Adenoid Cystic Carcinoma Cell Research Articles

Extracellular vesicles containing circMYBL1 induce CD44 in adenoid cystic carcinoma cells and pulmonary endothelial cells to promote lung metastasis.

Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs. MYBL1 is frequently overexpressed in ACC and has been suggested to be a driver of the disease. Here, we identified a circRNA derived from MYBL1 pre-mRNA that accompanied overexpression of MYBL1 in ACC. Overexpression of circMYBL1 was correlated with increased lung metastasis and poor overall survival in ACC patients. Ectopic circMYBL1 overexpression promoted malignant phenotypes and lung metastasis of ACC cells. Mechanistically, circMYBL1 formed a circRNA-protein complex with CCAAT enhancer binding protein beta (CEBPB), which inhibited ubiquitin-mediated degradation and promoted nuclear translocation of CEBPB. In the nucleus, circMYBL1 increased the binding of CEBPB to the CD44 promoter region and enhanced its transcription. In addition, circMYBL1 was enriched in small extracellular vesicles (sEVs) isolated from the plasma of ACC patients. Treatment with sEVs containing circMYBL1 in sEVs enhanced pro-metastatic phenotypes of ACC cells, elevated the expression of CD44 in human pulmonary microvascular endothelial cells (HPMECs), and enhanced the adhesion between HPMECs and ACC cells. Moreover, circMYBL1 encapsulated in sEVs increased the arrest of circulating ACC cells in the lung and enhanced the lung metastatic burden. This data suggests that circMYBL1 is a tumor-promoting circRNA that could serve as a potential biomarker and therapeutic target in ACC.

Anti-Tumor Activity and Mechanism of Silibinin Based on Network Pharmacology and Experimental Verification.

Silibinin is a flavonoid compound extracted from the seeds of Silybum marianum (L.) Gaertn. It has the functions of liver protection, blood-lipid reduction and anti-tumor effects. However, the potential molecular mechanism of silibinin against tumors is still unknown. This study aimed to assess the anti-tumor effects of silibinin in adenoid cystic carcinoma (ACC2) cells and Balb/c nude mice, and explore its potential mechanism based on network pharmacology prediction and experimental verification. A total of 347 targets interacting with silibinin were collected, and 75 targets related to the tumor growth process for silibinin were filtrated. Based on the PPI analysis, CASP3, SRC, ESR1, JAK2, PRKACA, HSPA8 and CAT showed stronger interactions with other factors and may be the key targets of silibinin for treating tumors. The predicted target proteins according to network pharmacology were verified using Western blot analysis in ACC2 cells and Balb/c nude mice. In the pharmacological experiment, silibinin was revealed to significantly inhibit viability, proliferation, migration and induce the apoptosis of ACC2 cells in vitro, as well as inhibit the growth and development of tumor tissue in vivo. Western blot analysis showed that silibinin affected the expression of proteins associated with cell proliferation, migration and apoptosis, such as MMP3, JNK, PPARα and JAK. The possible molecular mechanism involved in cancer pathways, PI3K-Akt signaling pathway and viral carcinogenesis pathway via the inhibition of CASP3, MMP3, SRC, MAPK10 and CDK6 and the activation of PPARα and JAK. Overall, our results provided insight into the pharmacological mechanisms of silibinin in the treatment of tumors. These results offer a support for the anti-tumor uses of silibinin.

Abstract LB022: Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model

Abstract Adenoid cystic carcinoma (ACC) is a rare type of salivary gland cancer. Despite the many advances made in helping understand the disease behavior and characteristics, the prevailing challenge in managing patients with ACC is the lack of clinically approved systemic therapy drugs to successfully treat those with advanced recurrent or metastatic disease. There are multiple promising candidate agents being evaluated preclinically and in early phase clinical trials, yet an effective drug with consistent overall response remains to be identified. AXL is a member of the TAM family of tyrosine kinase receptors, and its overexpression and activation is generally associated with poor prognosis and chemoresistance in many cancer types. Previous reports show AXL is significantly upregulated in a subset of ACC tumors. Here, we evaluate the tumor growth inhibition effects of a newly developed antibody-drug-conjugate targeting AXL (ADCT-601) in a xenograft ACC cell line model. MDA-ACC-01 cells express high levels of cell surface AXL as confirmed by biochemical analysis. The tumor growth inhibition of MDA-ACC-01 cell xenograft was tested in a single-dose drug administration study. Immunodeficient mice bearing ACC tumors were either injected with vehicle (n=7) or with ADCT-601 at 0.5 (n=9) or 1.0 mg/kg (n=7). ADCT-601 treatment with either 0.5 mg/kg or 1.0 mg/kg resulted in complete response (CR) for all tumor implants. To reaffirm the drug’s efficacy, we challenged the vehicle-treated tumor, prior to exceeding the tumor volume endpoint, with a single-dose of ADCT-601 at 1.0 mg/kg. Strikingly, by day 6 post-treatment, tumor volume began to shrink and eventually resulted in CR except in all but one case. These results demonstrate ADCT-601 is an effective drug with significant anti-tumor activity in our preclinical models and is worthy of additional investigation to determine its translational potential. Citation Format: Joseph O. Humtsoe, Anita Pothukuchi, Hyunseok Kang, Patrick Ha. Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB022.

