pharmaceuticals

Review
The Management of Phaeochromocytomas and Paragangliomas
in the Era of Precision Medicine: Where Are We Now?
Evidence-Based Systemic Treatment Options and Future Cluster
Oriented Perspectives
Alessandra Bracigliano 1,† , Antonella Lucia Marretta 2,† , Luigi Pio Guerrera 3 , Roberto Simioli 3 ,
Ottavia Clemente 3 , Vincenza Granata 4 , Anita Minopoli 5 , Giuseppina Della Vittoria Scarpati 3, *,
Fernanda Picozzi 3 , Lucia Cannella 3 , Antonio Pizzolorusso 3 , Francesca Di Gennaro 1 , Roberto Tafuto 6 ,
Maria Rosaria Sarno 7 , Ernesta Cavalcanti 5 , Dario Ribera 8 and Salvatore Tafuto 3

1 Nuclear Medicine Unit, Istituto Nazionale Tumori I.R.C.C.S. Fondazione “G.Pascale”, 80131 Naples, Italy;
[email protected] (A.B.); [email protected] (F.D.G.)
2 Medical Oncology Unit, Ospedale Ave Gratia Plena, San Felice A Cancello, 81027 Caserta, Italy;
[email protected]
3 Sarcoma and Rare Tumors Unit, Istituto Nazionale Tumori I.R.C.C.S. Fondazione “G.Pascale”,
80131 Naples, Italy; [email protected] (L.P.G.); [email protected] (R.S.);
[email protected] (O.C.); [email protected] (F.P.);
[email protected] (L.C.); [email protected] (A.P.);
[email protected] (S.T.)
4 Radiology Division, Istituto Nazionale Tumori I.R.C.C.S. Fondazione “G.Pascale”, 80131 Naples, Italy;
[email protected]
5 Laboratory Medicine Unit, Istituto Nazionale Tumori-IRCCS “Fondazione G. Pascale”, 80131 Napoli, Italy;
Citation: Bracigliano, A.; Marretta, [email protected] (A.M.); [email protected] (E.C.)
6 Division of Neurosurgery, Department of Neurosciences and Reproductive and Odontostomatological
A.L.; Guerrera, L.P.; Simioli, R.;
Clemente, O.; Granata, V.; Minopoli,
Sciences, Università Degli Studi Di Napoli Federico II, 80131 Naples, Italy; [email protected]
7 Division of Pharmacy, Istituto Nazionale Tumori I.R.C.C.S. Fondazione “G.Pascale”, 80131 Naples, Italy;
A.; Della Vittoria Scarpati, G.; Picozzi,
[email protected]
F.; Cannella, L.; et al. The 8 Medical Oncology Unit, Sessa Aurunca, Ospedale San Rocco, 81037 Caserta, Italy; [email protected]
Management of Phaeochromocytomas * Correspondence: [email protected]
and Paragangliomas in the Era of † These authors contributed equally to this work.
Precision Medicine: Where Are We
Now? Evidence-Based Systemic
Abstract: Pheochromocytomas (PCCs) and Paragangliomas (PGLs), commonly known as PPGLs
Treatment Options and Future Cluster
to include both entities, are rare neuroendocrine tumors that may arise in the context of hereditary
Oriented Perspectives. Pharmaceuticals
syndromes or be sporadic. However, even among sporadic PPGLs, identifiable somatic alterations
2024, 17, 354. https://doi.org/
in at least one of the known susceptibility genes can be detected. Therefore, about 3/4 of all PPGL
10.3390/ph17030354
patients can be assigned to one of the three molecular clusters that have been identified in the
Academic Editors: Marek Saracyn and last years with difference in the underlying pathogenetic mechanisms, biochemical phenotype,
Adam Daniel Durma
metastatic potential, and prognosis. While surgery represents the mainstay of treatment for localized
Received: 29 January 2024 PPGLs, several therapeutic options are available in advanced and/or metastatic setting. However,
Revised: 27 February 2024 only few of them hinge upon prospective data and a cluster-oriented approach has not yet been
Accepted: 5 March 2024 established. In order to render management even more personalized and improve the prognosis of
Published: 8 March 2024 this molecularly complex disease, it is undoubtable that genetic testing for germline mutations as
well as genome profiling for somatic mutations, where available, must be improved and become
standard practice. This review summarizes the current evidence regarding diagnosis and treatment
Copyright: © 2024 by the authors.
of PPGLs, supporting the need of a more cluster-specific approach in clinical practice.
Licensee MDPI, Basel, Switzerland.
This article is an open access article Keywords: phaeochromocytomas; paragangliomas; neuroendocrine tumors; molecular clusters;
distributed under the terms and management; cluster-specific approach
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

Pharmaceuticals 2024, 17, 354. https://doi.org/10.3390/ph17030354 https://www.mdpi.com/journal/pharmaceuticals

Pharmaceuticals 2024, 17, 354 2 of 22

1. Introduction
Pheochromocytomas (PCCs) and Paragangliomas (PGLs) are rare neuroendocrine
tumors (about 0.2–0.8 new cases per 100,000 people each year) originating from the chro-
maffin cells derived from the neural crest. PCCs and PGLs (commonly known as PPGLs, to
include both entities) are usually slow-growing, mostly catecholamine (CMN) producing
tumors, with 30–40% being hereditary [1–4].
The distribution by gender does not show significant differences, although a slight
predilection for females has been observed. They are most commonly diagnosed within the
third and sixth decades of life, even if they can arise over a wide age range [2,3,5]. Since
they usually exhibit indolent growth patterns, they can be detected incidentally in imaging
techniques [6].
PCCs originate from the cells of the adrenal medulla, a bilateral organ, located on
the top of each kidney, which is the greatest sympathetic paraganglion of the human
body. On the other hand, PGLs derive from extra-adrenal paraganglia: thus, they may be
located anywhere in the body, and they are commonly classified as sympathetic (thorax, ab-
domen, pelvis) or parasympathetic (predominantly head and neck, but even mediastinum)
depending on their origin.
Regardless of their development background, approximately 85% of paragangliomas
arise in the abdomen, while 12% of them in the anterior chest area, and finally about 3% in
head and neck. The latter ones, commonly denoted as Head-and-Neck (HN) PGLs, derive
exclusively from parasympathetic paraganglia: they are generally asymptomatic and less
likely to be metastatic than PGLs of other sites [1–6].
In this review, we summarize the current evidence regarding management of PPGLs,
supporting the need of a more cluster-specific approach in clinical practice in the era of
precision medicine.

2. Genetics and Molecular Classification of PPGLs: How They Affect Phenotype

PPGLs may be “apparently” sporadic (without any known genetic alterations) or arise
in the context of hereditary syndromes (30–40%) with germline mutations in one of the
currently identified PPGLs susceptibility genes. However, even sporadic PPGLs (almost
40–50% of all PPGLs) may bear identifiable somatic alterations in at least one of them [5–11].
This means that around 3/4 of PPGLs patients can be assigned to one well defined
molecular cluster, further confirming the importance of genetic testing for germline muta-
tions for every patient in PPGLs management and encouraging somatic tumor mutation
analysis as well, although this is still the subject of ongoing research [10,11].
However, limitations include the high costs of genetic testing and the long waiting
period required for a diagnosis.
Based on different pathogenetic mechanisms, three main molecular clusters have been
identified in the last years: the pseudohypoxia-associated cluster 1, the kinase signaling-
associated cluster 2 and Wnt signaling-associated cluster-3 [10–14].
Assigning a particular patient to one of these clusters may guide biochemical testing,
the choice of specific imaging modalities, may suggest different clinical behavior and long-
term prognosis, and eventually appropriate tailored treatments [10,11], thus rendering the
management of PPGLs more personalized.
However, a cluster specific-approach for the treatment of inoperable/metastatic dis-
ease has not yet fully entered routine clinical practice.

