Cell Adenoma Research Articles

Multi-organ carcinogenicity by inhalation exposure to 2-Bromopropane in rats.

The purpose of this study was to investigate the carcinogenicity of 2-bromopropane (2-BP) in rats. Male and female F344 rats were exposed by whole body inhalation to 2-BP vapor at concentrations of 0, 67, 200, and 600 ppm for 6h/day, 5 days/week for 2 years. All rats of both sexes exposed to 600 ppm died or became moribund within 85 weeks. Death/moribunditywas caused by 2-BP induced tumors. In males, significantly increased tumors were malignant Zymbal's gland tumors; sebaceous adenoma and basal cell carcinoma of the skin/appendage; adenocarcinoma of the small/large intestine; follicular cell adenoma of the thyroid; fibroma of the subcutis, and malignant lymphoma of the lymph node. In addition, an increased trend in tumor incidence was found in the preputial gland, lung, forestomach, pancreas islet, brain, and spleen. In females, significantly increased tumors were adenocarcinoma and fibroadenoma of the mammary gland, squamous cell papilloma of the vagina, and large granular lymphocytic leukemia of the spleen. In addition, an increased trend in tumor incidence was found in Zymbal's gland, the clitoral gland, skin, large intestine, pancreas islet, uterus, and subcutis. Particularly, malignant Zymbal's gland tumors were induced even in males exposed to the lowest concentration, 67 ppm. Two-year inhalation exposure to 2-BP resulted in multi-organ carcinogenicity in rats. Based on sufficient evidence of carcinogenicity in this study, 2-BP has the potential to be a human carcinogen.

Enhanced CT-based texture analysis and radiomics score for differentiation of pleomorphic adenoma, basal cell adenoma, and Warthin tumor of the parotid gland.

To evaluate the diagnostic performance of computed tomography (CT) radiomics analysis for differentiating pleomorphic adenoma (PA), Warthin tumor (WT), and basal cell adenoma (BCA). A total of 189 patients with PA (n = 112), WT (n = 53) and BCA (n = 24) were divided into a training set (n = 133) and a test set (n = 56). The radiomics features were extracted from plain CT and contrast-enhanced CT images. After dimensionality reduction, plain CT, multiphase-enhanced CT, integrated radiomics signature models and radiomics score (Rad-score) were established and calculated. The receiver operating characteristic (ROC) curve analysis was taken for the assessment of the model performance, and then comparison was conducted among these models. Decision curve analysis (DCA) was adopted to assess the clinical benefits of the models. Diagnostic performances including sensitivity, specificity, and accuracy of the radiologists were evaluated. Seven, nine, fourteen, and fourteen optimal features were used to constructed plain scan, arterial phase, venous phase, and integrated radiomics signature models, respectively. ROC analysis showed these four models were able to differentiate PA from BCA and WT, with the area under the ROC curve (AUC) values of 0.79, 0.90, 0.87, and 0.94 in the training set, and 0.79, 0.89, 0.86, and 0.94 in the test set, respectively. The integrated model had better diagnostic performance than single-phase radiomics model, but it had similar diagnostic performance to that of the radiomics model based on the arterial phase (p > 0.05). The sensitivity, specificity, and accuracy in the diagnosis of PA were 0.86, 0.46, and 0.70 for the non-subspecialized radiologist and 0.88, 0.77, and 0.84 for the subspecialized radiologist, respectively. Six venous phase parameters were finally selected in differentiating WT from BCA. The predictive effect of the model was favorable, with AUC value of 0.95, sensitivity of 0.96, specificity of 0.83, and accuracy of 0.92. The sensitivity, specificity, and accuracy in the diagnosis between WT and BCA were 0.26, 0.87, and 0.45 for the non-subspecialized radiologist and 0.85, 0.58, and 0.77 for the subspecialized radiologist, respectively. The CT-based radiomics analysis showed favorable predictive performance for differentiating PA, WT, and BCA, thus may be helpful in the clinical decision-making.

Epidemiological, Clinical, and Histopathological Features of Salivary Gland Tumors among 150 Sudanese Patients: 10 Years' Experience.

