N-Nitrosomorpholine-induced oncocytic transformation in rat endocrine organs.

BACKGROUND: N-Nitrosomorpholine (NMO) is one of the most common N-nitroso compounds. An oncocytic transformation has been demonstrated in renal tubules of NMO-treated rats. In our study, we aimed to investigate the potential transformation of oncocytic cells in 6 endocrine organs, i.e., thyroid, adrenal and pituitary glands, pancreas, testis, and bone, of NMO-exposed rats. METHODS: Thirty male rats were born and raised. Fifteen of them were given a single dose of 320 mg NMO per kg body weight, dissolved in drinking water, by a gavage tube. At the end of 52 weeks, the animals in both series were killed. Right after the killing, 6 different endocrine organs (hypophysis, thyroid, pancreas, adrenal gland, bone [femur], and testicles) of each animal were excised. RESULTS: There was no evidence of oncocytic cell development in the control group. In contrast, oncocytes were observed in 8 out of 13 NMO-treated rats: 2 in the adrenal sections, 1 in the thyroid sections, 3 in the pituitary sections, and 2 in the pancreas sections. Thesticle and bone sections were completely normal. CONCLUSIONS: We showed that NMO induced an oncocytic change in pancreas, thyroid, pituitary, and adrenal glands. To date, no identified specific environmental risk factors that lead to an oncocytic transformation in endocrine glands have been reported previously. Given the increasing prevalence of endocrine-disrupting chemicals in the environment, personal care products, manufactured goods, and food sources, there is a need to advance our understanding of the pathological mechanisms underlying oncocytosis in endocrine organs.

SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma.

BACKGROUND: Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy. METHODS: We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis. RESULTS: Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant. CONCLUSION: SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.

Effect of lymph node metastasis on the prognosis of patients with G2 phase stage pancreatic neuroendocrine tumors / 国际外科学杂志

Objective:To investigate the effect of lymph node metastasis on the prognosis of patients with G2 phase stage pancreatic neuroendocrine neoplasm(pNEN).Methods:A retrospective case control study was conducted to analyze the case data of 368 patients with pancreatic neuroendocrine tumors in G2 phase stage from January 1, 2010 to December 31, 2016 in SEER database, including 174 males and 194 females. According to whether lymph nodes were metastatic, they are divided into lymph node non metastatic (N0) group ( n=272) and lymph node metastatic (N1) group ( n=96). The Kaplan-Meier method and Log-rank test were used to compare the overall survival rate (OS) of patients in the N0 and N1 groups. The COX proportional risk model was used to evaluate whether N stage was an independent risk factor affecting prognosis. Count data were expressed as cases and percentage(%), and Chi-square test was used for comparison between the groups. Results:Among all patients, the OS of patients in the N0 group was better than that of patients in the N1 group. The OS of N0 patients at 1, 3, and 5 years was 96.3%, 92.7%, and 85.6%, respectively, while the OS of N1 patients at 1, 3, and 5 years was 92.6%, 82.1%, and 82.1%, respectively ( P=0.014). Multivariate analysis showed that age ( HR=2.245, 95% CI: 1.126-4.475, P=0.022) and N stage ( HR=0.457, 95% CI: 0.237-0.883, P=0.020) were independent prognostic factors for G2 phase pNEN patients. Conclusion:Lymph node metastasis is one of the independent prognostic factors in patients with G2 phase stage pNEN.

Characteristics of germline mutations in Korean patients with pheochromocytoma/paraganglioma.

BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing neuroendocrine tumours. PPGLs are a rare but important cause of secondary hypertension owing to their high morbidity and mortality. Patients with PPGL exhibit an increased prevalence of mutations in one of the PPGL susceptibility genes according to previous studies. We aimed to investigate the characteristics of germline mutations in the largest number of Korean patients with PPGL. METHODS: In this study, 161 patients with PPGL were evaluated. Phenotype data, including biochemical, pathological and anatomical imaging results, were collected. Germline mutations in 10 PPGL-related genes were tested by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: Approximately 21% of apparently sporadic PPGLs harboured germline mutations of the PPGL-related genes. The mutation carriers were younger at the first diagnosis and had more bilateral (28.6% vs 4.0%, p<0.001) and multifocal (11.4% vs 1.6%, p=0.027) PPGLs, but showed no metastatic risk (17.1% vs 11.1%, p=0.504), than non-mutation carriers. Missense mutation of SDHD p.V111I was found in this cohort of Asian patients, which was associated with unilateral pheochromocytoma with dominantly epinephrine production. CONCLUSION: This study covered the largest number of Korean patients with PPGL. To our knowledge, it is the first to compare results of targeted NGS panel with those of conventional sequencing methods in Asia. We demonstrated that the variant type, as well as the mutated gene, may determine the phenotype and prognosis of PPGLs.