2.1. Cluster 1
The pseudohypoxia-associated cluster is characterized by the activation of several
pathways mimicking hypoxia signaling and can be divided into two subclusters (1A,
1B) [10–12].
Cluster 1A groups tumors with predominantly germline mutations in Krebs-cycle-
related genes such as genes encoding succinate dehydrogenase subunits (SDHx, A, B, C,
D), succinate dehydrogenase complex assembly factor-2 (SDHAF2), malate dehydrogenase
Pharmaceuticals 2024, 17, 354 3 of 22

(MDH2) and fumarate hydratase (FH), while cluster 1b include tumors with either germline
or somatic mutations in VHL and EPAS genes [10–15].
Germline mutations in genes encoding the SDH subunits A, B, C, and D are associated
with the most common hereditary syndromes of PPGLs, formerly referred to as familial
pheochromocytoma-paraganglioma syndromes (PGL) type 5, type 4 (PGL4), type 3 (PGL3),
and type 1 (PGL1) respectively [9–11,14], while germline mutations in the VHL gene are
related to Von-Hippel Lindau disease. Less frequent familial forms are associated with
germline mutations in MDH2, SLC25A11 and FH genes [9–12,14,15].
Cluster 1 tumors include about 25–35% of all PPGLs and almost 50–60% of all
metastatic PPGLs: they are mainly located at extradrenal locations, particularly SDHx-
related tumors [11,12,16,17] while EPAS1-, FH- and VHL- related tumors may occur both
as PGLs and PCCs [11,12].
Most of the tumors belonging to this cluster have a noradrenergic biochemical phe-
notype (norepinephrine -NE- and its main metabolite normetanephrine—NMN) but may
also produce dopamine (DA) and its main metabolite 3-methoxytyramine (3-MT), with
normal or near normal levels of NE/NMN [9–12,18]. Of note, in some cases, particularly
for SDHx-mutated tumors and HNPGLs, no catecholamine production can be detected and
these tumors may be non functional [11,17,18].
Cluster 1-PPGLs, especially those harboring mutations in SDHx genes, are often
aggressive, multiple, metastatic with a poorer prognosis [9–12].

2.2. Cluster 2
The kinase signaling-associated cluster includes tumors harboring either germline or
somatic alterations in genes which modulate the PI3K/AKT/mTORC1 and RAS/RAF/ERK
pathways [10–14].
Genes belonging to this cluster include the RET gene and the NF1 gene which are
associated with Multiple Endocrine Neoplasia type 2 (MEN2) and with neurofibromatosis
type 1 respectively [13,14,19,20].
Cluster 2 includes approximately 50–60% of all PPGLs and almost 2–4% of all metastatic
PPGLs [10–12]. These tumors are predominantly located adrenally (PCCs) with a typical
adrenergic biochemical phenotype (epinephrine/metanephrine-E/MN-> both E/MN and
NE/NMN) [9–12,21].
The majority of cluster 2—related PPGLs usually have a better prognosis and low
metastatic potential.

2.3. Cluster 3
Wnt signaling-associated cluster include tumors that harbor exclusively somatic alter-
ations in genes regulating the Wnt and Hedgehog pathways [10–14].
They represent approximately 5–10% of all PPGLs and they are typically associated
with higher chromogranin A expression. Their catecholamine phenotype is still undefined.
Similarly to cluster 1 tumors, these neoplasms typically show aggressiveness as well
as early metastatic spread [10–12].

3. Clinical Presentation and Metastatic Potential

Clinical presentation of PPGLs is extremely variable and may depend on several factors
such as tumor location, size, local extension and/or distant involvement, the secretion
or not of catecholamines, the malignancy potential and aetiology (hereditary or sporadic
nature) [21].
Most of PPGLs, those deriving from sympathetic paraganglia, generally produce an
excessive amount of CMNs [11,21].
The release of catecholamines in excess can cause typical adrenergic and noradrenergic
symptoms: the most frequent include severe headache, sweating, palpitations, tremor, per-
sistent (cluster 1) or episodic hypertension (cluster 2); therefore, untreated PPGLs, can cause
severe damage, particularly to the cardiovascular system [2,6,13,22–25]. Cluster-specific
Pharmaceuticals 2024, 17, 354 4 of 22

differences have been reported with cluster 1 patients showing lower basic symptoms
scores compared to cluster 2 patients who typically present with paroxysmal symptoms.
Though rare, about 15% of the paragangliomas (those derived from parasympathetic
chains of the head and neck region, HNPGLs) have been traditionally classified as “non-
functional” or biochemically “silent”/“pseudo-silent” tumors since they usually do not
produce CMNs: common adrenergic-noradrenergic symptoms do not appear and therefore
they are harder to detect. As a consequence, they are incidentally found on imaging studies
done for other purposes or they may be diagnosed due to their compressive effect on the
surrounding structures when they reach a large size [10,11,17,21].

Metastatic Potential
All PGGLs are malignant and potentially metastatic and there are no clear-cut features
that can predict metastatic behavior: this explains why since the 4th edition of the WHO,
PPGLs have no longer been classified as benign and malignant [21,26].
Metastatic disease develops in 15–17% of all PPGLs with different metastatic potential
in PCCs (10%) and PGLs (35–40%) [5]. Parasympathetic PGLs (HNPGLs) show typically a
very low risk of malignant behavior (about 5%) [10,21,27,28].
Estimating the metastatic risk of these tumors is not feasible with histology alone and
remains an unmet need. Several scoring systems either based solely on morphological
parameters (PASS score, applicable only to PCCs) or combining morphological, immuno-
histochemical and analytical features (GAPP scale and COPPS score for both PCCs and
PGLs) have been proposed during the last years to predict the malignant potential and
identify more aggressive lesions. However, the WHO does not endorse but also does not
discourage their use [21,29].
According to 2021 ESMO Guidelines, a “high risk of metastases” can be established
when any patient presents with one or more of the following criteria: (A) tumor size ≥ 5 cm;
(B) any extra-adrenal PGL; (C) known SDHB germline mutation; or (D) plasma 3MT >
3 fold above the upper limit of normal [21,30].

