Version of Record: https://www.sciencedirect.

com/science/article/pii/S2213858723000384
Manuscript_2fb8a446fcfaea3beb470e21f28d74f4

Clinical guideline on the management of pheochromocytoma and paraganglioma in

patients harboring germline pathogenic variants in the succinate dehydrogenase subunit
D gene

Prof David Taïeb, MD, Prof George B. Wanna, MD, Maleeha Ahmad, MD, Prof Charlotte
Lussey-Lepoutre, MD, Prof Nancy D. Perrier, MD, Prof Svenja Nölting, MD, Prof Laurence
Amar, MD, Prof Henri J. L. M. Timmers, MD, Zachary G. Schwam, MD, Prof Anthony L.
Estrera, MD, Prof Michael Lim, MD, Erqi Liu Pollom, MD, Lucas Vitzthum, MD, Prof
Isabelle Bourdeau, MD, Ruth T. Casey, PhD, Prof Frédéric Castinetti, MD, Prof Roderick
Clifton-Bligh, PhD, Eleonora P.M. Corssmit, MD, Ronald R. de Krijger, MD, Jaydira Del
Rivero, MD, Prof Graeme Eisenhofer, PhD, Hans K. Ghayee, DO, Prof Anne-Paule Gimenez-
Roqueplo, MD, Prof Ashley Grossman, FMedSci, Prof Alessio Imperiale, MD, Prof Jeroen C.
Jansen, MD, Abhishek Jha, MBBS, Michiel Kerstens, MD, Prof Henricus P.M. Kunst, MD,
Prof James K. Liu, MD, Prof Eamonn R. Maher, MD, Prof Daniele Marchioni, MD, Prof
Leilani B. Mercado-Asis, MD, Prof Ozgur Mete, MD, Mitsuhide Naruse, MD, Prof Naris
Nilubol, MD, Prof Neeta Pandit-Taskar, MD, Prof Frédéric Sebag, MD, Akiyo Tanabe, MD,
Prof Jiri Widimsky, MD, Leah Meuter, BS, Prof Jacques W.M. Lenders, MD, Prof Karel
Pacak, MD

Authors affiliations (alphabetic order)

Maleeha Ahmad, Department of Neurosurgery, Stanford University School of Medicine,

Palo Alto, California, USA. [email protected]

Laurence Amar, Université Paris Cité, Inserm, PARCC, Equipe Labellisée par la Ligue
contre le Cancer, F-75015 Paris, France; Hypertension Unit, Hôpital Européen Georges
Pompidou, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
[email protected]

Isabelle Bourdeau, Division of Endocrinology, Department of Medicine and Research

Center, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada.
[email protected]

Ruth T. Casey, University of Cambridge Department of Medical Genetics, NIHR Cambridge

Biomedical Research Centre, Cancer Research UK Cambridge Centre, Cambridge
Biomedical Campus, Cambridge, UK. [email protected]

Frédéric Castinetti, Department of Endocrinology, Aix-Marseille University, Conception

Hospital, Marseille, France. [email protected]

Roderick Clifton-Bligh, Department of Endocrinology and Cancer Genetics Laboratory,

Royal North Shore Hospital Kolling Institute, St Leonards NSW Australia, University of
Sydney, Australia. [email protected]

Eleonora P.M. Corssmit, Center of Endocrine Tumors Leiden, Department of

Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands.
[email protected]

Ronald R. de Krijger, Department of Pathology, University Medical Center Utrecht, 3584

CX Utrecht, The Netherlands. [email protected]

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© 2023 published by Elsevier. This manuscript is made available under the Elsevier user license
https://www.elsevier.com/open-access/userlicense/1.0/
Jaydira Del Rivero, Developmental Therapeutics Branch, Rare Tumor Initiative, Center for
Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
[email protected]

Graeme Eisenhofer, Institute of Clinical Chemistry and Laboratory Medicine, University

Hospital Carl Gustav Carus at the TU, Dresden. [email protected]

Anthony L. Estrera, Department of Cardiothoracic and Vascular Surgery UTHealth

Houston, McGovern Medical School Memorial Hermann Hospital Heart and Vascular
Institute. [email protected]

Hans K. Ghayee, Division of Endocrinology and Metabolism, Department of Medicine,

University of Florida and the Malcom Randall VA Medical Center, Gainesville, Florida,
USA. [email protected]

Anne-Paule Gimenez-Roqueplo, Université Paris Cité, Inserm, PARCC, Equipe Labellisée

par la Ligue contre le Cancer, F-75015 Paris, France; Département de Médecine Génomique
des Tumeurs et des Cancers, Assistance Publique - Hôpitaux de Paris, Hôpital Européen
Georges Pompidou, F-75015 Paris, France. [email protected]

Ashley Grossman, Green Templeton College, University of Oxford, UK and NET Unit,
Royal Free Hospital, London, UK. [email protected]

Alessio Imperiale, Department of Nuclear Medicine and Molecular Imaging – Institut de

Cancérologie de Strasbourg Europe, IPHC, UMR 7178, CNRS, University of Strasbourg,
France. [email protected]

Jeroen C. Jansen, Department of Otorhinolaryngology, Leiden University Medical Center,

Leiden, The Netherlands. [email protected]

Abhishek Jha, Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National

Institute of Child Health and Human Development, National Institutes of Health, Bethesda,
Maryland, USA. [email protected]

Michiel Kerstens, Department of Endocrinology, University Medical Center Groningen,

Groningen, The Netherlands. [email protected]

Henricus P.M. Kunst, Department of Otolaryngology and Head & Neck Surgery - Dutch
Academic Alliance Skull Base Pathology, Radboud University Medical Center, Maastricht
University Medical Center+, Nijmegen / Maastricht, The
Netherlands. [email protected]

Jacques W.M. Lenders, Department of Internal Medicine, Radboud University Medical

Center, Nijmegen, The Netherlands. [email protected] and Department of
Medicine ΙΙI, University Hospital Carl Gustav Carus at the TU Dresden, Germany

Michael Lim, Department of Neurosurgery, Stanford University School of Medicine, Palo

Alto, California, USA. [email protected]

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James K. Liu, Department of Neurosurgical Surgery, Rutgers New Jersey Medical School,
Newark, New Jersey, USA. [email protected]

Charlotte Lussey-Lepoutre, Université Paris Cité, Inserm, PARCC, Equipe Labellisée par la
Ligue contre le Cancer, F-75015 Paris, France; Department of Nuclear Medicine, Pitié-
Salpêtrière Hospital, Sorbonne University, Paris, France. [email protected]

Eamonn R. Maher, University of Cambridge Department of Medical Genetics, Cambridge

Biomedical Campus, Cambridge, UK. [email protected]

Daniele Marchioni, Department of Otorhinolaryngology and Head and Neck Surgery,

University Hospital of Verona, Piazzale Aristide Stefani 1, 37126, Verona, Italy.
[email protected]

Lani Mercado-Asis, Section of Endocrinology and Metabolism, Department of Medicine,

Faculty of Medicine & Surgery, University of Santo Tomas Hospital, University of Santo
Tomas, Espana, Manila, Philippines. [email protected]

Ozgur Mete, Department of Laboratory Medicine and Pathobiology, University of Toronto

President, Endocrine Pathology Society, Toronto, Ontario, Canada. [email protected]

Leah Meuter, Stanford University School of Medicine, Department of Physician Assistant

Studies, Stanford, California, USA. [email protected]

Mitsuhide Naruse, Department of Endocrinology and Metabolism, National Hospital

Organization Kyoto Medical Center, Kyoto, Japan. [email protected]

Naris Nilubol, Surgical Oncology Program, National Cancer Institute, NIH, Bethesda,
Maryland, USA. [email protected]

Svenja Nölting, Department of Endocrinology, Diabetology and Clinical Nutrition,

University Hospital Zurich and University of Zurich, Zurich, Switzerland.
[email protected]

Karel Pacak, Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National

Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
[email protected]

Nancy D. Perrier, Department of Surgical Oncology, MD Anderson Cancer Center, Houston,

Texas, USA. [email protected]

Neeta Pandit-Taskar, Department of Radiology, Molecular Imaging and Therapy Service,

Memorial Sloan Kettering Cancer Center, New York. USA. [email protected]

Erqi Liu Pollom, Department of Radiation Oncology, Stanford University School of

Medicine, Palo Alto, California, USA. [email protected]

Fréderic Sebag. Department of Endocrine Surgery, Aix-Marseille University, Conception

University Hospital, Marseille, France. [email protected]

3
Zachary G. Schwam, Icahn School of Medicine at Mount Sinai, Department of
Otolaryngology-Head and Neck Surgery, New York, USA. [email protected]

David Taïeb, Department of Nuclear Medicine, Aix-Marseille University, La Timone

University Hospital, Marseille, France. [email protected]

Akiyo Tanabe, Division of Diabetes and Endocrinology, National International Center for
Global Health and Medicine, Tokyo, Japan. [email protected]

Henri J. L. M. Timmers, Department of Internal Medicine, Radboud University Medical

Center, Nijmegen, The Netherlands. [email protected]

Lucas Vitzthum, Department of Radiation Oncology, Stanford University School of

Medicine, Palo Alto, California, USA. [email protected]

George B. Wanna, Icahn School of Medicine at Mount Sinai, Department of

Otolaryngology-Head and Neck Surgery, New York, USA. [email protected]

Jiri Widimsky, 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. [email protected]

Short running title: SDHD-related pheochromocytoma and paraganglioma

Keywords: paragangliomas, genetics, guidelines, management, surgery, radiotherapy, SDHD

Corresponding author:

Karel Pacak, MD, PhD, DSc, Section on Medical Neuroendocrinology, Eunice Kennedy
Shriver National Institute of Child Health and Human Development, National Institutes of
Health, Building 10, CRC, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, Maryland
20892-1109, karel@mail/nih.gov, Fax: 1-301-402-0884, Phone: 1-301-402-4594

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SUMMARY

Patients with germline succinate dehydrogenase subunit D gene (SDHD) pathogenic

variants (i.e., paraganglioma 1 syndrome / PGL1) are predominantly affected by head and
neck paragangliomas (HNPGLs), which in less than 20% of patients may coexist with PGL
arising from other locations (e.g., adrenal medulla, paraaortic, cardiac/thoracic, and pelvic).
Given the higher risk of tumor multifocality and bilaterality for pheochromocytomas and
paragangliomas (PPGLs) due to 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 (watchful waiting) is often appropriate to characterize tumor behavior in
patients with these pathogenic variants. These patients should be referred to specialized high-
volume medical centers. This consensus statement aims to help physicians in clinical
decision-making process when caring for patients with SDHD PPGLs.

INTRODUCTION

Hereditary head and neck paragangliomas (HNPGLs) are the most common tumors in
patients with germline succinate dehydrogenase subunit D gene (SDHD) pathogenic variants.
They are typically slow-growing hypervascular tumors but have the potential to become
locally aggressive. HNPGLs can be found in all anatomic sites of distribution of
parasympathetic paraganglia such as in the middle ear cleft, in the jugular bulb, along the
vagus nerve, and in the carotid body (Figure 1). HNPGLs are rarely functional and are
inherited in 40-50% of cases. Patients with SDHD pathogenic variants may also develop
thoracic, retroperitoneal, and pelvic PGLs (in less than 20% of cases and rarely in isolation)
and, more rarely, gastrointestinal stromal tumors, renal cell carcinoma, and pituitary
adenomas.1 These tumors should be screened during the imaging work-up of patients.
Multifocality of PGL is observed in approximately 75% of cases; however, the overall risk of
metastatic disease is approximately 5%. Disease penetrance is parent-of-origin dependent
(genomic imprinting). After a paternal transmission of SDHD pathogenic variants, the
proportion of individuals that will develop PPGL throughout their life is 90-100% whereas
maternal transmission extremely rarely leads to tumor development. Genetic counseling and
testing are recommended for at risk individuals with PPGL screening for those with SDHD
pathogenic variants including cases of maternal inheritance.2

METHODOLOGY

The consensus included three chairpersons (DT, JWML, and KP) and one project
manager (LM). The project was initiated in May 2021 and started with the setting-up of the
working groups (steering and rating group members). The steering group included 12
members (GBW, MA, CLL, NP, SN, LA, HJLMT, ZGS, ALE, ML, ELP, LV). The rating
group members included the remaining coauthors of the consensus. All steering and rating
group members participating in the consensus development are experts in PPGL and represent

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a variety of countries, practice settings and disciplines (Endocrinology, Oncology, Surgery,
Radiotherapist, Radiology, Nuclear Medicine, Genetics, Pathology).
A first zoom meeting with the steering group was held on August 18, 2021. During the
meeting, the steering group members were requested to conduct their own literature searches
using PubMed (US National Library of Medicine) using proposed search strategies (See
Search strategy and selection criteria section). The steering group members were requested to
perform a review and critical analysis of the available literature, to draft relevant graded
recommendations (using GRADE) for each thematic area and supported by a concise
paragraph named Evidence with the most relevant references and possible figures and tables
that support evidence.
In February 2022, the rating group members received the proposed recommendations
with evidence and supplemental Tables but without the ratings of the strength of grading and
quality of evidence. Each rating group member voted whether they agreed or disagreed with
the narrative forms of the recommendations (strongly agree, agree, neither agree or disagree,
disagree, strongly disagree, don't know/other), and then rated the strength of the proposed
grading (1=strong, 2=weak) and quality of the evidence using the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) (⊕ to ⊕⊕⊕⊕).3
They could also leave further comments or suggestions about the reason why they
agreed/disagreed or why they did do any ratings (e.g. lack of expertise in a specific topic)
with the proposal (optional, not required).
The results of the responses from the rating group members were reported in
PowerPoint slides and presented to steering and rating group members during two initial
zoom meetings (May 2, 2022, May 18, 2022). During these meetings, any discordances
between the rating and steering groups were discussed in order to find consensus on the
phrasing of the recommendations and grades regarding the strength of the proposal and
quality of the evidence. After this initial period, two additional rounds of voting were
conducted with the rating group via Google Forms. Rating group members were requested to
indicate their agreement or disagreement with the phrasing of the recommendations, strength
of recommendation (GRADE) and quality of evidence. A total of two additional virtual
meetings (June 22, 2022, September 9, 2022) were conducted with the rating group and
steering group members in order to find a consensus. After the last meeting in September
2022, the chairpersons and project manager drafted the final version of the consensus
statement and sent the manuscript with supplemental files to all steering and rating group
members for final review and approval.

RECOMMENDATIONS

Healthcare environment for patients with SDHD PPGLs (R1)

R1. We recommend that all decisions in patients with SDHD PPGLs be discussed and
managed by an expert interdisciplinary tumor team familiar with the disease to ensure
favorable outcomes and appropriate follow-up (Grade 1 ⊕○○○).

Evidence
There is no solid evidence from clinical studies showing favorable outcomes if patients
are managed by an expert interdisciplinary team with expertise in PPGL. However, PPGL is a
complex and heterogeneous disease involving many organs in a variable way. Due to the
rarity of these tumors, most physicians will have limited experience in this field, in particular

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with covering the competencies of the different involved specialties. Therefore, this
recommendation is mainly based on the experience and conviction of many international
experts that interdisciplinary discussion of management decisions of patients with PPGL is
the optimal approach. Such approach facilitates tailoring of clinical management to the
individual patient level. This extends beyond diagnosis and treatment, even to offering the
most appropriate individualized follow-up and surveillance.4,5 Expert interdisciplinary teams
are operative in clinical centers specialized in PPGL. This includes but is not limited to the
ENS@T Centers of Excellence and the Clinical Centers of Excellence accredited by the
Pheochromocytoma Paraganglioma Alliance. This applies also to any clinical center as long
as regular interdisciplinary expert-team discussions are operational.

Initial work-up for patients with SDHD PPGLs (R2-R4)

R2. We recommend that patients with PPGL and germline SDHD pathogenic variants
should be evaluated by clinical assessment and biochemical measurements
(metanephrines in plasma or urine and plasma 3-methoxytyramine [MTY]) (Grade
1⊕⊕⊕○).

R3. We recommend performing head/neck magnetic resonance imaging (MRI) as the

first modality for patients with HNPGL to screen for assessment of multifocality and
tumor extension (Grade 1⊕⊕⊕○).

R4. To search for SDHD PPGL in patients on a whole-body scale, we recommend

performing whole-body anatomic imaging together with positron emission tomography
(PET) (preferably with radiolabeled somatostatin analogs) as the first choice (Grade
1⊕⊕⊕○).

Evidence
In patients with SDHD HNPGL, symptoms and signs are often delayed and related to
local mass effects caused by large tumors rather than catecholamine excess.
Patients with HNPGL with plasma normetanephrine levels more than double the upper
reference limit are rare (2.3%). Increased normetanephrine levels in SDHD patients are
therefore more likely to be related to the presence of PGL outside the head and neck region.6
Furthermore, up to 30% of HNPGLs produce dopamine, as indicated by increases in plasma
methoxytyramine (MTY).6-8 Urine MTY is not a useful biomarker of tumoral dopamine
production in these tumors since urine dopamine is derived almost exclusively from renal
uptake and decarboxylation of circulating 3,4-dihydroxyphenylalanine (DOPA). Biochemical
workup should include plasma (usually preferred) or urine metanephrines and plasma MTY.9-
11

Imaging plays a vital role in the evaluation of patients with SDHD PPGLs. Imaging
should encompass the base of the skull to the pelvis. Magnetic resonance imaging (MRI) with
angiography sequences (MRA) are the most sensitive radiological techniques for HNPGL
staging.12-15 Various MR acquisition protocols have been described in the literature, including
one large study that evaluated MRA in 157 HNPGL patients with germline pathogenic
variants (63/157 SDHD). In this study, a combination of contrast-enhanced three-dimensional
time-of-flight angiography at arterial phase and axial plane fast spin-echo T1-weighted
sequence with fat saturation showed a sensitivity and specificity of 88.7% and 93.7%,
respectively.16 For patients with skull base HNPGLs, temporal bone CT provides
irreplaceable information on the extent of bone involvement. Cervico-thoraco-abdominal-
pelvic PPGLs can also be visualized using computed tomography (CT). CT scan with

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intravenous contrast is less costly and time consuming than MRI and particularly useful for
perioperative planning. CT is therefore often preferred over MRI at initial evaluation of
patients, with the exception of certain pediatric cases or during pregnancy.
Functional imaging complements anatomic imaging for whole-body disease staging and
can exclude other potential diagnoses. Patients with SDHD PPGLs typically exhibit strong
somatostatin receptor subtype 2 expressions, which is reflected by the high sensitivity of
somatostatin-receptor (SSTR)-guided PET/CT using gallium-68 radiolabeled somatostatin
analogs.17-21 Its sensitivity approaches 100% for HN parasympathetic primary and metastatic
lesions, but it appears to be less sensitive for primary sympathetic tumors.22 However, more
extensive imaging data for patients with SDHD pathogenic variants are still lacking. 6-[18F]-
L-DOPA (6-[18F]fluoro-l-3,4-dihydroxy-phenylalanine (18F-FDOPA) PET has also shown
high sensitivity in the detection of SDHD-related HNPGLs23,24 and is a very good alternative
to SSTR PET using 68Ga-radiolabeled somatostatin analogs if these are unavailable.25 18F-
FDOPA, however, overlooks some sympathetic (outside head and neck area) PPGLs.26,27 18F-
FDG PET has shown excellent results in the evaluation of patients with PPGLs harboring
germline pathogenic variants in one of the four genes that encode the SDH complex
(collective termed as SDHx)28-31. However, this imaging modality has been surpassed by
SSTR PET 19 especially, in the detection of SDHD-related HNPGLs (sensitivity ranging 70-
90% for 18F-FDG versus nearly 100% for SSTR PET). Its lower clinical value is partially due
to the less favorable tumor-to-background uptake ratio than those of specific
radiopharmaceuticals and potential drawbacks due to uptake by brown adipose tissue and
reactive lymph nodes. Functional imaging findings should be interpreted by a physician who
is experienced in PPGL imaging and should consider possible pitfalls, variants, and caveats
(Table 1). Compared with PET/CT imaging, 123I-Metaiodobenzylguanidine (123I-MIBG) and
111
In-pentetreotide scintigraphy are suboptimal and should not be employed in a purely
diagnostic setting.

Evaluation of surgical interventions for patients with SDHD PPGLs (R5-R14)

Patients with SDHD-related HNPGLs

Recommendations

R5. We recommend that patients with vagal PGL rarely be considered for resection due
to the high risk of resultant vocal cord paralysis (Grade 1⊕⊕○○).

R6. We recommend that newly diagnosed patients with jugular, vagal, and carotid PGL
without compelling indications for treatment undergo an initial trial of observation to
characterize tumor behavior (Grade 1⊕⊕○○).

Evidence
Due to their slow-growing pattern, the axiom “first do no harm” is particularly relevant
to the management of patients with HNPGLs (Figure 2). Newly diagnosed patients with
SDHD pathogenic variants, notably those with non-tympanicum HNPGL and those without
an urgent indication for resection (severe or progressive symptoms/signs from cranial
neuropathy including brainstem compression, severe pain, bleeding, and brain ischemia), are
good candidates for an initial observation trial. Patients with tympanic PGL often present with
hearing loss and pulsatile tinnitus: resection is safe in experienced hands, often done on an
outpatient basis, and has a low incidence of complications.

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 Elective surgical resection of HNPGL should be avoided in elderly and debilitated
patients, as well as in those with an inability to tolerate specific cranial neuropathies.32-37
Thus, particular attention must be paid to the patient’s swallowing function and pulmonary
reserve as significant dysphagia and aspiration may result from damage to or sacrifice of the
lower cranial nerves.33,34,38 As these lesions are typically benign and indolent, a trial of
observation in these populations seems to be reasonable and justified.36,39,40 Vagal PGL, in
particular, pose a challenge as resection in most patients by default results in vagal nerve
sacrifice and resultant vocal cord paralysis.41,42 Surgical intervention on such lesions, should it
occur, is generally only performed after the vocal cord is already immobile and is not
performed on bilateral lesions as bilateral vocal cord paralysis often leads to the need for
tracheostomy.33 Similar caution must be exercised in other scenarios in which bilateral or
multifocal lateral skull base disease is present; an extant cranial neuropathy on the unoperated
or previously operated side can be devastating for recovery should bilateral paralysis arise
after the intervention.32,33,36 Exceptions can be made for patients with bilateral carotid or
jugular PGLs in which a staged approach is taken and there is minimal morbidity from
resection of the first/initial side (Figures 1 and 2). Primary lesions with distant metastasis and
metastases themselves, although rare, should be operated on only in select circumstances; this
is generally done with palliative intent, and the proposed intervention should not cause more
harm than relief.32 Additional consideration must be given to the patient’s preference. There
are no clear size cutoffs for when to refrain from operating on HNPGLs; we recommend that
patients be referred to an experienced team.

R7. We recommend intervening (which may include surgical resection) on patients with
HNPGL demonstrating sustained growth or compression of vital head and neck
structures and in those lesions that progress after radiation (Grade 1⊕⊕○○).

R8. We recommend that for patients with any jugular and large carotid/vagal PGL
undergoing surgery, preoperative angiography with embolization be considered.
Balloon occlusion testing should be considered if internal carotid sacrifice with
reconstruction is contemplated (Grade 1⊕⊕○○).

R9. We recommend an individualized multidisciplinary approach for patients with

multifocal HNPGLs, with particular attention paid to avoiding compromising important
neurovascular structures. Staging resection is key to minimizing potential
morbidity (Grade 1⊕○○○).

Evidence
Indications for surgery include active signs and symptoms, such as compression of head
and neck structures, in some cases sustained (especially more rapid) growth, intractable pain,
progression after radiation, extent cranial neuropathy, some catecholamine-secreting lesions
and/or a low likelihood of postoperative cranial neuropathies, and other sources of
morbidity.33,35,42,43 Small tumors in young and otherwise healthy patients are generally ideal,
with high local control rates.33 The surgeon must weigh the risk of new cranial neuropathies
and make informed decisions with the patient and team. For carotid PGLs, for example,
lesions with a higher Shamblin classification (i.e., degree of carotid artery involvement) have
a higher risk of cranial neuropathy.42 Additionally, tumors sized >5 cm have a higher cranial
neuropathy rate of 67% than lesions sized <5 cm (14%);33,44 when this is compared to the
natural history of other HNPGLs, new or progressive deficits are seen in 30-33% of
cases.39,40,45 Being able to compare the nerve deficit rates across modalities is an important
component of preoperative counseling and decision-making. To standardize reporting and

9
outcomes, jugulotympanic PGLs may be classified according to the Fisch 46 and Glasscock-
Jackson staging systems.47
Additionally, anticipating the extent of resection and involving the appropriate surgical
services is paramount; collaboration with vascular surgery should occur any time there is a
question as to the need for carotid sacrifice,48 and neurosurgery should be available for skull
base lesions with an intracranial extent. Carotid stenting or sacrifice with subsequent
reconstruction should only be used in select circumstances and those with adequate collateral
intracranial circulation.
The classic approach to patients with jugular PGLs requires ear canal overclosure and
facial nerve mobilization, resulting in facial paresis and significant conductive hearing loss.
To minimize morbidity, subtotal resection, particularly of large jugular PGLs with
preservation of the lower cranial nerve, may be considered.35,40
Preoperative angiography with embolization is recommended for all jugular, large (>4
cm), or locally invasive carotid/vagal PGLs. Balloon occlusion testing is recommended for
lesions that encase the internal carotid artery and in those where carotid sacrifice and
reconstruction are a remote possibility. The primary goal of preoperative embolization of
HNPGLs is to help achieve a dry surgical field to visualize key neurovascular structures
critical for reducing surgical morbidity and increasing the probability of gross total
resection.36,42,49 Angiography and embolization are not without risk, nor are they guaranteed
to be reflective of the body’s response to internal carotid artery disruption, and temporary or
permanent cranial neuropathy may result even with superselective embolization due to
migration of particles to the vasa nervorum of the affected nerves.
There is no simple algorithm that best addresses the therapeutic strategy in patients with
multifocal HNPGLs (Figure 3).32 An individualized approach is recommended, as is the use
of an experienced multidisciplinary team that includes various surgical teams, endocrinology,
radiation oncology, and speech and swallowing therapy. The estimation of when and how to
intervene is particularly difficult given that all lesions are not present simultaneously. The
possibility of future metachronous lesions further complicates the clinical case.32
Important determinants of treatment include the patient’s life expectancy, tumor
behavior, baseline neurological/cranial nerve status, swallowing function, and pulmonary
reserve.32,33 The overarching goals of treatment should be to exercise appropriate restraint,
minimize the risk of multiple and/or bilateral cranial nerve deficits, and not compromise the
major cerebral vasculature. In the case of bilateral tumors, staging should be implemented to
minimize bilateral, potentially devastating cranial neuropathies.32,33,42 While there is no wide
consensus on special circumstances, some groups advocate resecting multiple head and neck
tumors in a single stage if they are ipsilateral and anatomically close.32,42 In the case of
bilateral tumors, some authors recommend operating on the side with existing cranial
neuropathies and observing or radiating the contralateral side to avoid bilateral nerve palsies.
If no neuropathies exist preoperatively, resection of the smaller of the two lesions poses a
lower risk to the cranial nerves. If there is no nerve deficit, the contralateral side may be
subsequently attempted. If there is a postoperative deficit, the contralateral lesion should be
observed or radiated.32,42 Special consideration should be given to avoid baroreflex failure in
patients with bilateral carotid PGLs or intracranial hypertension in patients with bilateral
jugular PGLs. Resecting one side and staging resection of the contralateral tumor several
months later can decrease these complications and allow for compensation.32 If observation is
chosen, median growth rates in these lesions may be as low as 1.0 mm/year with a median
doubling time of 4.2-5.7 years40, depending on method of comparison (linear measurements
versus volumes) and the assumptions of the mathematical models utilized.

10
R10. We recommend a thorough cranial nerve examination and laryngoscopy before
and after surgical intervention or radiotherapy for patients with HNPGL (Grade
1⊕⊕○○).

R11. We recommend that in cases of postoperative facial nerve palsy, corneal protection
be prioritized to avoid exposure keratitis or corneal abrasion (Grade 1⊕⊕⊕○).

Evidence
Routine pre- and postoperative screenings for cranial neuropathies are recommended,
with a focused evaluation of the nerves at risk from surgical intervention. All patients should
be evaluated for palsies of VII-XII, as measured by symmetric facial movement, audiogram,
evaluation of swallow/dysphagia, flexible bedside laryngoscopy33, and evaluation of palate
rise, shoulder elevation, and tongue mobility. Additional facets of the neurological
examination may be incorporated depending on the specific lesion(s).
New cranial neuropathies are rather common after surgical intervention of patients with
HNPGLs, with particularly high rates in jugular PGLs with intracranial extension,50-52 large
and/or invasive carotid body PGLs,33,44 and virtually all vagal PGLs. However, new or
progressive deficits are also observed in 30-33% of patients with observed lesions.39,45 Cranial
neuropathies causing dysphagia, aspiration, or facial paralysis after HNPGLs resection may
prolong hospitalization and recovery and have a profound effect on the quality of life.

Patients with SDHD-related non-HNPGLs and pheochromocytomas

R12. We recommend that functional PPGLs (which are predominantly retroperitoneal)

be resected as an initial priority in patients with multifocal disease including HNPGLs
(Grade 1⊕⊕⊕○).

R13. We recommend that patients with non-HNPGL and pheochromocytoma (adrenal,

retroperitoneal, pelvic, or thoracic) be offered appropriate surgical consultation with an
experienced surgeon with knowledge of this specific disease. Tumor resection should be
considered when there are no absolute contraindications, especially when complete
tumor removal is possible (Grade 1⊕⊕⊕○).

R14. We recommend a limited role for palliative debulking in patients with locally
aggressive, large tumors with high probability of incomplete surgical resection, or
metastatic disease, but this can be considered in patients who are not responsive to
medical management or have debilitating sequelae such as pain or mass effects that
worsen quality of life (Grade 1 ⊕⊕○○).

Evidence
SDHD carriers have a high incidence of multifocality, and a thorough preoperative
cross-sectional nuclear medicine evaluation should be performed for complete surgical
planning. Biochemically positive PGLs can be present in the context of pathogenic variants
and are mostly related to retroperitoneal PPGLs. These tumors should be resected prior to
other surgical interventions because of the risk of a perioperative hypertensive crisis (see
R21).
The main objective of surgical resection for patients with SDHD-related PPGLs is to
improve symptoms by removing the source of excess catecholamine secretion, preventing
further tumor growth, and minimizing the risk of metastatic disease. The current estimated

11
rates of metastatic behavior in patients with SDHD-associated PPGLs range between 4.5 and
7.7%.53-55
Pheochromocytoma (PHEO) treatment is typically surgical and often amenable via
minimally invasive surgery. The technical approach can be either anterior or posterior
(posterior retroperitoneoscopic adrenalectomy) depending on surgical expertise. There are no
modalities to ensure complete removal of the medullary tissue unless the entire gland is
removed. Because of multifocality and potential for missing small tumors, a cortical-sparing
technique may not be always ideal. These factors should be taken into consideration and
weighed against the risk of potential adrenal insufficiency if contralateral tumor develops.
An open approach is recommended rather than a laparoscopic approach for most
patients with primary SDHD PPGLs when the size is >5–6 cm because of the need to assess
the locoregional nodal disease.56,57
Retroperitoneal extra-adrenal SDHD and others PGLs can be locally invasive with
major vessel involvement of the inferior vena cava, aorta, renal vein, and superior mesenteric
artery/vein. When technically possible, complete resection may require vascular
reconstruction. In a retrospective study including 29 patients with PGLs and major blood
vessel involvement, the authors report that overall survival was higher in patients who
underwent complete tumor resection than in those who underwent only medical
management.58 There are no prospective clinical trials directly comparing laparoscopic or
robotic versus open adrenalectomy for patients with PGLs. A few case reports have
demonstrated the effectiveness and safety of laparoscopic surgery for patients with small
tumors and no invasion into any surrounding structure.59 The difficulty lies in lack of
preparation for intraoperative identification of tumors that encroach on surrounding
structures. These tumors are more likely to be adherent without distinguishable tissue planes
and require proximal and distal vascular control, multiple vessel ligation, and potential
vascular reconstruction. Safe resection requires manual assessment, palpation, careful
retraction, and the ability to cross-clamp large vessels. Common locations of extra-adrenal
SDHD PPGLs include the bladder, heart, and the area between or above the aortic bifurcation
e.g., the inferior mesenteric artery (the organ of Zuckerkandl). Patients with PGLs that arise in
the pelvis can have unique presentations and deserve special attention during surgery, given
the proximity of these tumors to the parasympathetic region, especially in males, discussion
and consideration of subsequent sexual dysfunction should be considered and appropriately
discussed with a patient. Additionally, sexual dysfunction has been reported as a potential
complication after other pelvic and aortic surgeries, which must be discussed, especially for
patients with a PGL located in the organ of Zuckerkandl.
The management of patients with thoracic SDHD PGLs is complex and technically
challenging. Complete anatomical involvement of the tumor should be determined prior to
resection. En bloc removal provides the best long-term outcome and freedom from
recurrence. Cardiac SDHD PGLs, although rarely malignant, often involve cardiac structures
such as the left atrium and ventricle, pulmonary artery, and coronary arteries without a
distinct border.60 Imaging often underestimates the actual involvement at the time of operative
resection. Multiple cardiac chamber reconstruction may often be required with coronary
artery bypass if coronary vessels are involved, and in rare cases, cardiac auto transplantation
may be required. En bloc resection of the tumor is required in all cases. For patients with
thoracic, para-aortic, and pelvic PGLs, open operations allow for the manual interpretation of
two important aspects of the technical procedure: assessment of the extent of vascular wall
invasion and presence of lymph node disease. Interpretation of imaging and anticipation of
invasion or adherence to vessels are paramount in planning. The reactive formation,
particularly in chest structures, seems to be locally more difficult and requires specialized
cardiac surgical expertise.