The key to simplified management of an undescended parathyroid adenoma.

Undescended parathyroid adenoma is a rare cause of primary hyperparathyroidism that happens < 1% of cases. If not suspected, it can lead to a negative bilateral parathyroid exploration and extensive iatrogenic trauma. We propose that with proper imaging the correct diagnosis can be established to simplify surgical management. We describe two cases of patients who underwent a targeted neck exploration due to an undescended parathyroid adenoma diagnosed with an appropriate preoperative imaging protocol. With an appropriate imaging protocol for primary hyperparathyroidism and parathyroid hormone aspirates, an undescended parathyroid adenoma can be primarily diagnosed to guide a focused parathyroidectomy.

El adenoma paratiroideo no descendido ocasiona hiperparatiroidismo primario en <1% de los casos. Si no se sospecha, puede llevar a exploraciones negativas y trauma iatrogénico extenso. Proponemos que, con un protocolo imagenológico adecuado, se puede realizar un diagnóstico correcto, simplificando el abordaje quirúrgico. Describimos dos casos en que se realizó una exploración de cuello dirigida debido a un adenoma paratiroideo no descendido diagnosticado con un protocolo de imagen preoperatorio apropiado. Un protocolo de imagen apropiado para hiperparatiroidismo primario y aspirados de PTH pueden diagnosticar de manera inicial un adenoma paratiroideo no descendido para guiar una paratiroidectomía dirigida.

Case report of a man with multiple paragangliomas and pathogenic germline variants in both NF1 and SDHD.

We report a novel case of multiple paragangliomas in a patient who was identified with pathogenic variants in both NF1 and SDHD genes. The proband is a man with known familial NF1 disease, diagnosed clinically in childhood. Multiple head and neck paragangliomas (HNPGL) were found during investigations for acute left sided neurological symptoms, in the region of his known plexiform neurofibroma. He was referred for genetic counselling. He underwent surgery to remove a left carotid body tumor (CBT). A pheochromocytoma and paraganglioma gene panel was tested. Blood and HNPGL tumor DNA were analyzed by whole exome sequencing. In addition to the NF1 truncating variant c.5107delA, p.(Ser1703AlafsTer7), the SDHD truncating pathogenic variant c.3G > A, p.(Met1?) was found. Tumor sequencing showed no LOH of SDHD or NF1, but monoallelic loss of 11p15 and 11q12.2-q12.3 was observed. Co-occurrence of pathogenic variants in multiple cancer susceptibility genes is rare but possible, identified by the increased use of panel testing. This is the first description of a patient presenting with NF1 and SDHD dual pathology, with HNPGL development due to SDHD. This case illustrates the central role of genetic sequencing in PPGLs and the strong genotype-phenotype correlations of different genes.

Validation of Immunohistochemistry for Canine Proteins Involved in Thyroid Iodine Uptake and Their Expression in Canine Follicular Cell Thyroid Carcinomas (FTCs) and FTC-Derived Organoids.

Thyrotropin receptor (TSHR), sodium iodide symporter (NIS), pendrin, and thyroid peroxidase (TPO) are essential for the uptake of iodine by follicular thyroid cells. The aim of this study was to establish immunohistochemistry (IHC) protocols for TSHR, NIS, pendrin, and TPO in canine tissues and characterize their expression in organoids derived from canine follicular cell thyroid carcinoma (FTC) and in the respective primary tumors. This constitutes a fundamental step to establish organoids as a model to study the uptake of iodine in canine FTC. Commercially available antibodies directed against human proteins were selected. Antibody specificity was confirmed by western blot using lysates of the HTori-3 human thyroid cell line and healthy canine thyroid gland. IHC was validated using HTori-3 cells and a set of canine normal tissues including healthy thyroid gland. The expression of TSHR, NIS, pendrin, and TPO was evaluated in 3 organoid lines derived from FTC and respective primary tumors. All 4 antibodies produced specific bands by western blot and cytoplasmic labeling in follicular cells by IHC in both human HTori-3 cells and canine thyroid gland. NIS also showed basolateral membrane immunolabeling in follicular cells. All 4 proteins were highly expressed in organoids derived from FTC. The expression was similar or higher compared to the primary tumors. The results of this study characterize organoids derived from canine FTC as a suitable in vitro model to investigate iodine uptake, opening new research possibilities in the field of canine thyroid cancer therapy.

