Keywords

2.1 Introduction

Pheochromocytomas (PHEOs) are rare neuroendocrine tumors arising from the chromaffin cells of the adrenal medulla; those arising from extra-adrenal chromaffin cells are defined paragangliomas (PGLs). The acronym PPGL comprehends both PHEO and PGL. PPGL can synthesize and secrete catecholamines (epinephrine and norepinephrine) responsible for the associated clinical syndrome. PPGL prevalence varies from 0.2% to 0.6% in hypertensive patients, to less than 0.05% in the general population. PPGLs have approximately a 15–20% 10-year probability of recurrence and a 15–20% probability of developing metastatic disease [1]. Metastatic PPGL is defined by the presence or recurrence of metastatic lesions at sites where chromaffin tissue is normally absent. Metastases can appear even 20 years after the first diagnosis: the most common sites are locoregional lymph nodes, bone (50%), liver (50%) and lung (30%) [2]. The median time for metastasis discovery is about 5 years regardless of the stage [3].

2.2 Presentation

The clinical manifestations of these tumors are primarily related to the excessive secretion of catecholamines; the amount of circulating catecholamine and the different release patterns (paroxysmal, continuous or mixed patterns) account for the variability in clinical presentation. Headache, hyperhidrosis, and palpitations constitute the classic symptomatic triad associated with PPGL. However, patients may present with many other symptoms and signs: high blood pressure, headache, diaphoresis, tremors, pallor, facial flushing, shortness of breath, panic attack-type symptoms, dizziness, fatigue. Symptoms are typically paroxysmal and associated with paroxysmal hypertension. The frequency of paroxysmal attacks is highly variable: some patients experience paroxysmal episodes several times a day, others only every few months. Acute onset of symptoms may be triggered by exercise, increase in abdominal pressure, large meals, alcohol and medications (corticosteroids, ephedrine, phenylephrine, ACTH, phenothiazines, amphetamine, metoclopramide, antidepressants, some anesthetics). A variable proportion of patients (10–60% in different series) experience dizziness and faintness; these symptoms are an expression of orthostatic hypotension due to adrenergic receptor desensitization and intravascular volume depletion. About 10% of patients with secreting PPGL are normotensive, and usually reach the diagnosis either “incidentally” or thanks to application of surveillance programs in individuals carrying mutations in susceptibility genes.

Rare, serious complications of catecholamine hypersecretion are catecholamine-induced cardiomyopathies (CICMPs), which have a prevalence of 8–11% in PPGL [4]. The harmful effects of catecholamines on myocardial tissue give rise to several types of cardiomyopathies: dilated, hypertrophic, and Takotsubo. Regardless of the type of cardiomyopathy, the onset is often dramatic with acute heart failure or acute coronary syndrome. Severe hemodynamic impairment may evolve into a pheochromocytoma multisystem crisis, a rare complication with high mortality (15%), characterized by severe and prolonged hypotension with rapid progression to shock. Fortunately, with appropriate treatment these forms of cardiomyopathy are often reversible: perioperative management, surgery timing and anesthesiologic assistance must be carefully scheduled in these patients.

A less known complication of prolonged hypersecretion of catecholamines is severe constipation, which occurs in 6–7% of PPGL patients; in subjects with primary large tumors or bulky metastatic disease pseudo-obstruction may progress to paralytic ileus, bowel ischemia, and colonic perforation. Severe constipation, like catecholamine-induced cardiomyopathy, should be considered an important clue for perioperative risk stratification.

2.3 Biochemical Diagnosis

Patients with symptoms and signs compatible with catecholaminergic hyperincretion should be screened whether or not they are hypertensive. PPGL should also be excluded in subjects with changes in blood pressure during anesthesia or surgical intervention, in subjects with catecholamine-induced cardiomyopathy, in patients with adrenal incidentaloma (also if they are normotensive), in young lean individuals with diabetes mellitus type 2 (also if they do not have signs/symptoms of catecholamine excess) and in carriers of germline mutations in PPGL susceptibility genes [5].

Catecholamine excess is screened by biochemical tests: plasma or urinary free metanephrines are the most reliable indicator of tumor metabolism of catecholamines, superior to the assay of free catecholamines which are rather the expression of a secretory, often paroxysmal activity.

