Open access peer-reviewed chapter
Clinical features of the most frequent hereditary PPGL syndromes.
Abstract
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells. Almost 40% of all PPGLs cases are caused by germline mutations and 30–60% have somatic mutations. The incidence of hereditary syndromes in apparently sporadic cases is as high as 35%. Currently, more than 20 susceptibility genes have been identified, including at least 12 distinct genetic syndromes, with particular clinical features and prognosis. In this chapter, we summarize recent advances in the management of PPGLs from clinical diagnosis to targeted molecular treatment, based on the genetic profile. Classically, patients with PPGLs were diagnosed by sign and symptoms, e.g., hypertension (with or without paroxysms) and headache. Nowadays, about half of PPGLs are diagnosed as incidentalomas or during the surveillance screening in patients with known mutations for PPGL susceptibility genes, familial syndromes, or with a previous PPGL; a high percent of these patients have normal blood pressure. Plasma or urinary fractionated metanephrines remain the major biochemical tests for confirmation. Functional imaging, with a radiopharmaceutical chosen according to the tumor genotype and biology, improves tumor detection (notably for metastases and multifocal tumors) and links to targeted radionuclide therapy. Detecting the germline and somatic mutations associated with PPGLs is a promising approach to understand the clinical behavior and prognosis and to optimize the management of these tumors.
Keywords
- pheochromocytoma
- paraganglioma
- diagnosis
- treatment
- RET mutation
- succinate dehydrogenase mutation
- genetic diagnosis
- functional imaging
1. Introduction
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from chromaffin tissues localized outside the adrenal gland, in the paraganglia of sympathetic origin in the thorax, abdomen, and pelvis or of parasympathetic origin in the head and neck region [1].
The incidence of PHEOs and PGLs (PPGLs) is estimated at approximately 2–8 cases/million/year. This percentage may be underestimated based upon the finding that 0.05–0.1% of cases are incidentally detected in autopsy series [2]. Approximately 5–7% of the adrenal incidentalomas are PHEOs [3, 4]. About 80–85% of chromaffin-cell tumors are pheochromocytomas, whereas 15–20% are paragangliomas [4]. PPGLs may occur at any age, and they usually peak between the third and fifth decade of life [4, 5].
PPGLs are usually a benign disease. However, approximately 10–15% of them develop metastases. According to the latest World Health Organization (WHO) classification, all PPGLs are considered to have metastatic potential, changing the previous term “malignant” [6].
PPGLs can appear as sporadic tumors or as part of hereditary syndromes. Almost 40% of all PPGLs cases are caused by germline mutations and 30–60% have somatic mutations [1, 7]. Syndromic presentations, metastatic disease, multiple tumors, bilateral PHEOs, and pediatric PPGLs are clinical features associated with a higher likelihood of a gene mutation [4, 8].
As the incidence of hereditary syndromes in apparently sporadic cases is as high as 35%, in 2017, an International Consensus recommend NGS (Next-Generation Sequencing) to all patients with PPGLs (rather than using one gene at a time) [9]. Nowadays, at least 20 susceptibility genes have been identified, comprising at least 12 distinct genetic syndromes, 15 driver genes, and several new germline and somatic pathogenic variants of genes with disease-modifying potential [1, 7, 10]. These genes are divided into three molecular clusters:
Pseudohypoxia cluster 1 (1A and 1B)
Kinase-signaling cluster 2
Wnt signaling cluster 3.
Between the three clusters, differences in biochemical phenotype, clinical behavior, and long-term prognosis are noted [11, 12].
Cluster 1A-Krebs cycle-related genes (almost 100% are germline mutations, 4–12% of sporadic PPGLs) include succinate dehydrogenase subunits (SDHx [SDHA, SDHB, SDHC, SDHD]) (germline), succinate dehydrogenase complex assembly factor-2 (SDHAF2) (germline), fumarate hydratase (FH) (germline), mitochondrial glutamic-oxaloacetic transaminase (GOT2) (germline), malate dehydrogenase 2 (MDH2) (germline), 2-oxoglutarate-malate carrier (SLC25A11) (germline), dihydrolipoamide S-succinyltransferase (DLST) (germline), and isocitrate dehydrogenase 1 (IDH1) (somatic) [1, 12, 13].
