The Pathogenesis of Pheochromocytomas: Of Mice and Men

Pheochromocytomas are neuro‐endocrine tumors that arise from the neural crest derived adrenal medullary chromaffin cells, and produce catecholamines. The first description of a patient with pheochromocytomas was done by Fränkel in 1886, but the term pheochromocytoma was invented by the pathologists Ludwig Pick in 1912, after the Greek words phaios, meaning dark or dusky, and chroma, meaning color, which refers to the dark discoloration of the tumor cells in the chromium‐salt reaction. During embryonic development, cells of the neural crest migrate along preprogrammed pathways, and differentiate into a variety of cell types, such as the intraadrenal and extra‐adrenal chromaffin cells, and the autonomic ganglion cells. The adrenal medulla is composed of chromaffin cells, which are arranged in clusters, enclosed by sustentacular cells and a stromal network. Apart from these structures, the medulla is highly vascularized, and this is also seen in pheochromocytomas. In general, chromaffin cells are thought to store either adrenalin or noradrenalin, but cells containing both catecholamines have been reported in mice. Pheochromocytomas can produce dopamine, adrenalin, noradrenalin, or a combination, depending on their genetic background. Catecholamine production results in sustained, labile or paroxysmal hypertension, and if patients are not treated appropriately, pheochromocytomas will almost always cause fatal cardiovascular events or other devastating complications. Pheochromocytomas occur in approximately 1 or 2 per 100,000 adults in the USA per year (0.001‐0.002%), but the exact incidence is not precisely known. The true incidence of pheochromocytomas is probably higher (towards 0.05%) as one in twenty cases of the incidentally‐found adrenal masses during autopsy, magnetic resonance imaging (MRI), computed tomography (CT), or abdominal ultrasonography, is a pheochromocytoma

The relationships between school belonging and students' motivational, social-emotional, behavioural, and academic outcomes in secondary education:a meta-analytic review

This meta-analytic review examines the relationships between students' sense of school belonging and students' motivational, social-emotional, behavioural, and academic functioning in secondary education. Moreover, it examines to what extent these relationships differ between different student groups (grade level, SES), measurement instruments, and region. The meta-analysis included 82 correlational studies, published in peer-reviewed journals between 2000 and 2018. Results revealed, on average, a small positive correlation with academic achievement, and small to moderate positive correlations with motivational outcomes such as mastery goal orientations; with social-emotional outcomes such as self-concept and self-efficacy; and with behavioural outcomes such as behavioural, cognitive, and agentic engagement. A small negative correlation is observed with absence and dropout rates. Similar results are found across different student groups (grade level, SES). Although the results vary to some extent across measurement instruments and region, generally, the results reveal that school belonging plays an important role in students' school life

The predictive power of track recommendations in Dutch secondary education

In the transition from Dutch primary to secondary education, two indicators are used to place students in the right track: primary school teachers' track recommendations (TTR) and standardized achievement tests (SATs) at the end of primary school. Which indicator is better for placing students is a long-standing issue among educational researchers and professionals. Since 2015, the SAT is administered after the TTR has been given; previously, SAT was administered first. In the current study, it was investigated to what extent TTR and a commonly used SAT predict students' educational attainment after three years of secondary education for multiple cohorts before and after 2015. The results were compared for educational tracks and for different socio-economic status (SES) groups, using multiple samples approaching population data. For all educational tracks and SES groups the results show that TTR is a better predictor of educational attainment than SAT. Furthermore, large differential effects for SES were found. The change of administrative sequence in 2015 had no effect on the overall predictive accuracy: TTR remained the better predictor. The results give new insights into the predictive value of both TTR and SAT before and after the change in administration sequence

Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome

Adrenal medullary hyperplasias (AMHs) are adrenal medullary proliferations with a size b1cm, while larger lesions are considered as pheochromocytoma (PCC). This arbitrary distinction has been proposed decades ago, although the biological relationship between AMH and PCC has never been investigated. Both lesions are frequently diagnosed in multiple endocrine neoplasia type 2 (MEN2) patients in whom they are considered as two unrelated clinical entities. In this study, we investigated the molecular relationship between AMH and PCC in MEN2 patients. Molecular aberrations of 19 AMHs and 13 PCCs from 18 MEN2 patients were determined by rearranged during transfection (RET) proto-oncogene mutation analysis and loss of heterozygosity (LOH) analysis for chromosomal regions 1p13, 1p36, 3p, and 3q, genomic areas covering commonly altered regions in RET-related PCC. Identical molecular aberrations were found in all AMHs and PCCs, at similar frequencies. LOH was seen for chromosomes 1p13 in 8 of 18 (44%), 1p36 in 9 of 15 (60%), 3p12-13 in 12 of 18 (67%), and 3q23-24 in 10 of 16 (63%) of AMHs, and for chromosome 1p13 in 13 of 13 (100%), 1p36 in 7 of 11 (64%), 3p12-13 in 4 of 11 (36%), and 3q23-24 in 11 of 12 (92%) of PCCs. Our results indicate that AMHs are not hyperplasias and, in clinical practice, should be regarded as PCCs, which has an impact on diagnosis and treatment of MEN2 patients. We therefore propose to replace the term AMH by micro-PCC to indicate adrenal medullary proliferations of less than 1cm

Molecular alterations in dog pheochromocytomas and paragangliomas

Recently, genetic alterations in the genes encoding succinate dehydrogenase subunit B and D (SDHB and SDHD) were identified in pet dogs that presented with spontaneously arising pheochromocytomas (PCC) and paragangliomas (PGL; together PPGL), suggesting dogs might be an interesting comparative model for the study of human PPGL. To study whether canine PPGL resembled human PPGL, we investigated a series of 50 canine PPGLs by immunohistochemistry to determine the expression of synaptophysin (SYP), tyrosine hydroxylase (TH) and succinate dehydrogenase subunit A (SDHA) and B (SDHB). In parallel, 25 canine PPGLs were screened for mutations in SDHB and SDHD by Sanger sequencing. To detect large chromosomal alterations, single nucleotide polymorphism (SNP) arrays were performed for 11 PPGLs, including cases for which fresh frozen tissue was available. The immunohistochemical markers stained positive in the majority of canine PPGLs. Genetic screening of the canine tumors revealed the previously described variants in four cases; SDHB p.Arg38Gln (n = 1) and SDHD p.Lys122Arg (n = 3). Furthermore, the SNP arrays revealed large chromosomal alterations of which the loss of chromosome 5, partly homologous to human chromosome 1p and chromosome 11, was the most frequent finding (100% of the six cases with chromosomal alterations). In conclusion, canine and human PPGLs show similar genomic alterations, suggestive of common interspecies PPGL-related pathways

The role of AIP variants in pituitary adenomas and concomitant thyroid carcinomas in the Netherlands: a nationwide pathology registry (PALGA) study

Purpose: Germline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) have been identified often in the setting of familial isolated pituitary adenoma (FIPA). To date there is no strong evidence linking germline AIP mutations to other neoplasms apart from the pituitary. Our primary objective was to investigate the prevalence of AIP gene mutations and mutations in genes that have been associated with neuroendocrine tumors in series of tumors from patients presenting with both pituitary adenomas and differentiated thyroid carcinomas (DTCs). Methods: Pathology samples were retrieved from all pituitary adenomas in patients with concomitant DTCs, including one with a known germline AIP variant. Subsequently, two additional patients with known germline AIP variants were included, of which one presented only with a follicular thyroid carcinoma (FTC). Results: In total, 17 patients (14 DTCs and 15 pituitary adenomas) were investigated by targeted next generation sequencing (NGS). The pituitary tumor samples revealed no mutations, while among the thyroid tumor samples BRAF (6/14, 42.9%) was the most frequently mutated gene, followed by NRAS (3/11, 27.3%). In one AIP-mutated FIPA kindred, the AIP-variant c.853C>T; p.Q285* was confirme