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.