Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era of Personalized Genetic Diagnostic

*Sofia Maria Lider Burciulescu and Monica Livia Gheorghiu*

#### **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:


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 *Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era… DOI: http://dx.doi.org/10.5772/intechopen.108298*

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 (gainof-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.

#### **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.


#### **Table 1.**

*Clinical features of the most frequent hereditary PPGL syndromes.*

PPGLs can be sporadic or part of hereditary/familial syndromes, with specific clinical manifestations (**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].


*Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era… DOI: http://dx.doi.org/10.5772/intechopen.108298*

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**


#### *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 *Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era… DOI: http://dx.doi.org/10.5772/intechopen.108298*

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*

*Functional imaging* is recommended for presurgery staging of PHEO ≥5 cm for staging of metastatic/multifocal disease and after surgery of a (sympathetic) PGL or of metastatic/multifocal disease, and it is optional in follow-up in adult SDHx mutation carriers [1, 31].

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% [31–33].

[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, 31–34].

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].

#### **3. Special considerations for metastatic disease**

PPGL-related malignancy is defined as the presence of distant metastases in nonchromaffin 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), extraadrenal location, a dopaminergic phenotype (e.g., plasma methoxytyramine more than threeold above the upper reference limit), high Ki-67 index, the presence of a *SDHB* mutation [1, 8]. Histological scores are more reliable in ruling out than in predicting a malignant behavior: *Pheochromocytoma of the Adrenal Gland Score* (PASS) < 4 and *Grading of Adrenal Pheochromocytoma and Paraganglioma* (GAPP) score < 3 [1, 43, 44]. A thorough genetic testing is useful in appreciating the metastatic risk.

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 *Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era… DOI: http://dx.doi.org/10.5772/intechopen.108298*

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 [47–49].

There are some points to follow about metabolic activity of these tumors before addressing a specific therapy:


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) [50–53].

#### **4. Follow-up in patients with PPGL**

In general, every patient with any of the following criteria should undergo lifelong follow-up: [1, 4].


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].

#### **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

*Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era… DOI: http://dx.doi.org/10.5772/intechopen.108298*

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.

#### **Conflicts of interest**

The authors declare no conflicts of interest relevant to this manuscript.

#### **Author details**

Sofia Maria Lider Burciulescu1,2 and Monica Livia Gheorghiu1,2\*

1 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

2 C.I. Parhon National Institute of Endocrinology, Bucharest, Romania

\*Address all correspondence to: monicagheorghiu@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Nölting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, et al. Personalized management of pheochromocytoma and paraganglioma. Endocrine Reviews. 2022;**43**(2):199-239. DOI: 10.1210/endrev/bnab045

[2] Aygun N, Uludag M. Pheochromocytoma and paraganglioma: From epidemiology to clinical findings. Sisli Etfal Hastan Tip Bulteni. 2020;**54**(2):159-168. DOI: 10.14744/ SEMB.2020.18794

[3] Lenders JWM, Kerstens MN, Amar L, et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: A position statement and consensus of the working group on endocrine hypertension of the European Society of Hypertension. Journal of Hypertension. 2020;**38**(8):1443-1456. DOI: 10.1097/ HJH.0000000000002438

[4] Lenders JW, Duh QY, Eisenhofer G, et al. Endocrine Society. Pheochromocytoma and paraganglioma: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism. 2014;**99**(6):1915-1942. DOI: 10.1210/ jc.2014-1498

[5] Gheorghiu ML, Hortopan D, Dumitrascu A, Caragheorgheopol A, Stefanescu A, Trifanescu R, et al. Age-related endocrine tumors: Nonfunctioning adrenal tumors as compared to pituitary adenomas. Acta Endo (Buc). 2009;**5**:371-384. DOI: 10.4183/ aeb.2009.371

[6] Lam AK. Update on adrenal tumours in 2017 World Health Organization (WHO) of endocrine tumours. Endocrine Pathology. 2017;**28**(3):213-227 [7] Jhawar S, Arakawa Y, Kumar S, Varghese D, Kim YS, Roper N, et al. New insights on the genetics of pheochromocytoma and paraganglioma and its clinical implications. Cancers. 2022;**14**(3):594. DOI: 10.3390/ cancers14030594