4. Diagnosis and Staging

Diagnosis of PPGLs is clinical, biochemical, and radiological.
Guidelines accept word widely both plasma-free and urinary fractionated metanephrines
(MNs) for the screening and follow-up of PPGLs, although recent studies demonstrated a
higher sensitivity for plasma over urinary tests [11,21].
False positive results may be related to several conditions such as inappropriate
preclinical preparation (diet, incorrect blood sampling), the use of medications that interfere
with CMN metabolism, physical stress and laboratory errors. In these cases, tests must
be repeated under optimized conditions [10,11,21]. False negative results, despite being
less frequent, may be related to small and/or asymptomatic tumors and cluster 1 tumors
(DA-producing PPGLs, biochemically silent PGLs of the head and neck region or SDHB
mutated-neoplasms) [11,21].
The assessment of plasma 3MT may be useful in cluster 1 tumors [10,11], while the
measurement of chromogranin A is strongly recommended in biochemically silent PGLs,
particularly in those SDHB-mutated [10,21].
In patients with altered screening examinations, radiological tests are particularly im-
portant to detect and stage the tumorin order to plan the subsequent therapeutic approach.
Current evidence suggests that CT is generally more useful than MRI for initial
localization of PPGLs in biochemically positive patients because it is widely available,
cost-effective, and offers better spatial resolution than MRI [21,24,25,27,31].
Radiologically, PPGLs are usually solid, hypervascular, and well-circumscribed masses,
with sizes varying from 1 to 15 cm. Larger tumors may exhibit central necrosis, while
smaller ones typically display a uniform appearance. Moreover, certain PPGLs may simu-
late adenomas due to macroscopic fat or may exhibit high attenuation due to hemorrhage
or calcifications [6,14,21,24,25,27,31] (Figure 1).
Pharmaceuticals 2024, 17, 354 5 of 22

Figure 1. (A–F): (A). CT images in axial plane during arterial phase of contrast study. The lesion
indicated by the arrow appears as a heterogenous mass with rim enhancement. (B,C). MPR post
processing in coronal and sagittal planes during arterial phase. (D). CT images in axial plane during
portal phase of contrast study. The lesion indicated by the arrow appears heterogenous with rim
enhancement and without progressive contrast enhancement. (E,F). MPR post processing in coronal
and sagittal planes during portal phase.

For the screening of PCCs, CT scan shows a high sensitivity (almost 100%) but a low
specificity (50%) [11]. On CT scan, PCCs are generally more than 10 Hounsfield units (HU)
with a marked enhancement that can be heterogenous due to degenerative changes [12,31]
(Figure 1). Differential diagnosis with the less common lipid-poor adenomas may be
challenging as they also have more than 10 HU and show similar absolute and relative
percentages washout values [31].
MRI has similar sensitivity but higher specificity than CT for PCCs and is superior to
CT imaging for screening purposes of extra-adrenal PGLs, especially those of the head and
neck region [11].
Moreover, being free of ionizing radiations, it must be preferred for initial tumour
localization in children (10–20% of all PPGLs diagnoses) and pregnant women as well as
for life-long follow-up [11,21].
Typically, PPGLs show a high signal intensity on T2-weighted images (the characteris-
tic “light bulb” bright sign), with low signal intensity on T1-weighted images. However,
other lesions can also present with a “light bulb” feature including cysts, lipid-poor adeno-
mas and metastatic lesions and the signal intensity on T1 may increase in the presence of
fat or haemorrhage [11,21,31,32].
The use of dynamic contrast enhanced MRI (DCE-MRI) in atypical cases of adrenal
masses should be taken into account as its findings may be contributory to the results of
chemical shift MRI [33,34]. Furthermore, DCE-MRI showed to be particularly useful in
the diagnosis of HNPGLs, as their early initial avid enhancement is distinctive from other
cervical benign lesions [32,35,36].
In case of atypical pheochromocytomas that undergo cystic degeneration, integrating
MRI findings with those of correlative planar/hybrid radionuclide images should be
considered as tumour accumulation of MIBG and/or FDG in the residual solid tissue or in
Pharmaceuticals 2024, 17, 354 6 of 22

the peripheral tumour rim may help to classify properly these lesions and disclose their
real nature [37,38].
In all patients with PPGLs, except for those with low risk of metastatic disease, whole-
body CT or MRI must be performed before any surgical approach to rule out metastases or
multiplicity [10,11].
Functional imaging is recommended in case of inconclusive results on anatomic
imaging as well as for staging in patients with suspected metastatic disease as well as
multifocal disease [11,30].
The choice of the most sensitive technique for each case relies on the clinical as well as
biochemical profiles, and location of the primary tumour, which are also predictors of the
underlying genotype [21].
PPGLs cells express on their surface different molecular targets which allow images
to be obtained. These include several transporters with different capture mechanisms
(Norepinephrine, glucose and amino acid transporters for 123/131 I-MIBG, 18F-FDG or
18F-DOPA respectively) or membrane surface receptors (somatostatin receptors, SSTRs, for
68GA-DOTA-SST analogs) [21,31,32,36].
123/131 I-MIBG are both captured by the norepinephrine transporter: 123I MIBG
SPECT/CT sensitivity and specificity is extremely high for sporadic PCCs, though it
Pharmaceuticals 2024, 17, x FOR PEER REVIEW 7 of 23
dramatically decreases for PGLs (52–75%), especially for HNPGLs (18–50%) and for SDHx-
related tumours [21,31,32,36,39,40] (Figure 2A–C).

Figure
Figure 2.2. (A–F):
(A–F):Fusion
Fusionimages
images with
with 123I
123I MIBG
MIBG SPECT/CT
SPECT/CTinincoronal
coronal(A),
(A),sagittal
sagittal(B)
(B) and
and axial
axial
planes
planes (C)
(C) respectively showing high
respectively showing high radioligand
radioliganduptake
uptakeininaayoung
youngpatient
patientdiagnosed
diagnosed with
with PCC.
PCC. In
In (D,E), functional images from the same patient show high uptake of 68Ga-DOTA-SSA, with a
(D,E), functional images from the same patient show high uptake of 68Ga-DOTA-SSA, with a central
central cold area. In fusion image (F), a central spared area of necrosis is present.
cold area. In fusion image (F), a central spared area of necrosis is present.
18F-DOPA is a radiotracer
68Ga-DOTA-SSAs that accumulates
are somatostatin specificallythat
analog radiotracers in bind
sometoPPGLs
SSTRs.due to
68Ga-
increased
DOTA-SSA uptake by amino
PET/CT acid transporters:
is proving increasingly18F-DOPA
useful forPET/CT represents
the diagnosis the functional
of certain PPGLs
imaging
(per-lesion sensitivity > 90%): in particular, it showed excellent sensitivitymutated
of choice in cluster 1B and cluster 2 PPGLs, as well as in FH and
for detecting
polycythemia-related PPGLs [11,21,32,36]. In these cases, if not available, I123-MIBG
both primary tumors and metastatic lesions in cluster 1 mutation carriers (overall detection
SPECT/CT may
rate of 98.6% in be considered [21].
SDHB-mutated PPGLs) and it is considered the functional image of choice
Of note, a recently
for HNPGLs [21,27,31,32,36] published
(Figureprospective,
2D–F). single-institution study comparing 18 F-
FDOPA PET/CT with I123-MIBG SPECT/CT demonstrated that 18F-FDOPA has
noninferior sensitivity as well as similar specificity to 123I-MIBG SPECT/CT in the
diagnosis of PPGLs, but it is more sensitive in the assessment of recurrence and
metastases, further supporting its use in high risk PPGL in general and in those harboring
the above mentioned mutations [41].
Finally, 18F-FDG PET may be useful in metastatic disease in general and as functional
Pharmaceuticals 2024, 17, 354 7 of 22