Cluster 1B VHL/EPAS1-related genes (about 25% are germline mutations) comprise von Hippel-Lindau (VHL) tumor suppressor (germline/somatic), Egl-9 prolyl hydroxylase-1 and -2 (EGLN1/2 encoding PHD1/2) (germline), hypoxia-inducible factor 2α (HIF2A/EPAS1) (somatic), and iron regulatory protein 1 (IRP1) (1 case report) [1, 10, 11, 13].
Cluster 2 comprises mutations in genes encoding for a TK receptor (RET) (germline/somatic) genes encoding for the neurofibromin 1 (NF1) tumor suppressor (germline/somatic), Myc-associated factor X (MAX) (germline/somatic), HRAS (somatic), transmembrane protein 127 (TMEM127) (germline), and fibroblast growth factor receptor 1 (FGFR1) (somatic). Also, rare cases with mutations in genes encoding the receptor TKs MET (germline/somatic) and MERTK (germline), encoding B-Raf (somatic) are described [1, 12, 13].
Cluster 3 comprises the transcriptional coactivator 3 (MAML3) fusion gene (gain-of-function event) and somatic driver mutations (0% germline mutations) in the cold shock domain-containing E1 (CSDE1) [1].
Patients belonging to PPGL pseudohypoxia cluster 1 often present at a young age (<20 years of age,) and are predisposed to multiple tumors, recurrence, and metastatic behavior. At least 50–60% of all patients with metastatic PPGL display cluster 1 mutations. Metastatic risk of cluster 2-related PPGLs is low (2–3%), and RET, NF1, TMEM127, and MAX mutations are almost exclusively associated with PHEOs [1, 7, 14]. PPGLs with MAML3 fusion genes were all associated with metastatic disease and showed poor aggressive-disease-free survival [1, 8].
Routine screening in patients with PPGLs is recommended in patients known with mutations in PPGL susceptibility genes, in patients with syndromic features suggesting hereditary PPGLs, and in patients with previous PPGLs, [4].
The treatment options for patients with PPGL are increasingly based on the understanding molecular biology, genetic and epigenetic analyses of the tumors. During the last 20 years, the genetics approach, translational research, metabolomics, peptide receptor-based imaging and treatment, as well as immunotherapy greatly evolved. After the genetic era start, all the clinical, paraclinical features and treatment of PPGLs are reported to their genotype, in an attempt to allow a personalized diagnosis, management, and long-term follow-up of PPGLs.
In this chapter, we summarize recent advances in the management of PPGLs from clinical diagnosis to targeted molecular treatment.
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2. Advances in the diagnosis of PPGLs
2.1 Clinical diagnosis
2.1.1 Classical
PPGLs are tumors with a wide spectrum of manifestations, from typically symptomatic disease to asymptomatic disease. Symptoms are present in approximately 50% of patients with PPGLs and are typically paroxysmal. The classic triad of symptoms in patients with PPGLs consists of episodic headache, sweating, and tachycardia [1].
Approximately one-half have paroxysmal hypertension; most of the rest have either essential hypertension or normal blood pressure. Most patients with PHEO do not have the three classic symptoms, and patients with essential hypertension may have hypertension paroxysms. Sustained or paroxysmal hypertension is the most common sign of PPGLs, but approximately 5–15% of patients present with normal blood pressure. Headache is the second most described symptom. Other symptoms include forceful palpitations, tremor, pallor, dyspnea, generalized weakness, weight loss, orthostatic hypotension, polyuria, pallor, cardiomyopathy, panic attack-type symptoms (particularly in PHEOs that produce epinephrine) [1, 3].