[8] Fassnacht M, Assie G, Baudin E, et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2020;**31**(11):1476-1490. DOI: 10.1016/j. annonc.2020.08.2099

[9] NGS in PPGL (NGSnPPGL) Study Group, Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, et al. Consensus statement on next-generationsequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nature Reviews. Endocrinology. 2017;**13**(4):233-247. DOI: 10.1038/nrendo.2016.185

[10] Fishbein L, Leshchiner I, Walter V, et al. Cancer genome atlas research network. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;**31**(2):181-193. DOI: 10.1016/j.ccell.2017.01.001

[11] Jochmanova I, Pacak K. Genomic landscape of pheochromocytoma and paraganglioma. Trends Cancer. 2018;**4**(1):6-9. DOI: 10.1016/j. trecan.2017.11.001

[12] Gieldon L, William D, Hackmann K, et al. Optimizing genetic workup in pheochromocytoma and paraganglioma by integrating diagnostic and research approaches. Cancers (Basel). 2019;**11**(6). DOI: 10.3390/cancers11060809

*Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era… DOI: http://dx.doi.org/10.5772/intechopen.108298*

[13] Luchetti A, Walsh D, Rodger F, et al. Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis. International Journal of Endocrinology. 2015;**2015**:138573. DOI: 10.1155/2015/138573

[14] Timmers HJ, Kozupa A, Eisenhofer G, et al. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. The Journal of Clinical Endocrinology and Metabolism. 2007;**92**(3):779-786

[15] Taieb D, Kaliski A, Boedeker CC, Martucci V, Fojo T, Adler JR, et al. Current approaches and recent developments in the management of head and neck paragangliomas. Endocrine Reviews. 2014;**35**:795-819

[16] Plouin PF, Amar L, Dekkers OM, et al. European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma. European Journal of Endocrinology. 2016;**174**(5):G1-G10. DOI: 10.1530/ EJE-16-0033

[17] Geroula A, Deutschbein T, Langton K, Masjkur J, Pamporaki C, Peitzsch M, et al. Pheochromocytoma and paraganglioma: Clinical featurebased disease probability in relation to catecholamine biochemistry and reason for disease suspicion. European Journal of Endocrinology. 2019;**181**(4):409-420. DOI: 10.1530/EJE-19-0159

[18] Eisenhofer G, Huynh TT,

Elkahloun A, et al. Differential expression of the regulated catecholamine secretory pathway in different hereditary forms of pheochromocytoma. American Journal

of Physiology. Endocrinology and Metabolism. 2008;**295**(5):E1223-E1233. DOI: 10.1152/ajpendo.90591.2008

[19] Paul Robertson R. DeGroot's Endocrinology. 8th ed. Philadelphia: Elsevier; 2021

[20] Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: Which test is best? Journal of the American Medical Association. 2002;**287**(11):1427-1434. DOI: 10.1001/jama.287.11.1427

[21] Weismann D, Peitzsch M, Raida A, et al. Measurements of plasma metanephrines by immunoassay vs liquid chromatography with tandem mass spectrometry for diagnosis of pheochromocytoma. European Journal of Endocrinology. 2015;**172**(3):251-260. DOI: 10.1530/EJE-14-0730

[22] Eisenhofer G, Klink B, Richter S, Lenders JW, Robledo M. Metabologenomics of phaeochromocytoma and paraganglioma: An integrated approach for personalised biochemical and genetic testing. Clinical Biochemistry Review. 2017;**38**(2):69-100

[23] Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. The New England Journal of Medicine. 1999;**340**(24):1872-1879. DOI: 10.1056/NEJM199906173402404

[24] Timmers HJ, Pacak K, Huynh TT, et al. Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene. The Journal of Clinical Endocrinology and Metabolism. 2008;**93**(12):4826-4832. DOI: 10.1210/jc.2008-1093

[25] Eisenhofer G, Lenders JW, Goldstein DS, et al. Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clinical Chemistry. 2005;**51**(4):735-744. DOI: 10.1373/clinchem.2004.045484

[26] Eisenhofer G, Deutschbein T, Constantinescu G, et al. Plasma metanephrines and prospective prediction of tumor location, size and mutation type in patients with pheochromocytoma and paraganglioma. Clinical Chemistry and Laboratory Medicine. 2020;**59**(2):353-363. DOI: 10.1515/cclm-2020-0904

