Introduction
Phaeochromocytomas are chromaffin cell tumours characterised by the excessive production and secretion of catecholamines. These tumours usually arise in the adrenal medulla but occasionally from chromaffin cells of the sympathetic ganglia; here they are called paragangliomas. These tumours occur in approximately 0.5–2 patients per 1000 with hypertension [
1]. Diagnosis is typically made between the third and fifth decades; up to 30% of phaeochromocytomas have a genetic predisposition including syndromes such as von Hippel-Lindau syndrome, neurofibromatosis type 1 (NF-1) and multiple endocrine neoplasia (MEN) syndrome type II [
2,
3].
Approximately 15% of phaeochromocytomas are malignant [
4]. Patients may present with sustained or paroxysmal hypertension, with associated symptoms such as headaches, sweating, palpitations and tremor [
4], caused by the excessive release of catecholamines. Initial biochemical investigations include plasma and/or urine catecholamine and metanephrine levels. If these are elevated, imaging to locate a potential tumour includes CT and/or MRI scans. If these scans are inconclusive, nuclear medicine imaging using radiotracers
123I-metaiodobenzylguanidine (MIBG scan) [
1] and more recently gallium-68 dotatate PET (
68GA-PET) scans may also be useful [
5,
6].
Surgery (usually by laparoscopy) after preoperative alpha blockade is the recommended intervention. Alpha blocker therapy is traditionally used reduce the risk of perioperative cardiovascular complications [
1,
7]. The prognosis after surgery is very good for benign tumours; the 5-year survival rate is 95%; however, this drops to 50% in malignant tumours [
1]. Treatment of metastatic disease is not well understood due to tumour rarity. Chemotherapy, radionuclide agents such as iobenguane
131I, tyrosine kinase inhibitors such as sunitinib and immunotherapeutic agents such as pembrolizumab have been reported; however, clinical trials for these treatments are ongoing [
8]. Long-term follow-up is important in both benign and malignant pathology to ensure that recurrences are detected promptly [
1].
Ganglioneuromas are rare tumours of autonomic ganglion cells of the nervous system. They are usually benign and often arise in the posterior mediastinum and retroperitoneum. They rarely occur in the adrenal gland, accounting for 0.3–2% of all adrenal incidentalomas [
9]. Most adrenal ganglioneuromas are discovered incidentally on CT scans as they are largely asymptomatic and hormonally inactive. However, 30% of patients with ganglioneuromas are found to have raised plasma and urinary metanephrines [
10]. Diagnosis can only be confirmed on histology after resection and prognosis is extremely good [
9,
10].
Rarely, phaeochromocytomas may be part of a composite tumour [
11], where there is another type of tumour (usually of the same embryological origin, i.e. neural crest) present. Tumour types that co-exist with phaeochromocytomas are reported to include ganglioneuromas, schwannomas and ganglioneuroblastomas [
12,
13]. There are only a few documented cases in the literature, leading to uncertainty in the understanding of the pathogenesis and natural history of these conditions.
The aim of this study was to report cases of composite phaeochromocytomas seen in one centre and to undertake a systematic review of the published literature to increase the understanding of the epidemiology and clinical outcomes of these rare tumours.
Methods
The histology reports of all patients who underwent resection of phaeochromocytoma over a 19-year period were reviewed to identify patients with composite tumours (defined as a tumour including phaeochromocytoma as at least one of several components). Two patients were identified in a review of 115 reports.
A systematic review of literature was performed to identify all reports of patients with composite tumours including phaeochromocytoma. The online database Medline was searched (on April 16, 2020), via search engine PubMed using the following combination of keywords:
-
Phaeochromocytoma
-
Composite OR combined OR incidental OR complex OR co-existing OR coincidental OR associated
-
Paraganglioma OR ganglioneuroma OR neurofibroma OR schwannoma OR ganglioneuroblastoma OR neurilemmoma OR neuroendocrine carcinoma
The titles and/or abstracts of all articles retrieved by the search were reviewed independently by two authors to include original human studies on patients with composite tumours with phaeochromocytoma as one component. Studies on non-composite tumours, animal studies and those not written in the English language were excluded.
Full texts of articles considered suitable for inclusion were reviewed against the same criteria. The bibliography of included papers was also screened. Data from all included studies on demographics, clinic-pathological features and outcomes were collected in an excel spreadsheet and analysed. Included studies were also critically appraised using the Joanne Briggs Institute (JBI) critical appraisal checklist for case reports [
14]. One point was awarded for each question if appropriate. Scores were reported as a percentage of the total applicable questions.
Descriptive analyses included reporting of frequencies (or percentages) for categorical data; median (range) for nonparametric, continuous data and mean (SD) for parametric, continuous data.
As this was a systematic review of literature and presentation of case studies where all identifiable details have been removed, no formal permission has been obtained from the research department and patient consent was not deemed necessary.
Discussion
Composite phaeochromocytoma tumours are extremely rare [
9]. Two patients were identified in this unit over a 19-year period, in addition to the 94 patients identified in this review.
Genetic syndromes including neurofibromatosis 1, MEN 2A, von Hippel Lindau syndrome and watery-diarrhoea hypokalaemia-achlorhydria (WDHA) syndrome were only identified in 28% of patients, similar to patients with phaeochromocytoma alone—a review of 314 patients with phaeochromocytoma 27.4% with an underlying genetic cause [
74].
The pathogenesis of composite tumours is unclear. Apart from coincidental occurrence, alteration in the microenvironment of one tumour may favour the formation of a second tumour arising in the same area [
75].
Although not currently included in treatment guidelines [
7], recent small studies have shown
68Ga-dotatate PET scans to be more specific than MIBG in the diagnosis of phaeochromocytoma and paraganglioma (PPGL) tumours [
5,
6]. However, this imaging modality is not widely available.
Of 94 case reports, only seven reported use of alpha blocker therapy before surgery. Alpha blocker therapy pre-surgery is currently recommended in all patients with functional phaeochromocytoma-paragangliomas (PGGLs) to reduce the risk of hypertensive crisis [
7]. However recent studies have shown that alpha blockade may not have any effect on intraoperative blood pressure or mortality [
76‐
79].
This review is fairly comprehensive, but it is not possible to make clear recommendations on management based on a review of case studies. Another limitation of our review is the discrepancy in reporting quality amongst the case reports.
Conclusion
This review provides comprehensive demographic and clinical information on composite phaeochromocytomas published in the literature. These tumours affect men and women equally, with the majority of diagnoses occurring between the third and fifth decades. Clinical presentation can be classified into two main categories: cardiovascular and gastrointestinal. Adrenalectomy is the gold standard treatment and prognosis is good; however, these tumours remain extremely rare and their occurrence should prompt consideration for genetic testing.
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