Pathology of the Adrenal Cortex: a Reappraisal of the Past 25 Years Focusing on Adrenal Cortical Tumors

Abstract A reappraisal of the major advances in the diagnostic pathology of adrenal cortical lesions and tumors in the last 25 years is presented, with special reference to the definition of malignancy in primary adrenal cancer and its variants. Slightly more than 25 years ago, Weiss proposed his diagnostic scoring system for adrenal cortical carcinoma. This represented a milestone for adrenal pathologists and the starting point for further modifications of the system, either through minor changes in the scoring procedure itself or concentrating on some particular Weiss criterion such as mitotic index, integrated into alternative scoring schemes or algorithms that are currently under validation. Improvements in diagnostic immunohistochemistry have led to the identification of markers of cortical origin, such as Melan-A, alpha-inhibin, and SF-1 and of prognostic factors in carcinoma, such as the Ki-67 proliferation index and SF-1 itself. With regard to hyperplastic conditions, genetic investigations have allowed the association of the majority of cases of primary pigmented nodular adrenocortical disease (PPNAD) in Carney complex to mutations in the gene encoding the regulatory subunit 1A of protein kinase A (PRKAR1A). Other hereditary conditions are also associated with adrenal cortical tumors, including the LiFraumeni, Beckwith-Wiedemann, Gardner, multiple endocrine neoplasia type 1, and neurofibromatosis type 1 syndromes. Moreover, several advances have been made in the knowledge of the molecular background of sporadic tumors, and a number of molecules/genes are of particular interest as potential diagnostic and prognostic biomarkers

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Diagnostic and molecular aspects of adrenal cortical tumors

Adrenal cortical diseases are relatively rare but tumors are the most common in diagnostic practice. This is reflected by the content of this review. By studying familial syndromes in which they occur more frequently and the pathways involved in steroidogenesis and cortical growth, the molecular genetics of these tumors is being unraveled. Genome-wide approaches have also been helpful. The emerging data may complement standard histological investigation in diagnosis and prognosis

Adrenal medulla and paraganglia

Paraganglia are of two types, associated with either the sympathetic or parasympathetic nervous systems. Tumors arising from these are paragangliomas. The term “pheochromocytoma” is reserved for intra-adrenal tumors and the others should be defined with respect to type and site. These are rare tumors, but it is now realized that more than 30% arise in the context of familial disease. In addition to the well-recognized associations with multiple endocrine neoplasia types 2A and 2B, von Hippel–Lindau syndrome, and neurofibromatosis type 1, the familial paraganglioma syndromes related to mutations in the genes encoding the B, C, and D subunits of succinate dehydrogenase have now been defined. The diagnosis of malignancy is reserved for the presence of metastases in sites where paraganglial tissue would not be found. Local invasive growth may be lethal, but does not correlate with metastatic behavior. The identification of malignant potential in primary tumors can be difficult. Two recent multifactorial approaches show some promise in identifying tumors with a higher risk of metastasis, but benign behavior cannot be predicted with certainty. Emerging data from molecular genetic studies may be of help in future