PPGLs can produce life-threatening cardiovascular events including acute myocardial infarction, arrhythmias, Takotsubo cardiomyopathy, acute heart failure, or even sudden death [1, 3]. Diabetes or prediabetic states are also a complication of catecholamine-secreting PPGLs. Rarely, patients with a PPGL present with low blood pressure.
PPGLs can be sporadic or part of hereditary/familial syndromes, with specific clinical manifestations (Table 1).
| Multiple endocrine neoplasia | Medullary thyroid cancer, primary hyperparathyroidism |
| —type 2B | Medullary thyroid cancer, mucocutaneous neuromas, marfanoid status, ganglioneuromas of the gut/oral mucosa (Hirschsprung disease) |
| von Hippel–Lindau syndrome | Hemangioblastoma (cerebellum, spinal cord, or brainstem), retinal angioma, clear cell renal cell carcinoma, pancreatic neuroendocrine tumors or cysts |
| Neurofibromatosis type 1 | Neurofibromas, café-au-lait spots, axillary and inguinal freckling, iris hamartomas (Lisch nodules), osseous lesions, optic glioma, carcinomas (breast, lung, colorectal), sarcomas, GIST |
| Carney dyad, clear cell renal cell carcinoma, pituitary adenomas (mostly in SDHB, SDHD) |
Table 1.
Head and neck paragangliomas do not produce significant amounts of catecholamines; therefore, they are discovered during imaging studies or by signs of compression or infiltration of cranial or cervical structures, leading to cranial nerve palsies, hearing loss, pulsatile tinnitus, or dysphagia [15].
2.1.2 In the genetic diagnostic era
Due to the increased access to modern imaging techniques and genetic diagnosis, more PPGLs are nowadays diagnosed as incidentalomas or during surveillance screening, either due to genetic risk (germline mutations for one of the known PPGL susceptibility genes) or suspected hereditary syndromes with PPGLs or to a previous PPGL tumor; the clinical picture in these patients may be less suggestive, a higher percent of them having normal blood pressure or being asymptomatic [4, 16]. In a prospective multicentric series of 245 patients with PPGLs, 36% have been incidentally detected, 27% during surveillance, and only 37% due to clinical signs and symptoms [17].
Of note, the likelihood of a PPGL in the first two categories of patients is higher than in those suspected based on the clinical signs [3].
Although most of the symptoms are nonspecific, it has been reported that some signs and symptoms are more evident in screened patients with than without PPGL. Therefore, a score system including specific signs and symptoms has been developed to triage patients according to their likelihood of having PPGLs (−1 to +7 points) (applies to all clusters): [17].
1 point for the following specific sign: pallor, hyperhidrosis, tremor (max. 3 points)
1 point for the following specific symptom: palpitations, nausea (max. 2 points)
1 point for a body mass index (BMI) < 25 kg/m2 and
1 point for a heart rate of ≥85 beats per minute (bpm)
for obesity (BMI > 30 kg/m2) 1 point is subtracted.
A high clinical feature score (3 points or higher) indicates a 5.8-fold higher likelihood of having a PPGL.
Patients from cluster 2 PPGLs present with higher basic symptom scores and more often suffer from tremor, anxiety/panic, and pallor (related to catecholamine excess) compared with patients from cluster 1 [18].
Some reports suggest that patients with cluster 1-related PPGLs present more often with sustained hypertension caused by the continuous release of norepinephrine into the circulation, while patients with cluster 2-related PPGLs more commonly present with paroxysmal symptoms (so-called “spells”) caused by episodic excessive tumoral epinephrine secretion. These spells may be triggered by certain medications, food, beverages (containing tyramine such as red wine and beer), surgery, anesthesia, endoscopy, severe stress, or elevated intra-abdominal pressure (palpation, defecation, pregnancy) [1, 14, 18, 19].
Thus, in cluster 2-related PPGLs, the signs and symptoms are mainly of an episodic nature due to paroxysmal excessive secretory activity. In contrast, cluster 1 tumors, which show low catecholamine contents but higher rates of continuous secretion and less developed secretory control (sustained hypertension) [1, 14, 18].