12
 On occasion, SDHD PGLs may occur in a location where surgical resection cannot be
safely accomplished, and other therapies are required to control both hormone hypersecretion
and tumor growth.
A perioperative hemodynamic management plan should be devised to prevent
instability and complications during the perioperative period. Beyond pharmacological
preparation, this requires good communication among multiple specialties, including the
availability of experienced anesthesiologists. Excellent intraoperative communication with the
surgical team and understanding the half-life and effects of pharmacological agents are
important factors in the management of intravascular volume, heart rate, and blood pressure.
Palliative debulking rarely grants pharmacological independence; one study showed that
aggressive debulking for biochemical management alone may not be effective as only seven
of 24 cases had a partial biochemical response, with six of seven cases recurring within 12
months.61 The authors also reported that resection can selectively relieve certain tumor-
associated symptoms and signs such as pain.

Therapeutic radiation for patients with SDHD PPGLs (R15-R18)

Patients with SDHD-related HNPGLs

R15. We recommend therapeutic radiation as a treatment for patients with SDHD

HNPGLs, more specifically for patients with radiologically progressive or symptomatic
SDHD HNPGLs. Older patients with multiple comorbidities, and/or highly complex
surgical resectability of tumors with cranial nerve palsies, such as vagus nerve
involvement and contralateral lower cranial neuropathies, are strong candidates for
primary therapeutic radiation (Grade 1⊕⊕○○).

R16. We recommend therapeutic radiation for patients with post-surgical residual and
recurrent SDHD HNPGLs with progressive disease (Grade 1⊕⊕○○).

Evidence
We recommend a multidisciplinary discussion on therapeutic radiation for each patient
with SDHD HNPGLs (Figure 2).
Therapeutic radiation, specifically stereotactic radiosurgery (SRS), should be
considered the primary treatment for all patients with SDHD HNPGLs, including in elderly
patients, those with significant comorbidities, or those with cranial neuropathies.62-64
Hypofractionated SRS may be preferred in cases of contralateral lower cranial neuropathies or
multifocal disease involving the bilateral vagal nerves as it is an effective method to preserve
cranial nerves, even in large tumors. 65,66
Therapeutic radiation should be considered as a secondary treatment for progressive
lesions after surgical resection33 or planned as an adjuvant treatment 8–12 weeks after
subtotal resection.65 Single-fraction SRS is most effective in smaller tumors (maximum
diameter <3 cm)66 but has also demonstrated efficacy in residual tumors with volume ≤4 cm3.
These series found a median marginal tumor dose of 14 Gy with 80% of cases demonstrating
tumor stability and 20% with shrinkage and no clinical progression.67 Gamma knife
radiosurgery in patients with post-surgical jugulotympanic PGL patients also showed
volumetric tumor control and clinical control in 94.8% and 91.4% of cases, respectively.68

R17. We recommend SRS as the primary or complementary treatment for surgical

resection. Hypofractionated radiotherapy may be recommended for patients with larger
SDHD HNPGLs (Grade 1⊕⊕⊕○).

13
Evidence
Radiation therapy is a treatment modality that works with ionizing radiation, generating
free radicals causing breaks in DNA and cell death through apoptosis, as well as via mitotic
cell death.64,69 Conventional fractionated external beam radiation therapy is typically
delivered as intensity-modulated radiation therapy (IMRT). IMRT has been reported to have
control rates and toxicities similar to those of SRS.68,70,71 Compared to traditional multi-
fraction IMRT occurring over several weeks, SRS is one to five fractions. Each fraction is a
single daily fraction, thereby having no more than 5 days of SRS treatment for the same
efficacy of radiation therapy compared to IMRT. Furthermore, SRS has several advantages
over IMRT. First, SRS has a lower biological effective dose than conventional radiation
therapy, thereby reducing the radiation dose to the surrounding normal tissues. Second, SRS
also provides submillimeter accuracy of the tumor target with a steep dose gradient,
minimizing radiation exposure to nearby critical structures. Single-fraction SRS is considered
most effective in smaller tumors (maximum diameter <3 cm) and has also been shown to be
equally efficacious, with toxicity rates similar to or lower than those of hypofractionated
radiotherapy.66,72
There are multiple equivalents of SRS, with linear accelerator-based types such as linear
accelerator (LINAC), Gamma Knife, and CyberKnife being the most common.73 A meta-
analysis that examined radiosurgical treatment of patients with jugular PGLs showed that
Gamma Knife, LINAC, and CyberKnife technologies all exhibited similarly high rates of
tumor control (95%) and clinical control (97%) across all studies.74
A meta-analysis of 15 studies (2018) reviewing the treatment of patients with jugular
PGLs with SRS as the primary treatment showed tumor control, symptom control and
complications in 92%, 93%, and 8% of patients, respectively. The analysis also showed that
smaller tumor volumes predicted symptomatic improvement.75 The North American Gamma
Knife Consortium collated the outcomes of eight gamma knife radiosurgical centers that had
treated patients with jugular PGLs with a median tumor margin dose of 15 Gy (n=132, 134
procedures) and demonstrated actuarial tumor control of 88%, 5 years after radiosurgery.
Improvement in pre-existing cranial nerve deficits was observed in 11% of patients, new or
progressive cranial neuropathies were seen in 15%, and no mortality was noted (Supplemental
Table 1).76 In other smaller series of patients with jugular PGLs, tumor control was noted to
be 94.7-100%.77-79 Additionally, in previous small series reports, LINAC radiosurgery
treatment of patients with jugular PGLs showed tumor control rates of 91-100%.80-82 A long-
term series of jugular PGLs treated with frameless LINAC-based SRS over nearly two
decades demonstrated a 7-year progression-free survival of 97.0% and 7.7% grade 1/2
(Common Terminology Criteria for Adverse Events system) toxicities.83
Because carotid body SDHD PGLs are the most common type of HNPGLs, surgical
resection is the most common treatment. To date, only one systematic review has compared
the results of surgical resection to those of IMRT (not only including SDHD ones) in 2,302
patients across 80 publications.84 Long-term tumor control was noted in 94.5% of IMRT
patients and 93.8% of surgical patients. However, surgically induced cranial neuropathies are
four times more common than those induced by IMRT.
In a meta-analysis examining treatment outcomes for patients with vagal PGLs, local
tumor control rates were similar between surgery and therapeutic radiation (93.3%), with a
mean follow-up of 86.7 months.64
Radiation-induced malignancy rates have been historically difficult to assess because of
variability in follow-up, rarity of HNPGLs, and varying methods of radiotherapeutic
treatment.85 The Mayo Clinic reviewed the institutional data of all HNPGLs patients who
received either external beam radiation therapy or SRS and found no radiation-induced

14
malignancy.86 This is consistent with the historical risk of 0.28%87 and a recent publication
indicating that SRS is likely to have a lower risk of radiation-induced malignancy than
traditional external beam therapy because of a lower median dose.88

Patients with SDHD-related non-HNPGLs

R18. We suggest considering therapeutic radiation for patients with symptomatic or

progressive chest, abdomen, and pelvis SDHD PGLs that cannot be resected (Grade
2⊕○○○).