TGFβ-induced EN1 promotes tumor budding of adenoid cystic carcinoma in patient-derived organoid model.

Adenoid cystic carcinoma (ACC) and basal cell adenoma (BCA) share many histological characteristics and often need a differential diagnosis in clinical pathology. Recently, we found homeobox protein engrailed-1 (EN1) was a potential diagnostic marker for ACC in an organoids library of salivary gland tumors (SGTs). Here we aim to confirm EN1 as a differential diagnostic marker for ACC, and further investigate the regulatory mechanism and biological function of EN1 in tumor progression. The transcriptional analysis, quantitative polymerase chain reaction, Western blot and immunohistochemistry staining were performed and revealed that EN1 was specifically and highly expressed in ACC, and accurately differentiated ACC from BCA. Furthermore, TGFβ signaling pathway was found associated with ACC, and the regulation of EN1 through TGFβ was detected in the human ACC cell lines and patient-derived organoids (PDOs). TGFβ-induced EN1 was important in promoting tumor budding in the PDOs model. Interestingly, a high level of EN1 and TGFβ1 in the budding tips was observed in ACC clinical samples, and the expression of EN1 and TGFβ1 in ACC was significantly associated with the clinical stage. In summary, our study verified EN1 is a good diagnostic marker to differentiate ACC from BCA. TGFβ-induced EN1 facilitates the tumor budding of ACC, which might be an important mechanism related to the malignant phenotype of ACC.

Anti-NOTCH1 therapy with OMP-52 M51 inhibits salivary adenoid cystic carcinoma by depressing epithelial-mesenchymal transition (EMT) process and inducing ferroptosis

Salivary adenoid cystic carcinoma (ACC) is a common type of salivary gland cancer, and the mechanisms underlying its progression still remain poorly understood without efficient therapies. NOTCH1, an evolutionally conserved cell-cell signaling pathway, is involved in the progression of ACC. In our study, we attempted to explore whether NOTCH1 suppression using the monoclonal anti-NOTCH1 antibody OMP-52 M51 could be of potential for ACC treatment. Here, we identified NOTCH1 elevation in human ACC tissues compared with the matched normal samples. Patients with metastasis expressed much higher NOTCH1. We then found that OMP-52 M51 markedly reduced the expression of NOTCH1 and its intracellular active form NICD1 (NOTCH1 intracellular domain). Importantly, OMP-52 M51 markedly reduced the proliferation, migration and invasion of ACC cells. RNA-Seq and in vitro studies further showed that OMP-52 M51 significantly induced ferroptosis in ACC cells, indicated by the increased cellular malondialdehyde (MDA), iron contents and lipid ROS production, and decreased glutathione (GSH) levels. Further, remarkable glutathione peroxidase 4 (GPX4) reduction was detected in ACC cells with OMP-52 M51 treatment. However, promoting NOTCH1 expression markedly abolished the function of OMP-52 M51 to induce ferroptosis. Intriguingly, low-dose OMP-52 M51 strongly facilitated the capacity of ferroptosis inducer erastin to trigger ferroptotic cell death, revealing that OMP-52 M51 could improve the sensitivity of ACC cells to ferroptosis. In vivo, OMP-52 M51 administration suppressed tumor growth and induced ferroptosis in the constructed ACC xenograft mouse model. Collectively, our findings demonstrated that NOTCH1 inhibition by OMP-52 M51 represses the proliferation and epithelial-mesenchymal transition (EMT) in ACCs, and promotes ferroptosis, revealing the potential therapeutical application of OMP-52 M51 in ACC.