In RET-related PPGLs, for example, the predominant stimulation of beta-adrenoceptors by epinephrine is presumably responsible for the presentation of episodic tachycardia/palpitations and paroxysmal hypertension rather than sustained hypertension [18].
Interestingly, some patients may be asymptomatic, especially those with small (<2 cm) tumors where there is low catecholamine production or more generally in cases where tumors produce and metabolize but do not secrete appreciable amounts of catecholamines [3].
2.2 Biochemical diagnosis
Patients with clinical suspicion of PPGLs.
Patients with incidentally detected adrenal tumors during imaging (incidentalomas, in particular in those with tumor density > 10 Hounsfield units, HU).
Patients with known germline mutations predisposing for PPGL.
Patients with syndromic manifestations suggesting hereditary or syndromic PPGL.
Patients with personal or family history of PPGL should be biochemically tested [1, 3, 4]. There are regional, institutional, and international differences in the approach to the biochemical diagnosis of PPGL.
2.2.1 Classical
The diagnosis of pheochromocytoma is typically made by measurements of urinary and plasma fractionated metanephrines, with negative predictive values >99% at specificities of about 94% [1, 3, 4].
The “gold standard” in diagnosis/screening/follow-up is plasma-free metanephrines (superior to catecholamines, superior to urinary metanephrines), in supine position for at least 20 minutes before taking blood. The most reliable measurements are those made via liquid chromatography/mass spectrometry (LC/MS). A high suspicion for a PPGLs is when we found with more than a twofold increase above reference interval upper cutoffs. Plasma-free metanephrine levels correlate with tumor burden and progression [20, 21].
The adrenergic phenotype is defined by a tumor content of epinephrine that exceeds 5% of the contents of all catecholamines; this can be assessed by measurements of plasma metanephrine relative to normetanephrine, the metabolites of epinephrine and norepinephrine [22].
Adrenergic tumors invariably show additional increases in plasma or urinary normetanephrine; only rarely do these tumors show exclusive increases in metanephrine [18, 22].
Plasma 3-methoxytyramine is useful for detecting the rare dopamine-producing PPGLs [1, 23].
2.2.2 Advances in the genetic diagnostic era
There is a correlation between genotype and the biochemical secretion.
PPGLs of the cluster 1 group are characterized by lower tumoral catecholamine contents, but higher rates of catecholamine secretion per mass of tumor tissue, compared with cluster 2 adrenergic tumors [1, 20, 22, 23].
Increases of plasma-free normetanephrine and/or 3-methoxytyramine with no or minimal increases of metanephrines suggests uniquely and accurately to the diagnosis of a cluster 1 PPGL [1].
Exceptions to this “rule” include the biochemically silent head and neck PGLs and other silent PPGLs with SDHB pathogenic variant, associated with limited amounts of catecholamines in tumor tissue and no minimal increases in plasma normetanephrine or 3-methoxytyramine [24].
The association of cluster 1 mutations with a noradrenergic or dopaminergic phenotype is an excellent example of how catecholamine phenotypes are associated to genetic abnormalities: tumors due to cluster 1 mutations with a noradrenergic phenotype have a higher expression of HIF-2α/EPAS1 than other tumors; they also involve mutations that lead to stabilization of HIF-2α, an important player that blocks glucocorticoid-induced expression of phenyl ethanolamine, N-methyl transferase (PNMT), the enzyme that converts norepinephrine to epinephrine [22, 23, 25, 26].
Cluster 2 is associated with an adrenergic secretion pattern, reflecting a well differentiation of the chromaffin cells in this cluster and, furthermore, a lower tendency to malignant disease in this cluster. The exception to this involves PHEOs due to MAX mutations, in which lack of MAX prevents induction of PNMT by glucocorticoids [1, 23, 26].
Cluster 3-related PPGLs showed the highest chromogranin A overexpression among all clusters [1].
