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Disease Models & Mechanisms Jan 2018Restricted availability of cell and animal models is a rate-limiting step for investigation of salivary gland neoplasm pathophysiology and therapeutic response....
Restricted availability of cell and animal models is a rate-limiting step for investigation of salivary gland neoplasm pathophysiology and therapeutic response. Conditionally reprogrammed cell (CRC) technology enables establishment of primary epithelial cell cultures from patient material. This study tested a translational workflow for acquisition, expansion and testing of CRC-derived primary cultures of salivary gland neoplasms from patients presenting to an academic surgical practice. Results showed that cultured cells were sufficient for epithelial cell-specific transcriptome characterization to detect candidate therapeutic pathways and fusion genes, and for screening for cancer risk-associated single nucleotide polymorphisms (SNPs) and driver gene mutations through exome sequencing. Focused study of primary cultures of a low-grade mucoepidermoid carcinoma demonstrated amphiregulin-mechanistic target of rapamycin-protein kinase B (AKT; AKT1) pathway activation, identified through bioinformatics and subsequently confirmed as present in primary tissue and preserved through different secondary 2D and 3D culture media and xenografts. Candidate therapeutic testing showed that the allosteric AKT inhibitor MK2206 reproducibly inhibited cell survival across different culture formats. By contrast, the cells appeared resistant to the adenosine triphosphate competitive AKT inhibitor GSK690693. Procedures employed here illustrate an approach for reproducibly obtaining material for pathophysiological studies of salivary gland neoplasms, and other less common epithelial cancer types, that can be executed without compromising pathological examination of patient specimens. The approach permits combined genetic and cell-based physiological and therapeutic investigations in addition to more traditional pathologic studies, and can be used to build sustainable bio-banks for future inquiries.This article has an associated First Person interview with the first author of the paper.
Topics: Antineoplastic Agents; Carcinoma, Mucoepidermoid; Cell Differentiation; Cell Proliferation; Cell Survival; Culture Media, Conditioned; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Neoplasm Proteins; Protein Kinase Inhibitors; Salivary Gland Neoplasms; Signal Transduction; Transcriptome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 29419396
DOI: 10.1242/dmm.031716 -
Pathologie (Heidelberg, Germany) Nov 2022In recent years, the characterization of salivary gland tumors has undergone a major transformation. Morphologically defined entities could to a large extent also be... (Review)
Review
In recent years, the characterization of salivary gland tumors has undergone a major transformation. Morphologically defined entities could to a large extent also be characterized molecularly with an often distinct genotype. The first part of this article reviews the advances in the molecular characteristics of mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, secretory carcinoma, intraductal carcinoma, and hyalinizing clear cell carcinoma. The molecular genotype can be particularly useful in classifying unusual morphologic variants. Recurrent NTRK or RET gene fusions can be used not only as a diagnostic tool but also for potential targeted therapy.
Topics: Humans; Salivary Gland Neoplasms; Carcinoma, Mucoepidermoid; Carcinoma, Adenoid Cystic; Carcinoma, Acinar Cell; Carcinoma, Intraductal, Noninfiltrating
PubMed: 36227346
DOI: 10.1007/s00292-022-01123-y -
Journal of Cancer Research and... 2015Mucoepidermoid carcinoma (MEC) is typically located in the salivary, lacrimal, and tracheobronchial glands and rarely presents in the esophagus. MEC is commonly... (Review)
Review
Mucoepidermoid carcinoma (MEC) is typically located in the salivary, lacrimal, and tracheobronchial glands and rarely presents in the esophagus. MEC is commonly characterized by squamous cells, mucus-secreting cells, and intermediate cells. This report presents the case of a 57-years-old male with a three months history of cough and shortness of breath. Computer tomography (CT) scans revealed a tumor locating in the left hilar. The histological report was squamous carcinoma. After three circles of chemotherapy, the patient complained of dysphagia. The electronic gastroscope showed a protrusion which 30-34 cm from the incisors. The tumor was histopathologically determined to be MEC of esophagus. The patient refused to surgery and concurrent chemoradiotheray; so, radiotherapy and sequential chemotherapy were performed, and after one year of follow up, the disease of esophagus recurrence; the patient was died of hemorrhage of esophagus for tumor progression. The literatures of MEC are also reviewed in this study.
Topics: Carcinoma, Mucoepidermoid; Carcinoma, Squamous Cell; Esophageal Neoplasms; Fatal Outcome; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Radionuclide Imaging
PubMed: 26458663
DOI: 10.4103/0973-1482.140986 -
Journal of Ayub Medical College,... 2023Carcinomas of the salivary gland are known to be aggressive in nature, making them difficult to manage. The therapeutic options offered include excision of the gland...
