Pheochromocytomas are tumors arising from catecholamine-producing chromaffin cells of the adrenal medulla while paragangliomas (PGs) are tumors derived from extra-adrenal chromaffin cells (functional or nonfunctional)¹.

Pheochromocytomas and paragangliomas are neuroendocrine tumors that produce, store, and release catecholamines. They are indistinguishable at the cellular level and have similar clinical presentations. The clinical manifestations of pheochromocytomas are secondary to catecholamine excess and include hypertension (HTN), tachycardia, headaches, palpitations, diaphoresis, chest pain, anxiety, and weight loss¹.

Hypertension is the most common manifestation, occurring in up to 90% of cases, either sustained or paroxysmal as serious hypertensive crisis¹. Retroperitoneal paragangliomas are rare. While pheochromocytomas originate in the core of the adrenal glands, extra-adrenal paraganglioma tumors arise from ganglia along the sympathetic and parasympathetic chain. Most of them are functional, with symptoms and signs of catecholamine overproduction similar to those of pheochromocytoma, except for the variation in the anatomic location. The risk of malignancy may be as high as 20%-30% compared with a 10% risk of malignancy for adrenal pheochromocytoma².

We report the case of a 43-year-old obese female patient, former smoker, who was evaluated by the Department of Cardiology for resistant hypertension, headaches and palpitations. The urine catecholamine test revealed the following results: epinephrine 58 mcg/24 h (NV: 2-24 mcg/24 h) and norepinephrine 325 mcg/24 h (15-100 mcg/24 h). Plasma catecholamine concentrations were within normal ranges (epinephrine 70 pg/mL and norepinephrine 1320 pg/ mL). Plasma renin activity was 15.60 ng/mL/h (NV: 0.48‑4.80 ng/mL/h). The abdominal ultrasound did not evidence any particular finding. On magnetic resonance imaging (MRI) there was an expansive solid retroperitoneal and latero-aortic mass measuring 50 mm in the cephalocaudal plane and 41 mm posteriorly with hyperintense signal on T2-weighted images, characteristic of pheochromocytomas (light bulb sign) (Fig. 1).

Figure 1 A. The mass presents well-defined lobulated contours, heterogeneous enhancement with contrast medium and restricted movement of water molecules indicating hypercellularity. B. The lesion is in contact with the aorta and the flexure between the 3rd and 4th parts of the duodenum. The adrenal glands look normal. 

Once the diagnosis was made, treatment with doxasozin and labetalol was started. Laparoscopic surgery was decided. A heterogeneous smooth retroperitoneal mass measuring 4.3 × 3 × 2 cm in diameter, fibrous in consistency, was resected from the left lateral para-aortic region. Pathology examinations reports with haematoxylin and eosina were consistent with paraganglioma (Fig. 2). The immunohistochemical test confirmed the diagnosis with positive staining with synaptophysin. The patient evolved with favorable outcome and was discharged on postoperative day 4. Three months later, she was asymptomatic and her blood pressure was within normal ranges, without antihypertensive treatment. Eighteen months after surgery, the patient remained asymptomatic, with normal blood pressure levels without requiring medication; the catecholamine and renin levels were within normal parameters. Magnetic resonance imaging (MRI) and computed tomography (CT) scan were also performed at each visit, which reported absence of local recurrence or distant disease. The role of the paraganglia is to maintain blood pressure during the first years of life. After birth, paraganglia grow until the age of 12-18 months, when they regress and become microscopic remnants in adults³.

Figure 2 The pathology examination reports histological findings consistent with paraganglioma, with mitotic count of 0-1 mitosis per 10 highpower fields and without necrosis. There are few ganglia cells in the periphery, invasion of the fibroconnective capsule and infiltration of the adjacent adipose tissue. Section stained with haematoxylin and eosin. Magnification x10. 

Tumor proliferation of extra-adrenal chromaffin cells gives rise to paragangliomas². They can be classified into functional, chromaffin tumors or sympathetic paragangliomas, and non-functional, nonchromaffin tumors or parasympathetic paragangliomas. They account for 0.012% of all human tumors, with an incidence of 0.02-0.05 cases/100,000 inhabitants/year and are more common in women between the third and fifth decade of life. Paragangliomas occur in 0.05% to 0.1% of patients with sustained hypertension⁴. These tumors produce, store, and release catecholamines: dopamine (DA), epinephrine (Epi) and norepinephrine (NEpi). Catecholamines are partially or fully metabolized within the tumor by catechol-O-methyltransferase to inactive metabolites normetanephrine and metanephrine⁴. The most common extradrenal location in the abdomen is the sympathetic ganglia around the aorta, particularly in the organ of Zuckerkandl. They are usually single tumors (80-85%) and frequently present malignant transformation with metastasis in regional lymph nodes, lung, liver or bone. The presence of metastases suggests multiple paraganglioma⁴.

Paragangliomas can be secretory and produce catecholamines, or non-secretory. Secretory (sympathetic) paragangliomas usually occur in the thorax, abdomen and pelvis. The symptoms associated with hypersecretion include sustained or paroxysmal blood pressure elevations, headaches, episodic profuse sweating, palpitations, tremors, pallor, and anxiety. The classic tetrad of hypertension, headache, palpitations and sweating is common. These symptoms are usually paroxysmal, although sustained hypertension occurs between paroxysmal episodes in 50% to 60% of patients. The frequency, severity and duration of these episodes may vary and are often extremely difficult to manage. Hypertensive crisis may lead to cardiac arrhythmia, myocardial infarction and even death. Nonfunctional paragangliomas are usually asymptomatic and are detected incidentally³.

Diagnostic imaging techniques, 24-hour urine test for metanephrines and plasma catecholamines are essential for tumor diagnosis and localization. Catecholamine or metanephrine levels in patients with symptomatic paragangliomas are usually 2 or 3 times higher than the upper reference limits³. CT and MRI images are primary and fundamental tools for the diagnosis of paragangliomas which appear as hypervascularized mass; hypovascularization is exceptional⁴.

The definitive diagnosis is made by inmumohistochemichal testing of the specimen because cytology cannot differentiate between paragangliomas and other neuroendocrine tumors. The criteria for the diagnosis of malignancy are based on PASS (Pheochromocytoma of the Adrenal gland Scaled Score). A score ≥ 4/15 identifies tumors with a more aggressive biologic behavior⁵.

Open exploration and resection are the standard surgical treatment for PG; however, laparoscopic resection for PG is challenging due to the abnormal anatomic location, dense peritumoral adhesions, hypervascularization, and proximity to major blood vessels. Treatment with α- and β-adrenergic receptor blockers is necessary to avoid hemodynamic instability during the intervention⁶.

Alpha-adrenergic blockade should be initiated immediately after the diagnosis of any catecholaminesecreting tumor (pheochromocytoma, paraganglioma or, rarely, ganglioneuroma) has been made. Phentolamine is the agent most used. Alternative selective α-1 blockers are prazosin, doxazosin and terazosin⁵.

Beta blockers (propranolol, atenolol or labetalol) can be used in patients with tachyarrhythmia or on a routine basis and should always be preceded by complete α-adrenergic blockade to avoid hypertensive crisis, heart failure and acute pulmonary edema⁵. Five-year survival after oncologic resection of malignant paragangliomas is 52%. The possibility of late metastases requires indefinite follow-up every 6 months³.