Wnt/β-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication

Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases. In the current study, the patient with ACC whose tumor was negative for SEMA3A in the previous study, revisited our hospital with late metastasis of ACC to the cervical lymph node eight years after surgical resection of the primary tumor. We characterized this recurrent ACC, and compared it with the primary ACC using immunohistochemical methods. In the recurrent ACC, the duct lining epithelial cells, not myoepithelial neoplastic cells, showed an elevated Ki-67 index and increased cell membrane expression of C-kit, along with the expression of phosphorylated ERK. Late metastasis ACC specimens were not positive for β-catenin and lymphocyte enhancer binding factor 1 (LEF1), which were detected in the nuclei of perineural infiltrating cells in primary ACC cells. In addition, experiments with the GSK-3 inhibitor revealed that β-catenin pathway suppressed not only KIT expression but also proliferation of ACC cells. Moreover, stem cell factor (SCF; also known as KIT ligand, KITL) induced ERK activation in ACC cells. These results suggest that inactivation of Wnt/β-catenin signaling may promote C-kit-ERK signaling and cell proliferation of in metastatic ACC.

Clinical features and prognostic factors for malignant parotid tumors in children and adolescents: A population-based study

PurposeWe performed a population-based cohort study to investigate the clinical characteristics and survival rates of primary malignant parotid tumors (MPT) in children and adolescents. MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to identify all pediatric and adolescent patients with MPT who were diagnosed between 2000 and 2018. Based on a number of parameters, survival curves were produced using Kaplane-Meier estimates. The log-rank test was used to compare survival curves. The influence of each component on overall survival (OS) was examined using a multivariate Cox proportional hazards model. ResultsThere were 352 identified pediatric and adolescent patients with MPT. At diagnosis, the age ranged from 1.0 to 19 years, with a median of 15 years. Mucoepidermoid carcinoma (MC) (46.5 %) was the most common histological subtype, followed by acinar cell carcinoma (ACC) (36.4 %) and others (17.1 %) such as adenoid cystic carcinoma and squamous cell carcinoma. All patients had overall survival rates of 98.8 %, 95.6 %, and 94.6 % at 1-year, 3-year and 5-year, respectively. The results of the Cox proportional hazard regression showed that tumor grade, SEER stage, radiotherapy, and treatment regimens were significant independent predictors of overall survival. ConclusionsIn pediatric and adolescent MPT, tumor grade, SEER stage, adjuvant radiation, and treatment regimens were found to be important independent predictors of survival. More research is required to validate the role of adjuvant radiation.

Defining the relationship of salivary gland malignancies to novel cell subpopulations in human salivary glands using single nucleus RNA-sequencing.

Salivary glands have essential roles in maintaining oral health, mastication, taste and speech, by secreting saliva. Salivary glands are composed of several types of cells, and each cell type is predicted to be involved in the carcinogenesis of different types of cancers including adenoid cystic carcinoma (ACC), acinic cell carcinoma (AciCC), salivary duct carcinoma (SDC), myoepithelial carcinoma (MECA) and other histology. In our study, we performed single nucleus RNA-seq on three human salivary gland samples to clarify the gene expression profile of each complex cellular component of the salivary glands and related these expression patterns to expression found in salivary gland cancers (SGC) to infer cell of origin. By single nucleus RNA-seq, salivary gland cells were stratified into four clusters: acinar cells, ductal cells 1, ductal cells 2 and myoepithelial cells/stromal cells. The localization of each cell group was verified by IHC of each cluster marker gene, and one group of ductal cells was found to represent intercalated ductal cells labeled with HES1. Furthermore, in comparison with SGC RNA-seq data, acinar cell markers were upregulated in AciCC, but downregulated in ACC and ductal cell markers were upregulated in SDC but downregulated in MECA, suggesting that markers of origin are highly expressed in some SGC. Cell type expressions in specific SGC histology are similar to those found in normal salivary gland populations, indicating a potential etiologic relationship.

Preclinical 3D-model supports an invisibility cloak for adenoid cystic carcinoma

The tumour-cell based initiation of immune evasion project evaluated the role of Gipie in adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (A-253), from ninety-six 3D-ACC and A-253-immune co-culture models using natural killer cells (NK), and Jurkat cells (JK). Abnormal ACC morphology was observed in 3D-ACC immune co-culture models. Gipie-silencing conferred a “lymphoblast-like” morphology to ACC cells, a six-fold increase in apoptotic cells (compared to unaltered ACC cells, P ≤ 0.0001), a two-fold decrease in T regulatory cells (FoxP3+/IL-2Rα+/CD25+) (P ≤ 0.0001), and a three-fold increase in activated NK cells (NKp30+/IFN-γ+) (P ≤ 0.0001) with significantly higher release of granzyme (P ≤ 0.001) and perforin (P ≤ 0.0001).

