An In Vivo OctreoScan-Negative Adrenal Pheochromocytoma Expresses Somatostatin Receptors and Responds to Somatostatin Analogs Treatment In Vitro

Abstract

A 52-yr-old woman presented with hypertension, elevated urinary vanillylmandelic acid, metanephrines, normetanephrines, and plasma chromogranin A (CgA), but normal urinary catecholamine levels. Abdominal ultrasonography and subsequent MRI imaging showed a 3 cm nodular lesion of the right adrenal gland also visualized by ¹²³I-meta-iodobenzylguanidine scintigraphy consistent with a pheochromocytoma (PC). Her OctreoScan was negative. The patient underwent right adrenalectomy and histological examination showed a PC. The adrenal medulla tissue was examined for somatostatin (SRIH) receptor subtypes 1 to 5 (SSTR1 to 5) expression by RT-PCR. Cultured tumor cells were treated with either SRIH, Lanreotide (Lan), or an SSTR2 (BIM-23 120) or SSTR5 (BIM-23 206) selective agonist. CgA secretion was measured in the medium by ELISA and catecholamine levels by HPLC after 6h. Cell viability was assessed after 48h. RT-PCR analysis showed that SSTR1, 2, 3 and 4 were expressed. CgA secretion was significantly reduced by SRIH (- 80 %), Lan (- 35 %), and the SSTR2 selective agonist (- 65 %). Norepinephrine secretion was reduced by SRIH (- 66 %), Lan (- 40 %), and BIM-23 120 (- 70 %). Epinephrine and dopamine secretion was also inhibited by treatment with SRIH (- 90 % and - 93 %, respectively) and BIM-23 120 (- 33 % and - 75 %, respectively) but not by Lan. Cell viability was also significantly reduced by SRIH (- 30 %), Lan (- 10 %), and the SSTR2 selective agonist (- 20 %). The SSTR5 selective agonist did not modify either CgA and catecholamine secretion or cell viability. Our data show that SSTRs may be present in a PC although OctreoScan is negative in vivo, and that SRIH and its analogs may reduce both differentiated and proliferative functions in chromaffin cells in vitro. These findings suggest that SRIH analogs with enhanced SSTR2 affinity might be useful in the medical therapy of PC, even when an OctreoScan is negative.

Key words

Pheochromocytoma - Somatostatin - Somatostatin Receptors - Chromogranin A - Catecholamines