Salivary gland tumors (SGTs) are serious challenges to pathologists. Herein, we aimed to assess epidemiological and histopathological characteristics of SGTs among Sudanese patients. This retrospective descriptive study was undertaken at The pathology department in Khartoum State between 2008 and 2018. Patient records, histopathological reports, and slides were retrieved; and re-examined by two histopathologists. Diagnoses were reclassified according to the 2017 WHO classification of SGTs. Overall, 150 cases of Sudanese patients with SGT were included (90 [60%] males and 60 [40%] females). Among these, 105 were benign (70%) and 45 were malignant (30%). The parotid glands were the most common site for both benign and malignant tumors (77/150; 51%: 59 benign (76.6%) and 18 malignant [23.4%]). The next common site was the submandibular gland (54 [36%]: 38 benign [70.3%] and 16 malignant [29.7%]), followed by minor salivary glands (19 [12.7%]: 8 benign and 11 malignant [57.9%]). Benign gland entities included pleomorphic adenoma (88/105; 83.7%), oncocytoma (5/105; 4.8%), myoepithelioma (4/105; 3.8%), Whartin tumors (3/105; 2.9%), basal cell adenoma (3/105; 2.9%), and sialolipoma (2/105; 1.9%). Malignant gland entities included adenoid cystic carcinoma (12; 26.7%), mucoepidermoid carcinoma (10; 22,2%), acinic cell carcinoma (6; 13.3%), poorly differentiated carcinoma (4; 8.9%), adenocarcinoma NOS (not otherwise specified) (4; 8.9%), basal cell adenocarcinoma (3; 6.7%), carcinoma ex pleomorphic adenoma (3; 6.7%), polymorphous adenocarcinoma (2; 4.4%), salivary duct carcinoma (1; 2.2%), and epithelial-myoepithelial carcinoma (2.2%). SGTs shared several epidemiological and histopathological features, exhibiting high incidence in the parotid and submandibular glands, lower prevalence in minor glands, and greater male predominance.

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(>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.

A RETROSPECTIVE ANALYSIS OF INCIDENCE OF FACIAL NERVE DYSFUNCTION IN SUPERFICIAL PAROTIDECTOMY PATIENTS

Salivary gland neoplasms constitute 5 percent of head and neck tumors. Among them 80% arise from parotid gland , 10% from submandibular gland, 10% from sublingual and other minor salivary glands.In parotid neoplasms, 80% are benign and 20% are malignant. Most common benign tumor is pleomorphic adenoma, which accounts for 40-70% of all salivary gland neoplasms. Other benign parotid tumors are various monomorphic adenomas (warthin tumor, oncocytoma, basal cell adenoma, canalicular adenoma), ductal papilloma and capillary hemangioma. Most common malignant tumor is mucoepidermoid carcinoma, which is further divided into low and high grade tumors. Adenoid cystic carcinoma constitute 10% of all salivary gland neoplasms with characteristic indolent growth and perineural invasion. Rapid increase in size, pain and facial nerve palsy are signs of malignancy.Based on the location of tumor and pathological status supercial or total conservative parotidectomy can be done. Facial nerve as well as it's branches are very close to the gland, they are at high risk of injury.Therefore successful surgery depends on the indentication and preservation of facial nerve. Marginal mandibular nerve damage is most commonly encountered complication. Temporary neuropraxia is common and expected to recover with in few months following Surgery. It is mainly due to stretching of Vasa vasorum. The main objective of this AIMS AND OBJECTIVES: study is to access the incidence of facial nerve dysfunction as temporary or permanent, complete or incomplete in post supercial parotidectomy Patients. MATERIALS AND METHODS: A retrospective study was conducted from June 2016 to June 2019 in the department of general surgery, government general hospital, kakinada among the Patients who underwent surgery for parotid neoplasms. Am RESULTS: ong 50 remaining Patients, 36 were female and 14 were male patients with male to female ratio of 1:2.5. The mean age was 39+/-9 years. Among 54 Patients 50 underwent supercial parotidectomy .Among 50 Patients who underwent surgery, 18 were observed to have no complications in the immediate postoperative period. And 28 patients presented with transient facial weakness, which was incomplete and temporary in the immediate postoperative period. Only 4 patients had permanent facial weakness which was complete Overall inc CONCLUSION: idence of temporary and permanent facial nerve dysfunction in this study is 63.3% and 6.6% respectively without using any intraoperative monitoring with a nerve stimulator or magnication.And the incidence is mainly depending on the location of the tumor, extent of the surgery, excessive traction, proper anatomical knowledge and experience of the surgeon.