BACKGROUND
Carcinomas of the salivary gland are known to be aggressive in nature, making them difficult to manage. The therapeutic options offered include excision of the gland (maxillectomy in cases of palatal tumours), with or without lymph node dissection, proceeded with radiotherapy. Chemotherapy has not produced promising outcomes and has a minimal impact as a therapeutic alternative. Targeted therapy against human epidermal growth factor receptor 2 (HER-2), which is a commonly used treatment modality for their mammary analogues, is not being offered to these patients since scant literature is available showing its usefulness and no promising evidence is present regarding their efficacy and efficiency in such cases. The study aimed to evaluate and quantify the immunohistochemical expression of HER-2 in cases of adenoid cystic carcinoma (AdCC), mucoepidermoid carcinoma (MEC) and salivary duct carcinoma (SDC), which are analogues of similar tumours arising in breast tissue.
METHODS
A retrospective, cross-sectional study was carried out in the department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, duration of which was six months. A total of 45 cases (15 of each tumour) were taken, and sampled using non-probability convenience technique. The immunohistochemical marker, monoclonal HER-2 antibody (Leica microsystem Germany) was applied on appropriate blocks of all included cases. The staining pattern and intensity were recorded after visualizing the slides under a light microscope.
RESULTS
Seven cases of salivary duct carcinoma and a single case of mucoepidermoid carcinoma expressed positivity for HER-2, while no expression could be seen in the case of adenoid cystic carcinoma. A statistically significant difference was seen when HER-2 expression was compared among the aforementioned tumours.
CONCLUSIONS
The use of targeted therapy against HER-2 is limited to patients of salivary duct carcinoma and a fraction of patients suffering from mucoepidermoid carcinoma.
Topics: Humans; Carcinoma, Adenoid Cystic; Carcinoma, Mucoepidermoid; Biomarkers, Tumor; Cross-Sectional Studies; Retrospective Studies; Receptor, ErbB-2; Salivary Gland Neoplasms; Salivary Glands
PubMed: 37422821
DOI: 10.55519/JAMC-02-11647 -
Head and Neck Pathology Jun 2013Herein we test the following hypotheses: (1) High-risk Human Papillomavirus (HR-HPV) may be involved in the etiology of mucoepidermoid carcinoma (MEC), and (2) The...
Herein we test the following hypotheses: (1) High-risk Human Papillomavirus (HR-HPV) may be involved in the etiology of mucoepidermoid carcinoma (MEC), and (2) The detection rate of HR-HPV in MEC has been increasing over time. Ninety-eight archival MEC specimens from three institutions spanning three decades were studied for HPV16/18 E6/E7 transcripts. RNA was extracted from formalin-fixed paraffin embedded specimens and HPV16/18 E6/E7 expression assessed by nested reverse transcription polymerase chain reaction (RT-PCR). A subset of MEC were also studied for MECT1-MAML2 fusion transcripts by nested RT-PCR and amplicon sequencing. The HPV expression data was validated by immunofluorescence (IF) with monoclonal HPV16/18 E6 antibody, PCR with the GP5+/6+ consensus primers, and sequencing of RT-PCR amplicons. HPV genome was localized by in-situ hybridization with the Ventana Inform HPVIII Family 16 probe. P16(INK4a) overexpression and aberrant p53 expression were assessed by immunohistochemistry. HPV16 E6/E7 transcripts were demonstrated in (29/98) 30% of MEC by RT-PCR. HPV18 E6/E7 transcripts were demonstrated in 13/98 (13%) of MEC by RT-PCR. Seven of 98 tumors (7%) demonstrated both HPV16/18. No significant association was found between HPV status and gender, age, and tumor site. All 13 HPV18+ MEC were diagnosed between 2001 and 2010, whereas 45 MEC diagnosed from 1977 to 2000 were negative for HPV18 (p = 0.002). By contrast, there was no significant difference with respect to HPV16 detection and date of diagnosis. All MEC that were positive for E6 protein were also HPV16/18 positive by RT-PCR. Sequencing a subset of RT-PCR amplicons confirmed HPV type- and region-specific sequences. PCR using GP5+/6+ consensus primers demonstrated HPV status concordance in 9 of 10 cases. DNA degradation was present in the last case; the RT-PCR amplicons were sequenced from this case which confirmed the presence of HPV type- and region-specific sequences. Strong (+4/+4) and diffuse (>50%) nuclear and cytoplasmic p16 expression was seen in 64% of MEC in the glandular regions, and 18% of MEC in the solid, squamoid regions. No correlation was seen between p16 expression and HPV status. Twenty-nine MEC (22 HPV+ and 7 HPV-negative) were selected for further evaluation for p53 expression. Strong aberrant nuclear p53 expression was present in only 2/22 HPV + MEC (9%, both Grade 3); no HPV-negative MEC demonstrated aberrant p53 expression. MECT1-MAML2 fusion transcripts were demonstrated in 23/37 (62%) MEC. No significant association was found between the presence of the MECT1-MAML2 fusion transcripts and tumor grade, HPV status, gender, era of diagnosis (2000 and earlier vs. 2001-2010) or tumor site. We demonstrate for the first time that transcriptionally active HPV16/18 is common to MEC. These findings were validated by demonstrating concordant results by separate PCR with consensus primers, and/or confirming the presence of HPV type- and region-specific sequences in the RT-PCR amplicons. We also visualized E6 viral oncoprotein and HPV genome within tumor cells. HR-HPV is thus potentially implicated in the pathogenesis of MEC. The frequency of HPV18 detection is significantly increased in MEC diagnosed after 2001, whereas we found no differences in the HPV16 detection rates per era of diagnosis.