References

• 1 Pacak K, Linehan W M, Eisenhofer G, Walther M M, Goldstein D S. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma.  Ann Int Med. 2001;  134 315-329
• 2 Radin D R, Ralls P W, Boswell W D, Colletti P M, Lapin S A, Halls J M. Pheochromocytoma: detection by unenhanced CT.  Am J Roentgenol. 1986;  146 741-744
• 3 Bravo E L. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma.  Endocr Rev. 1994;  15 356-368
• 4 Neumann H P, Berger D P, Sigmund G, Blum U, Schmidt D, Parmer R J, Volk B, Kirste G. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease.  N Eng J Med. 1993;  329 1531-1538
• 5 Vieira A E, Mello M P, Elias L L, Lau I F, Maciel L M, Moreira A C, Castro M. Molecular and biochemical screening for the diagnosis and management of medullary thyroid carcinoma in multiple endocrine neoplasia type 2A.  Horm Metab Res . 2002;  34 202-206
• 6 Kudva Y C, Young W F Jr, Thompson G B. et al . Adrenal incidentaloma: an important component of the clinical presentation spectrum of benign sporadic adrenal pheochromocytoma.  The Endocrinologist. 1999;  9 77
• 7 Bondanelli M, Campo M, Trasforini G, Ambrosio M R, Zatelli M C, Franceschetti P, Valentini A, Pansini R, degli Uberti E C. Evaluation of hormonal function in a series of incidentally discovered adrenal masses.  Metabolism. 1997;  46 107-113
• 8 van der Harst E, de Herder W W, Bruining H A, Bonjer H J, de Krijger R R, Lamberts S W, van de Meiracker A H, Boomsma F, Stijnen T, Krenning E P, Bosman F T, Kwekkeboom D J. [(¹²³)I]metaiodobenzylguanidine and [(¹¹¹)In]octreotide uptake in benign and malignant pheochromocytomas.  J Clin Endocrinol Metab. 2001;  86 685-693
• 9 Kier R, McCarthy S. MR characterization of adrenal masses: field strength and pulse sequence considerations.  Radiology. 1989;  171 671-674
• 10 Shimon I, Taylor J E, Dong J Z, Bitonte R A, Kim S, Morgan B, Coy D H, Culler M D, Melmed S. Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid stimulating hormone, and prolactin regulation.  J Clin Invest. 1997;  99 789-798
• 11 Zatelli M C, Tagliati F, Taylor J E, Rossi R, Culler M D, degli Uberti E C. Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line TT.  J Clin Endocrinol Metab. 2001;  86 2161-2169
• 12 Zatelli M C, Tagliati F, Taylor J E, Piccin D, Culler M D, degli Uberti E C. Somatostatin, but not somatostatin receptor subtypes 2 and 5 selective agonists, inhibits calcitonin secretion and gene expression in the human medullary thyroid carcinoma cell line, TT.  Horm Metab Res. 2002;  34 229-233
• 13 Shimizu C, Kubo M, Takano K, Takano A, Kijima H, Saji H, Katsuyama I, Sasano H, Koike T. Interleukin-6 (IL-6) producing phaeochromocytoma: direct IL-6 suppression by non-steroidal anti-inflammatory drugs.  Clin Endocrinol. 2001;  54 405-410
• 14 Bondanelli M, Ambrosio M R, Franceschetti P, Margutti A, Trasforini G, degli Uberti E C. Diurnal rhythm of plasma catecholamines in acromegaly.  J Clin Endocrinol Metab. 1999;  84 458-2467
• 15 Invitti C, de Martin I, Bolla G B, Pecori Giraldi F, Maestri E, Leonetti G, Cavagnini F. Effect of octreotide on catecholamine plasma levels in patients with chromaffin cell tumors.  Horm Res. 1993;  40 156-160
• 16 Koriyama N, Kakei M, Yaekura K, Okui H, Yamashita T, Nishimura H, Matsushita S, Tei C. Control of catecholamine release and blood pressure with octreotide in a patient with pheochromocytoma: a case report with in vitro studies.  Horm Res. 2000;  53 46-50
• 17 Kopf D, Bockisch A, Steinert H, Hahn K, Beyer J, Neumann H P, Hensen J, Lehnert H. Octreotide scintigraphy and catecholamine response to an octreotide challenge in malignant phaeochromocytoma.  Clin Endocrinol. 1997;  46 39-44
• 18 Epelbaum J, Bertherat J, Prevost G, Kordon C, Meyerhof W, Wulfsen I, Richter D, Plouin P F. Molecular and pharmacological characterization of somatostatin receptor subtypes in adrenal, extraadrenal, and malignant pheochromocytomas.  J Clin Endocrinol Metab. 1995;  80 1837-1844
• 19 Eisenhofer G, Kaiser H R, Friberg P, Mezey E, Huynh T-T, Hiremagalur B, Ellingson T, Duddempudi S, Eijsbouts A, Lenders J. Plasma metanephrines are markers of pheochromocytoma produced by catecol-O-methyltransferase within tumors.  J Clin Endocrinol Metab. 1998;  83 2175-2185
• 20 Eisenhofer G, Lenders J, Linehan W M, Walther M M, Goldstein D S, Kaiser H R. Plasma normetanephrines and metanephrines for detecting pheochromocytoma in von Hippel-Lindau disease and multiple neoplasia type 2.  N Engl J Med. 1999;  340 1872-1879
• 21 Eisenhofer G, Huynh T-T, Hiroi M, Pacak K. Understanding catecholamines metabolism as a guide to the biochemical diagnosis of pheochromocytoma.  Rev Endocr Metab Dis. 2001;  2 297-311
• 22 van der Harst E, de Herder W W, de Krijger R R, Bruining H A, Bonjer H J, Lamberts S WJ, van der Meiracker A H, Stijnen T H, Boomsma F. The value of plasma markers for the clinical behaviour of phaeochromocytomas.  Eur J Endocrinol. 2002;  147 85-94