Abstract IA016: Vaccine approach for the interception of colon cancer

Abstract This year, in the US, an estimated 150,000 people will be diagnosed with colon cancer and ~52,000 will die of the disease. A vaccine approach is well suited to colon cancer prevention. First, a limited number of immunizations can be given over a short period of time to achieve a desired immune response. If immunologic memory develops, antigen specific T-cells will persist in the body for years, ready to be deployed when aberrant cells are detected. Finally, there are several well-defined high-risk populations that would be suitable for testing a preventative colon cancer vaccine including individuals (1) with a hereditary genetic syndrome such as familial adenomatous polyposis, (2) with a history of inflammatory bowel disease such as Crohn’s disease or ulcerative colitis, and (3) those with a history of hyperplastic colonic polyps. Vaccines targeting virally mediated cancers are effective, in part, because T-cells are primed to proteins involved in oncogenesis. The most common type of colon adenoma and invasive cancer associated antigens are non-mutated growth-related proteins that become markedly overexpressed in the disease state. Genes which are aberrantly up-regulated and conserved from adenoma to invasive colon carcinoma may encode overexpressed proteins that are associated with colon cancer initiation. Evaluating gene expression data derived from over 600 colorectal cancers, matched normal tissues, and colon adenomas we identified 160 genes overexpressed in the majority of adenomas and early-stage colon cancers, but not in normal tissues. Using siRNA screening we demonstrated 35 of those genes, when silenced, resulted in apoptosis or inhibition of growth of colon cancer cells and an adenoma cell line but not a non-neoplastic colon cell line. Of those genes, 16 have been shown to encode proteins that are overexpressed in both adenomas and colon cancer and are associated with disease progression and over a third of these proteins are immunogenic. These proteins could serve as potential candidate antigens for inclusion in a multi-antigen vaccine. Recently, we have identified epitopes within the natural sequences of non-mutated tumor antigens that only generate Th1 (Th1 selective) antigen specific T-cells. This discovery and the development of high throughput methods to both identify and screen putative Class II binding peptides for Th selective function has allowed us to develop antigen specific Th1 selective vaccines. A vaccine targeting CDC25B, COX2, and EGFR can inhibit intestinal tumor formation in both APCmin mice and mice with tumor induced by AOM. Concomitant use of NSAIDs potentiates the immune response generated with vaccination. The anti-tumor response observed after vaccination is significantly correlated with elevated CD8 T-cells found in the lesions and induced by immunization as well as high magnitude antigen specific T-cells identified in the spleen. These data validate a genomic approach to antigen discovery and anti-tumor efficacy of Th1 selective vaccines for colon cancer prevention. Citation Format: Mary Disis, Ying Liu, Lauren Corulli, Erin Rodmaker, Denise Cecil. Vaccine approach for the interception of colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA016.

Comparative Efficacy of AZD9496 and Fulvestrant on the Growth of Pituitary Adenoma via Blocking JAK2/STAT5B Pathway.

Total 158 gonadotropin-type pituitary adenoma tissue specimens were collected and the expression of ESR1 in gonadotropin-type pituitary adenoma and its association with the overall survival of patients were analyzed. Transcriptome-sequencing data containing 79 cases of gonadotropin-type pituitary adenoma was used to search for all ESR1-related genes. KEGG pathway enrichment analysis was performed to identify the altering pathway and targeting genes. The in vitro and in vivo pituitary models were used to evaluate the therapeutic efficacy of estrogen receptor (ER) inhibitors AZD9496 and fulvestrant. The mechanism of AZD9496 and fulvestrant in suppressing pituitary adenoma were also investigated. Low-level ESR1 had longer progression-free survival (PFS) in pituitary adenoma patients. ErbB signaling pathway was discovered as the main enriched pathway. Furthermore, the STAT5B gene was identified as a key ESR-1-related gene. The expression of STAT5B was significantly positively correlated with ESR1 expression in the pituitary adenoma. AZD9496, a novel ER inhibitor, exhibited a potent inhibitory effect on the growth of in vitro and in vivo pituitary adenoma cells, and its efficacy is comparable to the classic ER inhibitor, fulvestrant. Mechanically, the AZD9496 and fulvestrant significantly blocked JAK2/STAT5B pathway in GT1-1 cells and xenograft mice. Our results provide substantial evidence for the subsequent clinical use of AZD9496 in the treatment of patients with pituitary adenoma.

