Clinical and Translational Oncology https://doi.org/10.1007/s12094-021-02622-9 SPECIAL ARTICLE Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas R. Garcia‑Carbonero1 · F. Matute Teresa2 · E. Mercader‑Cidoncha3 · M. Mitjavila‑Casanovas4,5 · M. Robledo6,7 · I. Tena8,9 · C. Alvarez‑Escola10 · M. Arístegui11 · M. R. Bella‑Cueto12 · C. Ferrer‑Albiach13 · F. A. Hanzu14 Received: 22 January 2021 / Accepted: 7 April 2021 © The Author(s) 2021 Abstract Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromafn 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; anat- omy, 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 Pheochromocytoma · Paraganglioma · Diagnosis · Treatment · Genetic counseling · Multidisciplinary · Guidelines * R. Garcia-Carbonero 8 Scientifc Department, Medica Scientia Innovation Research [email protected] (MedSIR CORP), Ridgewood, NJ, USA 9 Medical Oncology Department, Hospital Provincial, 1 Medical Oncology Department, Hospital Universitario 12 Castellon, Spain de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Avda 10 Neuroendocrinology Unit, Endocrinology and Nutrition Cordoba km 5.4, 28041 Madrid, Spain Department, Hospital Universitario la Paz, Madrid, Spain 2 Radiology Department, Hospital Clínico San Carlos, Madrid, 11 ENT Department, Hospital General Universitario Gregorio Spain Marañón, Madrid, Spain 3 Endocrine and Metabolic Surgery Unit, General 12 Pathology Department, Hospital Universitario Parc Taulí, and Digestive Surgery Department, Hospital General Sabadell, Institut D’Investigació I Innovació Parc Taulí Universitario Gregorio Marañón, Madrid, Spain (I3PT), Universitat Autònoma de Barcelona, Sabadell, Spain 4 Nuclear Medicine Department, Hospital Universitario Puerta 13 Radiation Oncology Department, Hospital Provincial de Hierro, Majadahonda, Spain Castellón, Castellón, Spain 5 Grupo de Trabajo de Endocrino de la SEMNIM, Madrid, 14 Endocrinology and Nutrition Department, Hospital Clinic Spain Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain 6 Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, Madrid, Spain 7 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain Vol.:(0123456789)1 3 Clinical and Translational Oncology Introduction and in high-altitude PGLs [2]. PPGLs are commonly diag- nosed within the 4th and 6th decades, although these neo- Pheochromocytomas (PCCs) and paragangliomas plasms can occur over a wide age range. They appear at a (PGLs)—hereinafter PPGL to include both entities—are younger age when they occur as part of a hereditary syn- rare neuroendocrine tumors (NETs) that arise from chro- drome [5]. At pediatric ages, extra-adrenal PGLs account mafn cells of the adrenal medulla and the sympathetic/ for more than two-third of the cases, and four of fve cases parasympathetic neural ganglia, respectively. PPGLs often are associated with a hereditary form of the disease [6, 7]. secrete catecholamines (CMNs) that can mimic a wide Bilateral or multiple forms are mostly associated with range of medical disorders and may be lethal if misdiag- hereditary syndromes, but an advanced age at diagnosis or nosed or improperly handled. PPGLs are also character- the absence of family history does not exclude the possi- ized by a very heterogeneous natural history and a low to bility of carrying a germline mutation. In fact, between 14 moderate but unpredictable ability to metastasize. Surgical and 24% of clinically sporadic tumors may also be due to a resection may be challenging, including adequate timing germline mutation [8, 9]. and perioperative medical management, and optimal treat- The rate of metastatic disease (mPPGL) ranges from less ment of advanced disease is controversial. Over one-third than 1% to 79%, depending upon tumor site and size, age at of PPGLs are inherited, and adequate genetic counseling diagnosis and genotype [10, 11]. Although some features is key to implementing screening strategies and tailoring included size greater than 5 cm, extra-adrenal primary tumor therapy. All these factors make PPGL diagnosis and treat- site, or high levels of plasma 3-metoxitiramine (3-MT) [12] ment very complex, and clinical experience is