Topics: Carcinoma, Mucoepidermoid; Cell Transformation, Viral; DNA, Viral; DNA-Binding Proteins; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; In Situ Hybridization; Male; Middle Aged; Oncogene Proteins, Viral; Salivary Gland Neoplasms
PubMed: 23233027
DOI: 10.1007/s12105-012-0411-2 -
American Journal of Clinical Pathology Jan 2022Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic...
OBJECTIVES
Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic challenge. AciCC harbors a t(4;9) translocation increasing nuclear receptor subfamily 4 group A member 3 (NR4A3) expression, detectable by immunohistochemistry (IHC) on surgical resection (SR). NR4A3 IHC cytology data are limited. Here, we examine NR4A3 IHC on smears, cell blocks (CBs), and SRs of AciCC and its mimickers.
METHODS
Our cohort comprised AciCC (including high-grade transformation), secretory carcinoma, mucoepidermoid carcinoma (MEC), Warthin tumor, pleomorphic adenoma (PA), cellular PA, carcinoma ex-PA, oncocytic carcinoma, oncocytoma, and nodular oncocytosis. NR4A3 IHC (Santa Cruz Biotechnology and Origene antibodies) was positive if more than 5% tumor cells showed nuclear staining.
RESULTS
Among CBs, 90% of AciCC cases and none of the mimickers expressed NR4A3. Among SRs, 100% of AciCC cases showed diffuse NR4A3, whereas one high-grade MEC expressed focal NR4A3. Concordance was 95% with two antibody clones. Sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 100%, 100%, and 94.7% for CBs and 100%, 98.8%, 92.3%, and 100% for SRs, respectively. NR4A3 immunostaining was demonstrable on smears from an AciCC case.
CONCLUSIONS
NR4A3 IHC can be a robust diagnostic tool to identify AciCC, especially for cytology specimens.
Topics: Biomarkers, Tumor; Carcinoma, Acinar Cell; Carcinoma, Mucoepidermoid; DNA-Binding Proteins; Humans; Immunohistochemistry; Receptors, Steroid; Receptors, Thyroid Hormone; Salivary Gland Neoplasms
PubMed: 34508546
DOI: 10.1093/ajcp/aqab099 -
Cancer Science Jul 2017This study aimed to evaluate the clinical outcomes of patients with mucoepidermoid carcinomas in the head and neck treated with carbon-ion radiotherapy. Data from 26...
This study aimed to evaluate the clinical outcomes of patients with mucoepidermoid carcinomas in the head and neck treated with carbon-ion radiotherapy. Data from 26 patients who underwent carbon-ion radiotherapy in four facilities were analyzed in this multi-institutional retrospective study: the Japan Carbon-ion Radiation Oncology Study Group. The median follow-up time was 34 months. One patient experienced local recurrence, and the 3-year local control rate was 95%. One patient developed lymph node recurrence and five developed distant metastases. The 3-year progression-free survival rate was 73%. Five patients died, two of mucoepidermoid carcinoma and three of intercurrent disease. The 3-year overall survival rate was 89%. Acute mucositis and dermatitis of grade 3 or higher were experienced by 19% and 8% of patients, respectively; these improved with conservative therapy. Late mucositis and osteonecrosis of jaw were observed in 12% and 23% of patients, respectively. The 3-year cumulative rate of any late adverse event of grade 3 or higher was 14%. None of the patients died of the acute or late adverse events. Carbon-ion radiotherapy was efficacious and safe for treating mucoepidermoid carcinoma in this multi-institutional retrospective study (registration no. UMIN000024473). We are currently undertaking a prospective multicenter study.
Topics: Adult; Aged; Carcinoma, Mucoepidermoid; Disease-Free Survival; Female; Heavy Ion Radiotherapy; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Osteonecrosis; Retrospective Studies; Salivary Gland Neoplasms; Stomatitis; Treatment Outcome
PubMed: 28474791
DOI: 10.1111/cas.13270 -
International Journal of Molecular... Feb 2020Salivary gland aquaporins (AQPs) are essential for the control of saliva production and maintenance of glandular structure. However, little is known of their role in...