Coexistence of Papillary Microcarcinoma and Hurthle Cell Adenoma: a Case of Thyroid Collision Tumor

While thyroid cancers are usually present one type of cancer in the thyroid gland, rarely different thyroid cancers may found in one or two different lobes of the thyroid gland at the same time. A 70-years-old female patient presented with a long-standing neck swelling, especially on the left side, which was more prominent, recently increasing in size and causing shortness of breath. Due to tracheal compression and diagnosis of multi-nodular goiter, total thyroidectomy was performed. Histopathological examination revealed a thyroid collision tumor with papillary microcarcinoma on the right and hurtle cell adenoma on the left side. Due to its rarity, clinicians encountered difficulties in the diagnosis and treatment of thyroid collision tumors. We believe that to be aware of these rare entities by encouraging clinicians to report such cases enable to more solid conclusions to diagnosis and management of collision tumors.

Development of Human Adrenocortical Adenoma (HAA1) Cell Line from Zona Reticularis

The human adrenal cortex is composed of distinct zones that are the main source of steroid hormone production. The mechanism of adrenocortical cell differentiation into several functionally organized populations with distinctive identities remains poorly understood. Human adrenal disease has been difficult to study, in part due to the absence of cultured cell lines that faithfully represent adrenal cell precursors in the early stages of transformation. Here, Human Adrenocortical Adenoma (HAA1) cell line derived from a patient's macronodular adrenocortical hyperplasia and was treated with histone deacetylase inhibitors (HDACis) and gene expression was examined. We describe a patient-derived HAA1 cell line derived from the zona reticularis, the innermost zone of the adrenal cortex. The HAA1 cell line is unique in its ability to exit a latent state and respond with steroidogenic gene expression upon treatment with histone deacetylase inhibitors. The gene expression pattern of differentiated HAA1 cells partially recreates the roster of genes in the adrenal layer that they have been derived from. Gene ontology analysis of whole genome RNA-seq corroborated increased expression of steroidogenic genes upon HDAC inhibition. Surprisingly, HDACi treatment induced broad activation of the Tumor Necrosis Factor (TNF) alpha pathway. This novel cell line we developed will hopefully be instrumental in understanding the molecular and biochemical mechanisms controlling adrenocortical differentiation and steroidogenesis.

Fine needle aspiration of follicular lesions of the thyroid

Background: Fine needle aspiration (FNA) is a reliable method in the initial assessment of thyroid nodules. This study evaluated the accuracy of fine needle aspiration cytology (FNAC) in cases of follicular neoplasm (FN) on the basis of histologic diagnosis, and reviewed the cytologic findings of FN according to the FNAC.Method: Among the 100 cases diagnosed with thyroid Follicular Neoplasm by FNAC during the 3 year period from October 2020 to September 2022, 54 cases that had undergone thyroid surgery were available for review. Cytologic diagnosis was compared with the histologic diagnosis of each case.Results: Among the 54 cases with a cytologic diagnosis of thyroid FN, histologic diagnosis was as follows: 32 follicular adenomas (59.3%), 4 Hurthle cell adenomas (7.4%), 2 follicularcarcinomas (3.7%),10 nodular goitres (18.5%), 2 papillary carcinomas (3.7%), and 1 Hashimoto'sthyroiditis (3.7%), resulting in a diagnostic accuracy of FNAC for thyroid FN of 70.4%.Conclusion: This study shows that FNAC for thyroid FN is a useful primary screening method because when FN is diagnosed by FNAC, the rate of FN histological diagnosis is relatively high and however, adequate sampling and experience is a prerequisite for this procedure.

Role of MicroRNA-663b as an Oncogene in Colorectal Carcinoma on top of familial adenomatous polyposis cells.

Role of MicroRNA-663b as an Oncogene in Colorectal Carcinoma on top of familial adenomatous polyposis cells.

A Subset of Salivary Intercalated Duct Lesions Harbors Recurrent CTNNB1 and HRAS Mutations: A Molecular Link to Basal Cell Adenoma and Epithelial-Myoepithelial Carcinoma?

