Paraganglioma (Extraadrenal pheochromocytoma) 수요증례 Review Kyunghee University College of Medicine Department of Internal Medicine R3 Ha Sung Hyung

Pheochromocytomas produce, store, and secrete catecholamines. Usually derived from the adrenal medulla but may develop from chromaffin cells in or about sympathetic ganglia(extraadrenal pheochromoc- ytomas or paragangliomas) Related tumors(secrete catecholamins and produce similar clinical syndromes) - Chemodectomas derived from the carotid body, - Ganglioneuromas derived from the postganglionic sympathetic neurons.

"10-percent rule" Pheochromocytomas 10% bilateral 10% malignant 10% extra-adrenal

Organ of Zuckerkandl The Organ of Zuckerkandl (or paraaortic bodies) is a chromaffin body derived from neural crest located at the bifurcation of the aorta or at the origin of the inferior mesenteric artery. During the early gestational period as a homeostatic regulator of blood pressure, secreting catecholamines into the fetal circulation. The organ itself regresses in the late third trimester and following birth to form the aortico-sympathetic group of the adult paraganglia. The Organ of Zuckerkandl is of pathological significance in the adult as the most common extra-adrenal site of pheochromocytoma (paraganglioma),

Inheritance of paraganglioma Familial paragangliomas account for approx. 25% of cases ; often multiple, bilateral, occur at an earlier age. Mutations of the genes SDHD (previously known as PGL1), PGL2, and SDHC (previously PGL3) have been identified as causing familial head and neck paragangliomas. Mutations of SDHB play an important role in familial adrenal pheochromocytoma and extra-adrenal paraganglioma (of abdomen and thorax)

Pathology of paraganglioma Grossly as sharply circumscribed polypoid masses and have a firm to rubbery consistency, and highly vascular tumors and have a deep red color. Microscopicaly, ; arranged in distinctive cell balls, called ‘Zellballen’. These cell balls are separated by fibrovascular stroma and surrounded by sustenacular cells. - Differential diagnosis ; neuroendocrine tumors, middle ear adenoma, meningioma… Immunohistochemistry ; positive for chromogranin, synaptophysin, neuron specific enolase, serotonin and neurofilament.

Paragangliomas are described by their site of origin and are often given special names… Carotid paraganglioma Glomus tympanicum Glomus jugulare Vagal paragangliomas Other sites larynx, nasal cavity, paranasal sinuses, thyroid gland, and the thoracic inlet.

Clinical characteristics Sustained or paroxysmal hypertension is the most common sign. Classic triad — ‘episodic headache, sweating, palpitation’ - Headche: mild or severe, and variable in duration, occurs in up to 90%. - Sweating: occurs in up to 60 to 70%. - Other symptoms include dyspnea, generalized weakness, and panic attack-type symptoms…. A simplified diagnostic approach to pheochromocytoma. Medicine (Baltimore) 1991; 70:46.

Less common symptoms Pallor, Constipation, Orthostatic hypotension, Visual blurring, Papilledema, Weight loss, Polyuria, Polydipsia, ..may reflect the toxic effect of excess catecholamines Pheochromocytoma: New concepts and future trends. Kidney Int 1991; 40:544. Constipation, Increased ESR, Hyperglycemia, Leukocytosis, Psychiatric disorders, Dilated cardiomyopathy

DIAGNOSIS Biochemical Tests - Free Catecholamines - Metanephrines and VMA - Plasma Catecholamines - Plasma Metanephrines Provocation testing & Suppression testing phentolamine, glucagon, histamine, metoclopramide, and tyramine tests are rarely needed.

Clonidine suppression test Centrally acting alpha(2)-adrenergic receptor agonist that normally suppresses the release of catecholamines from neurons but does not affect from a pheochromocytoma. Clonidine (0.3 mg) is administered orally, and plasma catecho- lamines or metanephrines (before and three hours after) Essential HTN; P-catecholamine concentrations decrease ( norepi. + epi. <500 pg/mL or >50 percent decrease in norepi.) P-normetanephrine concentrations decrease (into normal range or >40 percent decrease) The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls. Arch Intern Med 1992; 152:1193.

Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab 2003; 88:2656.

Imaging of paraganglioma CT and MRI are often used to determine the extent of the tumor. MIBG (123-I-metaiodobenzylguanidine) 111-Indium-pentetreotide scintigraphy (Octreoscan), total body MRI, PET scanning…

Imaging of paraganglioma Superior and inferior abdominal paraaortic areas (75% of extraadrenal tumors) Urinary bladder (10%) Thorax (10%) Head, neck, and pelvis (5%) Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med 2003; 138:424.

Treatment (Preoperative Management) α-receptor blockade (phenoxybenzamine) : initial dose is 10 mg every 12 h (10 to 20 mg added every few days)… at least 10 to 14 days prior to surgery. Nitroprusside, calcium channel blocking agents, and possibly angiotensin-converting enzyme inhibitors β-Adrenergic receptor blocking agents ;10 mg propranolol three to four times per day

Treatment (Surgery) Surgical mortality is <2 or 3%. Monitoring ; continuous recording of arterial pr., CVP, EKG… Adequate fluid replacement ; Intraoperative hypotension responds better to volume replacement than to vasoconstrictors Hypertension and cardiac arrhythmias ; induction of anesthesia, intubation, manipulation of the tumor.  phentolamine, nitroprusside, propranolol…

Treatment (Unresectable and Malignant Tumors) Histologically and biochemically the same as benign ones. ( only local invasion or distant metastases, about 10% ) Surgical removal of the tumor to improve symptoms is the primary therapy for malignant pheochromocytoma. Metastatic lesions should be resected if possible. - external radiation therapy - cryoablation therapy - 131I-MIBG - Radiofrequency ablation

Prognosis and Follow-Up 5-year survival rate after surgery is usually >95%, the recurrence rate is <10%. (malignant pheochromocytoma ; the 5-year survival rate is usually <50%) Catecholamine excretion should be assessed at the reappearance of suggestive symptoms or yearly if the patient remains asymptomatic.