Review

. 2023 May;11(5):345-361.

doi: 10.1016/S2213-8587(23)00038-4. Epub 2023 Mar 31.

Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants

David Taïeb¹, George B Wanna², Maleeha Ahmad³, Charlotte Lussey-Lepoutre⁴, Nancy D Perrier⁵, Svenja Nölting⁶, Laurence Amar⁷, Henri J L M Timmers⁸, Zachary G Schwam², Anthony L Estrera⁹, Michael Lim³, Erqi Liu Pollom¹⁰, Lucas Vitzthum¹⁰, Isabelle Bourdeau¹¹, Ruth T Casey¹², Frédéric Castinetti¹³, Roderick Clifton-Bligh¹⁴, Eleonora P M Corssmit¹⁵, Ronald R de Krijger¹⁶, Jaydira Del Rivero¹⁷, Graeme Eisenhofer¹⁸, Hans K Ghayee¹⁹, Anne-Paule Gimenez-Roqueplo²⁰, Ashley Grossman²¹, Alessio Imperiale²², Jeroen C Jansen²³, Abhishek Jha²⁴, Michiel N Kerstens²⁵, Henricus P M Kunst²⁶, James K Liu²⁷, Eamonn R Maher¹², Daniele Marchioni²⁸, Leilani B Mercado-Asis²⁹, Ozgur Mete³⁰, Mitsuhide Naruse³¹, Naris Nilubol³², Neeta Pandit-Taskar³³, Frédéric Sebag³⁴, Akiyo Tanabe³⁵, Jiri Widimsky³⁶, Leah Meuter³⁷, Jacques W M Lenders³⁸, Karel Pacak³⁹

Affiliations

¹ Department of Nuclear Medicine, Aix-Marseille University, La Timone University Hospital, Marseille, France.
² Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA.
⁴ Université Paris Cité, Inserm, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France; Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
⁵ Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
⁶ Svenja Nölting, Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
⁷ Université Paris Cité, Inserm, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France; Unité d'hypertension artérielle, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁸ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
⁹ Department of Cardiothoracic and Vascular Surgery, UTHealth Houston, McGovern Medical School, Memorial Hermann Hospital Heart and Vascular Institute, Houston, TX, USA.
¹⁰ Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA, USA.
¹¹ Division of Endocrinology, Department of Medicine and Research Center, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
¹² Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
¹³ Department of Endocrinology, Aix-Marseille University, Conception University Hospital, Marseille, France; INSERM U1251, Aix-Marseille University, Conception University Hospital, Marseille, France.
¹⁴ Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia; Cancer Genetics Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia.
¹⁵ Department of Endocrinology, Center of Endocrine Tumors Leiden, Leiden University Medical Centre, Leiden, Netherlands.
¹⁶ Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
¹⁷ Developmental Therapeutics Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁹ Division of Endocrinology and Metabolism, Department of Medicine, Malcom Randall VA Medical Center, University of Florida, Gainesville, FL, USA.
²⁰ Université Paris Cité, Inserm, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France; Département de Médecine Génomique des Tumeurs et des Cancers, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
²¹ Green Templeton College, University of Oxford, Oxford, UK; NET Unit, Royal Free Hospital, London, UK.
²² Department of Nuclear Medicine and Molecular Imaging, Institut de Cancérologie de Strasbourg Europe, IPHC, UMR 7178, CNRS, University of Strasbourg, Strasbourg, France.
²³ Department of Otorhinolaryngology, Leiden University Medical Centre, Leiden, Netherlands.
²⁴ Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
²⁵ Department of Endocrinology, University Medical Center Groningen, Groningen, Netherlands.
²⁶ Department of Otolaryngology and Head & Neck Surgery, Dutch Academic Alliance Skull Base Pathology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Otolaryngology and Head & Neck Surgery, Dutch Academic Alliance Skull Base Pathology, Maastricht University Medical Center, Maastricht, Netherlands.
²⁷ Department of Neurosurgical Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA.
²⁸ Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital of Verona, Verona, Italy.
²⁹ Section of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine & Surgery, University of Santo Tomas Hospital, University of Santo Tomas, Manila, Philippines.
³⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Endocrine Pathology Society, Toronto, ON, Canada.
³¹ Medical Center and Endocrine Center, Ijinkai Takeda General Hospital, Kyoto, Japan.
³² Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³³ Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁴ Department of Endocrine Surgery, Aix-Marseille University, Conception University Hospital, Marseille, France.
³⁵ Division of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan.
³⁶ Third Department of Medicine, Department of Endocrinology and Metabolism of the First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
³⁷ Department of Physician Assistant Studies, Stanford University School of Medicine, Palo Alto, CA, USA.
³⁸ Department of Medicine ΙΙI, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
³⁹ Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address: karel@mail.nih.gov.