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.

The Role of Novel Immunohistochemical Markers for Special Types of Breast Carcinoma.

Some histologic special types of breast carcinoma harbor specific recurrent genetic alterations that are not seen in other types of breast carcinoma (no special type), namely adenoid cystic carcinoma, secretory carcinoma, and tall cell carcinoma with reversed polarity. These tumors have unique morphologic features, are triple-negative, that is, do not express hormone receptors or HER2, and are generally associated with a favorable prognosis. Adenoid cystic carcinoma, like its counterpart in other organs, shows a MYB-NFIB fusion gene that is the result of a recurrent t(6;9)(q22-23;p23-24) translocation. Other MYB alterations have been described that result in overexpression of MYB . Secretory carcinoma is characterized by an ETV6-NTRK3 gene fusion that is the result of recurrent (12;15);(p13;q25) translocation, which is also seen in mammary analog secretory carcinoma of the salivary gland. Tall cell carcinoma with reversed polarity shows IDH2 p.Arg172 hotspot mutations. Immunohistochemical antibodies have emerged that identify the underlying genetic alterations in these tumors and serve as useful diagnostic tools. This review will provide an update on the molecular features and diagnostic immunohistochemical markers that have become increasingly popular to aid in diagnosing these uncommon triple-negative breast tumors.

Abstract PO-071: Pseudonormal morphology of adenoid cystic carcinoma cells subverts the antitumor reactivity of immune cells

Abstract Objectives: Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer most frequently arising in the head and neck region. The ACC microenvironment exhibits low immunogenicity (low tumor infiltrating lymphocytes and dendritic cells). This scenario favours immune evasion and partially explains poor prognosis because of the activation of immune inhibitory proteins. Gipie is a hook-related protein, that is involved in protein trafficking. Gipie (HkRP3, encoded by CCDC88B) is associated with T cell maturation and inflammatory functions and target cell killing in natural killer (NK) cells. Gipie is present in ACC patient samples and cells. Therefore, we investigated proliferation, apoptosis, and morphologic changes caused by Gipie in oral and salivary gland cancer cells in presence of immune cells. Methods: We assayed UM-HACC-2A (adenoid cystic carcinoma), A-253 (mucoepidermoid carcinoma, MEC), SCC4, SCC9, SCC25, CAL27 (oral squamous cell carcinoma, OSCC), OKF6 (normal oral) cells cocultured with, NK-92 (natural killer), and Jurkat, Clone E6-1 (acute T cell leukemia) cells, to construct multiple salivary gland and oral cancer-immune cell co-culture models. Gipie silenced cancer cells (silencing maintained for 48 hours) in the cancer immune coculture models were compared with their unaltered subsets. Cancer-immune cells interactions were maintained for 16 hours. Overall three hundred thirty-six (336) co-culture models were used to determine apoptosis, immune activation, morphology, transmigration, and protein expression. Additionally, we performed targeted mass spectrometry analysis to identify changes in protein profiles. Results: ACC cells exhibited Pseudonormal morphology after interacting with immune cells in the 3D coculture model. Gipie-silenced ACC cells in coculture model transformed to “lymphoblast-like” morphology. Gipie-silenced ACC cells in co-culture model (n = 24) showed significant increase of apoptotic cells compared to unaltered ACC cells, lowering of T regulatory cells (FoxP3+/IL-2Rα+/CD25+) (n = 24), and increase of activated NK cells (NKp30+/IFN-γ+) (n = 24) with significantly higher release of granzyme (n = 12) and perforin (n = 12). Increased activation of immune cells (transmigration and fluorescence intensity) via 3D-z-stack images were observed in Gipie-silenced subsets (n = 24). MEC cells responses were significantly less compared to ACC in co-culture models followed by silencing of Gipie, while OSCC and OKF6 cell responses were negligible, under identical conditions. Conclusions: The presence of Gipie confers pseudonormal morphology to ACC cells thereby reducing immune attack. Thus, trafficking proteins may impact ACC cancer-immune cell interaction during conventional chemotherapy or monoclonal immunotherapy. Citation Format: Rajdeep Chakraborty, Charbel Darido, Giuseppe Palmisano, Arthur Chien, Aidan Tay, Thiri Zaw, Shoba Ranganathan. Pseudonormal morphology of adenoid cystic carcinoma cells subverts the antitumor reactivity of immune cells [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-071.

