystic Carcinoma is Promoted by Increased POFUT1 Expression [Journal of Hard Tissue Biology 32(1) Vol.32, 2023, pp 49-56

Erratum: Salivary Gland Adenoid Cystic Carcinoma is Promoted by Increased POFUT1 Expression [Journal of Hard Tissue Biology 32(1) Vol.32, 2023, pp 49-56

Salivary Gland Adenoid Cystic Carcinoma is Promoted by Increased POFUT1 Expression

Salivary Gland Adenoid Cystic Carcinoma is Promoted by Increased POFUT1 Expression

Vulvar Adenoid Cystic Carcinoma with Squamous Cell Carcinoma Component.

Adenoid cystic carcinoma (ACC) is a major histological type of salivary gland cancer but an uncommon form of vulvar cancer. Salivary gland ACC occasionally dedifferentiates into high-grade carcinoma, resulting in poor prognoses. The dedifferentiated component is usually a poorly differentiated cribriform or solid carcinoma, whereas squamous cell carcinoma (SCC) is exceptional. Herein, we report the case of a 78-year-old woman with vulvar ACC, including an SCC component. She presented with a vulvar nodule that had been present for 30 years and increased in size over the past few years. Magnetic resonance imaging showed a ball-like mass with high intensity on T1-weighted images and high intensity with non-uniformity on T2-weighted images. Considering the systemic and social conditions, the tumor was maximally resected without lymphadenectomy. Histologically, the tumor was composed of a marginal ACC component with a central SCC component. Stage IB vulvar cancer, which was assumed to originate from the Bartholin's gland, was diagnosed. She has survived over 2 years without additional treatments after the surgery. In this case, we assumed that slowly progressive indolent ACC could be dedifferentiated to high- grade SCC. According to our review of available literature, dedifferentiation of vulvar ACC with a high-grade SCC component has not been specifically documented. Although the nature of dedifferentiated vulvar cancer is unclear, it should be noted that high-grade dedifferentiation can occur in long-lasting vulvar masses.

LIS1 interacts with CLIP170 to promote tumor growth and metastasis via the Cdc42 signaling pathway in salivary gland adenoid cystic carcinoma.

Salivary gland adenoid cystic carcinoma (SACC) is one of the most common malignant tumors, with high aggressive potential in the oral and maxillofacial regions. Lissencephaly 1 (LIS1) is a microtubule-organizing center-associated protein that regulates the polymerization and stability of microtubules by mediating the motor function of dynein. Recent studies have suggested that LIS1 plays a potential role in the malignant development of tumors, such as in mitosis and migration. However, the role of LIS1 in SACC development and its related molecular mechanisms remain unclear. Thus, the effects of LIS1 on the proliferation, apoptosis, invasion and metastasis of SACC were studied, in vivo and in vitro. The results of immunohistochemical staining showed that LIS1 was highly expressed in SACC tissues, and its expression level was associated with malignant progression. In vitro, the results of CCK-8, TUNEL, wound healing and Transwell assays demonstrated that LIS1 promotes proliferation, inhibits apoptosis, and enhances the migration and invasion of SACC-LM cells. In vivo, knockdown of LIS1 effectively suppressed the growth of subcutaneous tumors in a mouse xenograft and distant metastasis of tumor cells in the metastasis model. The co-immunoprecipitation, immunofluorescence and western blot results also revealed that LIS1 binds to cytoplasmic linker protein 170 (CLIP170) to form a protein complex (LIS1/CLIP170), which activates the cell division control protein 42 homolog (Cdc42) signaling pathway to modulate the proliferation and anti-apoptosis of tumor cells, and enhanced invasion and metastasis by regulating the formation of invadopodia and the expression of MMPs in SACC-LM cells. Therefore, the present study demonstrated that LIS1 is a cancer promoter in SACC, and the molecular mechanism of the LIS1/CLIP170/Cdc42 signaling pathway is involved in the malignant progression, which offers a promising strategy for targeted therapy of SACC.