PMID: 37011647
PMCID: PMC10182476
DOI: 10.1016/S2213-8587(23)00038-4

Review

Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants

David Taïeb et al. Lancet Diabetes Endocrinol. 2023 May.

. 2023 May;11(5):345-361.

doi: 10.1016/S2213-8587(23)00038-4. Epub 2023 Mar 31.

Authors

Affiliations

¹ Department of Nuclear Medicine, Aix-Marseille University, La Timone University Hospital, Marseille, France.
² Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA.
⁴ Université Paris Cité, Inserm, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France; Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
⁵ Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
⁶ Svenja Nölting, Department of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
⁷ Université Paris Cité, Inserm, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France; Unité d'hypertension artérielle, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁸ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
⁹ Department of Cardiothoracic and Vascular Surgery, UTHealth Houston, McGovern Medical School, Memorial Hermann Hospital Heart and Vascular Institute, Houston, TX, USA.
¹⁰ Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA, USA.
¹¹ Division of Endocrinology, Department of Medicine and Research Center, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
¹² Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
¹³ Department of Endocrinology, Aix-Marseille University, Conception University Hospital, Marseille, France; INSERM U1251, Aix-Marseille University, Conception University Hospital, Marseille, France.
¹⁴ Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia; Cancer Genetics Laboratory, Kolling Institute, University of Sydney, Sydney, NSW, Australia.
¹⁵ Department of Endocrinology, Center of Endocrine Tumors Leiden, Leiden University Medical Centre, Leiden, Netherlands.
¹⁶ Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
¹⁷ Developmental Therapeutics Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁹ Division of Endocrinology and Metabolism, Department of Medicine, Malcom Randall VA Medical Center, University of Florida, Gainesville, FL, USA.
²⁰ Université Paris Cité, Inserm, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France; Département de Médecine Génomique des Tumeurs et des Cancers, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
²¹ Green Templeton College, University of Oxford, Oxford, UK; NET Unit, Royal Free Hospital, London, UK.
²² Department of Nuclear Medicine and Molecular Imaging, Institut de Cancérologie de Strasbourg Europe, IPHC, UMR 7178, CNRS, University of Strasbourg, Strasbourg, France.
²³ Department of Otorhinolaryngology, Leiden University Medical Centre, Leiden, Netherlands.
²⁴ Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
²⁵ Department of Endocrinology, University Medical Center Groningen, Groningen, Netherlands.
²⁶ Department of Otolaryngology and Head & Neck Surgery, Dutch Academic Alliance Skull Base Pathology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Otolaryngology and Head & Neck Surgery, Dutch Academic Alliance Skull Base Pathology, Maastricht University Medical Center, Maastricht, Netherlands.
²⁷ Department of Neurosurgical Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA.
²⁸ Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital of Verona, Verona, Italy.
²⁹ Section of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine & Surgery, University of Santo Tomas Hospital, University of Santo Tomas, Manila, Philippines.
³⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Endocrine Pathology Society, Toronto, ON, Canada.
³¹ Medical Center and Endocrine Center, Ijinkai Takeda General Hospital, Kyoto, Japan.
³² Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³³ Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁴ Department of Endocrine Surgery, Aix-Marseille University, Conception University Hospital, Marseille, France.
³⁵ Division of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan.
³⁶ Third Department of Medicine, Department of Endocrinology and Metabolism of the First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
³⁷ Department of Physician Assistant Studies, Stanford University School of Medicine, Palo Alto, CA, USA.
³⁸ Department of Medicine ΙΙI, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
³⁹ Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address: karel@mail.nih.gov.

