Pheochromocytomas and paragangliomas (PCCs/PGLs) are neural crest-derived tumours with a very strong genetic component. Here we report the first integrated genomic examination of a large collection of PCC/PGL. SNP array analysis reveals distinct copy-number patterns associated with genetic background. Whole-exome sequencing shows a low mutation rate of 0.3 mutations per megabase, with few recurrent somatic mutations in genes not previously associated with PCC/PGL. DNA methylation arrays and miRNA sequencing identify DNA methylation changes and miRNA expression clusters strongly associated with messenger RNA expression profiling. Overexpression of the miRNA cluster 182/96/183 is specific in SDHB-mutated tumours and induces malignant traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster appears as a potential driver in a subgroup of sporadic tumours. Altogether, the complete genomic landscape of PCC/PGL is mainly driven by distinct germline and/or somatic mutations in susceptibility genes and reveals different molecular entities, characterized by a set of unique genomic alterations.

Postoperative FDG-PET/CT should be performed routinely in patients with aggressive histology DTC.

RAI is not administered in many low-risk patients who can be reliably followed up with serum thyroglobulin determination on L-thyroxine treatment and neck ultrasonography. RAI may be administered in case of abnormality, and this delay will not reduce the chance of cure.

Our results demonstrate that a positive SDHD immunostaining predicts the presence of an SDHx gene mutation. Because SDHB negative immunostaining is sometimes difficult to interpret in the case of background, the addition of SDHD positive immunohistochemistry will be a very useful tool to predict or validate SDHx gene variants in PGL/PCC.

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors of neural crest origin. These tumors are caused by germline or somatic mutations in known susceptibility genes in up to 70% of cases. Over the past few years, the emergence of high-throughput technologies has enabled the unprecedented characterization of genomic alterations in PCC/PGL, and has improved our understanding of the molecular mechanisms that distinguish the different tumor subtypes. Integrated genomic analyses have shown that the mutation status of PCC/PGL susceptibility genes strongly correlates with multi-omics data. These observations not only emphasize the role of the long-standing susceptibility genes as the main drivers of PCC/PGL tumorigenesis, but also illustrate the functional interdependence between genomic and epigenomic alterations. In this review, we discuss the genomic landscape underlying PCC/PGL, its functional consequences for tumorigenesis and tumor progression, and the potential clinical relevance of this knowledge for the application of precision medicine for patients with PCC/PGL.

Background. Outcomes vary among patients with radioiodine refractory (RR) differentiated thyroid cancer (DTC). The prognostic factors for survival are not well-known, resulting in difficulty in selectingpatients for newtargetedtherapies.We assessed overall survival (OS) and cancer-specific survival (CSS) from RR-DTC to identify prognostic factors associated with survival. Patients and Methods. The data on all cases of metastatic RR-DTC treated in our center from 1990 to 2011 were retrospectively reviewed. Survival was estimated using the Kaplan-Meier method; associated prognostic factors were assessed using Cox's model. Results. Of 153 cases of metastatic DTC, 59% (n 5 91) met a criterion for RR: that is, 60% (n 5 55) had at least 1 metastasis without

Objective: Cervical ultrasound (US) scan is a key tool for detecting metastatic lymph nodes (N1) in patients with papillary thyroid cancer (PTC). N1-PTC patients are stratified as intermediate-risk and high-risk (HR) patients, according to the American Thyroid Association (ATA) and European Thyroid Association (ETA) respectively. The aim of this study was to assess the value of post-operative cervical US (POCUS) in local persistent disease (PD) diagnosis and in the reassessment of risk stratification in N1-PTC patients. Design: Retrospective cohort study. Methods: Between 1997 and 2010, 638 N1-PTC consecutive patients underwent a systematic POCUS. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of POCUS for the detection of PD were evaluated and a risk reassessment using cumulative incidence functions was carried out. Results: After a median follow-up of 41.6 months, local recurrence occurred in 138 patients (21.6%), of which 121 were considered to have PD. Sensitivity, specificity, NPV, and PPV of POCUS for the detection of the 121 PD were 82.6, 87.4 95.6, and 60.6% respectively. Cumulative incidence of recurrence at 5 years was estimated at 26% in ETA HR patients, 17% in ATA intermediate-risk patients, and 35% in ATA HR patients respectively. This risk fell to 9, 8, and 11% in the above three groups when the POCUS result was normal and to !6% when it was combined with thyroglobulin results at ablation. Conclusion: POCUS is useful for detecting PD in N1-PTC patients and for stratifying individual recurrence risk. Its high NPV could allow clinicians to tailor follow-up recommendations to individual needs.

Objective: In this report, we describe a new patient with unexplained familial bilateral pheochromocytoma. Following the recent description of TMEM127 as a new pheochromocytoma susceptibility gene, the aim of this study was to test the hypothesis of a causative TMEM127 gene mutation in this patient. Design: Pheochromocytoma susceptibility genes were analyzed in germline DNA and losses of heterozygosity (LOH) assessed by BAC array comparative genomic hybridization in tumor DNA. SDHB expression and S6 kinase (S6K) phosphorylation were analyzed by immunohistochemistry. Genomewide expression microarray studies were performed, and vascular density was quantified after CD34 immunohistochemistry. Results: A first germline variant was identified in the SDHB gene (c.158GOA; p.Gly53Glu). However, a positive SDHB immunostaining in the tumor indicated that this SDHB variant was a non-functional polymorphism. A novel TMEM127 germline mutation (c.140COA, p.Ala47Asp) associated with a 2q11 LOH was found. Transcriptome and immunohistochemical analyses showed that TMEM127-related pheochromocytoma clusterized with NF1-related and RET-related tumors in a large series of pheochromocytomas and paragangliomas, exhibited a reduced TMEM127 mRNA expression and displayed a low vascularization. The phosphorylation of S6K observed in this tumor was suggestive of an activation of the MTOR pathway. Conclusions: Pathological and genomic data demonstrated that a TMEM127 gene mutation not previously described was causative of a new case of familial bilateral pheochromocytoma. This report highlights the importance of supplementary analyses on tumor tissue to provide an accurate pheochromocytoma/paraganglioma genetic testing result to affected patients.