Paraganglioma – a cause of hypertension in a young patient

Introduction. Collections of neuroendocrine cells dispersed throughout the body are known as paraganglia and the tumor arising from these paraganglia are known as paragangliomas. Paragangliomas located along side the aorta are associated with the pheochromocytoma and they secrete and store catecholamines. Case report. We reported a 29-year-old woman with episodes of headache, palpitations, dizziness and sweats, associated with hypertension. Elevated urine catecholamines were consistent with pheochromocytoma. Nuclear magnetic resonance (NMR) was performed and the symptoms were caused by associated mediastinal and retroperitoneal paragangliomas. The tumors were surgically removed. In a 3-year follow-up period the patient had two recidivate lesions, one of them was surgically removed, and for the last one a 6month follow-up was recommended, because urine cathecholamine level was not significantly elevated and blood pressure was normal. Conclusion. Clinical and imaging data of patients with extra adrenal paragangliomas are not specific. Many of them may be asymptomatic even when the lesion is large, but if tumor is functional, diagnosis may be easier. Patients should be initially evaluated by determining catecholamine level, followed by computerized tomography (CT) or NMR to locate the primary lesion. Since there are no definite microscopic criteria for the distinction between benign and malignant tumors, radical excision and prolonged follow-up is necessary.


Introduction
Collections of neuroendocrine cells dispersed throughout the body are known as paraganglia and tumors arising from these paraganglia are known as paragangliomas 1 .The paraganglia based on their anatomic distribution can be divided into three groups: branchiomeric, intravagal and aorticosympathetic 2 .The branchiomeric and intravagal paragan-glia are associated with the parasympathetic nervous system and are located close to the major arteries and cranial nerves of the head and neck.
Aorticosympathetic paragangliomas or extra-adrenal pheochromocytomas are located along side of the aorta and are associated with the sympathetic nervous system.They secrete and store catecholamines.Symptoms such as hypertension, flushing, sweating, headache, diaphoresis, anxiety, tachycardia or palpitations are symptoms reported in patients with increased catecholamine secretion in functional tumors 3 .
Computerized tomography (CT) scans or magnetic resonance imaging (MRI) are very useful, but diagnoses of paragangliomas can only be made with careful histological and immunohistochemical evaluation 4 .Histologically, it is well circumscribed neoplasm composed of epithelioid cells with eosinophilic cytoplasm arranged in a group and peripherally surrounded by more spindle shaped cells.Immunohistochemical stains on the paraffin tissue specimen, including chromogranin, synaptophysin, and S100, confirm the neuroendocrine origin of this neoplasm.
The treatment of choice for paragangliomas is a complete surgical resection followed by a prolonged follow-up.This may be done by 6-month ultrasound and one-year CT or MRI examinations 5 .

Case report
We described a 29-year-old woman presented with a 5month history of headache, palpitations, dizziness, sweats, associated with hypertension (160/120 mm Hg), before any examinations.
Routine laboratory tests recommended before initiating therapy, which included urinalysis, blood glucose, hematocrit, creatinine, calcium and lipoprotein profile, were normal.Holter electrocardiographic monitoring revealed inverted T wave in D1, aVL, V4-V6 leads, which attended hypertension period.
Heart, thyroid and abdominal ultrasound, renal artery doppler and ophthalmology examination were made to exclude coarctation of the aorta, thyroid and parathyroid disease, renovascular hypertension, and the above tests were normal.
Pheochromocytoma should be suspected in patients with paroxysms of hypertension accompanied by headache, palpitations, pallor perspiration and 24-hour urinary metanephrine and normetanephrine is screening diagnostic test for this disease.This involves obtaining a special urine container, which has a small amount of preservative from a medical laboratory and filling it with one entire day's worth of urine.The test is somewhat inconvenient but well worth the trouble due to its reliability and unrivaled specificity.
Twenty-four-hour urine collections in our patient showed marked elevation of norepinephrine, light elevation of epinephrine and normal level of dopamine.
The first thoracic and abdominal MRI scan demonstrated a 30.7 23.6 15 mm mass in the right paravertebral region in the level of costotransversal articulation of Th10, with heterogeneous increased intensity on T2 weighted images, which suggested necrosis and cystic degeneration of lesion.The second lesion was 18 12.8 mm, with homogeneous high intensivity on T2 weighted images behind the right renal vein and laterally from the inferior vena cava (Figures 1 and 2).

