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

publishedVersionPaid Open Acces

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 testing in metastatic basal cell carcinoma

Background: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor. Objective: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC. Methods: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter. Results: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib. Limitations: In 2 patients there was insufficient qualitative DNA available for genetic analysis. Conclusions: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value

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

Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations

The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor