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

 

 Buy Article Permissions and Reprints

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.

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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 3 Bravo E L. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma.  Endocr Rev. 1994;  15 356-368
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 9 Kier R, McCarthy S. MR characterization of adrenal masses: field strength and pulse sequence considerations.  Radiology. 1989;  171 671-674
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar

E. C. degli Uberti. M. D.

Section of Endocrinology · Dept. of Biomedical Sciences and Advanced Therapies · University of Ferrara

Via Savonarola 9 · 44100 Ferrara · Italy

Phone: + 01139-0532-236682 ·

Fax: + 01139-0532-236514

Email: ti8@unife.it