[27] Niculescu DA, Ismail G, Poiana C. Plasma free Metanephrine and normetanephrine levels are increased in patients with chronic kidney disease. Endocrine Practice. 2014;**20**(2):139-144. DOI: 10.4158/EP13251.OR

[28] Gardner D. Dolores Shoback Greenspan's Basic and Clinical Endocrinology. Tenth ed. California, San Francisco: Lange; 2018

[29] Buitenwerf E, Berends AMA, van Asselt ADI, et al. Diagnostic accuracy of computed tomography to exclude pheochromocytoma: A systematic review, meta-analysis, and cost analysis. Mayo Clinic Proceedings. 2019;**94**(10):2040-2052. DOI: 10.1016/j. mayocp.2019.03.030

[30] Daniel E, Jones R, Bull M, Newell-Price J. Rapid-sequence MRI for long-term surveillance for paraganglioma and phaeochromocytoma in patients with succinate dehydrogenase mutations. European Journal of Endocrinology. 2016;**175**(6):561-570. DOI: 10.1530/ EJE-16-0595

[31] Taïeb D, Jha A, Treglia G, Pacak K. Molecular imaging and radionuclide

therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups. Endocrine-Related Cancer. 2019;**26**(11):R627-R652. DOI: 10.1530/ ERC-19-0165

[32] Gild ML, Naik N, Hoang J, et al. Role of DOTATATE-PET/CT in preoperative assessment of phaeochromocytoma and paragangliomas. Clinical Endocrinology. 2018;**89**(2):139-147. DOI: 10.1111/ cen.13737

[33] Jha A, Ling A, Millo C, et al. Superiority of 68Ga-DOTATATE PET/ CT to other functional and anatomic imaging modalities in the detection of SDHD-related pheochromocytoma and paraganglioma–a comparative prospective study. Journal of Nuclear Medicine. 2018;**59**(supplement 1):46. DOI: 10.1158/1078-0432.CCR-14-2751

[34] Janssen I, Blanchet EM, Adams K, et al. Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma. Clinical Cancer Research. 2015;**21**(17): 3888-3895. DOI: 10.1158/1078-0432. CCR-14-2751

[35] Taïeb D, Hicks RJ, Hindié E, et al. European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging procedure standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. European Journal of Nuclear Medicine and Molecular Imaging. 2019;**46**(10):2112-2137

[36] Castinetti F, Qi XP, Walz MK, et al. Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: An international retrospective

*Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era… DOI: http://dx.doi.org/10.5772/intechopen.108298*

population-based study. The Lancet Oncology. 2014;**15**(6):648-655. DOI: 10.1016/S1470-2045(14)70154-8

[37] Berends AMA, Kerstens MN, Lenders JWM, Timmers H. Approach to the patient: Perioperative management of the patient with pheochromocytoma or sympathetic paraganglioma. The Journal of Clinical Endocrinology and Metabolism. 2020;**105**(9):3088-3103. DOI: 10.1210/clinem/dgaa441

[38] Uslar T, San Francisco IF, Olmos R, Macchiavelo S, Zuñiga A, Rojas P, et al. Clinical presentation and perioperative Management of Pheochromocytomas and Paragangliomas: A 4-decade experience. J Endocr Soc. 2021;**5**(10): bvab073

[39] Steinsapir J, Carr AA, Prisant LM, Bransome ED Jr. Metyrosine and pheochromocytoma. Archives of Internal Medicine. 1997;**157**(8):901-906

[40] Patel D. Surgical approach to patients with pheochromocytoma. Gland Surgery. 2020;**9**(1):32-42

[41] Hescot S, Curras-Freixes M, Deutschbein T, et al. European network for the study of adrenal Tumors (ENS@T). Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono Study): A European network for the study of adrenal Tumors retrospective study. The Journal of Clinical Endocrinology and Metabolism. 2019;**104**(6):2367-2374. DOI: 10.1210/ jc.2018-01968