Evidence
Limited literature supports the role of external beam radiotherapy in the treatment of
patients with PGLs below the neck as these tumors are generally managed with surgical
resection. Radiation can provide high rates of local control for patients with advanced and
unresectable PGLs to both primary and metastatic sites.89-91 While dose and fractionation data
can be extrapolated from the HNPGL literature, radiation to the chest and abdomen has
unique considerations, including respiratory motion and interfraction deformation of anatomy
and organs at risk. Higher radiation doses have been associated with improved local control.89
The use of advanced radiation technologies, including IMRT and stereotactic body
radiotherapy with adequate motion management, can allow safe dose escalation in the setting
of radiosensitive structures such as the small bowel. Published series on radiation for patients
with non-HNPGLs have used standard fractionation (1.8–2 Gy/fraction) or fractionated
stereotactic ablative radiotherapy rather than single fraction SRS, as is commonly used in
patients with HNPGLs.

Medical management of patients with SDHD PPGLs (R19-R22)

R19. We recommend the use of alpha-adrenoceptor blockers as medical treatment for

the management of norepinephrine-associated manifestations (Grade 1 ⊕⊕○○).

R20. We recommend avoiding the use of medications that may elicit a catecholamine
crisis in patients with catecholamine-producing SDHD PPGLs who do not receive
appropriate adrenoceptor blockade (Grade 1 ⊕○○○).

R21. We recommend the use of alpha-adrenoceptor blockers prior to any surgical and
non-surgical treatment interventions in patients with SDHD PPGLs demonstrating
norepinephrine production (Grade 1 ⊕⊕○○).

R22. We do not recommend the use of medical treatment prior to interventions for
patients with exclusively dopamine-producing SDHD PPGLs (as indicated by isolated
elevation of plasma MTY) (Grade 1 ⊕○○○).

Evidence
Preoperative biochemical screening is mandatory to avoid rare but catastrophic
perioperative complications in patients treated surgically, regardless of the presence of
symptoms and signs. Patients with norepinephrine-producing SDHD PPGLs should be treated
with α-adrenoceptor blockade prior to any therapeutic intervention. Norepinephrine
production is defined and recognized by an elevation in plasma and/or urine normetanephrine.
Some patients also have concurrent elevation of plasma and/or urine norepinephrine. Tumors

15
displaying norepinephrine production (not only secretion as reflected by elevated
normetanephrine) require pretreatment. 92
In the case of tachycardia during α-adrenoceptor blockade, a β-adrenoceptor blocker
could be added. Metyrosine, which inhibits tyrosine hydroxylase and thereby catecholamine
biosynthesis, can be used as an add-on drug where available. Monotherapy with (non-
selective) β-adrenoceptor blockers can elicit hypertension and is contraindicated. The
exclusive production and subsequent secretion of dopamine by HNPGLs is unlikely to
provoke any significant hemodynamic effects.93
Even in rare cases of patients with larger dopamine-only producing SDHD PPGLs, or in
isolated metastatic cases of overwhelming dopamine excess patients are typically
normotensive or even hypotensive.94-96 Therefore, in patients with dopamine-only SDHD
HNPGLs, management with α-adrenoceptor blockers before any type of treatment is not
advised.
In contrast, preoperative adrenoceptor blockade can be considered in rare cases of
patients with norepinephrine-producing SDHD HNPGLs. It should be ascertained that there
are no additional sympathetic PPGLs as a source of norepinephrine for which treatment might
be prioritized. In a single-center series of 152 patients with 182 HNGLs97, 7.7% of tumors
were deemed clinically significant secretors of catecholamines based on the presence of
explicitly documented hyperadrenergic symptoms (sustained or intermittent palpitations,
tachycardia, diaphoresis, tremors, or new-onset hypertension in conjunction with at least one
of these other symptoms) and/or elevated levels of normetanephrine (i.e., ≥2-fold the upper
reference limit). This subgroup was treated with α- or β-adrenoceptor blockade prior to
surgery, radiotherapy, or during observation, whereas pretreatment was omitted in patients
with clinically insignificant increased normetanephrine levels. A review of anesthesia records
showed no instances of hemodynamic instability requiring vasopressors, aggressive fluid
resuscitation, or antihypertensives. Although a small number of patients with clinically
insignificant elevations of catecholamines did not have any identifiable perioperative
complications, whether they should also receive perioperative blockade remains debatable.
To our knowledge, a catecholamine crisis elicited by radiation therapy or systemic
therapy for patients with SDHD PPGL is not common. Nevertheless, in the case of
norepinephrine production usually reflected by elevated plasma normetanephrine but not
necessarily plasma norepinephrine, treatment with appropriate adrenoceptor blockade should
be considered before these interventions. Therefore, patients must be carefully monitored
before, during, and after any procedure and vigorously treated in cases of hemodynamic
instability. Postoperative baroreflex failure is associated with surgery and radiotherapy for
patients with bilateral carotid body SDHD PGLs; thus, hemodynamic complications must be
carefully considered.98
To control the symptoms and signs of catecholamine excess and to prevent complications
of therapeutic interventions, α-adrenoceptor blockers are widely used as the primary
treatment. Both α1-selective and competitive adrenoceptor blockers, such as doxazosin,
prazosin, or terazosin, and the non-selective and non-competitive α1- and α2-adrenoceptor
blocker phenoxybenzamine are used. These drugs are typically started at least 7–14 days
preoperatively with gradually increasing dosages until blood pressure targets are achieved.99
The efficacy of phenoxybenzamine and doxazosin has recently been investigated in
PRESCRIPT, the first randomized controlled trial on presurgical treatment in patients with
PPGLs.100 The primary endpoint was defined as the total time a patient’s blood pressure was
outside a predefined range intraoperatively. While there was no difference between the two
drugs, there was less intraoperative hemodynamic instability with phenoxybenzamine.
Additionally, metyrosine and calcium channel blockers can be used.101 The latter may be used
either as an adjunct to α-adrenoceptor blockers to control refractory hypertension or as

16
presurgical monotherapy in cases of normal to mildly elevated blood pressure levels or cases
of severe orthostatic hypotension when an α-adrenoceptor blocker is used. Tachycardia is
treated with either non-selective β- or β1-selective (preferably) adrenoceptor blocker. To
reduce the risk of preoperative orthostatic hypotension and postoperative hypotension, it is
common practice to employ a high-sodium diet and administer one to two liters of saline 24
hours prior to surgery, and use compressive stockings.101

Surveillance of patients with non-metastatic SDHD PPGLs (R23-R27)

R23. We suggest that treatment-naïve patients with SDHD PPGLs with no compelling
indication for treatment should be imaged at 3 to 6-months and at 1-year following
diagnosis to document the disease course and decide on treatment options (Grade
2⊕○○○).

R24. We suggest that patients surgically treated for primary functional PPGLs should
undergo measurement of plasma or urine metanephrines and plasma MTY by 8 weeks
post-treatment. Imaging could be done at 3-6 months. In patients in whom the PPGL
was not functional, imaging should be performed at 3–6 months (Grade 2⊕○○○).

Evidence
After patients with SDHD PPGLs have received a diagnosis, approximately 50% of
patients undergo treatment and the remaining undergo surveillance.102
Most patients with functional HNPGLs are recognized by an elevation of plasma and/or
urinary normetanephrine and methoxytyramine, even if they do not have catecholamine-
related signs and symptoms. Non-functionality is defined as normal plasma and urinary
normetanephrine and/or MTY or as plasma metanephrines that are too low according to tumor
size. 103
For patients with functional SDHD PPGLs, measurement of metanephrines should be
performed 2-8 weeks postoperatively.4,104 In patients with non-functional tumors who have
completely normal preoperative biochemistry, imaging should be done at 3-6 months to check
whether surgery was complete. Repeat imaging should be done 3–6 months after any therapy.
In patients with non-metastatic (M0) SDHD HNPGL cases, imaging should be repeated
at 3–6 months postoperatively since there are no clinically reliable predictors of metastasis.
This is particularly important in patients with large SDHD PPGLs. If the disease is stable,
annual imaging findings should be considered. The estimated median volume growth rate is
10-12% per year, 105,106 despite with no progression in 60% of SDHD-related PGLs.106

R25. We recommend that patients with SDHD PPGLs (regardless of surgical

history) undergo annual blood pressure measurements, clinical assessment, and
biochemical measurements to detect new PPGLs or metastases or progression (Grade
1⊕⊕○○).