18F-DOPA is a radiotracer that accumulates specifically in some PPGLs due to in-

creased uptake by amino acid transporters: 18F-DOPA PET/CT represents the functional
imaging of choice in cluster 1B and cluster 2 PPGLs, as well as in FH mutated and
polycythemia-related PPGLs [11,21,32,36]. In these cases, if not available, I123-MIBG
SPECT/CT may be considered [21].
Of note, a recently published prospective, single-institution study comparing 18
F-FDOPA PET/CT with I123-MIBG SPECT/CT demonstrated that 18F-FDOPA has nonin-
ferior sensitivity as well as similar specificity to 123I-MIBG SPECT/CT in the diagnosis
of PPGLs, but it is more sensitive in the assessment of recurrence and metastases, further
supporting its use in high risk PPGL in general and in those harboring the above mentioned
mutations [41].
Finally, 18F-FDG PET may be useful in metastatic disease in general and as functional
imaging of second choice in patients harbouring SDHx mutations (cluster 1A) and in cluster
1B tumours [21,31,32,39,42].
Besides staging, when facing metastatic disease, functional imaging play an important
role in the management of patients for whom radiometabolic treatment is being considered:
I123-MIBG SPECT/TC, if feasible, and 68Ga-DOTA-SSA PET/CT are used to assess the
affinity of the tumor for the available radiotracers in order to select the most proper
radiopharmaceutical for each patient [21,31].

5. Therapeutic Options
A multidisciplinary approach by an expert medical team is needed in order to de-
fine the most proper, personalized treatment plan based on both patient characteristics
(age, health status) and tumour features (location, size, extent, biochemical profile, func-
tional imaging and eventually genetic background), weighing the pros and cons of each
option [14,21].
Surgery represents the mainstay of therapy for the majority of localized PPGLs, when-
ever possible.
In advanced and metastatic disease, treatment options include symptomatic therapy
(alpha-blockers, beta-blockers, catecholamine synthesis inhibitors) for functional PPGLs in
order to prevent life-threatening events, systemic medical treatments such as chemotherapy,
targeted therapies, SS analogs (SSAs), radiometabolic therapy as well as loco-regional pro-
cedures (cytoreductive surgery, external beam radiotherapy, arterial embolization, cryother-
apy, RF ablation) [10,11,21,25,30].

5.1. Surgery
Radical surgical resection is the cornerstone of the treatment for the majority of local-
ized PPGLs as it remains the only potentially curative therapeutic option [21,30].
A careful preoperative planning is needed and includes precise anatomical characteri-
zation of the primary tumor (unifocal/multifocal location; extent to adjacent structures) as
well as a proper perioperative medical preparation [21].
Preoperative knowledge of the genetic status, in addition to other clinical variables,
may affect the chosen surgical approach.
As to PCCs, resection may be open or laparoscopic, since recurrence rates do not differ
among these two approaches [21]. Minimally invasive total adrenalectomy represents the
preferred surgical standard over adrenal sparing surgery in cluster 1 tumors since these
neoplasms harbor a high risk of recurrence and metastatic spread, especially if SDHB
mutated [11,21,25,43] and in cluster 3 tumors [25].
On the contrary, in cluster 2 PCCs, cortical sparing surgery can be considered as the
favored approach as it does not relate with decreased survival despite onset of recurrent
disease in 13% of patients with germline RET and VHL mutations [12,25,44].
As to localized PGLs, surgical resection also remains the main treatment, when feasible.
The risks related to surgery vary according to the site and it is influenced by the close
proximity or involvement of large vessels (internal carotid artery, aorta, mesenteric or renal
Pharmaceuticals 2024, 17, 354 8 of 22

arteries) and other anatomical structures (cranial nerves in case of HNPGLs) as well as by
the typical rich blood supply [21,25].
Among all the PGLs, surgical treatment of HNPGLs is particularly challenging. Up-
front surgery should be considered as first option in young patients, who often harbor
SDHx mutations, especially in the SDHB gene, being at higher risk of metastatic spread with
tumor growth [11,45]. Additional instances where surgery should be considered include
rapidly progressive symptoms, or in rare cases of refractory secreting tumors or suspected
malignancy [11]. However, in most cases of HNPGLs, watch and wait strategies or/and
non -surgical treatment options may be preferred, especially in elderly or frail patients, in
case of minimal or no symptoms and in those with multicentric lesions [11,21,46–48].
In advanced and metastatic setting, surgical resection of the primary tumor or metas-
tases might be considered cautiously on a case-by-case basis [11,30,49,50], as it may improve
symptoms related to CMN secretion or tumor mass effects.
However, the impact of surgical removal of the primary tumor in metastatic disease
on Overall survival (OS) still remains controversial, although recent studies suggested that
it may improve OS [49,50]. Of note, Gonzalez et al. demonstrated that, besides a better
symptoms control after surgical resection of the primary tumors, metastatic PPGLs patients
treated with surgery had longer median OS than those not treated surgically regardless of
their characteristics as well as tumor features [50].
In patients with functional PPGLs, both localized and metastatic, who undergo surgery,
an adequate perioperative medical management is mandatory in order to prevent poten-
tially life-threatening events: anesthesia, tumor manipulation, previous embolization or
biopsy during surgery, may determine excess of CMNs secretion, leading to hyperadrener-
gic symptoms and hypertensive crises [2,14,21].

5.2. Systemic Therapy

The management of metastatic PPGLs is challenging as there are only practiced stan-
dards of systemic therapy, that have been extensively adopted outside of controlled clinical
trials [10,11,21,51–54]. To date, the only FDA-approved treatment option in metastatic
disease is HSA 131 MIBG in the US.
The choice of the first line treatment and of subsequent therapy approaches depends
on the patients’ characteristics, clinical symptoms, tumor type, radioisotope tumor avid-
ity, disease burden (limited/extensive) as well as its aggressivity (limited stable disease,
extensive disease with slow/rapid progression) and available resources [11,14,21,25,54].
The same state of the art recommendations currently apply to all clusters.
Although a growing number of data suggest that these different molecular subtypes
may show a unique and personalized profile of sensitivity to specific drugs, a cluster
specific approach has not yet entered clinical routine practice [11,12].
Most of data that correlate therapy efficacy with mutational status focus on cluster
1 tumors, particularly the most aggressive SDH-mutated ones [11]. Less is known about
cluster 2 tumors as systemic treatment is infrequently necessary since only around 2–4% of
metastatic PPGLs belong to this cluster.

5.2.1. Chemotherapy
Chemotherapy should be considered as the first line treatment in patients who have
no significant uptake of radiotracers or with clear rapid disease progression, associated
with high tumor burden, or with severe uncontrolled symptoms due to CMNs secretion or
mass effect, in order to obtain disease control and/or symptom palliation [10,11,30,54,55].
The standard of care, despite the lack of prospective evidence, is still represented by
the combination of cyclophosphamide, vincristine, and dacarbazine (CVD), first proposed
by Keiser et al. in 1985 [56]. To date, this is one of the most established and longest studied
approaches in aggressive and rapidly progressive PPGLs [57–60] and it demonstrated to be
particularly effective in cluster 1 SDHB-mutated patients [58–60].
Pharmaceuticals 2024, 17, 354 9 of 22