Intercalated duct lesions (IDLs) are benign salivary gland proliferations that resemble normal intercalated ducts and are subdivided into hyperplastic, adenoma or hybrid types depending on circumscription. While IDLs were historically regarded as non-neoplastic, frequent association with basal cell adenoma (BCA) and epithelial-myoepithelial carcinoma (EMC) has raised the possibility that they are neoplastic precursors. In this study, we performed β-catenin immunohistochemistry and targeted molecular analysis on IDLs to clarify their pathogenesis. We identified 15 IDLs from the parotid glands of eight men and six women with a median age of 65years (range 42-85years). These lesions included nine hyperplastic, three adenoma, and three hybrid types. Nuclear β-catenin localization was present in 7 of 13 lesions tested (54%). Next generation sequencing was successfully completed in 12 IDLs, of which seven (58%) had likely oncogenic mutations. These included three recurrent CTNNB1 mutations in hyperplastic (n = 2) and hybrid (n = 1) lesions and two recurrent HRAS hotspot mutations in adenomas. Despite substantial heterogeneity, these findings confirm that a majority of IDLs are genuinely neoplastic, and some demonstrate molecular overlap with both BCA and EMC, supporting their theorized role as precursors to these tumors. Nevertheless, no oncogenic drivers were present in a significant subset of cases, suggesting that some IDLs may be truly reactive and hyperplastic. As such, IDL appear to represent a diverse morphologic and molecular spectrum that include both neoplastic and hyperplastic lesions. Reconsideration of the boundary between IDL and BCA in the future may be necessary to simplify classification.

Salivary Duct Cyst with Sialolithiasis in Upper Lip: A Rare Entity

AbstractSalivary duct cyst (SDC) is a true salivary gland pathology that rarely occurs in the upper lip. The proposed rarity of SDC is around 0.39% of all the salivary cystic lesions. It usually arises in the lower lip or the floor of the mouth and is prevalent in the sixth/eight decade of life. We report a case of 76-year-old male patient with a chief complaint of an abnormal growth of the upper lip. The growth had increased in size from the last two months. Clinically it was a well circumscribed, solitary, nodular, painless, mobile, noncompressible, soft growth. Excisional biopsy was performed. Histology revealed a SDC and sialolithiasis in the upper lip. This article aims to include SDC in the differential diagnosis of lesions in the upper lip. Their clinical and histopathology features mimic salivary gland pathology such as mucocele, pleomorphic adenoma, basal cell adenoma, low-grade mucoepidermoid carcinoma.

Clear evidence of the carcinogenic potential of anthracene: A 2-year feeding study in rats and mice.

Anthracene is an environmental pollutant and its adverse effects on human health have long been a concern due to its persistence and bioaccumulation properties. However, there is insufficient evidence for its chronic toxicity, especially carcinogenicity, in either humans or experimental animals. In this study, its carcinogenicity and chronic toxicity were investigated in compliance with the OECD test guideline 451 (OECD TG 451) and Good Laboratory Practice Standards. Fifty male and 50 female F344 rats and 50 female BDF1 mice were administrated 0, 8000, 20000, or 50000 ppm anthracene in the diet for 104 weeks, and 50 male BDF1 mice were fed diets containing anthracene at 0, 3200, 8000, or 20000 ppm. Anthracene treatment had no adverse effect on either the survival rate or general condition of the rats or mice during the study period. Body weights were lower or tended to be lower in the anthracene-treated groups than in the control groups. Increased incidence of hepatocellular carcinoma and hepatocellular adenoma was observed in male rats and female mice. Renal cell carcinoma and renal cell adenoma, fibroadenoma in the mammary gland, and uterine endometrial stromal sarcoma were increased in female rats. Transitional cell carcinoma and transitional cell papilloma in the urinary bladder were also increased in male and female rats. In addition, several different pre-neoplastic lesions were increased in the anthracene-treated male and female rats and female mice. These results provide clear evidence that oral administration of anthracene for 104 weeks has a carcinogenic effect in male and female rats and female mice.

Abstract A008: DNA methyltransferase 3A promotes inflammation-associated gastric cancer growth and presents a therapy target for gastric cancer

