Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that usually present with classic paroxysmal symptoms including headache, palpitation, anxiety and diaphoresis. Adrenergic and noradrenergic tumors are two biochemical types of PPGLs. The biochemical phenotype is important for predicting the location of the tumor, and the type of germline mutation. It is challenging for the clinician to diagnose this deadly disease due to the conditions with these non-specific symptoms. PPGLs are diagnosed with biochemical confirmation of catecholamine excess followed by anatomical localization. Biochemical testing should be considered for patients having paroxysmal symptoms or signs indicating catecholamine excess, paradoxic blood pressure response, resistant hypertension, incidental adrenal mass, previous diagnosis of PPGLs, family history of PPGLs, and syndromic features suggesting PPGLs. Initial biochemical tests for PPGLs are plasma free or urinary fractionated metanephrines. To get an accurate biochemical testing clinicians must obey rules for blood and urine sampling correctly. Anatomic and functional imaging modalities are used as needed. Genetic analysis by accredited laboratories is recommended for all patients. In this chapter, we review the diagnosis of PPGLs with a focus on clinical presentation, biochemical testing, imaging procedures and genetic analysis, guidance on when to perform case detection testing considering current case detection tests.

Pheochromacytomas and paragangliomas (PPGLs) are rare and potentially fatal tumors. It is very important to make accurate diagnosis or exclude diagnosis due to the high mortality and morbidity if left untreated and results in cure if timely treated. Also for some familial cases, establishing a correct diagnosis may ensure early recognition and treatment of affected family members. Additionally the malignancy prevalance of these tumors varies between 10-17% so case detection is important to plan the extent of the treatment [1]. 

Among patients tested for PPGLs, a small number of patients (less than 1%) actually have the tumor but real incidence may be higher because many of these tumors are missed or diagnosed during autopsy [2]. Pheochromocytoma was diagnosed in 4 out of 8486 autopsies (0.05%) [3]. The tumor is frequently considered but rarely found.

Other symptoms are tremors, weakness, fatigue, pallor, anxiety, nervousness, nausea, vomiting, and fever. Additionally affected patients may experience cerebrovascular accidents, transient ischemic attacks, acute respiratory distress syndrome, impaired renal function, acute tubular necrosis, and hypertensive nephrosclerosis. Rarely, new onset secondary diabetes may be seen in younger patients free of any risk factors [5].

Several studies have shown that plasma free metanephrines have high sensitivity for diagnosis of PPGLs (90-100%) [1,7,8]. Specificity of plasma free metanephrines varies between 79.4-97.6 %. Although urinary vanil mandelic acid (VMA) has high specificity, its use as an initial test is not recommended beause of its low sensitivity [9].

Plasma methoxityramine, an O-methylated metabolite of dopamine, may provide an additional benefit for the detection of PPGLs especially for head and neck paragangliomas.This biomarker can be used for dopamine-secreting tumors [10]. Also it is useful together with SDH mutation status, tumor size and location, for assesing the likelihood of malignancy [11].

Some factors may influence the levels of plasma free metanephrines. Smoking may increase them. It is recomended not to smoke for at least 4 hours before sample collection. Local anesthesics, lidocaine, halothane, MAO inhibitors, cocaine, and epinephrine-like drugs can interfere with the levels of plasma free metanephrines. Stressfull illness, renal failure, and cold-associated increased sympathetic nerve activity may cause misleading elevations in plasma free metanephrines. Food intake and physical exercise also do so. Use of symptahomimetics and stimulants such as caffeine can increase cathecolamine release therefore such phenomenon can be minimized by avoiding these agents before sample collection. Seated sampling may potentially cause misdiagnoses associated with sympathoadrenal activation and therefore preferably blood samples should be drawn from the patient in the supine position. If a positive test result is detected after the collection in the seated position, the test shoud be repeated in the supine position to rule out false positive cases. Urinary fractionated metanephrines can be preferable in low risk populations for centers unable to provide the supine position. Clonidine suppression test may help to distinguish true positive from false positive elevations. Another option to exclude false positive elevations of plasma metanephrines is measurement of chromogranin and urinary free metanephrines. Test results under the upper limit of normal for plasma free metanephrines exclude almost all cases of PPGLs except microscopic recurrent tumors, incidentally discovered small tumors (<1 cm), patients with hereditary predisposition to PPGLs, tumors producing only dopamine, head and neck non catecholamine-synthesizing paragangliomas and paragangliomas. Since plasma free and urinary fractioned metanephrines have high negative predictive value, further investigations are not needed for patients with test results falling within the reference intervals [12].