Significant racial differences in the incidence and behavior of the follicular variant of papillary thyroid carcinoma.

BACKGROUND: Increased detection of papillary thyroid cancer (PTC) has led to overtreatment of the largely indolent follicular variant (fvPTC). To guide management of non-aggressive lesions, we investigated whether race predicts PTC variant and tumor behavior. METHODS: Analysis of 258 973 patients from the National Cancer Database diagnosed with PTC in 2004-2014. Clinical and tumor information was compared by race. Multivariate logistic regression was used to predict fvPTC, extrathyroidal extension (ETE), and lymph node metastasis (LNM) of fvPTC. RESULTS: Blacks had the highest fvPTC rate (40% vs white 30%, Hispanic 26%, Asian 25%, P < .001). Blacks had higher odds of fvPTC (aOR = 1.33, 95% CI: 1.28-1.37) and lower odds of ETE than whites (aOR = 0.90, 95% CI: 0.82-0.99) (P < .001). Hispanics and Asians had lower odds of fvPTC (aOR = 0.89, 95% CI: 0.86-0.92 and aOR = 0.81, 95% CI: 0.79-0.84) and higher odds of LNM and ETE than whites (P < .001). CONCLUSIONS: Racial disparities in fvPTC incidence and behavior should be considered to optimize diagnosis and treatment planning.

A scoring system to predict recurrence in patients with differentiated thyroid cancer.

OBJECTIVES: Though predictive models have been constructed to determine the risk of recurrence in differentiated thyroid carcinoma, various aspects of these models are inadequate. Therefore, we aimed to construct, internally validate and implement on a mobile application a scoring system to determine this risk within 10 years. DESIGN: A retrospective cohort study in 1984-2016. SETTING: A Spanish region. PARTICIPANTS: We enrolled 200 patients with differentiated thyroid carcinoma without distant metastasis at diagnosis. MAIN OUTCOME MEASURES: Time-to-recurrence. A risk table was constructed based on the sum of points to estimate the likelihood of recurrence. The model was internally validated and implemented as a mobile application for Android. RESULTS: Predictive factors were follicular histology, T, N and multifocality. This risk table had a C-statistic of 0.723. The calibration was satisfactory. CONCLUSIONS: This study provides an instrument able to predict rapidly and very simply which patients with differentiated thyroid carcinoma have a greater risk of recurrence.

Diagnostic challenges in a patient with an occult insulinoma:68 Ga-DOTA-exendin-4 PET/CT and 68Ga-DOTATATE PET/CT.

Despite growing evidence for GLP-1R molecular-based imaging, successful localization of insulinomas may require the use of multiple imaging modalities. Not all benign insulinomas express the GLP-1R as expected. Our case demonstrates that there is a still an important role for traditional methods for the anatomical localization of an insulinoma.

Noncoding RNAs in endocrine malignancy.

Only recently has it been uncovered that the mammalian transcriptome includes a large number of noncoding RNAs (ncRNAs) that play a variety of important regulatory roles in gene expression and other biological processes. Among numerous kinds of ncRNAs, short noncoding RNAs, such as microRNAs, have been extensively investigated with regard to their biogenesis, function, and importance in carcinogenesis. Long noncoding RNAs (lncRNAs) have only recently been implicated in playing a key regulatory role in cancer biology. The deregulation of ncRNAs has been demonstrated to have important roles in the regulation and progression of cancer development. In this review, we describe the roles of both short noncoding RNAs (including microRNAs, small nuclear RNAs, and piwi-interacting RNAs) and lncRNAs in carcinogenesis and outline the possible underlying genetic mechanisms, with particular emphasis on clinical applications. The focus of our review includes studies from the literature on ncRNAs in traditional endocrine-related cancers, including thyroid, parathyroid, adrenal gland, and gastrointestinal neuroendocrine malignancies. The current and potential future applications of ncRNAs in clinical cancer research is also discussed, with emphasis on diagnosis and future treatment.