In the largest single-institution experience with chemotherapy (not only CVD regi-
men) involving 54 patients, 33% of patients experienced a response defined as improved
blood pressure control and/or reduced tumor size with statistically significant longer OS
compared to non-responders (6.4 years vs. 3.7 years, respectively). All responders had been
treated with dacarbazine and cyclophosphamide, plus at least another additional drug:
vincristine was included for 14 responders while doxorubicin for 12 responders [57].
Of note, none of the 4 patients (out of 9 tested) who harbored a mutation in the SDHB
gene, responded to chemotherapy. However, one patient SDHC-mutated was in the group
of responders [57].
In a systematic review of four different retrospective studies involving 50 patients
with metastatic PPGLs treated with CVD, Niemeijer et al. reported an overall response
rate (ORR) of 41% with a disease stability achieved in 14% of cases and a biochemical
response rate of 54% [58]. Interestingly, in the study of Huang which was included in this
metanalysis, 9 out of 18 evaluated patients harbored a presumed mutation in SDHB/D
genes and one had a confirmed SDHD mutation [59].
In 2018, Jawed et al. demonstrated that a prolonged CVD regimen (median of 20.5 cy-
cles) was particularly effective in 12 metastatic PPGL patients harboring SDHB muta-
tions/polymorphisms, further supporting its use in this population [60].
Temozolomide (TMZ), an orally administered alternative to intra-venous dacarbazine,
showed similar efficacy in patients harboring SDHB mutations, as a first line or second line
option. This evidence may rely on the hypermethylation of the O(6)-methylguanine-DNA
methyltransferase (MGMT) promoter and consequent low MGMT protein expression which
occur in SDHB-related tumors, thus rendering them particularly sensitive to this alkylating
agent [10,11,21].
Five partial responses (33%) as well as longer PFS (19.7 vs. 2.9 months) were described
in SDHB mutations carriers treated with temozolomide (150–200 mg/m2 /day d1-5 q28) in
a retrospective study of 15 patients (10 carried a germline mutation in SDHB gene) who
received TMZ as first line cytotoxic chemotherapy [61].
These results outline that TMZ may represent a reasonable first line alternative to CVD
in less aggressive cases or in frail patients, particularly in SDHB mutated patients.
Successful outcomes were also reported in SDHB-mutated patients treated with TMZ
metronomic schedules and high-dose lanreotide as second line option, [62]. This supports
its efficacy at reduced dose, particularly in SDHB mutated patient, when the standard dose
is poorly tolerated.
A phase II trial (NCT04394858) investigating the synergistic effect of adding olaparib
to TMZ is currently undergoing, based on the preclinical evidence of a higher activity of the
PARP DNA repair system in SDHB mutated PPGLs as well as a major therapeutic effect of
TMZ in mice with SDHB knockdown PPGL allograft treated in combination with Olaparib.

5.2.2. Targeted Therapy

Tyrosine Kinase Inhibitors [TKIs]
Being altered angiogenesis a key event in the pathogenesis of several PPGLs partic-
ularly in cluster 1 and some cluster 2 (RET-driven) tumors, a growing number of studies
have explored the use of TKIs in this disease during the last years [11,63].
Sunitinib was the first inhibitor proposed for the treatment of metastatic PPGLs and
also the best studied in this disease [10–12,21,30,63].
The phase II SNIPP trial evaluated sunitinib (50 mg daily for 4 weeks followed by
2 weeks off treatment corresponding to one cycle) in 25 progressive PPGL patients showing
a disease control rate (DCR) of 83%, and a mPFS of 13.4 months. Although the ORR was
low in the overall unselected populations, the 3 PR occurred were observed in patients
harboring germline mutations in SDHA, SDHB and RET respectively, thus suggesting
that sunitinib could be a viable therapeutic option in selected patients with cluster 1 or
2 tumors [64].
Pharmaceuticals 2024, 17, 354 10 of 22

The FIRSTMAPP trail (NCT01371201), the first randomized placebo-controlled trial

ever conducted in PPGLs, has given sunitinib a more robust indication in progressive
metastatic PPGLs, as a possible second line option. The primary endpoint was met with
a PFS at 12 months of 35.9% vs. 18.9% in the sunitinib arm compared to placebo [65].
However, it still remains to be seen from the final detailed data if patients bearing SDHB
mutations are really the best candidates for sunitinib [66].
Pazopanib, another TKI, showed moderate efficacy in a small PPGL cohort (n = 7, with
6 evaluable patients) with median PFS of 6.5 months and OS of 14.8 months. However,
only one patient experienced a confirmed PR and common severe toxicities were observed
such as hypertension (3/6) and Takotsubo cardiomyopathy (2/6) [67].
Axitinib is now being evaluated in a phase II trial in metastatic or locally advanced
PPGLs (NCT03839498). Preliminary data of another phase II study (NCT01967576) investi-
gating this drug in a similar setting showed its moderate efficacy: [11,68].
Recently, results of a retrospective study evaluating lenvatinib in 11 patients with
metastatic or advanced unresectable PPGLs have been published: a mPFS of 14.7 months
and an OS at 12 months of 80.8% (median not reached) were registered. Among the 8 pa-
tients with measurable disease (out of the 11 patients included), ORR was 63% (5/8 patients
had a PR). Despite the potential risk of worsening hypertension, lenvatinib may be a viable
treatment option for mPPGLs, Larger multicenter studies are needed to better define its
potential utility in this setting [69].
As an alternative to sunitinib, targeting c-Met through cabozantinib may be of par-
ticular relevance in metastatic PPGLs, since activating mutations of the MET gene have
recently been described. The TKI cabozantinib is currently under investigation for PPGL
patients in a small prospective clinical phase 2 study (NCT02302833) with promising pre-
liminary results (PR: 37%, SD: 55%, DCR: 92%, PFS: 16 months). Noteworthy, responders
included SDHB-mutant patients [66,70,71]. This is in accordance with the results of preclin-
ical studies on human PPGL primary cultures that showed significantly stronger efficacy
of cabozantinib in cluster 1 tumors, particularly SDHB-mutated, compared with cluster
2 tumors [66,72].
Besides the extrapolation from other tumors management, the combined use of TKI
plus immune checkpoint inhibitors might have a plausible rationale even in the treatment
of metastatic PPGLs. Based on the high expression of PDL-1/2 reported in resected PPGLs,
particularly in those belonging to cluster 1, TKIs may promote a vascular stabilization of
the micro-environment that facilitates immune-response [73].
A phase II, prospective clinical trial (NCT04400474) is now assessing the role of
Cabozantinib plus atezolizumab (CABATEN) in advanced and progressive tumors from
endocrine system, including PPGLs and may provide important clinical data. Results
are awaited.
Last but not least, two phase 2 trials studying the TKI anlotinib in advanced PPGLs
are now recruiting (NCT04860700, NCT05133349).
Given the side effects of TKI treatment (e.g., nausea, vomiting, diarrhea, skin rash,
hypertension, QTc prolongation), close monitoring of patients and adequate supportive
therapy are essential.

mTORC1 Inhibitor Everolimus

Hyperactivation of kinase activity (RAS/RAF/ERK or PI3K/AKT/mTOR pathways)
is a common finding in patients with cluster 2 PPGLs, thus offering the rationale for the
use of mTORC inhibitors.
Growing evidence from translational studies in human PCC models, including pri-
mary tumor cultures, suggested that everolimus alone but particularly in combination is
potentially effective in cluster 2-related tumors while it may be less effective in cluster
1-related disease [11,74].
Despite the robust translational evidence, only few and contradictory data derive
from both a small prospective phase 2 clinical trial (DCR of 71%; genetic background not
Pharmaceuticals 2024, 17, 354 11 of 22

assessed) and a small retrospective study (DCR of 25%; no known SDHx mutation included)
which evaluated everolimus alone in metastatic PPGLs patients [11,75–77].
The disappointing results of everolimus alone in vivo may be explained by the physi-
ological activation of compensatory short-term mechanisms of resistance in response to
mTORC1/p70S6K inhibition [74].
As already demonstrated in vitro, in vivo combination strategies may be useful to
overcome resistance. Although sunitinib/everolimus combination treatment seemed
to be less promising than other combining strategies in vitro, Ayala-Ramirez et al. re-
ported the case of a 20-year-old woman with a SDHB-mutated tumor who experienced
a long-term disease control under the mTORC1 inhibitor sirolimus in combination with
sunitinib [11,73,78].
Altogether these data point out that it may be worth studying combined targeted
therapies based on mTORC inhibitors even in cluster 1-related tumors, although they are
more likely to be effective in cluster 2-related tumors. A clinical trial is needed to evaluate
this therapeutic combination.

