J. Endocrinol. Invest. 12. 265-267 , 1989

CASE REPORT

Pentagastrin stimulation of calcitonin in pheochromocytoma does not always indicate Multiple Endocrine Neoplasia Type II MD. Hein*, J.M. Monchik**, and I.MD. Jackson* 'Division of Endocrinology, Department of Medicine and "Department of Surgery, Rhode Island Hospital, Brown University, Providence, Rhode Island, USA ABSTRACT. The diagnosis of pheochromocytoma in a 48-year-old man was confirmed by elevated catecholamine secretion and a left adrenal mass on computerized tomography. Because of a plausible family history for Multiple Endocrine Neoplasia Type II, a calcitonin level was determined which was elevated, and pentagastrin stimulation caused a 235% increase. These findings normalized fol-

lowing surgical removal of the single adrenal tumor. It is concluded that pentagastrin stimulation of calcitonin is not necessarily diagnostic of medullary thyroid carcinoma, and such a response in a patient presenting with pheochromocytoma may not indicate underlying Multiple Endocrine Neoplasia Type II.

INTRODUCTION Measurement of serum calcitonin (CT) is of critical importance in the diagnosis of medullary thyroid carcinoma (1). However, ectopic secretion of CT occurs from tumors arising in a number of other neuroendocrine tissues including the adrenal medulla (2-7). The association of pheochromocytoma with medullary thyroid carcinoma (Sipple's Syndrome) in Multiple Endocrine Neoplasia (MEN) Type II makes it important to know the source of circulating CT in patients presenting with pheochromocytoma, since both adrenals are eventually involved in the majority of cases with this syndrome (1). Indeed some authorities have recommended that bilateral adrenalectomy should be performed in a patient with MEN neoplasia type II, even if only one adrenal tumor is evident radiologically (8, 9). Pentagastrin stimulation of CT has been viewed as specific for medullary thyroid carcinoma or C-cell hyperplasia of the thyroid (1). Indeed, Mulder and Hackeng (7) found that pentagastrin produced no significant rise in CT secretion in other CT secreting tumors, including pheochromocytoma. However, we now describe marked pentagastrin stimulation of CT in a patient with sporadic pheochromocytoma. This

response disappeared after removal of a single adrenal tumor. CASE REPORT A 48-year-old, white male presented with a long history of episodic nausea, pallor, palpitations, pulsating headache and hypertension. His family history at the time of investigation included "thyroid disease" requiring surgery in his two sisters and severe hypertension in a 21-year-old nephew. On physical examination, his blood pressure was 150/80 with a pulse rate of 108/min. There was no orthostasis. The1hyroid was impalpable. On abdominal examination there were no masses or bruits. Computerized tomography of the abdomen revealed a large left adrenal mass. A diagnosis of pheochromocytoma was confirmed by increased total urinary catecholamines of 255/1g (1504 nmol)/ d (n < 100/1g [590 nmol]) and metanephrines of 15.3 mg (83.5 /1mol)/d (n 0.9 mg [4.9 /1mol]) as well as elevated plasma levels of norepinephrine and epinephrine. A serum CT (Nichol's Institute, CAl was elevated at 144 pg/ml (42 pmol/L) with a normal range of < 3-26 pg/ml « 0.9-7 .6 pmoI/L). Because of the plausible family history for MEN type lIa (subsequently not confirmed), a pentagastrin (Peptavlon, Ayerst) stimulation test was performed (Fig. 1). The baseline serum calcitonin of 151 pg/ml (44 pmol/L) rose to 373 pg/ml (109 pmol/L) at 2 min following injection. Following preoperative treatment with the alpha ad-

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Key-words. Pentagastrin. calcitonin , pheochromocytoma. Multiple Endocrine Neoplasia (MEN) Type II. Correspondence: Dr. Ivor M.D. Jackson. Division of Endocrinology, Rhode Island Hospital. 593 Eddy Street. Providence. Rhode Island 02903. USA Received October 12. 1988; accepted February 8. 1989.

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MD. Nein, JM Monchik, and I.MD Jackson

arose from a cryptic medullary thyroid carcinoma. The postoperative baseline serum CT was in the low normal range and rose only to 11 pg/ ml (3.2 pmol / L). The upper range of normal for pentagastrin stimulated calcitonin is 106 pg/ml (31 pmol/L).