difcult to provide useful information to assess the risk of metastasis, achieve due to their low incidence. In this context, the the presence of mutations in the succinate dehydrogenase Mut aim of this article was to provide practical clinical guide- complex iron sulfur subunit B (SDHB ) is the only univer- lines for the diagnosis and treatment of PPGLs from a sally accepted criterion associated with a high risk of distant multidisciplinary perspective. Experts from the national disease, both at diagnosis or during follow-up, ranging from societies of the diferent disciplines involved participated 20 to 70% in diferent patient cohorts [11–14]. Recent data in the elaboration of these guidelines, including clinical also suggest a higher metastatic risk in patients with muta- specialists from the Spanish Societies of Endocrinology tions in other genes involved in the Krebs cycle [15]. and Nutrition (SEEN), Medical Oncology (SEOM), Medi- Overall, the prognosis of PPGL is heterogeneous. Gof- cal Radiology (SERAM), Nuclear Medicine and Molecu- fredo et al. analyzed 508 PPGL patients from 18 US regis- lar Imaging (SEMNIM), Otorhinolaryngology (SEORL), tries (time frame 1988–2009) and reported a 5-year overall Pathology (SEAP), Radiation Oncology (SEOR), and Sur- survival (OS) rate of 58% for metastatic PCCs and 80% gery (AEC), and geneticists from the Spanish National for metastatic PGLs [16]. More recently, a retrospective Cancer Research Center (CNIO). study of 169 patients from 18 European centers (time frame 1998–2010) by Hescot et al. [14] reported a global 5-year OS rate of 62% and a median OS of 6.7 years for mPPGL. Epidemiology Anatomy, pathology and molecular The joint annual incidence of PPGL is estimated to be 2–8 pathways cases per million inhabitants. A recent study from Canada disclosed an annual incidence of 6.6 cases per million Anatomy inhabitants, half of them corresponding to pheochromocy- tomas and 37% of them to head and neck paragangliomas PCC (adrenal) and PGL (extra-adrenal) are neoplasms that [1], most of them known to be parasympathetic. Head and originate from chromafn cells of the autonomic nervous neck paragangliomas have geographic variations as a func- system, derived from the neural crest, and can be classifed tion of altitude [2]. In another study from Holland [3], the as either sympathetic or parasympathetic. The sympathetic annual incidence of PCCs and of sympathetic PGLs were system is distributed through the paraganglia of the prever- 4.6 and 1.1 cases per million inhabitants, respectively, tebral and paravertebral axes, reaching the abdominal organs which had increased compared to previous years likely due and innervating the urogenital system, and it includes the to improved diagnostic techniques and clinical awareness. adrenal medulla, which is considered the greatest paragan- The distribution by gender does not show signifcant glion. The parasympathetic system is distributed through the diferences, although a greater incidence in females has head and neck and mediastinum, following the territories been observed for vagal and jugulotympanic PGLs [4], of the glossopharyngeal (carotid and tympanic paraganglia) and vagus (jugular, upper and lower laryngeal, subclavian 1 3 Clinical and Translational Oncology and aortopulmonary) nerves [17]. These neoplasms are (15–20%), Von Hippel-Lindau (VHL) syndrome due to also grouped into cervicocephalic, thoracic and abdominal mutations in the VHL gene (9%), multiple endocrine neo- PPGLs [18]. plasia-2 (MEN2) syndrome due to mutations in the RET proto-oncogene (5%) and neurofbromatosis type 1 (NF-1) Histopathological features syndrome due to mutations in the NF1 gene (2%). Less frequent familial forms (< 1–2%) are caused by mutations The characteristic microscopic feature of PPGLs is the in the transmembrane protein 127 (TMEM127), MYC- proliferation of polygonal chromafn cells distributed in associated factor X (MAX), fumarate hydratase (FH), nests (zellballen, in German), surrounded by a fne capil- multiple endocrine neoplasia type 1 (MEN1), egg-laying- lary network and sustentacular cells, easily identifiable defective nine (egl-9)