Chromogranin A (CgA) is a soluble acidic protein that is commonly secreted and stored with cathecolamines by the chromaffin cells. Although it is a non-specific biomarker of neuroendocrine tumors, its elevated levels are found in 91% of PPGL cases and can be used for disease monitoring purposes [5].In combination with plasma normetanephrine, CgA enhances tumor detection by 22% in evaluation of succinate dehydrogenase (SDH) B-related PPGLs [13].

PPGLs can also secrete some peptide hormones other than catecholamines, including calcitonin, cytokines, parathyroid hormone-related peptide, erytropoietin, neuropeptide Y, and neuronspesific enolase and some of them may cause different clinical symptoms. For example ACTH production by the tumor cells can cause Cushing’s syndrome [14].

According to the literature, there are 17 PPGL susceptibility genes named as neurofibromatosis 1 (NF1), rearranged during transfection (RET), von Hippel-Lindau (VHL), succinate dehydrogenase D (SDHD), succinate dehydrogenase C (SDHC), succinate dehydrogenase B (SDHB), EGL nine homolog 1 (EGLN1/PHD2), kinesin family member 1B(KIF1β), succinate dehydrogenase assembly factor 2(SDH5/ SDHAF2), isocitrate dehydrogenase (IDH1), transmembrane protein 127 (TMEM127), succinate dehydrogenase A(SDHA), myc-associated factor X (MAX), hypoxia-inducible factor alpha (HIF2α), fumarate hydratase (FH), malate dehydrogenase 2 (MDH2) and BRCA-1 associated protein-1 (BAP1). However, the role of somatic or germline mutations in few of the latter need confirmation in further studies.

35% and 15% of PPGLs have germline and somatic mutations, respectively. In addition to this high frequency, the detection of such fatal hereditary disease for at-risk families justifies the evaluation of genetic examination for each PPGL patient despite financial cost considering the effect of the result on management. Nockel et al investigated the effect of preoperative genetic testing in PPGLs and found that preoperative knowledge of the germline mutation status affects the extent of adrenalectomy and the surgical approach [17]. However, the availability of molecular tests, resources and an accrediated laboratory is needed. Additionally, with the rise of a panel approach to molecular examining, it is recommended to prioritize molecular testing according to young age, positive family history, syndromic or metastatic presentation, multifocal involvement, bilateral adrenal disease and catecholamine biochemical phenotype. The mode of inheritance is most commonly autosomal-dominant and related diseases are NF-1, multiple endocrine neoplasia type 2 (MEN2), VHL syndrome, renal cell carcinoma with SDHB mutation, Carney triad, Carney Stratakis syndrome [18]. Evaluation of NF-1 gene is complex and testing is possible only in certain laboratories although the diagnosis of NF-1 can be established according to the clinical stigmas. However, the investigation of clinical signs to get the clues for underlying mutation in all patients presented with PPGLs, which is so important particularly in NF1-positive patients [1]. Several tumor characteristics such as biochemical phenotype, tumor location, and histological evaluation could help to prioritize molecular testing for patients without family history and syndromic features.