Clinical Prediction Nomograms to Assess Overall Survival and Disease-Specific Survival of Patients with Salivary Gland Adenoid Cystic Carcinoma.

Aim Salivary gland adenoid cystic carcinoma (SACC) is the second highest incidence of malignant salivary gland tumor. The purpose of this study was to establish nomograms combined with SACC patients based on the Surveillance, Epidemiology, and End Results (SEER) database. Methods Patients with SACC were included in the SEER∗Stat Database from 2004 to 2016. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to filter potential prognostic clinical variables. Multivariate analysis from the Cox proportional hazards model was performed to determine the independent prognostic factors on overall survival (OS) and disease-specific survival (DSS), applied to develop nomograms. The Schönfeld residual test verified the proportional hazard assumption. The discrimination and consistency of nomograms was assessed and validated according to concordance index (C-index), receiver operating characteristic (ROC) curves, and calibration curves using an internal 1,000 times bootstrap resampling. The nomogram's net clinical benefit was assessed through decision curve analysis (DCA). Results A total of 658 patients with SACC were included. Age, T stage, N stage, M stage, histologic grade, and surgery were independent prognostic factors for OS and DSS. Based on these independent prognostic factors, nomograms were developed to predict 3-, 5-, and 10-year OS and DSS. In the validation of 1,000 times bootstrap resampling, the C-index and ROC curves had good discriminatory ability. The calibration curves indicated excellent consistency between the predicted and actual survival results in the nomograms. The DCA curves demonstrated that the nomograms had good clinical benefit and were superior to the TNM stage and other variables. Conclusions Two nomograms developed in this study precisely predicted the 3-, 5-, and 10-year OS and DSS rates of patients with SACC in accordance with independent prognostic factors, and their clinical value is better than TNM staging, providing a prognostic reference for other SACC patients.

IMMUNOHISTOCHEMICAL ANALYSIS OF AUTOPHAGY-RELATED PROTEINS IN PLEOMORPHIC ADENOMAS AND ADENOID CYSTIC CARCINOMAS OF SALI

<h3>Objectives</h3> To evaluate the immunoexpression of autophagy-related proteins (Atg7, LC3A, p62, and phosphorylated mammalian target for rapamycin) in pleomorphic adenomas (PAs) and adenoid cystic carcinomas (ACCs) of the salivary glands. <h3>Study Design</h3> The percentages of cytoplasmic and nuclear staining for Atg7, LC3A, p62, and <i>P</i>-mTOR in neoplastic cells of 20 PAs and 14 ACCs were determined and correlated with histopathologic parameters. The results were analyzed statistically using the nonparametric Mann-Whitney test and Spearman correlation test. <h3>Results</h3> Cytoplasmic expression of autophagy-related proteins was observed in all cases of PA and ACC, with high median percentages of positivity for Atg7 and p62. Compared to ACCs, PAs exhibited higher cytoplasmic expression of Atg7, LC3A, and P-mTOR (<i>P</i> < .005), as well as higher nuclear expression of p62 (<i>P</i> < .0001). No significant differences in the immunoexpression of Atg7, LC3A, p62, and P-mTOR were observed according to histopathologic parameters of the tumors (<i>P</i> > .05). In PAs and ACCs, positive correlations were found for the immunoexpression of some autopaghy-related proteins (<i>P</i> < .05). <h3>Conclusions</h3> Autophagy may be involved in the pathogenesis of PA and ACC of the salivary glands. The upregulation of this intracellular degradation system and the reduced nuclear translocation of p62 could contribute to the aggressive biological behavior of ACC of salivary glands.

The expression and significance of vascular endothelial growth factor A in adenoid cystic carcinoma of palatal salivary gland.