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DISCUSSION It is now well established that a number of neoplasms, predominantly of neuroendocrine origin, synthesize and secrete CT (2). This peptide has been identified in pheochromocytoma tissue by radioimmunoassay and chromatographic characterization (4,6). On immunohistochemistry (3), immunoreactive CT has been localized to chromaffin granules. O'Connor et al. (4) demonstrated CT in the tissue from 9 of 15 pheochromocytomas, but no relation between tumor content and blood revel was found. Similar findings were reported by Weinstein et al. (5) in 4 patients. However, no dynamic studies of calcitonin secretion were undertaken by these investigators. Pentagastrin stimulation is a powerful stimulus for CT secretion in medullary thyroid carcinoma (7) and is used to screen patients with this disorder (1 ). The specificity of the test has been supported by reports of no or minimal « 20%) increase in serum CT from other tumors secreting CT (7). In our patient with pheochromocytoma who had an elevated basal CT there was a 235% increase following pentagastrin administration. Evidence that the adrenal medullary tumor was the source of the CT is supported by immunohistochemistry of the pheochromocytoma.

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Fig. 1 - Pentagastrin stimulation of calcitonin before and after surgical removal of a large left-sided pheochromocytoma. CT = calcitonin To convert values to pmol/ L, multiply by 0.2914.

renergic blocker phenoxybenzamine (60 mg/ d), the patient underwent a left adrenalectomy which demonstrated a 5 x 7 cm 150 g pheochromocytoma. Immunohistochemistry of the tumor was positive for calcitonin-producing cells (Fig. 2). Specificity of the immunohistochemistry was confirmed by known positive and negative controls run simultaneously. Postoperatively, a second pentagastrin stimulation test (Fig. 1) was performed to determine whether the CT had been secreted by the pheochromocytoma or

Fig.2 -Immunohistochemical staining for calcitonin (CT) in the adrenal medullary tumor using the peroxidase antiperoxidase (PAP) technique with a rabbit antiserum to human CT. The arrows indicate the brown granular staining for CT filling the cytoplasm of positive cells. Magnification X40.

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Calcitonin in pheochromocytoma

3. Hassoun J., Monges G., Giraud P., Henry J.R., Charpin C., Payan H, Toga M. Immunohisto-chemical study of pheochromocytoma. Am. J. Pathol. 114: 56, 1984.

Postoperatively the serum CT was in the low normal range, and after repeat pentagastrin injection remained well below the upper range of normal. We believe that this report is the first in a patient with a sporadic pheochromocytoma to demonstrate an elevated circulating CT able to be stimulated by pentagastrin and returning to normal postoperatively. The frequency of this response in such subjects will require further investigation. This study, however, suggests that pentagastrin stimulation of CT in a patient with pheochromocytoma should not per se be construed to indicate a diagnosis of underlying MEN Type II.

4. O'Connor D.T., Frigon R.P, Deftos L.J. Immunoreactive calcitonin in catecholamine storage vesicles of human pheochromocytoma. J. Clin. Endocrinol. Metab. 56: 582, 1983. 5. Weinstein R.S, Ide l.F. Immunoreactive calcitonin in pheochromocytomas. Proc. Soc. Exp. Bioi. MM. 165: 215, 1980. 6. Heath H. III, Edis A.J. Pheochromocytoma associated with hypercalcemia and ectopic secretion of calcitonin. Ann. Intern. Med. 91: 208, 1979.

ACKNOWLEDGMENTS We thank Dr. Ram Nayak, Department of Pathology, Rhode Island Hospital for the immunocytochemistry.

7. Mulder H, Hackeng W.HL Ectopic secretion of· calcitonin. Acta Med. Scand. 204: 253, 1978.

REFERENCES

8. Freider D.T., Thompson NW, Sisson J.C., Nishiyama R.H., Freitas J.E. Dilemmas in the early diagnosis and treatment of multiple endocrine adenomatosis. Type II. Surgery 82: 407, 1977.

1. Gagel R.F., Tashjian A.R.Jr., Cummings T., Papathnasopoulos N., Kaplan M.M., Delellis RA, Wolfe H.J., Reichlin S. The clinical outcome of prospective screening for multiple endocrine neoplasia Type 2a. An 18-year experience. N. Engl. J. Med. 318: 478, 1988.

9. lips K.J.M., Van Der Sluys Veer J., Alleman A., leo J.R., Wittebol P., Minder W.H., Kooiker C.J., Geerdink RA, Van Waes P.F.G.M., Hackeng W.H.l. Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2a (Sipple's syndrome). Am. J. Med. 70: 1051, 1981.

2. Milhaud G., Calmette C., Taboulet J., Julienne A., Moukhtar M.S. Hypersecretion of calcitonin in neoplastic conditions. lancet 1: 462, 1974.

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