Basal cell adenoma of parotid gland: two case reports and literature review.

Most of salivary tumors are benign in nature and are typically diagnosed and classified based on their histopathological presentation. Basal cell adenoma of the salivary glands is a rare, benign disease accounting for 1% to 3% of salivary gland tumors. Despite its low incidence, basal cell adenoma is the third most common benign tumor of the salivary gland after pleomorphic adenoma and Warthin's tumor. It usually appears as a firm and slow-growing mass. Due to the prognosis, differential diagnosis with basal cell adenocarcinoma, adenoid cystic carcinoma and basaloid squamous cell carcinoma is required. In this report, we present two cases; a 62-year-old woman who presented with an asymptomatic, and slow-growing mass and a 64-year-old woman with a static-sized mass in the parotid gland. In both cases, the mass was completely excised, postoperative pathology reports confirmed the diagnosis of basal cell adenoma. We also review the literature and discuss this rare entity.

Nuclear staining for pan-Trk by immunohistochemistry is highly specific for secretory carcinoma of breast: pan-Trk in various subtypes of breast carcinoma

AimsSecretory carcinoma of breast (SCB) typically harbours ETV6-NTRK3 gene fusion. Pan-Trk immunohistochemistry analysis (IHC) has been shown to be sensitive for SCB diagnosis. However, weak focal pan-Trk nuclear staining was...

Therapeutic inhibition of Bmi-1 ablates chemoresistant cancer stem cells in adenoid cystic carcinoma

ObjectivesAdenoid Cystic Carcinomas (ACC) typically show modest responseto cytotoxic therapy. Cancer stem cells (CSC) have been implicated in chemoresistance and tumor relapse. However, their role in ACC remains unknown. The purpose of this work was to evaluate the impact of targeting ACC CSCs with Bmi-1 inhibitors on resistance to cytotoxic therapy and tumor relapse. Materials and methodsTherapeutic efficacy of a small molecule inhibitor of Bmi-1 (PTC596; Unesbulin) and/or Cisplatin on ACC stemness was evaluated in immunodeficient mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in human ACC cell-lines (UM-HACC-2A,-14) or low passage primary human ACC cells (UM-HACC-6). The effect of therapy on stemness was examined by salisphere assays, flow cytometry for ALDH activity and CD44 expression, and Western blots for Bmi-1 (self-renewal marker) and Oct4 (embryonic stem cell marker) expression. ResultsPlatinum-based agents (Cisplatin, Carboplatin) induced Bmi-1 and Oct4 expression, increased salisphere formation and the CSC fraction in vitro and in vivo. In contrast, PTC596 inhibited expression of Bmi-1, Oct4 and pro-survival proteins Mcl-1 and Claspin; decreased the number of salispheres, and the fraction of ACC CSCs in vitro. Silencing Claspin decreased salisphere formation and CSC fraction. Both, single agent PTC596 and PTC596/Cisplatin combination decreased the CSC fraction in PDX ACC tumors. Notably, short-term combination therapy (2 weeks) with PTC596/Cisplatin prevented tumor relapse for 150 days in a preclinical trial in mice. ConclusionTherapeutic inhibition of Bmi-1 ablates chemoresistant CSCs and prevents ACC tumor relapse. Collectively, these results suggest that ACC patients might benefit from Bmi-1-targeted therapies.

Functional profiles of curatively treated adenoid cystic carcinoma unveil prognostic features and potentially targetable pathways

Adenoid cystic carcinoma (ACC) of salivary gland is a slowly growing tumor showing a propensity for delayed recurrence, with decreased survival rates. The identification of poor prognosis patients may help in defining molecular-based targeted strategies in this rare disease orphan of new treatments. Through a gene expression microarray-based approach followed by GSE functional analysis the expression profile of 46 primary untreated ACC samples and of ACC (h-TERT) tumor cells was analyzed. Patients who experienced early relapse showed enrichment in proliferation-related gene sets, including the G2-M checkpoint, E2F and myc targets, and in gene sets related to IFN signaling and aberrant proteostasis (FDR < 0.1), indicating increased mitotic and transcriptional activity in aggressive ACC. Similar functions were enriched in ACC samples classified by immunohistochemical staining as p63-negative, which exhibited increased protein burden and activation of pro-survival stress response pathways compared to p63-positive tumors. Compared to ACC tissues, ACC (h-TERT) cells share transcriptional features of aggressive p63-negative tumors. These data suggest association of specific pathway alterations with histopathological features of ACC, as recapitulated by p63 testing in patient prognostic stratification, anticipating new avenues for therapeutic intervention.