[42] Leijon H, Remes S, Hagström J, Louhimo J, Mäenpää H, Schalin-Jäntti C, et al. Variable somatostatin receptor subtype expression in 151 primary pheochromocytomas and paragangliomas. Human Pathology. 2019;**86**:66-75. DOI: 10.1016/j. humpath.2018.11.020

[43] King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, et al. Metastatic pheochromocytoma / paraganglioma related to primary tumor development in childhood or adolescence: Significant link to SDHB mutations. Journal of Clinical Oncology. 2011;**29**(31):4137- 4142. DOI: 10.1200/JCO.2011.34.6353

[44] Kimura N, Takayanagi R, Takizawa N, et al. Phaeochromocytoma Study Group in Japan. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocrine-Related Cancer. 2014;**21**(3):405-414

[45] Crona J, Lamarca A, Ghosal S, Welin S, Skogseid B, Pacak K. Genotypephenotype correlations in pheochromocytoma and paraganglioma: A systematic review and individual patient meta-analysis. Endocrine-Related Cancer. 2019;**26**(5):539-550

[46] Al-Sharefi A, Javaid U, Perros P, et al. Clinical presentation and outcomes of phaeochromocytomas/paragangliomas in neurofibromatosis type 1. European Endocrinology. 2019;**15**(2):95-100

[47] Ilanchezhian M, Jha A, Pacak K, Del Rivero J. Emerging treatments for advanced/metastatic pheochromocytoma and paraganglioma. Current Treatment Options in Oncology. 2020;**21**:85

[48] Mak IYF, Hayes A, Khoo B, Grossman A. Peptide receptor radionuclide therapy as a novel treatment for metastatic and invasive Phaeochromocytoma and paraganglioma. Neuroendocrinology. 2019;**109**:287-298

[49] Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: Effective treatment with a combination of cyclophosphamide, vincristine,

and dacarbazine. Annals of Internal Medicine. 1988;**109**(4):267-273

[50] Bechmann N, Moskopp ML, Ullrich M, et al. HIF2α supports pro-metastatic behavior in pheochromocytomas/paragangliomas. Endocrine-Related Cancer. 2020;**27**(11):625-640. DOI: 10.1530/ ERC-20-0205

[51] Remacha L, Santos M, et al. Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics. 2019;**9**:4946-4958. DOI: 10.7150/thno.35458

[52] Nölting S, Grossman A, Pacak K. Metastatic Phaeochromocytoma: Spinning towards more promising treatment options. Experimental and Clinical Endocrinology & Diabetes. 2019;**127**:117- 128. DOI: 10.1055/a-0715-1888

[53] Druce MR, Kaltsas GA, Fraenkel M, Gross DJ, Grossman AB. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: Experience with the mTOR inhibitor everolimus (RAD001). Hormone and Metabolic Research. 2009;**41**(9):697-702. DOI: 10.1055/s-0029-1220687

[54] Amar L, Pacak K, Steichen O, Akker SA, Aylwin SJB, Baudin E, et al. International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nature Review in Endocrinology. 2021;**17**:435-444. DOI: 10.1038/s41574-021-00492-3

[55] Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: From genetics to personalized medicine. Nature Reviews. Endocrinology. 2015;**11**(2):101-111

### *Edited by Diana Loreta Păun, Pasquale Cianci and Enrico Restini*

The book presents an in-depth exploration of adrenal anatomy, physiology, and pathology, authored by a multidisciplinary team of international experts, providing an exposition of the current state of knowledge in the field of adrenal diseases and offering insights into the evolution of their management. The addressed pathologies are intricate and diverse, encompassing conditions such as Cushing's disease, primary aldosteronism, pheochromocytoma, and congenital adrenal hyperplasia. Each pathology chapter delves into etiopathogenic aspects, clinical evidence, and therapeutic recommendations. This publication caters equally to endocrinologists and professionals from various medical disciplines, serving as a valuable resource for information on the adrenal gland from both a physiological and pathological perspective.

Published in London, UK © 2024 IntechOpen © Mohammed H. Nizamudeen / iStock

Adrenal Glands - The Current Stage and New Perspectives of Diseases and Treatment

Adrenal Glands

The Current Stage and New Perspectives of

Diseases and Treatment

*Edited by Diana Loreta Păun,* 

*Pasquale Cianci and Enrico Restini*