Plasma metanephrines and urinary free metanephrines have higher and comparable sensitivity (99% and 97%, respectively) [6]. Plasma 3-methoxytyramine can be used to detect rare dopamine-producing tumors and could also be a useful biomarker to assess the risk of malignancy. Plasmatic biochemical tests are associated with a high rate of false positive results: this is usually due to high sympathetic activity during blood sampling. To overcome this procedural error, blood sampling should be performed in a quiet room, after at least 20–30 min of supine rest; if the procedure cannot be performed with adequate accuracy, it is better to omit the plasma assay and rely on the urine test alone. A twofold increase of the upper cut-off values in one plasma metabolite or any increase in two or more metabolites have a high positive predictive value, and the patient should be referred for imaging studies [5]. Drug or food interference is responsible for false positive results: tricyclic antidepressants, α-blockers, cocaine, levodopa, MAO inhibitors, sympathomimetics, sulfasalazine may cause increased catecholamine metabolites. Caffeine, tea, alcohol, cheese, bananas, almonds, hazelnuts, vanilla should be discontinued 3 days before blood or urine sampling. Plasma chromogranin is also recommended in subjects with a clinical probability for PPGL (incidentaloma, genetic risk) once the plasma free metanephrines, 3-methoxytyramine and urinary metabolites are negative [5].

2.4 Perioperative Management

Perioperative management requires optimization of blood pressure, heart rate control and restoration of volume depletion. The alpha-adrenergic blockers doxazosin or phenoxybenzamine are traditionally considered the treatment of choice and should be given also to normotensive patients if biochemistry is indicative of catecholamine secretion. Doxazosin is a selective and competitive α1 adrenergic blocker that is given at a dose ranging from 2 to 32 mg/day in three times. Phenoxybenzamine, a non-selective and non-competitive α1–α2 adrenergic blocker, is given at a standard dose of 10 mg twice daily and can be titrated as necessary; it is not available in Italy but it is commonly prescribed in northern Europe and America. Alpha-blockers should be started at least 7–14 days before surgery [5, 7]. This recommendation has been critically questioned as it is only based on observational studies without solid evidence that the therapy with α-blockers confers any advantage in reducing perioperative mortality [8, 9]. This criticism has not received consensus and the guidelines confirm the indication for preoperative therapy with α-blockers [5, 10]. Beta-adrenergic receptor blockers can be added to control the heart rate, but only after at least 2 days of α-adrenoceptor blockade, to prevent a hypertensive crisis due to unopposed α-adrenergic receptor vasoconstriction when beta-adrenergic receptor-mediated vasodilation is blunted.

If blood pressure control is suboptimal, a calcium antagonist or renin-angiotensin blocker system can be added. Target blood pressure is lower than 130/80 mmHg in a sitting position, with a systolic blood pressure not lower than 90 mmHg while standing. A high sodium diet (5 g/day) and generous fluid intake (2.5 L/day) should be encouraged in the week before surgery; for patients with labile blood pressure values and hemodynamic instability, intravenous fluid replacement the day before surgery should be suggested.

PPGL surgery has a high risk of in intraoperative hemodynamic lability; induction of anesthesia, intubation, insufflation of peritoneum, tumor manipulation, can all trigger massive catecholamine release, so the presence of an experienced anesthesiologist is needed.

Postoperative hypotension should be treated with generous intravenous fluid replacement; also prolonged and severe hypoglycemia may appear after surgery, especially after resection of large secreting tumors: these conditions may be incorrectly diagnosed as expressions of hypoadrenalism, since after unilateral adrenalectomy adrenal function is preserved. Steroid replacement therapy is required after extensive surgery resulting in bilateral adrenalectomy or sometimes after unilateral adrenalectomy and adrenal sparing surgery on the contralateral gland.

2.5 Staging

The American Joint Committee on Cancer (AJCC) established the tumor-nodes-metastasis classification (TNM) (Table 2.1). The size of the primary tumor is a clinical predictor of metastasis, based on studies of survival and ability to metastasize; the cut-off of 5 cm was chosen to identify the transition between category T1 and T2.