R26. We recommend that a whole-body MRI be performed at least every 2–3 years to
detect new SDHD PPGLs, metastases, or progression. Initially, more frequent imaging
follow-up is recommended for patients with unoperated PPGL and/or metastasis (Grade
1⊕⊕○○).

R27. We suggest the use of SSTR PET/CT on an individual basis to screen for disease
progression in patients with non-metastatic PPGL (Grade 2⊕○○○).

17
Evidence
Overall, the prognosis of patients with SDHD PPGLs remains excellent, with no
substantial increase in mortality observed in a Dutch sample of SDHD variant carriers.107
However, patients with SDHD are at risk of developing recurrence, metastasis, or progression.
Therefore, patients should receive lifelong follow-up, and quality of life should be monitored.
In one meta-analysis, the pooled risk for metastasis was 4% for patients with SDHD PGLs
versus 13% for patients with SDHB PGLs.55 A postoperative analysis of 47 SDHx patients
(n=33 SDHD) followed for a median of 2.7 years showed that 11% developed local
recurrence.102 Disease penetrance was very high in the presence of SDHD PGLs, but the
occurrence of metachronous tumors may be delayed.108-110 A study that included 93 patients
with SDHD-associated HNPGLs found that a diagnosis of biochemically positive PPGLs was
made in 30% of cases (with five glomus PGLs). The diagnosis was made at the initial
screening in 63% of cases, whereas 37% of cases were detected after repeated biochemical
screening. In this study, only patients in whom urinary excretion catecholamines and/or
metabolites was above the reference limit were subjected to imaging.110 In a follow-up study
performed over 22 years, new PGLs were found in 73% of cases, the majority of which were
HNPGLs. Eight patients (4%) developed PHEOs, and 12 (5%) developed sympathetic
PGLs.111 The diagnosis of a biochemically positive lesion is critical to avoid risks related to
catecholamine crises. Therefore, an annual assessment of plasma metanephrines in the follow-
up of patients with SDHD should be mandatory.112 To limit radiation exposure to patients,
whole-body MRI or multiple standard MRIs should be performed first.112,113 If possible and
based on current clinical assessment, the administration of gadolinium-based contrast agents
could be avoided because of the risk of deposition in the brain. PET/CT can be performed
every three to five years on an individual basis to screen for multifocality and metastasis.114

Surveillance and management of patients with advanced/metastatic SDHD PPGLs (R28-

R34)

R28. We recommend the use of SSTR PET/CT to evaluate disease progression in

patients with metastatic PPGL (Grade 1⊕⊕○○).

R29. We recommend characterizing disease progression in the setting of an

interdisciplinary tumor board using clinical information, biochemistry, and imaging
(Grade 1 ⊕⊕○○).

R30. We recommend active surveillance for patients with asymptomatic (or stable
symptoms/signs) or stable/very slow-growing metastatic lesions (stable disease >12
months), particularly in patients with low tumor burden (Grade 1 ⊕⊕○○).

R31. We recommend considering local therapies (e.g., surgery, therapeutic radiation,

interventional radiology procedures) for patients with symptomatic oligometastatic
SDHD PPGL without contraindication who cannot be otherwise controlled or in those
with lesions at risk of more severe local complications (Grade 1⊕⊕○○).

R32. We recommend targeted radionuclide therapy as the first-line systemic therapy for
SSTR- or MIBG-positive metastatic tumors with moderate-to-high tumor burden and
without evidence of rapidly progressive disease (Grade 1 ⊕⊕○○).

18
R33. We recommend chemotherapy as the first-line therapy in cases of rapid
progression or high visceral tumor burden and possibly as second-line therapy if there is
rapid progression following other systemic therapies (Grade 1 ⊕⊕○○). 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.

R34. We recommend either tyrosine kinase inhibitors (sunitinib) (Grade 1 ⊕⊕⊕○) or

temozolomide (Grade 1 ⊕⊕○○) in cases of progressing tumors not eligible for PRRT or
MIBG or following progression to radionuclide therapy or CVD.

Evidence
Assessment of disease progression mainly relies on anatomical and functional imaging
in selected cases (preferably PET/CT using somatostatin analogs). The Consensus on
Molecular Imaging and Theranostics in Neuroendocrine Tumors has recently proposed that
detection of new lesion(s) (after exclusion of pitfalls) by functional imaging with the same
tracer can be considered sufficient to define progression.115 However, data are too scarce to
provide any recommendation in the setting of patients with metastatic SDHx PPGLs.
In a study that included therapy-naïve patients with metastatic PPGLs, 87% of patients
who experienced progressive disease at one year had progressive disease at baseline.
Therefore, an imaging work-up three months after the diagnosis of metastatic disease may be
recommended.116
As SDHD-related PPGL metastases are often associated with slow progression, active
surveillance may be reasonable for patients with low tumor burden (Figure 4).
Surgery for the primary tumor (see R15) and locoregional treatments should be
considered on an individual basis in the setting of a multidisciplinary board. Patient
preparation was recommended for all local interventions, similar to that for surgery.
The European Society of Hypertension recommends targeted radionuclide therapy for
patients with slow/moderate disease progression with a moderate tumor burden (Figure 4).
Targeted radionuclide therapy of metastatic/inoperable PPGLs is a palliative treatment, with
rare cases demonstrating complete responses. The goals of therapy are stabilization/regression
of progressive, metastatic, or inoperable tumors, amelioration of symptoms, and control of
disease-specific cardiovascular effects. The choice between the two systemic radiotherapeutic
options (peptide receptor radionuclide therapy-PRRT or 131I-MIBG) is mainly dependent on
the imaging phenotypes seen on SSTR PET and 123I-MIBG.117 If a radiopharmaceutical is
superior in targeting most or all of a patient’s lesions, that compound is favored. If both
radiopharmaceuticals localize similarly, other issues related to toxicity and morbidity must be
considered. Additional issues to be considered are reimbursement and inpatient versus
outpatient therapies. Peptide Receptor Radionuclide Therapy (PPRT) is favored when the
patient has a low marrow reserve or baseline leukopenia/thrombocytopenia due to a lower
potential for marrow toxicity (especially compared to 18.5GBq 131I-MIBG). Owing to the less
differentiated nature of SDHD PPGLs and their usual parasympathetic origin, PRRT is
utilized more than MIBG therapy in this setting. Supplemental Tables 2 and 3 summarize the
results from clinical studies investigating PRRT, low- and high-specific-activity MIBG
therapy, and potential side effects. The disease control rate (DCR) for patients with PPGLs
with PRRT in most retrospective studies was ≥ 80%, and the progression-free survival (PFS)
was 17–39 months. In the largest meta-analysis of 234 pooled PPGLs patients treated with
PRRT, a high DCR of 90% was reported.118 However, only 71% of patients showed
progressive disease at treatment initiation, which complicates drawing conclusions. Another