2.2.3 Factors causing misleading plasma MN
Plasma-free MN and NMN levels are frequently elevated in patients with chronic kidney disease, particularly in those on dialysis [27], severe illness narcotic or alcohol withdrawal, anxiety, sleep apnea, essential hypertension, physical exercise. Other substances/aliments that interfere with MN measurements are: nicotine, coffee, sympathomimetics, amphetamine, local anesthetics, lidocaine, cocaine, halothane, MAO inhibitors, bananas, peppers, pineapples, walnuts. There can be seasonal variations in plasma normetanephrine levels with 20% higher levels during winter [20, 28].
2.3 Imaging diagnosis
After the confirmation of the catecholamine hypersecretion, tumor location detection is needed.
2.3.1 Classical
In general, computed tomography (CT) imaging has a high sensitivity (around 100%) but a low specificity (50%) for the screening of PHEOs. It has the highest screening sensitivity if in native phase, the tumor has >10 Hounsfield units (HU) [29].
On the other hand, magnetic resonance imaging (MRI) has a higher sensitivity for head and neck and sympathetic PGLs, compared with CT. MRI is overall preferable for children and long-term follow-up of children and adults [30].
Regarding metastatic PPGLs, CT scan is superior to MRI for lung metastases, whereas MRI is superior to CT for liver metastases [29, 30].
Scintigraphy. 123/131I- meta-iodobenzylguanidine (MIBG) is the most specific radiopharmaceutical for PPGLs (specificity>95%); its sensitivity is decreased in small tumors and/or those associated with SDHx mutations [1, 30, 31].
2.3.2 Advances in the genetic diagnostic era
According to the most recently published guideline for functional imaging of PPGLs, the most sensitive imaging method for cluster 1A SDHx-related disease is functional imaging with somatostatin receptor analogs (SSA) positron emission tomography-computed tomography ([68Ga]-DOTA-SSA PET/CT) with a sensitivity of 94–100% [31, 32, 33].
[68Ga]-DOTA-SSA PET/CT is the most sensitive imaging modality in the diagnosis and screening of cluster 1A SDHx-related PPGLs (mostly PGLs), since these tumors strongly express the somatostatin receptor 2 (SSTR2). In contrast, cluster 1B VHL/EPAS1-related PPGLs (specifically PHEOs) show stronger expression of the L-type amino-acid transporter and less SSTR2 expression. Therefore, [18F] FDOPA PET/CT is more sensitive than [68Ga]-DOTA-SSA PET/CT for these patients. Due to cluster 2-related tumors intra-adrenally located (exceptions, HRAS- and FGFR1-related PGLs in the Chinese population), anatomic abdominal imaging with CT or MRI is usually sufficient for tumor localization [1, 31, 32, 33, 34].
If there are inconclusive results on anatomic imaging (e.g., very small tumors, multifocality, distorted anatomy), PHEOs ≥5 cm, or for staging of metastatic disease, the most sensitive functional imaging method for all cluster 2-related PHEOs (>1 cm) is [18F] FDOPA PET/CT [35].
For the cluster 3, the most sensitive functional imaging modality is unknown [1].
2.4 Treatment
For locoregional disease, surgery should always be the first-line therapy, whenever possible. Minimally invasive adrenalectomy is the preferred surgical standard [36].
Although cortical-sparing surgery is associated with development of recurrent disease in about 13% of patients with germline mutations in RET or VHL, this is not associated with decreased survival and can be considered for less aggressive PPGLs. Adrenal-sparing surgery should not be favored over total adrenalectomy in most cluster 1 tumors, due to a high risk of recurrence and metastatic spread, particularly SDHB-mutant tumors [4, 36].
Current recommendations from the US Endocrine Society Practice Guideline and the Working Group on Endocrine Hypertension of the European Society of Hypertension agree that alpha-adrenoceptor blockade should be given for 7–14 days before surgery [3, 4]. There is no specific consensus on blood pressure and heart rate targets; however, it is recommended to reach a seated blood pressure target <130/80 mmHg [4, 37, 38].