Fig. 2 -Toracoabdominal magnetic resonance (MR) scan demonstrated paravertebral paragangliomas
Elevated urinary catecholamines and MRI scan were consistent with an aorticosympathetic paraganglia in the right paravertebral space.
Preoperative management -all patients with pheochromocytoma and paraganglioma undergoing surgery should receive preoperative medical management to minimize operative and postoperative complications.The main goal of preoperative management is to normalize blood pressure, heart rate and protect a patient from the effects of high levels of circulating catecholamines during surgery, which may cause hypertensive crises and arrhythmias.Preoperative management in this case included -adrenergic antagonists, -adrenergic antagonists, calcium channel blockers and catecholamine synthesis inhibitors.The thoracic lesion was surgically removed without complications, and four months later an abdominal mass was removed, too.The characteristic of tumors were the same, they were incapsulated, without capsular invasion, solid formed, with abundant vascularisations, composed of epithelioid cells, with eosinophilic cytoplasm, surrounded with stromal septa.Immunohistochemistry showed strong positive staining of vimentin, S-100 protein, chromogranin, synaptophysin, thus the diagnosis of paraganglioma was confirmed (Figures 3 and 4).In one-year follow-up period, hypertension was persistent and in 24-hour urine collections catecholamines level was higher than normal.Functional imaging with metaiodobenzylguanidine was done and the result was normal, focal lesion was not reviewed.
It has been proposed that all patients diagnosed with a pheochromocytoma or paraganglioma should consider genetic testing to early identificate a hereditary syndrome and early screening for other associated tumors and eventual identification of family members who are at risk.Many cases of familial paraganglioma are caused by mutations in the succinate dehydrogenase (succinate: ubiquinone oxidoreductase) subunit gene SDHD.
Genetic testing showed that the patient was negative for a succinate dehydrogenase (SDH) subunit B mutation.
Multislice abdominal CT scan demonstrated inhomogeneously enhancing a soft-tissue mass of 20.8 mm located in the right paravertebral area, in front of the anterior crus of adrenal gland, behind the inferior vena cava (Figure 5).After the third surgical intervention, histopatological characteristics of the tumour indicated paragangliomas.Postoperatively, the patient was normotensive and exhibited catecholamine levels within the normal range.

Fig. 5 -Multislice computed tomography (CT) demonstrated a soft-tissue mass a 20.8 mm located in the right paravertebral area
Follow-up in six months was recommended.After 18 months MRI scan demonstrated 16 15 mm recidivate tumour in the right retroperitoneal area in front of the anterior crus of the adrenal gland, behind surgical clips.Abdominal ultrasound demonstrated 14 mm hypoechoic lesion in the position of the right adrenal gland (Figure 6).However, catecholamine level was not significantly increased and blood pressure was normal.

Discussion
Paragangliomas are extra-adrenal pheochromocytomas that arise from chromaffin cells in the sympathetic (localized in the retroperitoneum and the thorax) or parasympathetic (next to the aortic arch, neck, and skull base) neural paraganglial.They account for 10% of adult pheochromocytomas 1 .
Extraadrenal paragangliomas affect patients in the 2nd or 3rd decade of life 6 .It has been reported that 10%-40% of extra-adrenal paragangliomas are malignant 7 .Distant metastasis is the only reliable criteria for confirming malignancy.Local tissue invasion or pathological evidence of nuclear pleomorphism or mitotic activity do not necessarily imply malignancy 8 .
Functioning extra-adrenal paragangliomas represent more than 10% of all pheochromocytomas 9 .Functional paragangliomas secrete norepinephrine and normetanephrine and account for 30-60% of tumors 10 .If secretory tumor is present, patients undergo paroxysmal episodic hypertension, as well as the typical triad of symptoms associated with pheochromocytomas: palpitations, headache and profuse sweating.The nonsecretory type most commonly presents as abdominal pain or mass 11 and a large proportion of these tumors are incidentally discovered in normotensive patients during imaging evaluation for other reasons 12 .
The diagnosis is usually established with high urine catecholamine metabolites, VMA and metanephrine levels 11 .The imaging modality of choice for primary tumor evaluation and staging is CT of the thorax, abdomen and pelvis.
On CT, retroperitoneal paraganglioma appears as a hypervascular mass.Areas of intralesional hemorrhage and necrosis can be frequently seen as the tumor enlarges.They are commonly located in the para-aortic region, and they may be confused with other retroperitoneal tumors, especially pancreatic tumors 13 .MRI is more sensitive than CT in detecting extra-adrenal tumors.Scintigraphy with 123-I labelled MIBG offers superior specificity than CT and MRI imaging 14 .Genetic disorders involving mutations within the succinate dehydrogenase B and D units (SDHB, SDHD) and the von Hippel-Lindau (VHL) gene places an increased risk in the development of extra-adrenal paragangliomas and adrenal pheochromocytomas 15 .
The differential diagnosis of spinal paraganglioma includes metastases, multiple myeloma and other highly vascular tumors.Differentiation of paragangliomas from these tumors is frequently not possible on MRI and CT, because of considerable overlap in their imaging findings 1 .Thus, histopathological findings are the only adequate diagnosis for paragangliomas.
Surgical excision remains the mainstay of treatment.Since there are no definite microscopic criteria for the distinction between benign and malignant tumors, radical excision is the treatment of choice and prolonged follow-up is necessary.

Conclusion
Clinical and imaging data of patients with extra adrenal paragangliomas are not specific.Many of them may be asymptomatic even when the lesion is large, but if tumor is functional, diagnosis may be easier.Patients should be initially evaluated by determining catecholamine level, followed by CT or MRI to locate the primary lesion.Since there are no definite microscopic criteria for the distinction between benign and malignant tumors, radical excision and prolonged follow-up is necessary.

Fig. 1 -
Fig. 1 -Thoracic magnetic resonance image (MRI) demonstrated lesion in the right paravertebral region in the level of Th 10 vertebra.Abdominal MRI demonstrated lesion behind the right renal vein, laterally from the v. cava inferior

Fig. 6 -
Fig. 6 -Ultrasound showed a hypoehoic mass in the positin of the right adrenal gland