Diagnosis and Management of Tumors of the Adrenal Medulla

Abstract

The adrenal medulla consists of chromaffin cells, the site of catecholamine biosynthesis. Pheochromocytomas are chromaffin-cell tumors; 80 - 85 % arise from the adrenal medulla and 15 - 20 % arise from extra-adrenal chromaffin tissues (paragangliomas). Neuroblastomas are primitive tumors that derive from the same blastic precursor as in pheochromocytomas, and are distributed along the sympathetic nervous system. Pheochromocytomas account for 6.5 % of incidentally discovered adrenal tumors; they are found in 50 % of patients with multiple endocrine neoplasia 2A (MEN 2A) and 5 - 25 % of patients with von Hippel-Lindau (VHL) syndrome. Neuroblastomas are the most common solid extra-cranial tumors in children, and account for 7 - 10 % of all tumors. The diagnosis of pheochromocytoma should first be established biochemically by measuring plasma free metanephrines (the measurement of urinary fractionated metanephrines is the second choice). Measurements of homovanillic acid (HVA), norepinephrine and vanilmandelic acid (VMA) in urine are a necessity in patients with suspected neuroblastoma. Anatomical (radiological) imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is necessary for both pheochromocytomas and neuroblastomas. Functional (nuclear medicine) methods are useful for both tumors. Scintigraphy with [¹²³I]-metaiodobenzylguanidine is the specific functional imaging test of first choice; if this is not available, scintigraphy with [¹³¹I]-MIBG is the second choice. Other newer specific modalities that have been used for evaluating pheochromocytomas include positron emission tomography (PET) with [¹⁸F]-F-fluorodopamine (F-DA) and [¹⁸F]-F-dihydroxyphenylalanine (DOPA). These should be used when MIBG scintigraphy is negative. Primary treatment for both types of tumor is surgical; chemotherapy is used for inoperable disease. After successful surgery, survival of patients with benign, sporadic pheochromocytomas is believed to be equal to that of the general population. Depending on the extent of disease and age, patients with neuroblastomas have cure rates of 15 - 90 %.

Key words

Pheochromocytoma - paraganglioma - neuroblastoma - metanephrines - radionuclide imaging - surgery - laparoscopy

