Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.

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.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval.

: Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes life- threatening sequelae. Tremendous progress in biochemical testing, imaging, genetics and pathophysiological understanding of the tumours has far-reaching implications for physicians dealing with hypertension and more importantly affected patients. Because hypertension is a classical clinical clue for PPGL, physicians involved in hypertension care are those who are often the first to consider this diagnosis. However, there have been profound changes in how PPGLs are discovered; this is often now based on incidental findings of adrenal or other masses during imaging and increasingly during surveillance based on rapidly emerging new hereditary causes of PPGL. We therefore address the relevant genetic causes of PPGLs and outline how genetic testing can be incorporated within clinical care. In addition to conventional imaging (computed tomography, MRI), new functional imaging approaches are evaluated. The novel knowledge of genotype-phenotype relationships, linking distinct genetic causes of disease to clinical behaviour and biochemical phenotype, provides the rationale for patient-tailored strategies for diagnosis, follow-up and surveillance. Most appropriate preoperative evaluation and preparation of patients are reviewed, as is minimally invasive surgery. Finally, we discuss risk factors for developing metastatic disease and how they may facilitate personalised follow-up. Experts from the European Society of Hypertension have prepared this position document that summarizes the current knowledge in epidemiology, genetics, diagnosis, treatment and surveillance of PPGL.

The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each anatomic site, to be used throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to improved patient management and enhanced epidemiological research.
Pheochromocytoma and paraganglioma are uncommon and are frequently overlooked in registry data sets. Malignant criteria have previously been defined only when there was metastatic disease.
With recent recognition of a significant inheritance association and the development of risk stratification tools, this data set was created in order to obtain more meaningful outcomes and management data, using similar criteria across the global pathology community. Issues related to key core and non-core elements, especially clinical hormonal status, familial history, tumor focality, proliferative fraction, adverse or risk stratification features, and ancillary techniques, are discussed in the context of daily application to these types of specimens.
The ICCR data set, developed by an international panel of endocrine organ specialists, establishes a pathology-standardized reporting guide for pheochromocytoma and paraganglioma.

The management of head and neck paragangliomas (HNPGLs) has changed significantly in recent years. There is, however, an absence of guidance in the literature regarding the optimal means of managing this challenging disease. This consensus document, developed by the British Skull Base Society, sets out recommendations for management of HNPGLs. A preliminary document was produced on the basis of current practice in 3 large UK skull base centers, incorporating relevant peer-reviewed evidence. This document was then modified by discussion within these units, through a national survey of British Skull Base Society members, and through discussion with stakeholders. A consensus was reached on the management of all forms of HNPGL. All patients should be managed by a multidisciplinary team and require initial surgical, endocrine, and genetic assessments as well as magnetic resonance imaging of the head, neck, chest, abdomen, and pelvis. Long-term preservation of function is the primary treatment goal, with conservative management the first choice treatment for most tumors. Radiotherapy is a safe, effective treatment for growing tumors in most cases, although there is a limited role for surgery. Screening of family members in high-risk groups is mandatory. These guidelines should help standardize high-quality care for patients with HNPGLs.

Dear Editor, In this journal, a few years ago, we presented a Bayesian (critical) appraisal of the-then recent-American Endocrine Society\'s guidelines regarding the diagnosis and management of pheochromocytoma/paraganglioma (PPG). This year, the European Society of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging have introduced new guidelines regarding functional imaging (i.e. by means of Nuclear Medicine modalities) of PPG. In light of this, we believe that it is appropriate to present a new relevant Bayesian assessment. In the new guidelines the following functional imaging modalities are covered: iodine-123-metaiodobenzylguanidine (123I-MIBG) single photon emission tomography (SPET), indium-111-diethylenetriamine pentaacetic acid (111In-DTPA)-pentetreotide (111In-pentetreotide) SPET, fluorine-18-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET), 18F-fluorodeoxyglucose (18F-FDG) PET and PET with various gallium-68-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (168Ga-DOTA)-coupled somatostatin agonists (68Ga-SSTa). Based on a pretest probability of 15% for extra-adrenal disease and the reported sensitivity and specificity for each modality, we calculated likelihood ratios (LR) for a positive and a negative test (LR+ and LR-, respectively). In the absence of a given specificity in the guidelines we used levels of 55% for 18F-FDG and 85% for 68Ga-SSTa (the latter is a level that we used in our previous assessment), which have been validated in a recent meta-analysis. Using LR+ and LR- with Fagan\'s nomograms we calculated the post-test probability of extra-adrenal PPG. Only the LR+ for 18F-FDOPA was over 10 and no LR- was lower than 0.1, shifting to an important degree the probability of a diagnosis (clinicians have to bear in mind that an LR- may not be useful, since absence of radionuclide uptake does not imply absence of PPG if biochemistry is positive). It is evident that functional imaging of PPG has become more diversified and tailored according to each patient\'s history and genetic background. Nevertheless, the diagnostic characteristics of all methods (biochemical and imaging) are still not perfect; they are rather complimentary to each other. Biochemical evaluation should be done first, since functional imaging of PPG is advised to be performed in patients with biochemically-proven disease.

OBJECTIVE: Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results.
METHODS: Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals.
CONCLUSIONS: Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (68Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (123I)/iodine-131 (131I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.

Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.