CT features of neuroendocrine tumor of the pancreas: report of 28 cases / 中华胰腺病杂志

Objective To observe computed tomography features of neuroendocrine tumor of the pancreas.Methods Computed tomography scans for 28 patients with pathologically proven neuroendocrine tumor of the pancreas were retrospectively analyzed.The data of tumor locations,diameters of the tumor and internal composition,pattern of enhancement,changes of biliary and pancreatic duct,and lymphatic metastasis,remote metastasis were recorded.Results A total of 32 lesions were detected,24 lesions were single lesions,while 4 lesions were multiple lesions (2 lesions within pancreas).The shapes of these lesions were nodule-like or mass-like.Eighteen lesions were located in pancreatic tail,10 in pancreatic head,2 in pancreatic body,and 2 between pancreatic tail and body.Among the lesions located in pancreatic head,pancreatic duct dilation were detected in 5 cases,bile duct dilation in 1 case,both biliary and pancreatic duct dilation in 2 cases,and no dilation in the remaining 2 cases.The diameters of the tumor ranged from 1.0 to 20.0cm (mean5.1 cm),and the size was ＜2 cmin 1 case,2 ～5 cm in 23 cases; ＞5 cm in 8 cases.After enhancement,the lesions were enhanced to different degrees,and the peak value occurred in the pancreatic phase.Twenty-three lesions invaded adjacent vessels or organs,and lymphatic metastasis was observed in 5 cases,remote metastasis were recorded in 6 cases.Conclusions Neuroendocrine tumor of the pancreas has certain features on computed tomography.It is highly likely to make the pre-operative diagnosis when clinical data is also taken into consideration.

Improved Benefit of SPECT/CT Compared to SPECT Alone for the Accurate Localization of Endocrine and Neuroendocrine Tumors.

OBJECTIVE: To assess the clinical utility of SPECT/ CT in subjects with endocrine and neuroendocrine tumors compared to SPECT alone. MATERIAL AND METHODS: 48 subjects (31 women;17 men; mean age 54±11) with clinical suspicion or diagnosis of endocrine and neuroendocrine tumor had 50 SPECT/CT scans (32 Tc-99m MIBI, 5 post treatment I-131, 8 In-111 Pentetreotide, and 5 I-123 MIBG). SPECT alone findings were compared to SPECT/CT and to pathology or radiological follow up. RESULTS: From the 32 Tc-99m MIBI scans, SPECT accurately localized the lesion in 22 positive subjects while SPECT/CT did in 31 subjects. Parathyroid lesions not seen on SPECT alone were smaller than 10 mm. In five post treatment I-131 scans, SPECT alone neither characterized, nor localized any lesions accurately. SPECT/CT revealed 3 benign etiologies, a metastatic lymph node, and one equivocal lesion. In 8 In-111 Pentetreotide scans, SPECT alone could not localize primary or metastatic lesions in 6 subjects all of which were localized with SPECT/CT. In five I-123 MIBG scans, SPECT alone could not detect a 1.1 cm adrenal lesion or correctly characterize normal physiologic adrenal uptake in consecutive scans of the same patient with prior history of adrenelectomy, all of which were correctly localized and characterized with SPECT/CT. CONCLUSION: SPECT/CT is superior to SPECT alone in the assessment of endocrine and neuroendocrine tumors. It is better in lesion localization and lesion characterization leading to a decrease in the number of equivocal findings. SPECT/CT should be included in the clinical work up of all patients with diagnosis or suspicion of endocrine and neuroendocrine tumors. CONFLICT OF INTEREST: None declared.

Expression of ghrelin and its receptor GHS-R 1A in pancreatic endocrine tumors and the plasma levels of ghrelin and leptin / 中华胰腺病杂志

Objective To study the plasma and intratumoral levels of ghrelin, leptin and their relationship and clinical significance in patients with pancreatic endocrine tumor.Methods Preoperative plasma levels of ghrelin and leptin were detected by ELISA in 11 patients with pancreatic endocrine tumors and 28 normal controls.Expressions of ghrelin and its receptor GHS-R 1A were tested in 11 tumors and 27 paired control tissues by immunohistochemistry staining, and they were correlated with the clinicopathological characteristics.Results The plasma levels of ghrelin was ( 16.0 ± 5.0) pg/ml, which was significantly lower than that in normal controls [ (21.0 ± 2.0) pg/ml, P = 0.047 ].The plasma levels of leptin was (0.34 ±0.03 ) ng/ml, which was not significantly different with that in normal controls [ 0.38 ± 0.04) ng/ml ].There was positive association between plasma levels of leptin and ghrelin (P =0.015 ), but was not associated with clinicopathological parameters.The plasma levels of leptin in control group was positively associated with BMI (P = 0.002), but they were not associated in patients with tumor.The expression rate of ghrelin in tumor tissue was significantly lower than that in control group (64% vs 100%, P = 0.004 ).But the expression rate of GHS-R I A was not significantly different between the two groups.The expression of ghrelin and GHS-R1A in tumor was not significantly associated with clinicopathological parameters.Conclusions The ghrelin and its receptor GHS-R 1A were extensively expressed in pancreatic endocrine tumors, and the serum levels of ghrelin and leptin was changed.