Under the highlight of microarray studies PPGLs have been broadly distributed into two clusters according to the expression profiles. Cluster 1 includes pseudohypoxia-driven tumors displaying VHL,SDH, EGLN1 and HIF2A mutations. Cluster 2 includes the kinase signalling tumors that have RET, NF1, KIF1Bβ, MAX, TMEM127 and presumably H-RAS mutations. Sporadic tumors are in between these two clusters [19,20].

The mutated gene SDHB was found the most common and endowed with the highest risk of malignancy [21]. It was detected in 30% of metastatic PPGLs. Patients with SDHB mutations are diagnosed at younger ages and are also associated with thoracic or abdominal extra-adrenal PPGLs [22]. The predominant biochemical typing is hypersecretion of dopamine or dopamine and norepinephrine. Also, increased levels of 3-methoxytyramine could help to diagnose SDHB mutation or other malignant tumors. Multiple tumors are found in SDHB carriers, however the penetrance of these mutations is low, so these patients could not be diagnosed until tumor detection. SDHC, SDHAF2 and SDHA mutations are rare, so clinical evidence is limited.

SDHC mutations are benign and frequently associated with multiple head and neck tumors; the same applies to SDHAF2 mutations at a similar age for sporadic tumors. Renal cell carcinoma, papillary thyroid carcinoma, pituitary adenoma, Carney-Stratakis dyad, and Carney triad have also been associated with SDH mutations. Current evidence suggests that SDH mutations may clinically arise as a metabolic tumor syndrome [5]. Therefore, SDH carriers who lack a positive family history for PPGLs should be inquired about the presence of SDH related tumors such as pituitary adenoma and renal cell carcinoma.

Germline mutation in the RET proto oncogene is the underlying mutation in multiple endocrine neoplasia (MEN) type 2A and 2B. Inheritance is autosomal dominant in MEN2 with high penetrance. However, genetic variations related RET proto-oncogene cause subtle changes in clinical presentation. Pheochromocytomas seen in MEN2 are almost always benign, frequently bilateral, adrenal and hypersecrete metanephrine.

NF1 is an autosomal dominant disease due to an inactivating mutation in the tumor supressor gene named NF1. 50% of PPGLs in NF1 are familial and the rest are de novo mutations. PPGL is a rare component of NF1 that generally presents in the fourth or fifth decade and many patients also develop cutaneous manifestations. They usually present in a benign fashion with unilateral adrenal gland involvement, however, 12% of PPGLs can be malignant and occasionally bilateral.

VHL syndrome is a rare autosomal dominant syndrome classified according to the likelihood of developing PPGLs. Patients with VHL type 1 have a low risk of developing PPGL while type 2 have an increased risk. VHL type 2 sub-classifies into 3 groups: Type 2A is termed pheochromocytoma with low incidence of renal cell carcinoma (RCC), 2B is termed pheochromocytoma with high incidence of RCC, and 2C is termed sporadic PPGL. PPGLs in VHL patients are frequently benign, intraadrenal and bilateral. Also mediastinal, abdominal and pelvic sympathetic paragangliomas and head and neck parasympathetic paragangliomas have been reported. VHL patients have increased normetanephrine levels in contrast to those with NF1 and MEN-2 mutations.

Current evidence showed additional rare genes associated with development of PPGLs. The tumor suppressor gene TMEM127 linked with mTOR kinase pathway has been found in relation with pheochromocytoma development. MAX protein functions as both an activator and suppressor gene associated with oncogenic pathways. However, which mechanism causes the PPGL is unclear. Tumors can be either adrenal or extra-adrenal and adrenal tumors are often bilateral and in malign behaviour. KIF1β is a rare germline mutation associated with PPGL and neuroblastoma. EGLN1, also named PHD2 gene mutations cause familial paraganglioma through pseudohypoxic mechanisms. Loss of function of FH leads to the activation of pseudohypoxia driven pathways as in SDH mutations. MDH2 mutation causes a deletion in the tumor suppressor gene leading to the inhibition of the HIFα pathway and malignant PPGLs. HRAS and HIF2α are well known somatic mutations that cause PPGL.