Table 2.1 AJCC TNM and stage definitions for pheochromocytoma and paraganglioma
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TNM and AJCC prognostic stage groups have been shown to correlate with overall survival. Stage I includes patients who have very low metastatic potential and excellent prognosis, with the exception of patients with mutant succinate dehydrogenase subunit B gene (SDHB) for whom, even in the presence of tumor <5 cm without invasion of surrounding tissues, the risk of metastasis is higher: patients with SDHB germline mutation can be considered already stage II, regardless of the size of the tumor [3].

2.6 Prognostic Factors

PPGL has the potential to metastasize and is therefore defined as tumor with uncertain biological behavior. When not metastatic at onset, distinguishing a benign PPGL from tumors with metastatic potential is very challenging. Several anatomopathological, molecular and biological characteristics have been identified as possible prognostic factors of malignancy. A Ki67 index greater than 3% is a reliable indicator of proliferating cells and predictor of tumor progression (high specificity); however, it is often low or negative in PPGL (low sensitivity). It has been well demonstrated that norepinephrine-secreting tumors (predominantly paragangliomas) are more frequently malignant than those secreting epinephrine (almost exclusively PHEOs), and high plasmatic 3-methoxytyramine correlates with poorly differentiated PPGL.

The Pheochromocytoma of the Adrenal gland Scaled Score (PASS) is a scoring system which involves multiple histological features (Table 2.2) [11]. A PASS ≥4 is suggestive for PPGL with metastatic potential, with 50% sensitivity and 45% specificity. Unfortunately, the reliability of the PASS is affected by the subjective interpretation of the pathologist, limiting its clinical utility.

Table 2.2 PASS (Pheochromocytoma of the Adrenal gland Scaled Score)
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The GAPP (Grading system for Adrenal Pheochromocytoma and Paraganglioma) scoring system includes histopathologic characteristics and biochemical profile (Table 2.3) [11]. According to the GAPP score, PPGLs are classified as well, moderately, and poorly differentiated, and this classification correlates with 10-year survival rates (83%, 38%, and 0%, respectively).

Table 2.3 GAPP (Grading system for Adrenal Pheochromocytoma and Paraganglioma) score
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The analysis of gene expression in tumor tissue has highlighted how detection of a larger number of somatic mutations is associated with worse outcome. The presence of a germline mutation of SDHB gene is a well-known predictor of malignancy. About 50% of SDHB-mutated patients have a metastatic disease at onset or develop metastasis during the follow-up. The presence of SDHB mutation is also associated with reduced median overall survival (42 vs. 244 months in non-SDHB mutant metastatic PPGL) [11]. An up-to-date GAPP score (M-GAPP) includes loss of SDHB immunohistochemistry staining as a surrogate for SDHB expression but it has yet to be validated (Table 2.4).

Table 2.4 M-GAPP score
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Recent molecular studies have identified three different molecular signatures in PPGL; in accordance with the germinal and/or somatic mutation leading to the activation of oncogenic signaling pathway, the tumor is attributed to a specific cluster: the pseudo-hypoxic cluster, the kinase cluster, and the Wnt cluster. These three molecular clusters differ in phenotype and clinical behavior. Somatic or germinal mutations in the Krebs cycle-associated genes (SDHx, FH, MDH2, GOT2, SLC25A11, DLST, IDH1) and VHL/EPAS1 related genes (PHD1/2, EGLN1, EPAS1, IRP1) cause activation of pseudohypoxic pathway (cluster 1) and are associated with a more aggressive behavior.

2.7 Postoperative Follow-Up

Patients operated on for PPGL need a follow-up of at least 10 years to screen for local or metastatic recurrences. Patients with high risk of recurrence or malignancy (genetic risk, very large tumors, unfavorable prognostic factors) should be offered lifelong follow-up. Plasma and/or urinary free metanephrines should be tested annually; subjects with normal preoperative levels of metanephrines and elevated chromogranin-A should be screened with annual chromogranin-A assessment. For patients with completely negative preoperative biochemistry, follow-up should be performed with imaging examinations every 1–2 years [12].