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

Abdominal pheochromocytomas and paragangliomas (PPGLs) are characterized by the overproduction of catecholamines, which are associated with hemodynamic instability (HDI) during surgery. Therefore, perioperative management to prevent intraoperative HDI is imperative for the surgical treatment of PPGLs. Owing to the rarity and heterogeneous nature of these tumors, pre-surgical prediction of HDI is a clinical dilemma. The reported risk factors for HDI include perioperative preparation, genetic background, tumor conditions, body composition, catecholamine levels, and surgical approach. Additionally, several personalized algorithms or models including these factors have been developed. The first part of this review outlines the prediction models that include clinical features such as tumor size and location, body mass index (BMI), blood glucose level, catecholamine levels, and preoperative management with α-adrenoceptor blockade and crystal/colloid fluid. We then summarize recently reported models that consider additional factors such as genetic background, radiomics, robotic-assisted surgical approach, three-dimensional visualization, and machine-learning models. These findings suggest that a comprehensive model including risk factors is the most likely approach for achieving effective perioperative management.

Pheochromocytomas and paragangliomas (PPGLs) represent the highest degree of heritability of any known tumor types in humans. Previous studies have characterized a dramatic difference between Chinese and European Caucasians with regards to both genetics and clinical features of PPGLs. The proportion of PGLs in Chinese patients was higher than in Caucasians, and the prevalence of metastasis was much lower in Chinese patients. Compared with Caucasians, there were more pathogenic variants (PVs) found in HRAS and FGFR1, but less in NF1 and SDHB. There were less germline PVs found in Chinese patients. Importantly, in Chinese patients, there was a large proportion of PGLs with PVs found in HRAS and FGFR1, mostly with epinephrine-producing capacity. This finding provided solid evidence that genetics (cluster 1 vs. 2), rather than location (PCC vs. PGL), determines the catecholamine-producing phenotype. Besides, the lower prevalence of SDHB partially explained lower occurrence of metastatic lesions in Chinese patients. These findings underscore the importance of considering ethnic differences when evaluating PPGLs and patient outcomes.

While the establishment of human phaeochromocytoma and paraganglioma (PPGL) cell lines has proven to be particularly difficult over several decades of research, there are other reliable pre-clinical PPGL models currently available. This review provides a summary of these models, together with our recently established personalised drug screening platform using patient-derived PPGL primary cultures. Such currently available PPGL models include murine and rat PPGL cell lines, of which only one cell line (PC12) is publicly accessible through a cell repository, and PPGL animal models, of which the patient-derived xenograft models are promising but complex to establish. We have developed next-generation implementation of human PPGL primary cultures, enabling reliable and personalised drug screening and an individualised analysis of tumour drug responsivity based on the tumour's unique genetic, biochemical, immunohistochemical and clinical profile. Overall, reliable PPGL models, including patient-derived primary culture models, are essential to advance pre-clinical research in the field of PPGLs.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours. Around 20-25 % of patients develop metastases, for which there is an urgent need of prognostic markers and therapeutic stratification strategies. The presence of a MAML3-fusion is associated with increased metastatic risk, but neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed. We have compiled a cohort of 850 patients, which has shown a 3.65 % fusion prevalence and represents the largest MAML3-positive series reported to date. While MAML3-fusions mainly cause single pheochromocytomas, we also observed somatic post-zygotic events, resulting in multiple tumours in the same patient. MAML3-tumours show increased expression of neuroendocrine-to-mesenchymal transition markers, MYC-targets, and angiogenesis-related genes, leading to a distinct tumour microenvironment with unique vascular and immune profiles. Importantly, our findings have identified MAML3-tumours specific vulnerabilities beyond Wnt-pathway dysregulation, such as a rich vascular network, and overexpression of PD-L1 and CD40, suggesting potential therapeutic targets.

Head and neck paragangliomas (HNPGLs), rare neuroendocrine tumors that mainly arise from parasympathetic ganglia along the cranial nerves, are challenging due to anatomic origin, tendency to aggressive neurovascular and skull base infiltration, unpredictable metastatic potential, radio-chemoresistance, and risk of multiplicity. Symptoms range from mild to life threatening depending on location/size, but rarely relate to catecholamine excess. Risk factors include female sex and pathogenic germline variants in genes affecting hypoxia signaling (foremost succinate dehydrogenase genes). Diagnostic work-up relies on imaging, measurements of plasma free metanephrines/methoxytyramine, genetic testing, and pathology/immunohistochemistry. Management is tailored to patient/tumor characteristics and encompasses wait-scan, upfront surgery, debulking surgery, and radiotherapy. Presurgical embolization is recommended, except for small tympanic and tympanomastoid tumors. Presurgical stenting is required for internal carotid artery involvement, and two-stage surgery for intradural extension. Current treatments for metastatic/inoperable HNPGL are non-curative, and long-term follow-up should be recommended for all patients to monitor local recurrence and new tumors.

Pheochromocytomas and sympathetic paragangliomas (PPGL) are rare neuroendocrine tumors originating from chromaffin tissue of the adrenal medulla and extra-adrenal sympathetic paraganglia. Historically, many of these tumors were diagnosed postmortem, earning pheochromocytomas the moniker "great mimic" due to their diverse clinical manifestations that can resemble various other conditions. Over time, the clinical presentation of PPGL has evolved, with a shift from symptomatic or postmortem diagnoses to more frequent incidental discoveries or diagnoses through screening, with postmortem identification now being rare. The development of a clinical scoring system has improved the identification of patients at increased risk for PPGL. Notably, the proportion of PPGL patients with normal blood pressure ranges from 15 % to 40 %, varying based on the clinical context. Despite the tumor's reputation, PPGL is an exceedingly rare cause of resistant hypertension. Management of a pheochromocytoma crisis has advanced, with several classes of drugs available for treatment. However, PPGL during pregnancy remains a significant concern, associated with substantial maternal and fetal mortality rates. Additionally, PPGL can present as rare disorders, including catecholamine-induced cardiomyopathy, Cushing syndrome, and urinary bladder PGL. Given these varied presentations, heightened awareness and prompt recognition of PPGL are crucial for timely diagnosis and treatment, ultimately improving patient outcomes. In this article, we offer an in-depth analysis of the diverse clinical presentations of PPGL, highlighting their complexity and the associated diagnostic and treatment strategies.

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.

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.

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.