0021-972X/90/7006-1559$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright© 1990 by The Endocrine Society
Vol. 70, No. 6 Printed in U.S.A.
A Case of Pheochromocytoma Producing Parathyroid Hormone-Related Protein and Presenting with Hypercalcemia* SATOSHI KIMURA, YOJI NISHIMURA, KEN YAMAGUCHI, KOICHI NAGASAKI, KAORU SHIMADA, AND HISANORI UCHIDA Departments of Infectious Diseases and Applied Immunology (S.K., K.S.) and Surgery (Y.N., H.U.), Institute of Medical Science, University of Tokyo, and the Growth Factor Division, National Cancer Center Research Institute, (K. Y., K.N.) Tokyo, Japan
ABSTRACT. A 54-yr-old man with a left adrenal pheochromocytoma showed mild hypercalcemia and elevated nephrogenous cAMP. Serum levels of PTH and 1,25-dihydroxyvitamin D3 were not elevated. Postoperatively, serum calcium and nephrogenous cAMP declined to normal ranges. Pathologically, the tumor was a benign pheochromocytoma. The clinical findings resembled those of humoral hypercalcemia of malignancy (HHM), and PTH-related protein (PTHrP) immunoreactivity was detected in the tumor extract at a concentration of 80.7 pmol/g wet wt, which is high compared to levels in malignant tumors causing HHM. Production of PTHrP was further con-
firmed by the demonstration of PTHrP mRNA with Northern blot hybridization analysis. Gel filtration of the extract revealed the presence of at least two different molecules with both immunological and biological activities. One of the peaks appeared close to PTHrP-(l-34), and the other between cytochrome-c and BSA. The latter showed a higher bioactivity to immunoreactivity ratio. These data indicate the multiplicity of PTHrP molecules in pheochromocytoma and support the idea that PTHrP produced by pheochromocytoma causes hypercalcemia in a similar fashion as HHM. (J Clin Endocrinol Metab 70: 1559-1563, 1990)
H
YPERCALCEMIA is a rare but well documented complication in patients with pheochromocytoma. Other than pheochromocytoma associated with primary hyperparathyroidism, known as multiple endocrine neoplasia type II, four mechanisms have been proposed as the pathogenesis of hypercalcemia in these patients: 1) stimulation of bone resorption by catecholamines (1), 2) stimulation of PTH secretion from the parathyroid glands by catecholamines (2, 3), 3) ectopic production of PTH by pheochromocytoma (4-6), and 4) production of a calcium-mobilizing humoral agent(s) other than PTH by pheochromocytoma (7). The last possibility has been strengthened by the recent observation by Stewart et al. (8) that pheochromocytoma produced a novel factor that stimulated bone resorption and renal cortical adenylate cyclase in vitro, but differed from PTH. More recently, PTH-related protein (PTHrP) has been identified in malignant tumors causing humoral
hypercalcemia of malignancy (HHM) (9-11), and its cDNA and whole amino acid sequence have been determined (12). Recent evidence (13, 14) indicates that the peptide may be the major factor that causes HHM. In 1988, mRNA for the peptide was also found in two cases of hypercalcemic pheochromocytomas (15), and two forms of adenylate cyclase-stimulating activity were confirmed in one of the tumors (16). The amount of the peptide, however, has not as yet been quantitated. In addition, information on the molecular forms of PTHrP present in pheochromocytoma is limited. We describe a case of a benign pheochromocytoma which produced PTHrP and presented with hypercalcemia. The amount of the peptide was quantitated by RIA and the molecular size heterogeneity of bioactivity and immunoreactivity was compared.
Case Report
Received November 20,1989. Address all correspondence and requests for reprints to: Dr. Satoshi Kimura, Department of Infectious Diseases and Applied Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan. * This work was supported in part by Grants-in-Aid for Cancer Research 62-26 and 1-33 from the Ministry of Health and Welfare, Japan.
A 54-yr-old man was transferred to our hospital in August 1988 because of a left adrenal tumor. He had experienced occasional episodes of palpitation for 10 yr before admission. Otherwise, he had no medical problems. On admission, his blood pressure was 144/70 mm Hg, and heart rate was 88 beats/ min (regular). Computed tomographic scan, ultrasonography,
1559
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KIMURA ET AL.
and angiography all revealed a well defined left adrenal tumor, about 5 x 6 cm. Urinary excretion of catecholamines were: norepinephrine, 811-1.020 /ig/day (normal, 10-90); epinephrine, 9.0-23 Mg/day (normal,
Vol. 70, No. 6 Printed in U.S.A.
A Case of Pheochromocytoma Producing Parathyroid Hormone-Related Protein and Presenting with Hypercalcemia* SATOSHI KIMURA, YOJI NISHIMURA, KEN YAMAGUCHI, KOICHI NAGASAKI, KAORU SHIMADA, AND HISANORI UCHIDA Departments of Infectious Diseases and Applied Immunology (S.K., K.S.) and Surgery (Y.N., H.U.), Institute of Medical Science, University of Tokyo, and the Growth Factor Division, National Cancer Center Research Institute, (K. Y., K.N.) Tokyo, Japan
ABSTRACT. A 54-yr-old man with a left adrenal pheochromocytoma showed mild hypercalcemia and elevated nephrogenous cAMP. Serum levels of PTH and 1,25-dihydroxyvitamin D3 were not elevated. Postoperatively, serum calcium and nephrogenous cAMP declined to normal ranges. Pathologically, the tumor was a benign pheochromocytoma. The clinical findings resembled those of humoral hypercalcemia of malignancy (HHM), and PTH-related protein (PTHrP) immunoreactivity was detected in the tumor extract at a concentration of 80.7 pmol/g wet wt, which is high compared to levels in malignant tumors causing HHM. Production of PTHrP was further con-
firmed by the demonstration of PTHrP mRNA with Northern blot hybridization analysis. Gel filtration of the extract revealed the presence of at least two different molecules with both immunological and biological activities. One of the peaks appeared close to PTHrP-(l-34), and the other between cytochrome-c and BSA. The latter showed a higher bioactivity to immunoreactivity ratio. These data indicate the multiplicity of PTHrP molecules in pheochromocytoma and support the idea that PTHrP produced by pheochromocytoma causes hypercalcemia in a similar fashion as HHM. (J Clin Endocrinol Metab 70: 1559-1563, 1990)
H
YPERCALCEMIA is a rare but well documented complication in patients with pheochromocytoma. Other than pheochromocytoma associated with primary hyperparathyroidism, known as multiple endocrine neoplasia type II, four mechanisms have been proposed as the pathogenesis of hypercalcemia in these patients: 1) stimulation of bone resorption by catecholamines (1), 2) stimulation of PTH secretion from the parathyroid glands by catecholamines (2, 3), 3) ectopic production of PTH by pheochromocytoma (4-6), and 4) production of a calcium-mobilizing humoral agent(s) other than PTH by pheochromocytoma (7). The last possibility has been strengthened by the recent observation by Stewart et al. (8) that pheochromocytoma produced a novel factor that stimulated bone resorption and renal cortical adenylate cyclase in vitro, but differed from PTH. More recently, PTH-related protein (PTHrP) has been identified in malignant tumors causing humoral
hypercalcemia of malignancy (HHM) (9-11), and its cDNA and whole amino acid sequence have been determined (12). Recent evidence (13, 14) indicates that the peptide may be the major factor that causes HHM. In 1988, mRNA for the peptide was also found in two cases of hypercalcemic pheochromocytomas (15), and two forms of adenylate cyclase-stimulating activity were confirmed in one of the tumors (16). The amount of the peptide, however, has not as yet been quantitated. In addition, information on the molecular forms of PTHrP present in pheochromocytoma is limited. We describe a case of a benign pheochromocytoma which produced PTHrP and presented with hypercalcemia. The amount of the peptide was quantitated by RIA and the molecular size heterogeneity of bioactivity and immunoreactivity was compared.
Case Report
Received November 20,1989. Address all correspondence and requests for reprints to: Dr. Satoshi Kimura, Department of Infectious Diseases and Applied Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan. * This work was supported in part by Grants-in-Aid for Cancer Research 62-26 and 1-33 from the Ministry of Health and Welfare, Japan.
A 54-yr-old man was transferred to our hospital in August 1988 because of a left adrenal tumor. He had experienced occasional episodes of palpitation for 10 yr before admission. Otherwise, he had no medical problems. On admission, his blood pressure was 144/70 mm Hg, and heart rate was 88 beats/ min (regular). Computed tomographic scan, ultrasonography,
1559
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 00:08 For personal use only. No other uses without permission. . All rights reserved.
KIMURA ET AL.
and angiography all revealed a well defined left adrenal tumor, about 5 x 6 cm. Urinary excretion of catecholamines were: norepinephrine, 811-1.020 /ig/day (normal, 10-90); epinephrine, 9.0-23 Mg/day (normal,
