Pheochromocytoma and paraganglioma: Diagnosis, genetics, management, and treatment

Hypertension (HT) is a major cardiovascular risk factor that affects 10% to 40% of the general population in an age-dependent manner. Detection of secondary forms of HT is particularly important because it allows the targeted management of the underlying disease. Among hypertensive patients, the prevalence of endocrine HT reaches up to 10%. Adrenal diseases are the most frequent cause of endocrine HT and are associated with excess production of mineralocorticoids (mainly primary aldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). In addition, a few rare diseases directly affecting the action of mineralocorticoids and glucocorticoids in the kidney also lead to endocrine HT. Over the past years, genomic and genetic studies have allowed improving our knowledge on the molecular mechanisms of endocrine HT. Those discoveries have opened new opportunities to transfer knowledge to clinical practice for better diagnosis and specific treatment of affected subjects. In this review, we describe the physiology of adrenal hormone biosynthesis and action, the clinical and biochemical characteristics of different forms of endocrine HT, and their underlying genetic defects. We discuss the impact of these discoveries on diagnosis and management of patients, as well as new perspectives related to the use of new biomarkers for improved patient care.

Paragangliomas are neuroendocrine tumours of the sympathetic and parasympathetic nervous systems originating from neural crest cells. Less than 1% of paragangliomas in the heart originate from intrinsic cardiac ganglia cells in the posterior wall of the atria, atrioventricular groove, and along the root of the great vessels. We describe the tumour characteristics, patient demographics, presentation, means of diagnosis, pathology correlation, management, and outcome in 11 patients with intrapericardial paragangliomas. To the authors' knowledge, this is the largest case series reported, with emphasis on multimodality imaging findings.

The aim of this chapter is to report the indications and data on efficacy and toxicity of radionuclide therapy in pediatric patients, highlighting the precautions that have to be taken as compared to adult patients.

In particular, children with Neuroblastoma (NB), the most common extracranial tumor of pediatric age, may refer with a metastatic disease at diagnosis in 50% of cases. ¹²³I-meta-iodobenzylguanidine (m-IBG) scintigraphy is a “corner stone” in the diagnosis, staging and restaging of NB. The therapeutic approach for high-risk NB includes induction chemotherapy, followed by surgery and myelo-ablative chemotherapy associated to autologous hematopoietic stem cell transplantation. ¹³¹I-mIBG therapy is indicated in high-risk NB patients with persistence of mIBG-avid metastatic disease, and has an overall response of 30%.

The toxicity can include gastrointestinal distress and tachycardia during the infusion, hematologic toxicity in the weeks following the administration, and long-term hypothyroidism or secondary malignancies. Precautions include symptomatic management of symptoms during the infusion (antiemetics, beta-blockers), careful monitoring of blood values with substitution of red blood cells/platelet or autologous stem cells infusion whenever needed, and thyroid blockade. Patients should be always monitored for the insurgence of secondary tumor, such as papillary thyroid cancer.

Other frequent cancers in children are malignant pheochromocytomas (PCCs) and paragangliomas (PPGs) that originate in the adrenal medulla and in the extra-adrenal ganglia; malignancy occurs in 10% of PCCS and 20–40% of PPGs. For these tumors ¹²³I-mIBG whole-body scan has a relevant diagnostic role. ¹³¹I-MIBG therapy is indicated in all cases with inoperable PPCs and PPGs; in addition, patients with metastatic disease, in course of progression and/or intractable, can be considered eligible for mIBG therapy.

The toxicity includes gastrointestinal, hematological, and endocrine side effects (as observed in the NB scenario), more serious complications include renal damage of respiratory distress. Precautions include symptomatic treatments of acute side effects, hematologic substitution, and generous hydration.

Children and young adults may also develop differentiated thyroid cancer (DTC). Differently from adults, pediatric DTC may present diffuse infiltrative pattern throughout the thyroid gland and can be more frequently associated to extensive lymph node and lung metastastization. Thyroidectomy is the principal therapeutic approach and ¹³¹I radionuclide therapy is an important therapeutic option especially for those patients at intermediate- or high-risk of disease relapse/persistence after surgery.

The toxicity is usually mild and includes temporary salivary dysfunction, gastrointestinal distress, hematological parameters drop, gonadal damage, and, in patients with extensive lung localizations, pulmonary fibrosis.

Precautions include vigorous hydration, administration of candies to stimulate the salivary flow, and symptomatic treatment of the gastroenteric side effects. Sperm banking can be considered in young male patients receiving high activities. The hematological side effects are usually self-resolving. Dosimetry approaches should be used in patients with diffuse lung involvement, as the pulmonary fibrosis is strictly dose-dependent.