Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations.

Keywords: Diagnosis; Genetic counseling; Guidelines; Multidisciplinary; Paraganglioma; Pheochromocytoma; Treatment.

Fig. 1

Diagnostic algorithm for PPGLs. CT computed tomography, FDG fluorodeoxyglucose, HNPGL head and neck paraganglioma, MN metanephrine, Mtx metastasis, NMN normetanephrine, MIBG metaiodobenzylguanidine, 3-MT 3-methoxytyramine, MRI magnetic resonance imaging, PCC pheochromocytomas, PGL paragangliomas, PPGL pheochromocytomas and paragangliomas, SSTRI somatostatin receptor imaging, VHL von Hippel-Lindau. a Plasma 3-MT: only in high clinical suspicion of dopamine-secreting tumors/hereditary syndromes associated with HNPGL. b Chromogranin A: nonspecific neuroendocrine tumor marker that may be considered if high clinical suspicion of silent PPGLs. c Recommended at diagnosis only in cases of high suspicion of metastasis, particular if there is family history or silent tumor. d 123-I-MIBG versus ¹¹¹In/⁹⁹mTc/⁶⁸ Ga SSTRI, is recommended before MIBG versus radionuclide-SSTR analogs treatment

Fig. 2

Typical morphological and functional imaging of PPGLs. a, b Axial contrast-enhanced CT portal (a) and delayed phase (b) of the upper abdomen showing the pheochromocytoma in the right adrenal gland (yellow arrowhead). Intravenous contrast administration typically enhances avidly due to the capillary-rich framework of the tumor. c, d Coronal T2-weighted MRI images revealed a homogeneous pheochromocytoma (c) in the right adrenal gland (yellow arrowhead), and other pheochromocytomas in the left adrenal gland (yellow arrowhead) with central necrosis are characteristically “light-bulb” bright lesions on T2-weighted imaging (d). Pheochromocytomas are potentially malignant (10%), and the only reliable criterion for the diagnosis of malignancy is metastatic spread. e A 61-year-old woman with metastatic cervical paraganglioma. 68 Ga-DOTATOC PET/CT study showing bilateral laterocervical lymph nodes, mediastinal involvement and multiple bone metastases. f A 56-year-old man was diagnosed with a 44 × 39-mm right adrenal incidentaloma. After right adrenalectomy, a histological study showed pheochromocytoma without evidence of malignancy. Negative genetic study. During follow-up, he presented with recurrence. Body scan with 123-I-MIBG shows lesions in the right renal cell and multiple peritoneal implants, some in contact with the liver surface without being able to rule out secondary infiltration. The patient has received treatment with 131I-MIBG with stabilization of the disease

Fig. 3

Therapeutic algorithm of metastatic paragangliomas. CVD, Cyclophosphamide, Vincristine, Dacarbazine; MIBG, 123-I-Metaiodobenzylguanidine; MGMT, O-methylguanine-DNA methyltransferase; RF, radiofrequency; RT, radiotherapy; SDH, Succinate dehydrogenase; SSTRI, somatostatin receptor imaging; TKI, Tyrosine kinase inhibitors; TMZ, Temozolomide