PMID: 37011647
PMCID: PMC10182476
DOI: 10.1016/S2213-8587(23)00038-4

Abstract

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.

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Conflict of interest statement

Declaration of interests DT has received personal honoraria for lectures and consulting and support for meeting attendance from Advanced Accelerator Applications and Novartis. CL-L has received personal honoraria for lectures and support for meeting attendance from Ipsen. SN has received research grant to their institution from German Research Foundation. LA has received personal honoraria for lectures from Servier and Ipsen. ALE has received fees for consulting from WL Gore and fees for participation on an advisory board from Artivion. ML has received research grants to their institution from Arbor, Bristol Myers Squibb, Accuray, Biohaven, and Urogen; honoraria for research consulting from VBI Vaccines, InCephalo Therapeutics, Merck, Pyramid Bio, Insightec, Biohaven, Sanianoia, Hemispherian, Novocure, Noxxon, InCando, Century Therapeutics, and CraniUs; honoraria for non-research consulting from Stryker; is a shareholder of Egret Therapeutics; holds patents for the combination of immunotherapy and local chemotherapy to treat malignancies (10864180) and focused radiation to augment immune-based strategies against cancer (9132281); and is a member of the data and safety monitoring board of Cellularity. ELP has received fees for participation on an advisory board from Vysioneer. RTC has received personal honoraria for lectures from Novartis, support for meeting attendance from Ipsen, and serves as a board member for the Society for Endocrinology clinical committee and the UK and Ireland Neuroendocrine Tumour Society clinical committee. JKL has received honoraria for lectures from and is a consultant for Stryker. ERM has received fees for consulting and personal honoraria for lectures from MSD. NN has received an intramural research grant from the National Institutes of Health. NP-T has received research grants to their institution from Innervate, Clarity pharma; fees for consulting from Progenics, Lantheus, and Innervate Lifesciences. NP-T is a member of the data and safety monitoring board of Progenics and Lantheus, and serves as a board member for Society of Nuclear Medicine and Molecular Imaging. All other authors declare no competing interests.

Figures

**Figure 1.. Different potential locations of HNPGLs**
HNPGL may arise from the carotid bifurcation (purple), the nodose ganglion (green), jugular bulb (pink), and middle ear (red) and invade adjacent structures within the head and neck. Arrows indicate the potential patterns of local tumor extension for a given tumor type.

**Figure 2.. Current synthesis of the important clinical facts that contribute to the decision-making process**
cf means refer to; MRA, magnetic resonance angiography; SSTR PET/CT, somatostatin receptor PET/CT showing tumor multifocality; M0, absence of metastasis; M1, presence of metastasis; MTY, plasma 3-methoxytyramine; TKI, tyrosine kinase inhibitors.

**Figure 3.. Management of patients with SDHD-related HNPGLs with special emphasis on tumor multifocality**
Jugular PGLs are also named jugulotympanic PGLs; SRS, stereotactic radiosurgery (preferred radiotherapeutic option); RT, hypofractionated radiotherapy; CN, cranial neuropathy; PD, progressive disease; MET, metastatic; TRT, targeted radionuclide therapy; Adx, adrenalectomy; HNPGLs, head and neck paragangliomas; PGL, paraganglioma; VCT, vocal cord palsy *For patients without preoperative neuropathy #Some authors prefer to start on the side of the larger tumor

**Figure 4.**
Management of patients with metastatic *SDHD*-related PPGLs TKI, tyrosine kinase inhibitors * In patients in whom CVD is not tolerated, not wished by the patient or if there are contraindications to CVD, tyrosine kinase inhibitors (sunitinib) or temozolomide can be used as alternative agents, carefully evaluating their adverse effects.

See this image and copyright information in PMC

References

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Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants

Affiliations

Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases