Clinicopathological correlates of adrenal Cushing's syndrome.

Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease.

Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association.

Germline mutations in Von Hippel-Lindau (VHL), succinate dehydrogenase subunit B (SDHB), SDHC, and SDHD have been detected in individuals with synchronous or metachronous pheochromocytoma/paraganglioma (PHEO/PGL) and renal cell carcinoma (RCC). Most recently, FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial RCC. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC driven by a novel germline mutation in the TMEM127 gene. Morphologically, both the PHEOs and multilocular RCC were indistinguishable from those associated with VHL disease. However, at the biochemical level, the predominant adrenergic catecholamine profile distinguishes this presentation from SDH- and VHL-related PHEOs. This case justifies the prioritization of genetic testing for germline TMEM127 in individuals with RCC and PHEO with a predominantly adrenergic phenotype.

Predictive value of metastatic cervical lymph node ratio in papillary thyroid carcinoma recurrence.

BACKGROUND: The purpose of this study was to determine whether the proportion of metastatic cervical lymph nodes resected (metastatic lymph node ratio [MLNR]) predicted papillary thyroid carcinoma (PTC) recurrence, and whether MLNR could alter the predictive ability of TNM nodal classification for recurrence in PTC. METHODS: We conducted a retrospective review of patients with PTC who underwent a total or near-total thyroidectomy with at least 1 lymph node removed at our institution. RESULTS: Of 253 patients, 35 (13.8%) developed recurrent disease. The total MLNR (ratio between total metastatic lymph nodes and total number of lymph nodes resected) independently predicted PTC recurrence (odds ratio [OR], 1.024; 95% confidence interval [CI], 1.010-1.039; p = .001). In receiver operating characteristic (ROC) curve analysis, TNM nodal classification with total MLNR had greater accuracy in predicting PTC recurrence than did TNM nodal classification alone (0.726 and 0.675, respectively). CONCLUSION: MLNR is an independent predictor of PTC recurrence and enhances the predictive value of TNM nodal classification.