Vasoactive intestinal peptide-secreting-tumor,report of 4 cases / 中华普通外科杂志

Objective To evaluate the diagnosis and treatment of vipoma based on our experience on 4 cases.Method Clinical manifestations,laboratory examination,imaging features,surgical findings,and pathology of 4 patients with vipoma admitted in our hospital from 1991 were discussed.Results Watery diarrhea and hypokalemia were the main clinical manifestations.Hepatic metastasis OCCurred in two patients.Tumor located in the head of the pancreas in one case.Two tumors were shown in the pancreatic body and one tumor was in the pancreatic tail.Resection of tumor and hepatic metastatic lesions with repeat resection of metastases Was performed in 1 patient.Resection of the pancreatic body and tail was done in one patient.Pancreatoduodenectomy Was performed in one patient.Laparotomy only was done in one patient because of invasion of the superior mesenteric vein and duodenum.Conclusion Typical symptoms play an important role in the diagnosis of vipoma.Hepatic metastasis is common.Surgery is the most effective means for treatment.

The diagnosis, treatment and clinicopathologic analysis on gastrointestinal neuroendocrine carcinomas / 中国普通外科杂志

Objective To investigate the clinicopathologic features of gastrointestinal neuroendocrine carcinomas. MethodsThe diagnosis and treatment results of 45 cases were studied, and clinicopathologic features and immunohistochemical expressions of NSE, Syn and CgA were detected.ResultsMicroscopically carcinomas were divided into three types: type Ⅰ(25 cases), type Ⅱ(10 cases) and type Ⅲ(10 cases). The histologic categories were correlated with lymph node metastasis significantly( P0.05). The 5-year survival rate for type Ⅰ, type Ⅱ and type Ⅲ was 70%, 65% and 52%, respectively.ConclusionsThe combination of NSE, Syn and CgA immunohistochemical stainnig is necessary for the diagnosis of gastrointestinal neuroendocrine carcinomas. The histologic classification is coincident with the requirement of clinical treatment and prognosis.

Role of LFMPS in the preoperative localization of pancreatic endocrine tumors / 中华消化内镜杂志

Objective To assess the clinical value of low-frequency mini - probe sonography ( LFMPS) in preoperative localization of pancreatic endocrine tumors comparing with other imaging methods. Methods Twenty one cases with suspected pancreatic endocrine tumors were enrolled from June 2000 to June 2002, we compared the diagnostic results of LFMPS, transcutaneous ultrasonography ( US) , helico-computed tomography ( HCT) and magnetic resonance imaging (MRI) with surgical localization and histopathological results by using Fujinon 7. 5 MHz miniature probe and SP-701 ultrasonic system. Results Sixteen pancreatic insulinomas and 1 extra pancreatic VIPoma (vesoactive intestinal polypeptide tumor) were confirmed by surgery and histopathological examination in 17 of the 21 patients, and the rest 4 patients didn't receive surgical procedure because of the negative results in all imaging studies. Among pancreatic lesions, they located on head, body and tail in 9, 3 and 4 cases respectively; the average diameter of all 17 lesions was 2. 02cm. LFMPS correctly localized the tumor in 14 of 17 patients (82. 4% ) while CT in 15 of 17 patients (88. 2% ) , MRI in 12 of 17 patients (70. 6% ) and US in 9 of 17 patients (52. 9% ). Besides, the diagnostic accuracy of LFMPS in detection of small size (

Pancreatic stem cell-like cells in histogenesis of pancreatic endocrine tumors / 中华内分泌代谢杂志

Specimens from 12 cases of pancreatic endocrine tumors were investigated by light and electron microscopy and immunohistochemical staining. Pancreatic stem cell-like cells with special characteristics of pancreatic stem cell were found in the proliferating small ductules and dispersed at the margins of pancreatic endocrine tumors in all the cases studied.