5.2.3. Immunotherapy
Although PPGLs are associated with the highest rate of single germline mutations
of any oncological disease, they present some of the lowest rates of somatic mutations
among tumors.
Furthermore cluster-1 mutations, related to tumor “pseudohypoxia” under normoxic
conditions, have always been claimed to prevent immune system recognition by interfering
with T cell effector function, impairing tumor infiltration, activating immune-suppressive
monocytes and increasing the expression of PDL1 and its receptor, thus resulting in immune
suppression and tolerance [10,79,80]. Of note, a substantial number of apparently sporadic
PPGLs may show a similar molecular profile as those that carry germline mutations of
SDHx gene [81].
Altogether these data may explain why PPGLs have generally been expected to be
associated with low immunogenicity and no or minimal inflammation or infiltration of T
cells [81].
However, the results of a recent small prospective phase 2 clinical trial (NCT02721732)
evaluating pembroluzimab in rare solid tumors including metastatic PPGLs suggested
that immunotherapy may be a viable strategy in selected PPGLs patients with no other
remaining therapeutic options [81,82].
Of note, in the PPGL cohort (11 patients) 4 patients achieved the primary endpoint,
defined as the non-progression rate at 27 weeks after the treatment had started. Interestingly,
two SDHx-mutated patients were included: one harboring a mutation in SDHD gene
showed a prolonged stable disease while the other one who carried a SDHB alteration,
despite a rapid substantial reduction in tumor size, did not meet the primary study endpoint
since the response was not maintained due to a long recovery for severe liver toxicity [81].
Despite being interesting as well as promising, these data are too scant to assume a unique
benefit for cluster 1 SDHB/D mutation carriers, as previously postulated [11,81].
It is well worth pointing out that the positive responses observed seemed to be
independent of genetic backgrounds, PDL-1 expression or the presence of infiltrating
mononuclear inflammatory cells in the primary tumor [81,82]. This highlights the urgent
need to better define hypothetical correlations between genetic cluster affiliation and
therapeutic response even in immunotherapy [11].
A phase II trial (NCT02834013), evaluating the combination of nivolumab plus ipili-
mumab (arm I) vs. nivolumab alone (arm II) in patients with rare tumors, including PPGLs,
is currently undergoing [10]. Results are awaited.
Further investigation is needed into other factors that may contribute to the success or
failure of immunotherapy, such as exposure to non-self-antigens microbially derived that
mimic human cell antigens in PPGLs or combinations with other systemic therapies, such
as TKIs, as already mentioned above.
Pharmaceuticals 2024, 17, 354 12 of 22

In this regard, a phase 1/2, first-in-human study (NCT04187404) to assess the safety,
tolerability, immunogenicity, and preliminary efficacy of EO2401, an innovative cancer
peptide therapeutic vaccine in combination with nivolumab, for treatment of HLA-A2
positive patients with locally advanced or metastatic adrenocortical carcinoma or metastatic
PPGLs has recently started recruiting and is undergoing.

5.2.4. Cold Somatostatin Analogs (Biotherapy)

“Cold” somatostatin analogs (SSAs), octreotide LAR and lanreotide autogel, have been
established as a cornerstone of the anti-proliferative therapy for midgut and pancreatic
NETs. Interestingly, several PPGLs overexpress SSTRs, mainly SSTR2, particularly cluster 1
SDHx-related PGLs, which also show best responses to PRRT [10,83,84].
It could be hypothesized that SSAs may decrease HIF-α expression in PPGL cells,
as already shown in NET cells. This may explain why they can be particularly effective
in PPGLs with disruption of the Krebs cycle such as SDHx-related PPGLs in which a
constitutive activation of the HIF pathway is described [11,85].
Although few case reports on clinical stabilization of metastatic PPGLs under SSAs
have been published, there is still a lack of prospective or retrospective studies to either
strengthen or refute these claims [84,86–91].
Similarly to PRRT, functional imaging with 68Ga-SSAs may help to select the patients
who may benefit from cold analogs, which may represent a viable alternative in metastatic
PPGLs, particularly those of the head and neck region and SDHx mutated, when PRRT is
not feasible due to its limited availability and high costs.
A recent a retrospective study by Fischer et al. reported an overall DCR of 100%
with first-line “cold” SSAs (6 patients, 3 SDHx-mutated), while of 67% with first-line PRRT
(22 patients, 11 SDHx mutated) which increased to 73% in the SDHx subgroup. Interestingly,
the authors showed that SSTR2 positivity was not only significantly associated with SDHB-
and SDHx-related PPGLs, but with metastatic disease regardless of SDHB/SDHx mutation
status [85].
As SSAs are well tolerated, they may represent a viable therapy option for slowly
progressing metastatic PPGLs, if larger studies confirm their efficacy.
A phase II prospective study (NCT03946527), the LAMPARA trial, is currently ongoing
to assess the role of lanreotide in patients with advanced disease.
However, on an individual case-by-case decision, especially when PRRT is not feasible,
they may already be considered in clinical practice as an effective therapeutic strategy with
the aim of disease stabilization.

5.3. RadioLigand Therapy [RLT]

According to the most recent guidelines, RLT can represent a valid first line therapeutic
option in patients with slowly to moderately progressive disease and documented tumor
uptake of the corresponding radioisotope [21,30].
The rationale for this approach relies on the evidence that around 80% of metastatic
PPGLs express on their cell surface higher density of SSTRs, particularly SSTR2, or nore-
pinephrine transporter than normal cells [85,92,93].
Overexpression of SSTR2 and norepinephrine transporter exerts a critical role in the
uptake of radiolabeled SSAs (177Lu or 90Y-SSAs) and of 131I-MIBG respectively, making
them a theragnostic target for the treatment of metastatic PPGLs [85,93].
Functional imaging studies with 123I-MIBG and/or radiolabeled SSAs should be
performed in order to assess the affinity of the tumor cells for the radiotracer and to choose
the most proper radiopharmaceutical for each case [94,95].
Patients with 123I-MIBG-avid metastatic PPGLs (less likely positive in cluster 1 SDHx-
mutated tumors) may benefit from conventional 131 I-MIBG or High-Specific-Activity (HSA)
131 I-MIBG therapy, while patients with high uptake of radiolabeled SSAs (particularly
cluster 1 SDHx-mutated PPGLs) may benefit from PRRT with 177Lu or 90Y-DOTA-SSAs.
Pharmaceuticals 2024, 17, 354 13 of 22