Solid Variant of Adenoid Cystic Carcinoma Coexisting with Invasive Squamous Cell Carcinoma in Uterine Cervix – A Case Report with Immunoprofile

Primary adenoid cystic carcinoma of cervix is a rare entity. Co-existence of adenoid cystic carcinoma with squamous cell carcinoma is even more rare. Here we present the case of an 85 year old postmenopausal lady who presented with on and off vaginal bleeding and was found to have a hard cervical mass. Hysterectomy with bilateral salpingo-oophorectomy was done and histopathological evaluation revealed coexisting solid variant of adenoid cystic carcinoma and squamous cell carcinoma. High grade squamous intraepithelial lesion was seen adjacent to invasive squamous cell carcinoma. Adenoid cystic carcinoma was positive for CD117 and squamous cell carcinoma was positive for p63. Both the components were also immunoreactive for p16.

BASAL CELL ADENOMA OF PAROTID GLAND: A RARE CASE REPORT AND REVIEW OF LITERATURE

Salivary gland tumors are uncommon and constitute about 2.0 to 6.5 % of all head and neck tumors. Basal cell adenoma (BCA), which is classied in benign salivary gland tumors by WHO in 1991, is a rare neoplasm. Incidence rate of BCA is 1.0 %–3.7 % of all salivary gland tumors with most frequent location is the parotid gland(&gt;80% cases of BCA) and other sites such as the upper lip, buccal mucosa, lower lip, palate and nasal septum rarely affected. It usually presents as a rm and mobile slow-growing mass. Histologically, it consists of a monomorphic population of basaloid epithelial cells that are arranged in the solid, trabecular, tubular and membranous patterns. It is important to differentiate BCA from benign tumor like pleomorphic adenoma showing absence of chondromyxoid stroma in former and malignant tumor like basal cell adenocarcinoma, adenoid cystic carcinoma and basaloid squamous cell carcinoma. We report a case of BCA of the parotid gland in 59 year male. We also review the literature and discuss the diagnosis and management of this rare entity.

Epidemiological and clinical characteristics of 407 salivary glands neoplasms in surgically treated patients in 2010-2020

INTRODUCTION Tumors of the salivary glands account for approximately 3 to 4% of all head and neck neoplasms. It is estimated that 10-15% of them are malignant. The most common benign tumor is pleomorphic adenoma, while the most common malignant tumors are adenoid cystic carcinoma and mucoepidermoid carcinoma. Neoplasms of the salivary glands are extremely histologically diverse, which results from the complex embryogenesis of the salivary glands. The identified risk factors for tumors of the salivary glands are: ultraviolet radiation, ionizing radiation, viral infections, nicotine and alcohol. MATERIAL AND METHOD The aim of the study was an epidemiological analysis of patients with salivary gland neoplasms, the distribution and histopathological characteristics of individual neoplasms treated at the Department of Otorhinolaryngology of the Medical University of Warsaw in 2010-2020. The diagnoses were analyzed according to the latest WHO 2017 histological classification of salivary gland tumors. In addition, the material was supplemented with data on the 5-year survival rates of patients with malignant neoplasms obtained from the Registry of Marital Status. RESULTS AND DISCUSSION The material contained 407 neoplasms of the salivary glands over a 11-year period, of which malignant neoplasms accounted for 17.4%. The malignant tumors were dominated by: adenoid cystic carcinoma (28,2%), mucoepidermoid carcinoma (12,7%), and acinic cell carcinoma (9,9%). Lymphomas (15,5%) were also a large group. The benign neoplasms were dominated by pleomorphic adenoma (54.1%) and Warthin&apos;s tumor (36%). Tumors of the salivary gland the most often affected the parotid gland (92%). CONCLUSIONS The obtained data are consistent with the general epidemiological data described in the current literature.

AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling

Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients. Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis. Given the role of NOTCH signaling in regulating tumor cell behavior, NOTCH inhibitors represent an attractive potential therapeutic strategy for this subset of ACC. AL101 (osugacestat) is a potent γ-secretase inhibitor that prevents activation of all four NOTCH receptors. While this investigational new drug has demonstrated antineoplastic activity in several preclinical cancer models and in patients with advanced solid malignancies, we are the first to study the therapeutic benefit of AL101 in ACC. Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.