The most frequently used drugs are the nonselective and noncompetitive alpha-1/2-adrenoceptor blocker phenoxybenzamine [4, 37, 38].
The tyrosine hydroxylase inhibitor metyrosine, which inhibits catecholamine synthesis, can additionally help to prevent pre- and intraoperative hemodynamic instability when given in combination with phenoxybenzamine. The combination treatment reduces blood pressure fluctuations [38, 39].
The mortality rate for PPGL surgical treatment has decreased from about 40% in the past to 0–3% in contemporary series, probably as a result of better preoperative treatment and surgical techniques [1, 40].
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3. Special considerations for metastatic disease
PPGL-related malignancy is defined as the presence of distant metastases in non-chromaffin tissues (e.g., bone and lymph nodes) [41]. Approximately 10%–15% of PHEOs and 35–40% of PGLs develop metastases [42].
The metastatic potential of a PPGL is evaluated based on tumor size (≥5 cm), extra-adrenal location, a dopaminergic phenotype (e.g., plasma methoxytyramine more than threeold above the upper reference limit), high Ki-67 index, the presence of a
At least 50–60% of all patients with metastatic PPGL carry cluster 1 mutations. In a retrospective study investigating 169 patients, 50% of all patients with metastatic disease had cluster 1 tumors (42% SDHB-related tumors), only 4% had cluster 2 tumors, and 46% had apparently sporadic disease [1, 43, 45].
Overall, the highest metastatic risk is reported for SDHB (35–75%), SDHA (30–66%), and HIF2A/EPAS1 mutation carriers (>30%). (1,33,34) Moreover, there also seems to be an increased metastatic risk for patients with FH mutations, while an intermediate risk (15–29%) has been shown for SDHD mutation carriers and an intermediate-to-low risk for SDHC and VHL (5–8%) mutation carriers [1, 42, 45].
Metastatic risk of cluster 2-related PPGLs is low, and RET, NF1, TMEM127, and MAX mutations are almost exclusively associated with PHEOs [43]. MEN2B is associated with a higher metastatic risk compared with MEN2A. The metastatic risk of NF1-related PHEOs is also low (2–12%) [1, 46].
Cluster 3 PPGLs were all associated with metastatic disease and showed poor aggressive-disease-free survival (e.g., a short time until the occurrence of either distant metastases, local recurrence, or positive regional lymph nodes [1].
There are practiced standards of therapy for metastatic PPGLs including chemotherapy (cyclophosphamide, vincristine, and dacarbazine [CVD] scheme, or temozolomide monotherapy), radionuclide therapy ([131I]-MIBG, [177Lu]-DOTATATE), tyrosine kinase inhibitors (TKIs) (sunitinib, cabozantinib), and immunotherapy [47, 48, 49].
There are some points to follow about metabolic activity of these tumors before addressing a specific therapy:
positivity on [123I]-MIBG scan for low or high-specific-activity [131I]-MIBG (expressing the norepinephrine transporter system, less likely positive for SDHx-mutated PPGLs).
68Ga-DOTATATE scan for [177Lu] DOTATATE therapy (expressing SSTR2, particularly SDHx-mutated PPGLs),
PD-L1 status for pembrolizumab, demethylating agents (especially for SDHx-mutated tumors), possibly HIF-2α inhibitors (particularly for cluster 1 PPGLs) poly (ADP-ribose) polymerase (PARP) inhibitors together with temozolomide (specifically for SDHx-mutated tumors) [46, 47, 48, 50, 51, 52].
Additionally, antiresorptive therapies, such as bisphosphonates and denosumab, are administered in the case of large and numerous bone metastases [38].
For Cluster 2-specific there are some indications for systemic therapy approaches, such as: [131I] MIBG therapy; kinase signaling pathway–related TKIs (sunitinib, cabozantinib, LOXO-292, lenvatinib, axitinib) and other specific targeted signaling pathway inhibitors alone and in combination (PI3K/AKT/mTORC1 inhibitors and RAF/MEK/ERK inhibitors) [50, 51, 52, 53].