To explore the VEGF-A expression in salivary gland adenoid cystic carcinoma tissues and detect the relationship between the mechanism of occurrence, development and metastasis of jaws with salivary gland adenoid cystic carcinoma and VEGF-A expression. Paraffin samples from 58 cases of SACC of the palate and ten cases of normal salivary gland tissues were collected. The expression levels of VEGF-A protein were detected using the immunohistochemistry EnVision system. Among the 58 cases, there were 20 cases of the cribriform type, 17 cases of the tubular type, and 21 cases of the solid type. There were 9 cases with lymph node metastasis and 21 cases without lymph node metastasis. And there were 8 cases of T1, 15 cases of T2, and 7 cases of T3/T4. The positive expression rate of VEGF-A in SACC of the palate was 74.1%, which was higher than that found in normal salivary gland tissues (10%). The VEGF-A was localized in the cytoplasm/cell membrane. VEGF-A is highly expressed in SACC of the palate. The level of expression is closely related to the pathological grade, lymph node metastasis, and clinical stage of the tumor, and it can thus be used as an important indicator for judging the biological behavior of SACC of the palate.

The Semaphorin 3A-AKT axis-mediated cell proliferation in salivary gland morphogenesis and adenoid cystic carcinoma pathogenesis

We recently demonstrated that Semaphorin 3 A (Sema3A), the expression of which is negatively regulated by Wnt/β-catenin signaling, promotes odontogenic epithelial cell proliferation, suggesting the involvement of Sema3A in tooth germ development. Salivary glands have a similar developmental process to tooth germ development, in which reciprocal interactions between the oral epithelium and adjacent mesenchyme proceeds via stimulation with several growth factors; however, the role of Sema3A in the development of salivary glands is unknown. There may thus be a common mechanism between epithelial morphogenesis and pathogenesis; however, the role of Sema3A in salivary gland tumors is also unclear. The current study investigated the involvement of Sema3A in submandibular gland (SMG) development and its expression in adenoid cystic carcinoma (ACC) specimens. Quantitative RT-PCR and immunohistochemical analyses revealed that Sema3A was expressed both in epithelium and in mesenchyme in the initial developmental stages of SMG and their expressions were decreased during the developmental processes. Loss-of-function experiments using an inhibitor revealed that Sema3A was required for AKT activation-mediated cellular growth and formation of cleft and bud in SMG rudiment culture. In addition, Wnt/β-catenin signaling decreased the Sema3A expression in the rudiment culture. ACC arising from salivary glands frequently exhibits malignant potential. Immunohistochemical analyses of tissue specimens obtained from 10 ACC patients showed that Sema3A was hardly observed in non-tumor regions but was strongly expressed in tumor lesions, especially in myoepithelial neoplastic cells, at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the Sema3A-AKT axis promotes cell growth, thereby contributing to morphogenesis and pathogenesis, at least in ACC, of salivary glands.

Polar Vessel: A New Ultrasound Sign for Complementary Diagnosis of Major Salivary Gland Adenoid Cystic Carcinoma.

To investigate the characteristic ultrasonographic findings of adenoid cystic carcinoma (ACC) in major salivary glands and identify the value of polar vessel in color Doppler flow imaging (CDFI) for the diagnosis of ACC. From January 2017 to December 2021, 76 patients with parotid and submandibular gland tumors, including 14 patients with ACC, as confirmed by surgery and histopathology, were enrolled. Their clinicopathologic information and ultrasound (US) features were recorded and analyzed. The performance of polar vessel in CDFI for differentiating ACC from non-ACC (benign tumors and mucoepidermoid carcinoma [MEC]) was analyzed. ACC in the major salivary gland was more likely to be associated with pain symptoms (P=.027) and unclear borders and rough edges in grayscale US (P=.002, .015, respectively) than benign tumors. Compared to MEC, ACC tended to feature a homogeneous internal echo (P=.008). ACC of the major salivary gland had a significantly higher incidence of polar vessel sign than that of non-ACC (benign tumors and MEC) (P <.0001, .0001, respectively). The polar vessel sign showed good performance in distinguishing between ACC and non-ACC, with an area under the receiver operating characteristic curve of 0.857, a sensitivity of 71.4%, a specificity of 100%, and an accuracy of 94.7%. Positive predictive value and negative predictive value were calculated at 100% and 93.9%, respectively. The US sign of polar vessel has high diagnostic efficiency, and it may have important potential for use as a new complementary sign for the diagnosis of ACC in major salivary glands.