Salivary gland aquaporins (AQPs) are essential for the control of saliva production and maintenance of glandular structure. However, little is known of their role in salivary gland neoplasia. Salivary gland tumors comprise a heterogeneous group of lesions, featuring variable histological characteristics and diverse clinical behaviors. Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. The aim of this study was to evaluate the expression of AQP1, AQP3, and AQP5 in 24 MEC samples by immunohistochemistry. AQP1 expression was observed in vascular endothelium throughout the tumor stroma. AQP3 was expressed in epidermoid and mucosal cells and AQP5 was expressed in mucosal cells of MEC. These proteins were expressed in the human MEC cell line UH-HMC-3A. Cellular ultrastructural aspects were analyzed by electron microscopy to certificate the tumor cell phenotype. In summary, our results show that, despite the fact that these molecules are important for salivary gland physiology, they may not play a distinct role in tumorigenesis in MEC. Additionally, the in vitro model may offer new possibilities to further investigate mechanisms of these molecules in tumor biology and their real significance in prognosis and possible target therapies.
Topics: Adult; Aquaporin 1; Aquaporin 3; Aquaporin 5; Carcinoma, Mucoepidermoid; Cell Line, Tumor; Epithelial Cells; Female; Humans; Immunohistochemistry; Male; Microscopy, Electron; Middle Aged; Phenotype; Pilot Projects; Salivary Gland Neoplasms; Survival Rate
PubMed: 32075009
DOI: 10.3390/ijms21041287 -
Head and Neck Pathology Jul 2013Salivary gland tumors constitute a heterogeneous group of uncommon diseases that pose significant diagnostic and therapeutic challenges. However, the recent discovery of... (Review)
Review
Salivary gland tumors constitute a heterogeneous group of uncommon diseases that pose significant diagnostic and therapeutic challenges. However, the recent discovery of a translocation-generated gene fusion network in salivary gland carcinomas as well in benign salivary gland tumors opens up new avenues for improved diagnosis, prognostication, and development of specific targeted therapies. The gene fusions encode novel fusion oncoproteins or ectopically expressed normal or truncated oncoproteins. The major targets of the translocations are transcriptional coactivators, tyrosine kinase receptors, and transcription factors involved in growth factor signaling and cell cycle regulation. Notably, several of these targets or pathways activated by these targets are druggable. Examples of clinically significant gene fusions in salivary gland cancers are the MYB-NFIB fusion specific for adenoid cystic carcinoma, the CRTC1-MAML2 fusion typical of low/intermediate-grade mucoepidermoid carcinoma, and the recently identified ETV6-NTRK3 fusion in mammary analogue secretory carcinoma. Similarly, gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign pleomorphic adenomas. Continued studies of the molecular consequences of these fusion oncoproteins and their down-stream targets will ultimately lead to the identification of novel driver genes in salivary gland neoplasms and will also form the basis for the development of new therapeutic strategies for salivary gland cancers and, perhaps, other neoplasms.
Topics: Adenoma, Pleomorphic; Carcinoma, Adenoid Cystic; Carcinoma, Mucoepidermoid; Humans; Oncogene Proteins, Fusion; Salivary Gland Neoplasms
PubMed: 23821214
DOI: 10.1007/s12105-013-0462-z -
World Journal of Surgical Oncology Jan 2017Mucoepidermoid carcinoma of salivary glands usually metastasizes to the lungs, liver, bone, brain, and skin. We report a rare case of distant metastasis of high-grade...
BACKGROUND
Mucoepidermoid carcinoma of salivary glands usually metastasizes to the lungs, liver, bone, brain, and skin. We report a rare case of distant metastasis of high-grade mucoepidermoid carcinoma of the parotid to the ipsilateral bulbar conjunctiva of the eye.
CASE PRESENTATION
Sixty-year-old male of Kashmiri origin presented to our tertiary care referral cancer institute with exophytic lesion of the left bulbar conjunctiva following his treatment for mucoepidermoid cancer of ipsilateral parotid gland, 9 months back. The lesion was biopsied and reported as high-grade mucoepidermoid carcinoma. Radiological imaging showed no other site of recurrence. The patient underwent orbital exenteration and final histopathological evaluation reported the lesion as mucoepidermoid carcinoma.
CONCLUSIONS
Distal metastasis from mucoepidermoid carcinoma to bulbar conjunctiva is very rare and to the best of our knowledge has not been previously reported.
Topics: Carcinoma, Mucoepidermoid; Conjunctival Neoplasms; Eye Neoplasms; Humans; Male; Middle Aged; Parotid Neoplasms; Prognosis
PubMed: 28061862
DOI: 10.1186/s12957-016-1077-0