Best practice & research. Clinical endocrinology & metabolism最新文献

Pheochromocytomas and paragangliomas (PPGLs) represent a unique subset of neuroendocrine neoplasms (NENs) characterized by their genetic diversity and potential for catecholamine secretion. Similar to epithelial NENs, all PPGLs are classified as malignant neoplasms that are associated with a variable risk of metastatic spread. PPGLs arise from neuroendocrine cells of the adrenal medulla (intra-adrenal paraganglia) or extra-adrenal paraganglia. Advances over the past two decades have significantly enhanced our understanding of the biological and genetic underpinnings of these neoplasms, resulting in robust genotype-phenotype (e.g., morphology, anatomic distribution, catecholamine profile, biomarker profile, risk of metastasis) correlations that guide diagnosis and prognostication. The 2022 WHO classification of PPGLs emphasizes a shift away from morphology-only diagnostic approaches by ensuring the integration of morphology with functional, structural and pathogenesis-related biomarker studies into routine pathology practice when assessing PPGLs. This paradigm is critical in distinguishing metastatic disease from multifocal primary tumors, particularly in patients with germline mutations - a hallmark of PPGLs, with germline susceptibility observed in at least 40 % of cases. This review provides practicing pathologists with a concise update on modern diagnostic and risk assessment strategies for PPGLs, focusing on the integration of biomarkers, genetic profiling, and morphological features. It also addresses emerging challenges, such as identifying metastatic potential and distinguishing these from synchronous lesions, to improve multidisciplinary care of these patients.

Pathogenic variants (PVs) in EPAS1, which encodes hypoxia-inducible factor-2α (HIF-2α), could be the underlying genetic cause of about 3%-6% of pheochromocytoma and paragangliomas (PPGLs). EPAS1-related PPGLs may occur as isolated tumors or as part of Pacak-Zhuang Syndrome (PZS) with two or more of a triad of PPGL, polycythemia, and somatostatinoma. HIF-2α plays a critical role in the regulation of the cellular hypoxia pathway. When a gain-of-function PV is acquired, HIF-2α evades steady-state hydroxylation by the prolyl hydroxylase type 2 (PHD2), which accelerates von Hippel-Lindau (VHL)-mediated proteasomal degradation. In this situation, HIF-2α is stabilized and can translocate to the nucleus, inducing the expression of several genes involved in tumorigenesis. This leads to the development of PPGL and other manifestations of PZS. EPAS1-related PPGLs usually occur in the second or third decade of life, more frequently in females, and are usually multiple, adrenal and extra-adrenal, and norepinephrine-secreting. In addition, these tumors carry an increased metastatic potential and have been reported with metastatic disease in up to 30% of cases. While polycythemia is fairly common in PZS, somatostatinomas are rare. It has been suggested that the character of the acquired PV in EPAS1, which affects its binding to PHD2, correlates with certain phenotypes in PZS. PVs in EPAS1 that have been found in related sporadic PPGLs have also been associated with hypoxic conditions including cyanotic congenital heart disease, hemoglobinopathies and high altitude. Understanding the hypoxia pathway and its role in the pathogenesis of PPGL may open a new avenue for developing effective therapies for these tumors. Indeed, one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs.

The complexity of omes - the key cellular ensembles (genome and epigenome, transcriptome, proteome, and metabolome) - is becoming increasingly understood in terms of big-data analysis, the omics. Amongst these, proteomics provides a global description of quantitative and qualitative alterations of protein expression (or protein abundance in body fluids) in response to physiologic or pathologic processes while metabolomics offers a functional portrait of the physiological state by quantifying metabolite abundances in biological samples. Here, we summarize how different techniques of proteomic and metabolic analysis can be used to define key biochemical characteristics of pheochromocytomas/paragangliomas (PPGL). The significance of omics in understanding features of PPGL biology that might translate to improved diagnosis and treatment will be highlighted.

Phaeochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours which arise from chromaffin cells of the adrenal medulla or extra-adrenal autonomic ganglia. PPGL most commonly present in adulthood but can arise in childhood and adolescence with an estimated annual incidence of 0.5 cases per million children per year. There have been significant advances in the diagnosis and management of PPGL over the past 2-3 decades based largely on the study of adult patients. These advances in clinical knowledge can be applied to paediatric patients but like other cancers, paediatric PPGL must be viewed as a distinct subset with their own specific challenges and opportunities for improved clinical care. This review article provides an overview on the diagnosis and management of PPGL in children focusing on recent international guidance.

Significant advances have been made in the past few decades in surgical management and outcomes of patients with pheochromocytoma and paraganglioma. Improvements in preoperative hypertensive control with the implementation of alpha- and beta-adrenergic blockade has resulted in better intra-operative blood pressure control and less incidence of hypertensive crises, which had been a large source of morbidity in the past. Emphasis on anesthesia and surgical team communication has also assisted in minimizing intraoperative hypertensive events at critical points of the operation. Shifting away from open resection, the now standard-of-care laparoscopic and minimally invasive adrenalectomy offers less pain, shorter hospitalizations, and quicker recoveries. Patient underlying germline mutations can guide the timing, approach, and extent of surgery. Postoperative outcomes have significantly improved with recent advancements in perioperative care in addition to regimented biochemical and radiographic surveillance. Here, we highlight the recent advancements in surgical approaches and outcomes for patients with pheochromocytoma and paraganglioma.

Radiomics revolutionizes medical imaging by providing quantitative analysis that complements traditional qualitative assessments through advanced computational techniques. In this narrative review we have investigated the impact of succinate dehydrogenase (SDH) pathogenic variants on the radiomic profile of ¹⁸F-FDG, ¹⁸F-DOPA, and ⁶⁸Ga-DOTA-peptides PET in paragangliomas, focusing on head and neck localizations (HNPGLs). This influence manifests in uptake intensity and textural heterogeneity, revealing a complex radiomic landscape that may reflect specific tumor behaviors and mutation statuses. By combining radiomic analysis with genetic data, we will gain new insights into the relationship between PET imaging features and underlying molecular changes. In the future, we envision an approach integrating macroscopic indices, such as lesion location, size, and SUV, with advanced computer-based algorithms. This comprehensive analysis could facilitate in vivo predictions of SDH pathogenic variants, thereby encouraging genetic testing, and ultimately improving patient outcomes.

The topic of the diagnosis of phaeochromocytomas remains highly relevant because of advances in laboratory diagnostics, genetics, and therapeutic options and also the development of imaging methods. Computed tomography still represents an essential tool in clinical practice, especially in incidentally discovered adrenal masses; it allows morphological evaluation, including size, shape, necrosis, and unenhanced attenuation. More advanced post-processing tools to analyse digital images, such as texture analysis and radiomics, are currently being studied. Radiomic features utilise digital image pixels to calculate parameters and relations undetectable by the human eye. On the other hand, the amount of radiomic data requires massive computer capacity. Radiomics, together with machine learning and artificial intelligence in general, has the potential to improve not only the differential diagnosis but also the prediction of complications and therapy outcomes of phaeochromocytomas in the future. Currently, the potential of radiomics and machine learning does not match expectations and awaits its fulfilment.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with clinical heterogeneity and a high association with hereditary disease, affecting approximately 30 % of the cases. Differences in the presentation and genetic etiologies of PPGLs have been demonstrated between Chinese and European patients. The frequency of germline genetic diagnosis was remarkably higher in Brazilian patients (∼50 %) compared with other cohorts (Chinese 21 %, European 31 %, and The Cancer Genome Atlas Program cohort 27 %). Interestingly, germline SDHB genetic defects were also more prevalent in Brazilian patients (17 %) with PPGLs when compared with other cohorts (3-9 %). The SDHB exon 1 deletion was responsible for approximately 50 % of the SDHB pathogenic/likely pathogenic variants in Brazilian patients with PPGLs due to a founder effect. The germline SDHB exon 1 deletion represents ∼10 % of the germline drivers in Brazilian patients (and possibly in Latin America). Therefore, a single diagnostic PCR for the SDHB exon 1 deletion might be very useful in clinical practice for genetic testing and counseling of patients with PPGLs in Latin America.