Tomography: Computed Tomography (CT) is the first recommended imaging modality for detection of PPGLs because it offers excellent spatial resolution for thorax, abdomen and pelvis. PPGLs can have different appearence (homogeneous or heterogeneous, solid, complex or cystic) on CT. Larger tumors tend to have necrosis, and hemorrhage. Calcifications may be found in 10% of cases. Nearly all pheochromocytomas have an attenuation value of greater than 10 HU [23]. But pheochromocytomas that contain small amounts of fat can have attenuation values similar to adenomas measuring less than 10 HU [25]. On the other hand the presence of hemorrhage can cause high density apperance. A tumour greater than 110 HU in the arterial phase is probably a pheochromocytoma. Additionally pheochromocytomas can mimic adenomas demonstrating absolute contrast washout values 60% or higher, or relative contrast washout values 40% or higher. Although contrast agents may precipitate a hypertensive crisis, nonionic ones are safe and therefore contrast CT can be performed in unmedicated patients. CT can detect tumors as small as 5 mm and most of these tumors are located in the abdomen therefore CT scan should be the first-choice imaging modality [1].

Magnetic Resonance Imaging: Magnetic Resonance Imaging (MRI) is recommended for patients with suspected skull base, head and neck paragangliomas, those with history of allergy to CT contrast agents or carrying surgical clips or suggested to avoid radiation (pregnant women, children, patients with germline mutation and those with recent radiation exposure). The classic MRI finding of PPGLs is a marked hyperintensity known as “light-bulb” bright lesion on T2-weighted images, but this sign can be detected in 11-65% of cases [26]. This is thought to be related to the difference between the amount of fluid contained in the cystic-necrotic and in the cellular homogenous areas of the tumour. PPGLs are characteristically isointense to muscle and hypointense as compared to liver on T1- wieghted images. Pheochromocytomas characteristically exhibit avid enhancement after the injection of gadalonium but the presence of necrosis may change the enhancement pattern especially centrally. Diffusion-weighted imaging (DWI) is an imaging modality allowing insight into tissue cellularity and cell membrane integrity. Evaluation of DWI may have a role in distinguishing benign from malignant tumors during the preoperative evaluation [25].

Sensitivity of MRI ranges from 86 to 100%. But as with CT, possible false positive and false negative findings should be kept in mind to make differential diagnosis accurately.

¹²³I- and ¹³¹I-Metaiodobenzylguanidine: Metaiodobenzylguanidine (MIBG) is concentrated by the sympathomedullary tissue through an active amine transport system and then stored in cytoplasmic vesicles. Pretreatment with Lugol iodine is recommended to saturate thyroid uptake and to prevent accumulation of MIBG in thyroid. The uptake of MIBG is proportional to the number of the vesicles within the tumor cells and characteristic appearence of the PPGL occurs.

Because imaging with ¹²³I- MIBG has a better sensitivity and a lower radiation exposure than ¹³¹I-MIBG, only ¹²³I-MIBG is recommended for PPGLs imaging [26]. Also MRI and CT can be used in combination with ¹²³I-MIBG-single-photon emission computed tomography (SPECT) for better localisation.

Sensitivity of ¹²³I-MIBG has been reported beween 85-88% for pheochromocytomas and between 56-75% for paragangliomas with a specificity of 70-100% and 84-100%, respectively. Affinity variations in the amine transport system,loss of amine transport system in dedifferantiated tumors and variations in the amount of cytoplasmic granules, presence of tumor necrosis may reduce its sensitivity [25]. Also the sensitivity of ¹²³MIBG in patients with SDHB related paragangliomas and skull base and neck, chest, bladder, metastatic disease and recurrent paragangliomas is low. Several drugs can decrease uptake of MIBG so these drugs should be with held for 2 weeks before the procedure: 1) Sympathomimetics 2) Agents that block cathecolamine transport through norepinephrine transporter such as tricyclic antidepressants, cocaine and 3)calcium channel blockers and combined α- and β-receptor blockers [1].