On the basis of two trials, HSA I-131 meta-iodobenzylguanidine (HSA I-131 MIBG,
AZEDRA® ) was FDA- approved in July 2018 for the treatment of patients aged 12 years
and older with I-MIBG–avid unresectable, advanced localized or metastatic PPGLs who
require systemic therapy [21,30,96–99].
This is the first and is currently the only FDA–approved drug to treat unresectable,
locally advanced, or metastatic PPGLs: prior treatment paradigms in this setting included
the research and compassionate use of conventional low-specific-activity I-131 MIBG.
In the phase 2 trial (NCT00874614) the primary endpoint (reduction in baseline antihy-
pertensive medication by at least 50%, lasting for at least 6 months) was met by 25% of all
patients who received at least one therapeutic dose and 32% of patients who received 2 ther-
apeutic doses. Among 64 patients with evaluable disease after at least one therapeutic dose,
59 (92%) had a PR (23%), or stable disease (69%), as the best objective response [97–99].
HSA I-131MIBG showed higher efficacy and safety compared to I-131MIBG at low-
specific-activity since it consists almost entirely of 131 I-labeled MIBG and contains a signif-
icantly smaller amount of un-labeled drug thus reducing the frequency of life-threatening
side effects during or shortly after drug administration related to abnormal increase of
circulating catecholamines [100–104].
According to the most recent ESMO guidelines, although EMA has not approved
HSA-131I MIBG yet, 131I-MIBG could be considered as first line approach in patients with
unresectable or metastatic PPGLs with slow to moderate progression and/or high tumor
burden at baseline displaying avid uptake of 123I MIBG in all tumoral lesions (evidence III,
A) [30].
An alternative viable approach in the same setting, especially for cluster 1 SDHx-
related PPGLs, is PRRT which use SSAs labeled with isotopes delivering a cytotoxic
radionuclide [30].
PRRT was firstly approved by FDA for the treatment of GEP-NETs that are somato-
statin receptor-positive [105].
Even though evidence for its use in metastatic PPGLs with high uptake of 68Ga-
labeled SSA is limited (V,B according to 2021 ESMO guidelines), several small retrospective
and few prospective studies suggest a high efficacy in metastatic PPGLs, especially in
SDHB-mutated tumors [21,30,106–111].
Furthermore, although all radiopharmaceuticals share some common side effects,
such as fatigue, toxicity to the kidneys and liver, nausea, vomiting, and low blood counts,
PRRT carries a definitely lower risk of toxicity, particularly haematological, than both HAS
131I-MIBG and conventional 131I-MIBG therapy [106].
In 2011, a prospective study by Imhof et al. evaluating the efficacy and safety of
90Y-DOTA-TOC in metastasized neuroendocrine cancers showed a particularly long OS in
metastatic paraganglioma patients (n = 28), thus suggesting a high therapeutic potential of
PRRT in this orphan disease [107].
In 2017, Kong et al. [106] evaluated the effectiveness of PRRT in controlling hyperten-
sion in 20 consecutive retrospectively reviewed patients with advanced or metastatic PPGLs
and high SSTR expression, who received 177Lu-DOTATATE PRRT with at least 3 months of
follow-up from completion of treatment. Indication for PRRT was uncontrolled secondary
hypertension in 14 patients and non-functional progressive metastatic disease or recurrence
in 6 patients. Among the 14 patients who were given 177Lu-DOTA-octreotate treatment for
uncontrolled symptoms, 8 required a lower dosage of antihypertensive medication after
treatment, 5 did not need any changes in their medication dosage, and 1 patient was lost
to follow-up. Of the14 patients evaluable for CT response, 5 (36%) had disease regression
(29% partial and 7% minor response) while 7 (50%) had stable findings. The study found
that the mPFS was 39 months, while the mOS was not reached with a median follow-up
time of 28 months. Intestingly, of the 20 patients treated with 177Lu-DOTATATE, 7 had
SDHB mutation while 1 was SDHD mutated.
In another retrospective study, Nastos K. et al. [108] compared PRRT with 90Y-
dotatate or 177Lu-dotatate and (131) I-MIBG treatment in 22 patients with progressive or
Pharmaceuticals 2024, 17, 354 14 of 22

metastatic PPGLs, retrieved from their department’s database for the period from 1998
to 2013. Although patients who received PRRT experienced both statistically significant
increased PFS and response to treatment when compared to those who received 131I-MIBG
(p < 0.05), there was no significant difference in OS (p = 0.09). However, when comparing
only patients diagnosed with PGLs, PFS, response to treatment and OS were all significantly
higher in the PRRT treatment group.
In a recent meta-analysis published by our group in 2023, we assessed the efficacy of
PRRT treatment based on 177Lu-DOTATATE and 90Y-DOTATOC in 213 patients affected
by PPGLs. The primary endpoint was the correct quantification of DCR: a pooled DCR
of 83% and 76% for 177Lu-DOTATATE and 90Y-DOTATOC treatments respectively was
found, with a good toxicity profile [109].
Altogether these findings provide encouraging results for the effectiveness of PRRT in
treating metastatic PPGLs, particularly for SDHx-related PGLs.
Currently, several clinical trials are underway in order to provide more robust evidence.
NCT03206060 is a recruiting open-label, single-arm, multi-center phase 2 trial evalu-
ating efficacy and safety of Lu-177-DOTATATE in both SDHx-mutated and “apparently
sporadic” progressive, SSTRs positive PPGLs.
NCT04711135 is an ongoing study assessing the safety and dosimetry of Lutathera in
adolescent patients (12 to <18 years old) with SSTRs positive GEP-NETs and PPGLs.
Finally, a phase I/II study (NCT 02592707) evaluating safety, tolerability, biodistri-
bution, dosimetry and preliminary efficacy of satoreotide tetraxetan (177Lu-IPN01072) in
unresectable SSTRs positive GEPNETs, lung carcinoids, and PPGLs is currently underway.
This study could provide an additional research perspective to identify therapeutic options
for PPGLs.

5.3.1. Future Perspectives Cluster-Oriented

Although cluster-specific therapy of metastatic PPGLs has not yet entered clinical
routine practice, the distinctive molecular pathology suggests that some therapeutic op-
tions may be more effective than others in a particular cluster, as already shown in some
retrospective clinical studies [11].
Potentially interesting novel targeted therapy approaches for PPGLs must be even
more cluster-oriented, especially for cluster-1 and cluster-3 related tumors which are more
frequently metastatic.
Especially for cluster 1-related tumors, new perspectives under evaluation include
HIF-2α inhibitors, histone deacetylase (HDAC) inhibitors, DNA demethylating agents, D2
receptor antagonists and, as already mentioned above, PARP inhibitors (particularly in
combination with TMZ) [10,11] (Table 1).
Belzutifan, a second-generation HIF-2α inhibitor, which has already demonstrated its
efficacy among patients with VHL-associated renal cancer is currently being evaluated in
an open-label, single-group phase II trial (NCT04924075, MK-6482-015) in patients with
advanced or metastatic PPGLs with adequately controlled blood pressure (ORR as primary
endpoint) [112].
Another HIF2α inhibitor, DFF332, as single agent and in combination with everolimus
or spartalizumab, plus the adenosine A2A receptor antagonist taminadenant is currently
under investigation in a phase 1 trial in tumor patients with HIF-stabilizing mutations,
including PPGLs (NCT04895748).
Recently, the promising results of a phase II trial (NCT03034200) evaluating an oral
selective antagonist of the dopamine D2 receptor (ONC201) in neuroendocrine tumors and
desmoplastic small round cell tumors (DSRCT) have been published, showing the greatest
benefit especially in metastatic PPGLs. Of 10 patients with metastatic PPGLs enrolled, 50%
(5/10; 3 SDHB-mutated) exhibited a PR and 2 patients (1 SDHB-mutated) had SD for more
than 3 months, with good tolerability [113].
Pharmaceuticals 2024, 17, 354 15 of 22

Table 1. Main characteristics of PPGLs according to molecular clusters [10–14].

