Rethinking pheochromocytomas and paragangliomas from a genomic perspective.

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.

Screening in asymptomatic SDHx mutation carriers: added value of ¹8F-FDG PET/CT at initial diagnosis and 1-year follow-up.

PURPOSE: Specific recommendations on screening modalities for paraganglioma (PGL) and phaeochromocytoma (PCC) in asymptomatic SDHx mutation carriers (relatives) are still lacking. We evaluated the added value of (18)F-FDG PET/CT in comparison with morphological imaging at initial diagnosis and 1 year of follow-up in this population. METHODS: The study included 30 consecutive relatives with a proven SDHx mutation who were investigated by (18)F-FDG PET/CT, gadolinium-enhanced magnetic resonance angiography of the head and neck, thoracic/abdominal/pelvic (TAP) contrast-enhanced CT and/or TAP MRI. (123)I-MIBG scintigraphy was performed in 20 subjects and somatostatin receptor scintigraphy (SRS) in 20 subjects. The gold standard was based on pathology or a composite endpoint as defined by any other positive imaging method and persistent tumour on follow-up. Images were considered as false-positive when the lesions were not detected by another imaging method or not confirmed at 1 year. RESULTS: At initial work-up, an imaging abnormality was found in eight subjects (27%). The final diagnosis was true-positive in five subjects (two with abdominal PGL, one with PCC and two with neck PGL) and false-positives in the other three subjects (detected with (18)F-FDG PET/CT in two and TAP MRI in one). At 1 year, an imaging abnormality was found in three subjects of which one was an 8-mm carotid body PGL in a patient with SDHD mutaion and two were considered false-positive. The tumour detection rate was 100% for (18)F-FDG PET/CT and conventional imaging, 80% for SRS and 60% for (123)I-MIBG scintigraphy. Overall, disease was detected in 4% of the subjects at the 1-year follow-up. CONCLUSION: (18)F-FDG PET/CT demonstrated excellent sensitivity but intermediate specificity justifying combined modality imaging in these patients. Given the slow progression of the disease, if (18)F-FDG PET/CT and MRI are normal at baseline, the second imaging work-up should be delayed and an examination that does not expose the patient to radiation should be used.

Thyroid function at the third trimester of pregnancy in a Northern French population.

OBJECTIVES: During pregnancy, the production rate of thyroid hormone increases when iodine intake is sufficient. However, the appropriateness of the free thyroxin (FT4) immunoassay is questionable. We have therefore evaluated prospectively the thyroid function in pregnancy and the relevance of the FT4 immunoassay. PATIENTS AND METHODS: The thyroid function of 114 pregnant, healthy Parisian women with mild iodine deficiency was studied at the third trimester of pregnancy, 55 of whom served as their own control three months after delivery, and the results were compared to North American reference values. RESULTS: All French pregnant women showed an increase in thyroxin binding globulin (TBG) serum levels. FT4 levels decreased by about 30% at the third trimester of pregnancy, as compared to 10-15% in the American population. Moreover, the increase in total thyroxin (TT4) secretion represented only 27%, as compared to 50% in the American population. Linear regression model analysis showed a positive correlation between levels of TT4 and TBG, TT4 and FT4, as well as FT4 and free thyroxin index (FTI). CONCLUSION: The hypothyroxinemia at the third trimester of pregnancy was more prominent in the Parisian population and insufficient iodine intake could be responsible for the deficient increase in TT4. It is therefore concluded that the inability of the thyroid to establish the required equilibrium could be corrected by systematic iodine supplementation before pregnancy. Finally, the strong correlation between FT4 and FTI suggests that the quality of FT4 test immunoassay is appropriate for estimating FT4 serum levels during pregnancy.