¹¹¹I-Pentetreotide: PPGLs can sometimes express somatostatin receptors which allows the use of pentetreotide (an analogue of somatostatin) for diagnosis. Pentetreotide is not used as first lin    e diagnostic workup because of its low sensitivity but it may be used in the evaluation of MIBG-negative PPGLs that no longer express the amine transporter system and for detection of metastases [27].

Positron Emission Tomography: In recent years, PET has been widely available and used for diagnosis of PPGLs because of its high sensitivity. PET scan performed together with a corresponding CT increases the sensitivity. The Endocrine Society recommends using 18F-FDG PET/CT for assessment of known metastatic PPGLs [1].

Various radiotracers have been used for the diagnostic workup of patients with PPGLs. The most commonly used radiotracer is ¹⁸F-FDG, an analogue of glucose that is taken up by the glucose transporter. A high standardised uptake value (SUV) reflects increased intracellular tumor metabolism thus allowing tumour detection. On the other hand caution should be exercised as FDG PET is not specific for PPGLs and many types of tumor may be detected by this technique. Several studies have demonstrated a superiority of FDG PET over MIBG scintigraphy for diagnosis of metastatic PPGLs particularly in patients with SDHB mutation [27,28].

Newer and more specific radiotracers have been developed. ¹⁸F-Fluorodopa (FDOPA), a catecholamine precursor that is taken up through amino acid transporters, is specific for neuroendocrine tumors. Its sensitivity for diagnosis of head and neck paragangliomas is extremely high.

Another specific tracer is 18F-Fluorodopamine which is taken up with high affinity by norepinephrine transporters. Its high sensitivity for PPGLs supports its use in MIBG negative patients.

Studies with ⁶⁸Ga-labeled DOTA peptides (DOTATOC, DOTATATE and DOTANOC) have demonstrated a high sensitivity for neuroendocrine tumors including PPGLs [29]. However, these data are limited and tracers are not widely available for suggesting their routine use.

Current evidence showed that these tumors might exhibit a genotype-specific imaging phenotypes especially for those with germline mutations. It may be reasonable to use a stepwise imaging approach for PPGLs according to the genotype. For example, VHLrelated PPGL cells express the cell membrane norepinephrine transporter system at lower rates than MEN2-related tumor cells [30]. Since MIBG has low affinity for these cells than ¹⁸F-fluorodopamine, it is no surprise that 18F-FDA PET is more sensitive than 123I-MIBG scintigraphy in patients with VHL-related pheochromacytomas [31]. ¹⁸F-FDG PET CT has a perfect sensitivity for SDHB positive metastatic PPGLs while ¹²³I-MIBG scintigraphy has much lower performance(about 50% or less) [32]. Increased FDG uptake may be related to SDHB-specific tumor biology rather than an increased metabolic rate [33].

Despite several studies including demographic data, imaging modalities, genetic testing, microarray analysis, and immunohistochemistry were conducted to clarify this issue, there are no clear markers to predict which patients tend to develop metastatic disease during the management. Well known risk factors that increase malignancy risk are extra-adrenal location of the tumor, the size of the primary tumor, the presence of SDHB mutation, the age at primary tumor diagnosis, and increased levels of plasma methoxytyramine [34-37]. Moreover, distinguishing benign from malignant PPGLs and establishing the diagnosis of malignant PPGLs is particularly challenging in cases without metastatic lesions. Despite being more commonly seen in malignant tumours, PPGL capsular or vascular invasion is not a specific feature for malignancy [25]. 

In pregnant women only ultrasongraphy and MRI can be used. Abdominal ultrasonography is rapid, cheap, and tolerable but it has low sensitivity especially in small tumors. MRI with gadalonium is another imaging procedure in these patients. Other diagnostic procedures such as CT, MIBG, other nuclear imaging modalities and biopsy are contraindicated in pregnancy because of their serious adverse effects [39,40].

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