Abstract Gastric cancer (GC) remains the third leading cause of cancer-related death worldwide. While inflammation is a well-established driver of gastric tumorigenesis, only a small subset of GC patients responds to immunotherapy. One proposed mechanism of immune escape is silencing tumor-antigen expression, and thereby avoiding immune recognition. DNA methyltransferases (DNMTs) are the enzymes responsible for DNA methylation and hence, for the epigenetic silencing of gene expression of tumor-antigens and other immune-related molecules. Interestingly, they are often overexpressed in solid tumors. Epigenetic drugs inhibiting these DNMTs have shown anti-tumor effects in combination with immune checkpoint inhibitors. Here we are studying the role of DNMTs, specifically DNMT3A, in GC mouse models and the possibility of combining DNMT inhibitors with immunotherapy for the treatment of GC. This project utilises various mouse models of GC. We established a Dnmt3a-overexpressing inflammation-driven GC mouse model (gp130FF, A33Dnmt3a). In a second mouse model, mutant Kras, Pi3kca and Tp53 expression results in highly advanced invasive gastric carcinoma formation (KPT model). We successfully established GC organoids of one of these triple mutant tumors, which can be injected subcutaneously into wild type mice and result in allograft tumor formation. DNMT3A overexpression was detected in human GC specimen and associated with bad overall survival of patients. Gastric adenomas of our gp130FF, A33Dnmt3a mouse model have a 10-fold elevated Dnmt3a expression. Importantly, tumor-specific Dnmt3a overexpression significantly increased gastric tumor burden. We have conducted DNA methylation and gene expression analyses to identify differently methylated and expressed genes between gp130FF and gp130FF, A33Dnmt3a gastric adenoma cells. Treatment with the DNMT inhibitor decitabine reduced tumor growth in the inflammation-driven gp130FF gastric adenoma mouse model. In the KPT model, we have identified DNMT3A as being highly expressed in the invasive front of tumors, their liver metastases as well as in the allograft tumors established by the KPT organoids. In this model of advanced GC, treatment with the DNMT inhibitor decitabine significantly decreased tumor growth and we are currently investigating the efficacy of decitabine in combination with anti-PD-1 and/or anti-CTLA-4 immunotherapy. Taken together, we provide evidence for a driver function of Dnmt3a in gastric tumorigenesis and gastric tumor growth. In addition, our findings encourage further studies to investigate the potential of DNMT inhibitors for the treatment of GC. Citation Format: Anne Huber, Christine Dijkstra, Yuba Bhandari, Hariharan Easwaran, Stephen Baylin, Matthias Ernst, Moritz Eissmann. DNA methyltransferase 3A promotes inflammation-associated gastric cancer growth and presents a therapy target for gastric cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A008.

MicroRNA-149 Regulates Proliferation, Migration, and Invasion of Pituitary Adenoma Cells by Targeting ADAM12 and MMP14

ObjectivePituitary adenomas (PAs) can adapt an aggressive phenotype by invading adjacent brain structures with rapid cellular proliferation. Previous studies demonstrated that excessive expression of metalloproteases ADAM12 and MMP-14 is instrumental for the active proliferation and invasiveness of PA cells in vitro and of tumors in vivo. However, the mechanisms regulating ADAM12 and MMP-14 expression in PAs remain unclear.MethodsTarget gene prediction and transcriptomic profiling of invasive vs. noninvasive human PA samples were performed to identify miRNA species potentially involved in the regulation of ADAM12 and MMP14. For cellular analyses of miRNA functions, two mouse PA cell lines (AtT20 and TtT/GF) were transfected with miR-149-3p and miR-149-5p, respectively. The effects of miR-149 (3p and 5p) on expression levels of ADAM12 and MMP14 were determined by Western blotting followed by an analysis of proliferation and colony formation assays, scratch migration assays, and invasion assays.ResultsA significant downregulation of miRNA-149 was observed in invasive vs. noninvasive PA (0.32 vs. 0.09, P<0.0001). In AtT-20 and TtT/GF mouse PAs cells, transfection of mimic miRNA-149 (3p and 5p) caused a significantly reduced cell proliferation and matrigel invasion, whilst the effect on cell migration was less pronounced. Both strands of miRNA-149 (3p and 5p) markedly reduced protein levels of ADAM12 and MMP-14 by at least 40% in both cell lines.ConclusionThis study proved that the invasiveness of PA cells is, at least partly, regulated by miRNA-149-dependent expression of ADAM12 and MMP-14.

Evaluating the expression pattern of the opioid receptor in pituitary neuroendocrine tumors (PitNET) and the role of morphine and naloxone in the regulation of pituitary cell line growth and apoptosis

PurposeThe expression pattern of the opioid receptor (MOR) in pituitary neuroendocrine tumors (PitNET) and the possible effect of morphine and naloxone on GH3 cell growth and apoptosis were evaluated. MethodsThe 114 pituitary tissues including non-functioning, GH-producing and ACTH-producing PitNET and healthy cadaver pituitary tissues were included. The expression level of the MOR gene and protein was assessed using real-time PCR and Western blot. The association with patient demographic characteristics was assessed. Morphine and naloxone were applied to assess their possible pharmacological role in GH3 pituitary adenoma cell death. The cytotoxic effect, the apoptosis rate, the cell cycle distribution, the content of reactive oxygen species and the caspase 3 activity were measured. ResultsMOR gene levels increased significantly in pituitary neuroendocrine tumors (PitNET) compared to the healthy pituitary samples. The increased level of MOR gene expression was prominent in invasive functional and non-functional pituitary tumors. A consistent expression pattern was demonstrated for MOR protein levels in PitNET samples. A dose- and time-dependent reduction in the rate of GH3 pituitary cells was observed after morphine treatment with an IC50 of 483 µM after 24 h of incubation. Morphine induced early apoptosis, accumulation of cells in sub-G1 phase, increase in cellular ROS levels and caspase-3 activity. The observed effects of morphine were reversed after MOR blockade using 10 and 25 µM naloxone. ConclusionThe possible contributing role of the MOR in pituitary tumor cell growth and the putative pharmaceutical effect of morphine in pituitary neuroendocrine tumor cell death (PitNET) is illustrated

