Discussion (834 words):

Pheochromocytomas and paragangliomas (PPGLs) are uncommon neuroendocrine tumours that originate from chromaffin cells in the autonomic nervous system. Pheochromocytomas develop in the adrenal medulla, while paragangliomas develop outside the adrenal glands. The new classification of tumours of the adrenal medulla and extra-adrenal paraganglia, as outlined in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumours [6], includes subtle terminology changes and advances in the understanding of paragangliomas and their tumours. It also addresses the relationship between paraganglioma and pheochromocytoma, the staging system for these tumours and the use of immunohistochemistry for predicting pathogenic mutations. Additionally, it provides information on the use of composite scores to predict the risk of metastasis and progression-free survival in cases of pheochromocytomas and paragangliomas. Historically, PPGLs were considered two distinct entities. The new classification describes pheochromocytomas as a tumour within the spectrum of paragangliomas, defining them as a neuroendocrine neoplasm originating from chromaffin cells of the adrenal medulla and categorised as an intra-adrenal paraganglioma. PPGLs have one of the highest heritability rates, at approximately 40%, and over 20 genes have been implicated, some of which are associated with syndromic forms (RET, VHL, EPAS1, NF1, FH) [7]. PPGLs are currently divided into three clusters based on genetic involvement: cluster 1 includes genes related to the Krebs cycle and the hypoxia signalling pathway; cluster 2 includes genes related to the kinase signalling pathway; and cluster 3 includes CSDE1 and UBTF-MAML3 genes [8]. The prevalence of these tumours ranges from 0.04 to 0.95 cases per 100,000 people annually [9]. Among individuals with hypertension, prevalence varies from 0.2% to 0.6% [10]. A recent meta-analysis suggested that the classic symptoms are not as widespread as previously thought. Only 60% of patients reported headaches, 60% reported palpitations and 52% reported sweating, with other symptoms less common [11]. The most prevalent symptom of PPGLs is hypertension, which affects up to 95% of patients. Of these, 75% will have severe hypertension, and 7-17% will experience a catecholamine-induced hypertensive crisis [12]. The diagnosis of PPGLs primarily depends on a combination of biochemical analysis and imaging techniques. Initial biochemical tests for PPGLs should include measuring plasma-free metanephrines or urinary-fractionated metanephrines. With clear biochemical evidence of PPGLs, the preferred imaging approach involves CT scans for locating them. MRI is the secondary imaging method if CT results are inconclusive or when patients are unsuitable candidates for contrast-enhanced CT. In cases with a high risk of metastases or multifocal disease, functional imaging is recommended to assess the disease’s characteristics and detect metastatic growth [8]. At present, the sole treatment option offering a potential cure for PPGLs is surgical removal. Surgery is performed with the aim of eliminating both the risks associated with excessive hormone secretion and tumour growth. The effects of excessive hormones should be diligently managed through medical therapy before and during the surgical procedure [13]. Surgical removal of PPGLs is a high-risk procedure, and patients undergoing such surgery require comprehensive perioperative planning. Haemodynamic instability, marked by hypertensive crises and profound hypotension, is the primary concern during surgery. Before the procedure, all patients should receive alpha-receptor blockers to manage the symptoms of excess catecholamines and control blood pressure. Using unopposed beta-blockers should be avoided until alpha-blockers are initiated. A high-sodium diet during alpha-blocker therapy and saline infusion 24 hours before surgery are also recommended [11]. Intraoperatively, hypertensive crises should be managed with a sufficiently deep level of anaesthesia and short-acting parenteral antihypertensive drugs, such as nitric oxide modulators, calcium channel blockers, alpha-adrenergic antagonists and magnesium sulphate. Tachyarrhythmia can be treated by administering beta-adrenergic antagonists. Interestingly, recent research indicates that alpha-2-adrenergic agonists, like dexmedetomidine, may be effective in reducing catecholamine availability [14]. However, as those authors discussed, the risks of cardiac, renal and hepatic comorbidities or obesity were excluded using a single, clinically-approved low-dose infusion of dexmedetomidine, which makes such a study difficult to generalise, highlighting the need for further research. In case of a sudden decrease in sympathetic activity after isolating the tumour, vasoconstrictor drugs combined with a crystalloid infusion may be necessary to control severe, refractory hypotension [15]. In the postoperative phase, haemodynamic instability and hypoglycaemia are the two primary complications [11]. Hypotension typically results from a rapid decline in circulating catecholamines after tumour removal, the residual effects of preoperative hypotensive medications, hypovolaemia, blood loss or the downregulation of adrenoreceptors. Hypoglycaemia typically occurs a few hours after tumour removal. The mechanism is believed to involve increased insulin secretion due to the decrease in circulating catecholamines [16]. This report describes the case of a patient with a long history of hypertension attributed to ADPKD and renal failure. Regular radiological follow-up for a prior ablated myxoid liposarcoma showed no recurrence, the stability of a hypodense lesion medial to the right kidney and a benign left pararenal lesion. Although no major symptoms and no complications during prior surgery had suggested the presence of PPGLs, she presented with profound haemodynamic instability during a left nephrectomy, because of a previously unknown PPGLs that the surgical team had not been able to prepare for in advance.