Genes Mutations Biochemical Most Sensitive Metastatic Risk

Phenotype Functional
Imaging Modality
Krebs cycle-related predominantly Predominantly 68 Ga DOTA SSA High-intermediate
Cluster 1
genes: SDHx, germline noradrenergic PET/CT
SDHAF2 FH, and/or
MDH2, IDH, dopaminergic
SLC25A11
Pseudohypoxia either germline noradrenergic [18F] F DOPA Intermediate
VHL/EPAS 1 and somatic PET/CT
related-genes:
VHL, EPAS1/2,
PHD1/2, IRP1
Cluster 2 Kinase signaling: both germline and typical adrenergic [18F] FDOPA Low
RET, NF1, MAX, somatic (epinephrine/metan PET/CT
HRAS, TMEM127 ephrine-E/MN->
both E/MN and
NE/NMN)
Cluster 3 Wnt signaling: somatic unknown unknown High-intermediate
MAML3, CSDE1

Despite the typical high expression of D2 receptors in PPGLs [114], discerning whether
DRD2 antagonism, ClpP agonism or both contributed to responses in metastatic PPGLs is
not easy in the absence of correlative studies on tissues [113,115].
Furthermore, given the SDHB mutational status of 4 responders and the ability of
another imipridone compound with similar profile to downregulate SDH-A/B in other
cancer preclinical models, it could be interesting to evaluate a possible enhanced efficacy
of ONC201in SDH deficient tumors. This may shed light on new potential biomarkers,
such as DRD2 expression, ClpP status, SDH x mutations, or some combination of them, to
explore in metastatic PPGLs [115].
As to cluster 3-related PPGLs, targeting Wnt signaling seems to be a reasonable option.
Of note, both the PORCN inhibitor WNT974, which inhibits Wnt signaling, and the ß-
catenin inhibitor PRI-724 showed good efficacy in several NET cell lines, thus shedding
light on a new potential therapeutic target in metastatic PPGLs [11,116].
Although cluster 2-related PPGLs show a very low metastatic risk, it is well worth
mentioning that a phase 2 pediatric trial (MATCH, NCT04284774) evaluating tipifarnib, a
farnesyl-transferase inhibitor that disrupts HRAS function, in patients with HRAS-mutant
tumors, including pheochromocytomas, is currently recruiting and may provide important
data for PPGL management (Table 2).

5.3.2. Locoregional Procedures

The greatest experience with conventional external beam radiotherapy (cERBT) or
stereotaxic radiosurgery derive from the treatment of HNPGLs, where these approaches
have been used as alternatives to surgery for locations with high surgical risk (carotid or
intracranial involvement) or when patients are not candidates for surgery (elderly and/or
frail patient, minimal or no symptoms, bilateral and/or multifocal tumors) [11,21,48,117].
In oligo-metastatic PPGLs, locoregional approaches including radiotherapy, stereo-
taxic surgery, radiofrequency ablation or cryoablation, percutaneous ethanol injection, may
represent reasonable options for local control and managing mass effect symptoms or
hormone-related symptoms [11,21,37,118–120]. However, indications must be individual-
ized and discussed within multidisciplinary team as no prospective data are available.
Pharmaceuticals 2024, 17, 354 16 of 22

Table 2. Summarizes the possible novel therapeutic approaches under evaluation in ongoing trials.

Trial Phase Therapy Disease Status

Advanced PPGLs+ pancreatic
Neuroendocrine Tumor (pNET), both
NCT04924075 II Belzutifan Recruiting
unselected for germline VHL mutations
and selected (+other tumors)
DFF332 alone and in
Advanced and/or recurrent Clear cell
combination with
renal cell carcinomas and other
NCT04895748 I/Ib everolimus or Recruiting
malignancies with HIF stabilizing
spartalizumab, plus
mutations, including PPGLs
taminadenant
Olaparib+ temozolomide
NCT04394858 II Advanced and/or metastatic PPGLs Recruiting
vs. temozolomide alone
NCT04284774 Metastatic HRAS-mutant tumors,
II Tipifarnib Recruiting
(pediatric) including PCCs

6. Follow-Up Recommendations
Ten-year follow-up is recommended for all patients with resected PPGLs, as they
are all considered at risk of tumor recurrence. However, it must be intensified and ex-
tended to the whole life in patients with hereditary forms or considered to be at high
risk of metastatic disease [21]. Currently, no specific follow-up protocols are established:
monitoring strategies must include regular biochemical testing as well as imaging studies.
Whenever possible, such follow-up should be performed by multidisciplinary team at a
tertiary center [21].

7. Conclusions
PPGLs are rare, complex and still little-known clinical entities in the scientific re-
search landscape.
Early detection, genetic testing, and a multidisciplinary approach are of utmost im-
portance for a proper management. Surgery, if feasible, must be the first-line treatment for
localized PPGLs as it represents the only curative option.
In advanced and/or metastatic settings, several therapeutic options are available: the
choice among them must be tailored to the unique characteristics of the patient and the
tumour considering the benefits and risks of each option. However, only few of them hinge
upon prospective data.
Several clinical trials prospectively assessing the role of strategies which have already
been adopted in research and compassionate programmes, evaluating new combinations,
and testing novel targeted therapy approaches, even more cluster-oriented, are currently
underway. Results are awaited.
Based on the growing preclinical evidence, it is undoubtable that genetic testing for
germline mutations as well as genome profiling for somatic mutations, where available,
must be improved and become standard practice in order to render management even
more cluster-specific as well as personalized and improve the prognosis of this rare and
molecularly complex disease.

Author Contributions: Conceptualization, A.B. and A.L.M.; methodology L.P.G.; software, A.P.
and A.M.; validation, V.G. and R.S.; formal analysis, D.R. and O.C.; investigation, F.P., L.C. and
A.P.; resources, R.T. and D.R.; data curation, A.L.M.; writing—original draft preparation, L.P.G. and
G.D.V.S.; writing—review and editing, A.B. and A.L.M. and G.D.V.S.; visualization, E.C., F.D.G. and
M.R.S.; supervision, S.T. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Pharmaceuticals 2024, 17, 354 17 of 22

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.
Acknowledgments: We thank Minitery of Health, the non-profit organization Lega Italiana Per La
Lotta Contro i Tumori (LILT) of Naples and Alessandra Trocino, Librarian at the Library of Istituto
Nazionale Tumori Fondazione ‘G Pascale’, Naples, Italy, for her excellent bibliographic service
and assistance.
Conflicts of Interest: The authors declare no conflict of interest.

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