The estimated incidence of PPGL is 2 to 8/ million of the population per year, giving an estimated annual incidence of 130– 520 new patients a year in the United Kingdom. Presenting symptoms of these rare tumours are most commonly related to catecholamine excess, and include headache, palpitations, paroxysmal hypertension, anxiety, abdominal pain, and excessive sweating. PPGL are often diagnosed incidentally following cross- sectional imaging studies.
Paragangliomas in the abdomen and pelvis commonly arise from the aortic bifurcation or the so- called organ of Zuckerkandl, but can also occur in the urinary bladder. Mediastinal paraganglioma are rare but can develop from para- aortic (middle mediastinum) and para- vertebral (posterior mediastinum) sympathetic chain ganglia. PPGL and HNPGL may be familial and/ or multifocal (in which case a genetic cause should be suspected) and/ or there may be a previous history of wild- type gastrointestinal stromal tumour (GIST) or renal cell carcinoma (which are each associated with germline mutations in succinate dehydrogenase (SDH) subunit genes (see next)). Although most PPGL are benign (~85– 90%), current predictors of malignant or aggressive tumours are imprecise and therefore in 2017, the World Health Organization (WHO) classification of adrenal tumours abolished the term ‘benign’ for PPGL, stating that all PPGL should be considered to have metastatic potential.
Histologically, PPGL are identified microscopically by a characteristic ‘zellballen’ pattern, referring to nests of polygonal/ spindle shaped cells on a rich vascular network and immunohistochemical stains such as; synaptophysin, chromogranin A and S100 are used to confirm a diagnosis of PPGL. In 2017, the first staging system for PPGL (but not HNPGL) was proposed by the American Joint Committee on Cancer (AJCC) and includes tumour size, lymph node metastases, and distant metastases. Tumour size (>5 cm), local invasion and extra- adrenal abdominal location are predictors of malignancy as is the detection of a germline pathogenic SDHB variant.
Surgery remains the first line treatment option for PPGL and, when possible, a minimally invasive approach is favoured. In the genomics era, surgical management can also be tailored based on the genetic aetiology of PPGL. Patients with certain hereditary syndromes (e.g. multiple endocrine neoplasia type 2 [MEN2], von Hippel Lindau disease [VHL], neurofibromatosis type 1 [NF1]) are at risk of bilateral phaeochromocytomas and cortical sparing surgery reduces the morbidity associated with bilateral adrenalectomy and requirement for lifelong glucocorticoid and mineralocorticoid replacement. Although patients with SDH sub unit gene (SDHX) mutations and MAX gene mutations may develop bilateral phaeochromocytoma, the higher risk of malignancy negates the benefit of cortical sparing surgery and total adrenalectomy should be considered for these patients.
Long- term surveillance strategies are influenced by the tumour location and the detection of a germline predisposition. Current guidelines recommend lifelong surveillance for young patients, patients with a large or an extra- adrenal tumour and those with a known hereditary predisposition. Patients with a small (<5 cm) presumed sporadic phaeochromocytoma undergo a minimum of 10 years clinical surveillance for disease recurrence. Postoperative surveillance includes annual biochemical testing for patients with secretory PPGL or cross- sectional imaging with CT/ MRI every 1– 2 years for patients with non- secretory PPGL.