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4. Follow-up in patients with PPGL
In general, every patient with any of the following criteria should undergo lifelong follow-up: [1, 4].
germline mutation predisposing for PPGL.
history of paraganglioma.
age < 20 years at initial diagnosis.
tumor size ≥5 cm.
multiple or recurrent PPGLs.
noradrenergic/dopaminergic phenotype.
Children with an initial diagnosis of SDHx mutation should firstly undergo a clinical examination including blood pressure measurements, plasma-free normetanephrine and 3-methoxytyramine (or urinary normetanephrine), and MRI (base of the skull to pelvis) [54, 55].
After negative initial screening, a clinical evaluation and blood pressure measurement annually, hormonal samples every 2 years, and an MRI (base of the skull to pelvis) every 2–3 years are recommended. Usually, after initial screening, MRI can be performed without gadolinium enhancement, but preferably with diffusion-weighted imaging for maximal sensitivity [1, 4, 55].
For adults, the similar situation is recommended-lifelong follow-up, apart from more frequent biochemistry every year (plasma is preferred, including plasma measurements of 3-methoxytyramine and no consensus for chromogranin A). In adults, initial screening should include functional imaging (PET/CT), but there is no recommendation for alternating MRI and PET/CT during follow-up [4, 55].
For patients with a history of an SDHA/B PPGL (highest metastatic risk), biochemistry every 6 months to 1 year and imaging every 1–2 years are reasonable [4, 41, 55].
For patients with a history of an SDHC/D/AF2- or VHL-related PPGL with a lower metastatic risk, biochemistry every year and imaging intervals of 2–3 years are sufficient [4, 54].
For asymptomatic RET mutation carriers, every year follow-up for PHEOs including clinical investigation and hormonal samples should begin between 11 and 16 years of age—depending on the high or moderate risk for PHEOs specific to the codon involved in RET mutation (always consider the risk of medullary thyroid carcinoma and primary hyperparathyroidism) [1, 4].
Patients with a history of an RET-related PHEO should have a lifelong follow-up with yearly clinical investigation and hormonal sampling; for patients with high and moderate risk for PHEOs (depending on the specific RET mutation), follow-up may include abdominal/pelvic MRI every 5 years [1, 4, 54].
Despite a rather low metastatic risk of NF1-related PHEOs, most recently published guidelines recommend the initiation of a biochemical screening of asymptomatic NF1 mutation carriers every 3 years from the age of 10 to 14 years [1, 4, 22].
For each patient with first diagnosis of a cluster 2-related PPGL ≥5 cm, a chest CT is recommended for exclusion of metastatic disease; however, this is unnecessary in the long-life follow-up of these mutation carriers because cluster 2-related diseases are related to a low metastatic risk and almost exclusively adrenal location of the tumor [1, 4, 22].
New discovered genes in the last 5 years: CSDE1(somatic), H3F3A(somatic), UBTFMAML3(somatic), IRP1(somatic), SLC25A11(somatic), DLST (germline), MERTK (somatic), MET (somatic and germline), FGFR1(somatic), SUCLG2(somatic) [7].
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5. Final considerations
Cluster-specific management regarding patient education, diagnostics (biochemistry, imaging), and follow-up are already widely acknowledged. Cluster-specific, genetically driven therapy requiring NGS of individual tumors may be an essential part of the management of these tumors in the future.
The ongoing PROSPHEO registry trial (NCT03344016), together with novel artificial intelligence approaches, might be able to answer the question as to the optimal follow-up for PPGL patients and aid in achieving the goal of preventing metastatic spread and death from PPGLs [1].
In conclusion, PPGLs are rare tumors with unique molecular and phenotypic landscapes. Diagnosing the germline and somatic mutations associated with PPGLs is a promising approach to understand the clinical behavior and prognosis and to personalize and thus optimize the management of these tumors.
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Conflicts of interest
The authors declare no conflicts of interest relevant to this manuscript.
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