19
meta-analysis of 201 pooled PPGLs patients treated with PRRT reported an overall response
rate of 25% and DCR of 84%.119
For rapidly progressing disease or high visceral tumor burden, chemotherapy with
cyclophosphamide, vincristine, and dacarbazine (CVD) is the recommended first-line
therapy.4,120-126 CVD should be the second-line therapy following progression to targeted
radionuclide therapy in the case of rapid progression or high visceral tumor burden (Figure
4).
Targeted systemic therapies (tyrosine kinase inhibitors [TKIs]) or temozolomide should
be considered following progression after targeted radionuclide therapy or subsequent
progression after CVD (Figure 4). For sunitinib, the first randomized placebo-controlled
clinical trial (FIRST-MAPP) (n=78) showed a DCR of 35.9% over 12 months and a
significant improvement in median PFS in the sunitinib group compared to the placebo group
(8.9 versus 3.6 months).127 The results of the FIRST-MAPP trial have yet to be published in a
peer-reviewed journal. Another prospective clinical trial (n=25) that investigated sunitinib in
patients with PPGLs reported a response rate of 13%, stable disease in 70% of patients over 3
months (DCR 83%), and a DCR of 61% over 6 months. All patients with SDHx-related
disease showed partial response or stable disease. 128
For temozolomide, two retrospective studies indicate efficacy in patients with metastatic
PPGLs including SDHx pathogenic variant cases: one retrospective study in patients with
PPGLs (n=14 with 10 SDHB cases) reported an overall DCR of 80% with a partial response
rate of 33% (according to RECIST plus PERCIST), with all responders being SDHB
pathogenic variants carriers (overall PFS 13.3 months, with a significantly longer PFS of 19.7
versus 2.9 months in SDHB versus non-SDHB pathogenic variants carriers).129 Another
retrospective study (n=17 with one SDHA-, one SDHC-, and seven SDHB-pathogenic variant
cases, 15 patients evaluable by RECIST, one SDHC, and one SDHB partial response) reported
a DCR of 67% (partial response 40%, stable disease 27%, overall median PFS 2.2 years,
median PFS 1.3 years for SDH pathogenic variants carriers, and 5.5 years for non-carriers).130
Thus, whether temozolomide has a specific benefit for SDH pathogenic variant carriers
remains unclear. Other studies are described in Supplemental Table 2.
It is worth mentioning that TKIs may worsen hypertension; thus, careful follow-up and
aggressive antihypertensive dosage adjustment prior to and during TKI therapy are needed. In
the case of progression following sunitinib or temozolomide treatment, an alternative
treatment can be used. Following the progression of both approaches, inclusion in a clinical
trial should be investigated. Similar to other neuroendocrine tumors, anti-resorptive therapies
are recommended for patients with SDHD PPGL patients with widespread bone metastases.131

CONCLUSION

All patients with SDHD pathogenic variants should be managed by an expert

interdisciplinary team and require clinical, endocrine as well as imaging work-up to screen
and diagnose PPGL at a whole-body scale. This can be achieved by combination of
morphological imaging and in most patients by SSTR PET/CT. In patients with HNPGL,
long-term preservation of cranial nerve function is a main concern when considering
treatment. Therapeutic radiation can complement or be an alternative to surgery in certain
situations. Life-long surveillance is mandatory to screen for new PPGL, disease progression
and/or metastases. Management of metastatic PPGL mainly relies on hormonal secretion,
disease extension and pace of growth. This guideline should help standardize high quality
care for PPGL patients with SDHD pathogenic variants.

20
Acknowledgements

Thank you to Alicia A. Livinski, National Institutes of Health Library, Bethesda, MD,
USA for assistance with this project and manuscript.

Contributors

DT, JL and KP were the chairpersons of the guideline. They organized and oversaw all
procedures. LM was the project manager of the guideline. The literature search and the
original draft of the different parts of manuscript were done by the steering committee
members (GBW, MA, CLL, NP, SN, LA, HJLMT, ZGS, ALE, ML, ELP, LV). The rating
group members (all authors except chairpersons, project manager and steering committee
members) participated to the different rounds of voting. Following each voting round, all
authors took part in the discussions and provided comments on the narrative form of the
recommendations and evidence sections. The steering committee members revised the
manuscript according to votes and all comments. All authors approved the final submission.

Declaration of Interests

DT has received personal honoraria for lectures and consulting from AAA/Novartis and
support for meeting attendance from AAA/Novartis.
GBW has nothing to declare.
MA has nothing to declare.
CLL has received personal honoraria for lectures from Ipsen and support for meeting
attendance from Ipsen.
NP has nothing to declare.
SV has received research grant to the institution from German Research Foundation.
LA has received personal honoraria for lectures from Servier and Ipsen.
HJLMT has nothing to declare.
ZGS has nothing to declare.
ALE has received fees for consulting from WL Gore and fees for advisory board from
Artivion.
ML has received research grants to the institution from Arbor, BMS, Accuray, Biohaven,
Urogen, honoraria for research consulting from VBI, InCephalo Therapeutics, Merck,
Pyramid Bio, Insightec, Biohaven, Sanianoia, Hemispherian, Novocure, Noxxon, InCando,
Century Therapeutics, CraniUs, honoraria for non-research consulting from Stryker. ML is a
shareholder of Egret Therapeutics. ML holds various patents. ML is a member of the Data
and Safety Monitoring Board of Cellularity.
ELP has received fees for advisory board from Vysioneer.
LV has nothing to declare.
IB has nothing to declare.
RTC has received personal honoraria for lectures from Novartis, support for meeting
attendance from Ipsen. RTC serves as a board member for Society for Endocrinology clinical
committee UKINETS clinical committee.
FC has nothing to declare.
RCB has nothing to declare.
EPMC has nothing to declare.
RRDK has nothing to declare.
JDR has nothing to declare.
GE has nothing to declare.

21
HKG has nothing to declare.
APGR has nothing to declare.
AG has nothing to declare.
AI has nothing to declare.
JCJ has nothing to declare.
AJ has nothing to declare.
MK has nothing to declare.
HPMK has nothing to declare.
JKL has received honoraria for lectures from Stryker and is a consultant for Stryker.
ERM has received fees for consulting from MSD, personal honoraria for lecture from MSD.
DM has nothing to declare.
LBMA has nothing to declare.
OM has nothing to declare.
MN has nothing to declare.
NN has received an intramural research grant from the NIH.
NPT has received research grants to the institution from Innervate, Clarity pharma, fees for
consulting from Progenics, Lantheus, innervate. MPT is a member of the Data and Safety
Monitoring Board of Progenics, Lantheus. MPT serves as a board member for SNMMI.
FS has nothing to declare.
AT has nothing to declare.
JW has nothing to declare.
LM has nothing to declare.
JWML has nothing to declare.
KP has nothing to declare.

Funding statement
This work was supported, by the Intramural Research Program of the National Institutes
of Health, Eunice Kennedy Shriver National Institute of Child Health and Human
Development.

Search strategy and selection criteria

The steering group members were requested to conduct their own literature searches in
PubMed (US National Library of Medicine) using search strategies with controlled
vocabulary MeSH terms and keywords for the condition of interest and section topic.
Searches were limited to those articles published after 2000. The search strategies combined
the term Paraganglioma and the following terms into separate searches for each section topic:
"Succinate Dehydrogenase", SDHD, "positron emission tomography", PET/CT,
"Radiotherapy"[MeSH], "Endocrine Surgical Procedures"[MeSH], "General
Surgery"[MeSH], Radiofrequency, Chemoembolization, Cryoablation, "Thermal Ablation",
Surveillance, "Follow-up", Chemotherapy, Sunitinib, "Temozolomide", Immunotherapy,
"Peptide receptor radionuclide therapy", PRRT, DOTATATE, DOTATOC, DOTANOC,
Somatostatin, MIBG. During screening of the results, articles were excluded if they were
animal studies, case reports or case series, and not published in English.

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Legends

Table 1. Summary of potential pitfalls in SSTR PET and 18F-FDOPA PET

interpretation
SSTR PET: Somatostatin receptor positron emission tomography
18
F-FDOPA: 6-[18F]-L-DOPA (6-[18F]fluoro-l-3,4-dihydroxyphenylalanine

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.

31
Table 1.

PET radiopharmaceuticals Pitfalls

SSTR analogs Uncinate process
Stellate ganglia
Splenunculi (accessory spleens), splenosis
Pancreatic heterotopia
Pancreatic serous cystadenoma
Bone hemangioma, enchondroma, fibrous dysplasia
Active chronic inflammation (e.g., sarcoidosis,
tuberculosis, Hashimoto's thyroiditis)
Other tumors (e.g., meningioma, breast cancer, renal
cancer, lymphoma, thyroid neoplasms, glioma,
neuroblastoma)
18 Solid pseudopapillary tumor of the pancreas
F-FDOPA
Thyroid neoplasm
Pituitary adenoma
Squamous cell carcinoma
Poorly differentiated adenocarcinoma
Melanoma
Multiple myeloma
Hepatocellular carcinoma
Schwannoma
Chondrosarcoma