CT of hemorrhagic adrenal adenomas: radiologic-pathologic correlation.

To describe the appearance of chronically hemorrhagic adenomas on adrenal protocol CT and correlate imaging with pathologic findings. Retrospective case series of adult patients with resected adrenal adenomas showing internal hemorrhage at histology. Seven of nine patients underwent pre-operative adrenal protocol CT and 2/7 underwent unenhanced CT with portal venous phase CT. Two abdominal radiologists in consensus assessed the CT images for the presence of calcifications, macroscopic fat, cystic/necrotic appearance, and the presence, pattern, and percent nodule volume of areas < 10 HU on unenhanced CT. Absolute washout was calculated using a large ROI, and ROIs on the highest and lowest attenuating regions on the portal venous phase. Mean adenoma length was 4.9cm. All adenomas had areas measuring < 10 HU on unenhanced CT, ranging from < 20 to > 80% nodule volume. Calcifications were present in 4/9 adenomas and gross fat in 4/9 on CT. Of the seven cases with adrenal protocol CT, the absolute washout was < 60% in 5/7 using the large ROI, 5/7 using the low attenuation ROI, and 7/7 using the high attenuation ROI. At histology, all nine cases had microscopic evidence of hemorrhage, lipid rich adenoma cells, and fibrosclerosis. Myelolipomatous changes were identified in 4/9 cases, with the remaining five cases showing lipomatous metaplasia without a myeloid component. Chronically hemorrhagic adrenal adenomas demonstrated variable areas < 10 HU on unenhanced CT corresponding to lipid rich adenoma cells. Absolute washout was most often < 60%, hypothesized to be due to fibrosclerosis within the adenomas.

Intercalated Duct Adenoma of the Parotid Gland

&#x0D; &#x0D; &#x0D; &#x0D; A 56-year-old man presented with a 10-year history of gradually enlarging left pre-auricular mass. No biopsies were done. He underwent superficial parotidectomy which showed an enlarged parotid gland measuring 6 x 5.5 x 2 cm with a 0.5 x 0.2 x 0.2 cm discrete, cream-brown, ovoid intraparenchymal solid nodule. The latter was the lesion of interest.&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; Microscopic examination of the nodule shows a well-circumscribed, encapsulated proliferation of closely packed tubular ducts surrounded by non-neoplastic, otherwise histologically unremarkable lobules of serous acini with an intact ductal system. (Figure 1) The tubules within the nodule are lined by simple cuboidal cells having bland, uniform, round nuclei and moderate amounts of eosinophilic cytoplasm. (Figure 2) In some of these tubules, serous acinar cells containing coarse basophilic granules partly line the lumina, adjacent to or around the cuboidal cells. (Figure 3) Based on the morphological features, a diagnosis of intercalated duct adenoma (IDA) was rendered, occurring in a background that is suggestive of sialadenosis.&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; Intercalated duct adenomas are mostly asymptomatic, benign neoplasms identified incidentally in salivary glands removed for diverse lesions of either benign or malignant etiology.1-4 They are most often found in the parotid gland of adults ranging from 41 to 73 years (mean 57 years) with a female-to-male ratio of 3:2.1,2&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; They belong to a group of ductal proliferations known as intercalated duct lesions (IDL) which are composed of compact proliferation of tubular ducts that are lined by cuboidal ductal cells. Scattered tubules have serous acinar cells complexed with the ductal cells, while others have inconspicuous myoepithelial cells that surround them. Intercalated duct lesions are arbitrarily divided into IDA – if encapsulated and discretely separated from adjacent acinar units, and intercalated duct hyperplasia (IDH) - if unencapsulated and blending into the adjacent acinar units.3-5&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; The ductal cells of IDA resemble those of non-neoplastic intercalated ducts on immunohistochemistry, staining diffusely with CK7 and S100, and focally for ER and lysozyme while CK14 and Calponin highlight the thin myoepithelial cells surrounding the ductal cells.1,3,4 Immunohistochemical stains for myoepithelial cells were not requested as we felt that the participation of acinar cells in a characteristic manner was sufficiently diagnostic of the entity.&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; Important benign differential diagnoses of IDA include striated duct adenoma, canalicular adenoma and basal cell adenoma.2,3 Striated duct adenoma and canalicular adenoma can both be distinguished from IDA due to lack of myoepithelial and acinar cells; the latter is also more commonly found in the minor salivary glands.2,3 Basal cell adenoma and adenocarcinoma on the other hand are challenging differential diagnoses due to significant overlaps in morphology. They tend to be larger (usually &gt;10 mm) with prominent bilayering of luminal cells and distinct basaloid abluminal cells that show palisading. Basal cell adenocarcinoma importantly demonstrates an invasive growth pattern.3,5 IDA on the other hand are small and infrequently seen macroscopically, most often measuring less than 5 mm in diameter.2&#x0D; Both IDA and IDL in general have an excellent prognosis upon complete surgical excision and recurrences are not reported. However, IDA’s frequent co-occurrence with other salivary gland tumors has led to it being hypothesized as a potential precursor of salivary gland tumors, particularly of epithelial-myoepithelial carcinomas.1-2 Its coexistence with sialadenosis has not been previously reported. The diagnosis of IDA in conjunction with other salivary gland pathologies is therefore important to further elucidate the clinical, histopathological, and possible molecular nature and relationships of this lesion.&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D;

ODP098 Hyperparathyroidism Caused by Two Large Water Clear Cell Adenomas

Abstract Background In ambulatory settings, primary hyperparathyroidism is the most prevalent cause of hypercalcemia. Approximately 85% of primary hyperparathyroidism cases are caused by a solitary parathyroid adenoma; other causes include diffuse parathyroid hyperplasia, multiple parathyroid adenomas, and parathyroid cancer. Chief cell adenomas are the most prevalent; adenomas can also consist of oxyphil cell adenomas, lipoadenomas, or mixed cell adenomas. Water clear cell adenoma (WCCA) is a rare tumor formed of large clear cells with foamy pink cytoplasm. Fewer than 30 cases have been recorded in the literature. Case A 52-year-old male with polyuria and polydipsia, diagnosed with hypercalcemia was referred to an endocrinologist. His calcium was 10.9 mg/dl, corresponding parathyroid hormone (PTH) 74 pg/ml, 24-hour urine calcium 818 mg/24hr, vitamin D 25–hydroxy 24.2 ng/ml. He was referred to an endocrine surgeon. A 4-dimensional CT scan revealed soft tissue masses posterior to the thyroid and in the tracheoesophageal groove, consistent with potential parathyroid masses. In the operating room, baseline intraoperative PTH (ioPTH) was 371 pg/ml. A large left superior gland was removed from its normal position, and the ioPTH dropped to 104 pg/ml at 10 minutes post-resection, followed by a rise to 525 pg/ml. A large descended (ectopic) right superior gland was then identified and resected, and the ioPTH decreased to 72, 44, and 57 pg/ml at 10, 15 and 20 minutes post-resection. The remaining parathyroid glands were not identified due to adipose tissue in the neck and likely gland suppression in the setting of high PTH. The pathology report of the two excised glands (left superior 3.2×1.7×0.5cm and 3.703g, right superior 3.4×1.3×0.4cm and 1.86g) demonstrated water clear cell tissue. Post-operatively, patient's polyuria and polydipsia resolved. Labs collected 3 months after surgery demonstrated normalization of the calcium and PTH. The patient was advised to continue follow up every six months. Conclusion Water clear cell parathyroid adenomas are extremely rare. Water clear-cell lesions are considered indolent because excised adenomas are markedly larger than conventional adenomas and grow to a considerable size before becoming biochemically active and diagnosed. Clinical presentation of water clear cell parathyroid lesion is like other causes of primary hyperparathyroidism. The only way to diagnose is via histopathological examination. In rare cases, clear cell renal carcinoma can metastasize to the parathyroid gland causing a similar presentation. Additionally, the rate of hypercalcemia recurrence is higher in WCCA as compared to chief cell adenoma. Therefore, closer follow up of these patients is recommended. Reporting additional cases will aid in our understanding of this uncommon entity, elucidating possible causes/associations, natural history, typical appearances, and post-treatment prognosis. Presentation: No date and time listed