Pheochromocytoma-paraganglioma (ORPHA:573163)
A rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla (pheochromocytoma) or from sympathetic and parasympathetic ganglia (paraganglioma). These tumors are most often benign and may produce catecholamines in excess causing hypertension and sometimes severe acute cardiovascular complications.
Epidemiology
Pheochromocytomas and paragangliomas (PPGL) are rare, occurring in 0.1 to 0.6% of patients with hypertension and 5% with adrenal incidentaloma. The incidence is approximately 0.57 per 100,000 person-years (0.46 for pheochromocytomas and 0.11 for paragangliomas).
Clinical description
The symptomatology may be related to hypersecretion of catecholamines. It is variable, fluctuating, non-specific and even sometimes completely non-existent. Hypertension is the most common sign and can be permanent (50-60%) or paroxysmal (35%) and associated with orthostatic hypotension. Blood pressure can also be normal, especially in patients with low or no hypersecretion. A sudden discharge of catecholamines can cause paroxysmal symptoms that may or not occur concomitantly: headache (60-90%), sweating (55-75%), and palpitations (50-70%). The specificity and sensitivity of this triad for the diagnosis of pheochromoctyoma and/or catecholamines-producing paraganglioma are 94% and 91% respectively. Ten to 15% of PPGL are diagnosed after an acute cardiomyopathy, the most frequent being the Takotsubo cardiomyopathy. The others symptoms, less frequent, are general impairment, weight loss, constipation, anxiety, hyperglycemia and nausea. Head and neck paraganglioma are classically non-secreting tumors: the discovery could be made because of the palpation of a cervical mass or a swelling sometimes pulsatile, tinnitus, hypoacousia or even paralysis of the cranial nerves (dysphonia, dysphagia...). In genetically determined forms, others tumors or signs may be associated. For instance, gastrointestinal stromal tumors in patients with Carney-Stratakis syndrome.
Etiology
About 40% of PPGL occur in the context of an autosomal inherited syndrome. More than 15 predisposing genes have been identified (SDHA, SDHB, SDHC, SDHD, RET, VHL, NF1, TMEM127, MAX, FH...). About 60% are sporadic but up to 30% of sporadic tumors actually carry somatic mutations in these known susceptibility genes.
Diagnostic methods
The diagnosis of secreting PPGL is based on plasma free metanephrines or 24-hour urinary fractionated metanephrines measurements. A radiological evaluation is necessary to locate the tumor with conventional and nuclear medicine imaging. Biopsy should not be performed due to the high risk of acute catecholamines-induced hypertensive crisis and of hematoma. An early onset and/or the presence of multiple, extra-adrenal PPGL, bilateral pheochromocytoma or of metastases suggest a genetic form.
Differential diagnosis
In patients with paroxysmal symptoms, main differential diagnoses are panic disorder, hot flashes, carcinoid syndrome.
Antenatal diagnosis
Prenatal diagnosis is not performed except for patients with VHL disease. Genetic testing may be offered to children at risk over 6 years old.
Genetic counseling
Genetic testing is recommended for all patients diagnosed with PPGL because 40% of cases occur in the context of an autosomal inherited syndrome. Moreover, patient follow-up is adapted according to the mutated gene (for example, intensive follow-up for SDHB mutation because the risk of malignancy is increased). It is also important to offer screening to first-degree relatives of mutation-carriers.
Management and treatment
For catecholamines-producing PPGL, referral treatment is surgical excision. Patients need to undergo preoperative alpha-adrenergic blockade and rehydration for preventing hypertensive crisis during surgery. In case of tachycardia, a cardioselective beta-blocker can be added in a second step. Radiotherapy can be proposed for non-functioning paragangliomas of the skull base and neck. Indeed, the risk of neurovascular damage is important with surgery. For metastatic PPGL, there is no consensus. The therapeutic decision requires a multidisciplinary discussion by an expert team (surgery, metabolic or conventional radiotherapy, embolization, chemotherapy, targeted therapy...). Patients management should be organized in a referral center.
Prognosis
The acute cardiovascular complications (sudden death, acute stress cardiomyopathy, myocardial infarction, heart failure...) represent the most frequent causes of morbi-mortality. Moreover, a metastatic evolution or a recurrence can be observed in about 15% of the cases, especially in cases of genetic predisposition.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Pr Laurence AMAR  - Dr Alexandre BUFFET  - Dr Nelly BURNICHON  - Dr Erika CORNU  - Pr Anne-Paule GIMENEZ-ROQUEPLO