References

• 1 Bornstein S R, Oelkers W. Adrenal function and metabolism.  Horm Metab Res. 2004;  36 341-345
• 2 Lack E E. Tumors of the adrenal gland and extra-adrenal paraganglia. Washington DC; Armed Forces Institute of Pathology 1997
• 3 Eisenhofer G, Lenders J W, Pacak K. Biochemical diagnosis of pheochromocytoma.  Front Horm Res. 2004;  31 76-106
• 4 Ilias I, Shulkin B, Pacak K. New functional imaging modalities for chromaffin tumors, neuroblastomas and ganglioneuromas.  Trends Endocrinol Metab. 2005;  16 66-72
• 5 van den Berg R. Imaging and management of head and neck paragangliomas.  Eur Radiol. 2005;  15 1310-1318
• 6 Neumann H P, Bausch B, McWhinney S R, Bender B U, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith W M, Munk R, Manz T, Glaesker S, Apel T W, Treier M, Reineke M, Walz M K, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C. Germ-line mutations in nonsyndromic pheochromocytoma.  N Engl J Med. 2002;  346 1459-1466
• 7 Eisenhofer G, Goldstein D S, Walther M M, Friberg P, Lenders J W, Keiser H R, Pacak K. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results.  J Clin Endocrinol Metab. 2003;  88 2656-2666
• 8 Pacak K, Ilias I, Adams K T, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour.  J Intern Med. 2005;  257 60-68
• 9 Argiris A, Mellott A, Spies S. PET scan assessment of chemotherapy response in metastatic paraganglioma.  Am J Clin Oncol. 2003;  26 563-566
• 10 Neumann H P, Cybulla M, Shibata H, Oya M, Naruse M, Higashihara E, Terachi T, Ling H, Takami H, Shuin T, Murai M. New genetic causes of pheochromocytoma: current concepts and the clinical relevance.  Keio J Med. 2005;  54 15-21
• 11 Boedeker C C, Ridder G J, Schipper J. Paragangliomas of the head and neck: diagnosis and treatment.  Fam Cancer. 2005;  4 55-59
• 12 Pacak K, Linehan W M, Eisenhofer G, Walther M M, Goldstein D S. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma.  Ann Intern Med. 2001;  134 315-329
• 13 Beltsevich D G, Kuznetsov N S, Kazaryan A M, Lysenko M A. Pheochromocytoma surgery: epidemiologic peculiarities in children.  World J Surg. 2004;  28 592-596
• 14 Elder E E, Elder G, Larsson C. Pheochromocytoma and functional paraganglioma syndrome: no longer the 10 % tumor.  J Surg Oncol. 2005;  89 193-201
• 15 Brink I, Hoegerle S, Klisch J, Bley T A. Imaging of pheochromocytoma and paraganglioma.  Fam Cancer. 2005;  4 61-68
• 16 Elsayes K M, Narra V R, Leyendecker J R, Francis I R, Lewis J S Jr, Brown J J. MRI of adrenal and extraadrenal pheochromocytoma.  AJR - Am J Roentgenol. 2005;  184 860-867
• 17 Beck O, Fassbender W J, Beyer P, Kriener S, Neumann H P, Klingebiel T, Lehrnbecher T. Pheochromocytoma in childhood: implication for further diagnostic procedures.  Acta Paediatr. 2004;  93 1630-1634
• 18 Opocher G, Conton P, Schiavi F, Macino B, Mantero F. Pheochromocytoma in von Hippel-Lindau disease and neurofibromatosis type 1.  Fam Cancer. 2005;  4 13-16
• 19 Kaltsas G A, Papadogias D, Grossman A B. The clinical presentation (symptoms and signs) of sporadic and familial chromaffin cell tumours (phaeochromocytomas and paragangliomas).  Front Horm Res. 2004;  31 61-75
• 20 Lee K L, Ma J F, Shortliffe L D. Neuroblastoma: management, recurrence, and follow-up.  Urol Clin North Am. 2003;  30 881-890
• 21 Morgenstern B Z, Krivoshik A P, Rodriguez V, Anderson P M. Wilms’ tumor and neuroblastoma.  Acta Paediatr Suppl. 2004;  93 78-84
• 22 Eisenhofer G, Lenders J W, Goldstein D S, Mannelli M, Csako G, Walther M M, Brouwers F M, Pacak K. Pheochromocytoma Catecholamine Phenotypes and Prediction of Tumor Size and Location by Use of Plasma Free Metanephrines.  Clin Chem. 2005;  51 735-744
• 23 Eisenhofer G, Goldstein D S, Sullivan P, Csako G, Brouwers F M, Lai E W, Adams K T, Pacak K. Biochemical and clinical manifestations of dopamine-producing paragangliomas: utility of plasma methoxytyramine.  J Clin Endocrinol Metab. 2005;  90 2068-2075
• 24 Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma.  J Clin Endocrinol Metab. 2004;  89 479-491
• 25 Ilias I, Alesci S, Pacak K. Current views on imaging of adrenal tumors.  Horm Metab Res. 2004;  36 430-435
• 26 Kann P H. Endoscopic ultrasound imaging of the adrenals.  Endoscopy. 2005;  37 244-253
• 27 Kann P H, Wirkus B, Behr T, Klose K J, Meyer S. Endosonographic imaging of benign and malignant pheochromocytomas.  J Clin Endocrinol Metab. 2004;  89 1694-1697
• 28 Taieb D, Sebag F, Hubbard J G, Mundler O, Henry J F, Conte-Devolx B. Does iodine-131 meta-iodobenzylguanidine (MIBG) scintigraphy have an impact on the management of sporadic and familial phaeochromocytoma?.  Clin Endocrinol (Oxf). 2004;  61 102-108
• 29 Sturgeon C, Kebebew E. Laparoscopic adrenalectomy for malignancy.  Surg Clin North Am. 2004;  84 755-774
• 30 Diner E K, Franks M E, Behari A, Linehan W M, Walther M M. Partial Adrenalectomy: The National Cancer Institute Experience.  Urology, in press (doi:10.1016/j.urology.2005.01.009) . ; 
• 31 Yip L, Lee J E, Shapiro S E, Waguespack S G, Sherman S I, Hoff A O, Gagel R F, Arens J F, Evans D B. Surgical management of hereditary pheochromocytoma.  J Am Coll Surg. 2004;  198 525-534
• 32 Neumann H PH, Reincke M, Bender B U, Elsner R, Janetschek G. Preserved Adrenocortical Function After Laparoscopic Bilateral Adrenal Sparing Surgery for Hereditary Pheochromocytoma.  J Clin Endocrinol Metab. 1999;  84 2608-2610
• 33 Nambirajan T, Leeb K, Neumann H P, Graubner U B, Janetschek G. Laparoscopic adrenal surgery for recurrent tumours in patients with hereditary phaeochromocytoma.  Eur Urol. 2005;  47 622-626
• 34 Brauckhoff M, Gimm O, Brauckhoff K, Dralle H. Repeat adrenocortical-sparing adrenalectomy for recurrent hereditary pheochromocytoma.  Surg Today. 2004;  34 251-255
• 35 Sandoval C, Strom K, Stringel G. Laparoscopy in the management of pediatric intraabdominal tumors.  JSLS - J Soc Laparoend Surg. 2004;  8 115-118
• 36 Hwang J, Shoaf G, Uchio E M, Watson J, Pacak K, Linehan W M, Walther M M. Laparoscopic management of extra-adrenal pheochromocytoma.  J Urol. 2004;  171 72-76
• 37 Brouwers F M, Lenders J W, Eisenhofer G, Pacak K. Pheochromocytoma as an endocrine emergency.  Rev Endocr Metab Disord. 2003;  4 121-128
• 38 John H, Ziegler W H, Hauri D, Jaeger P. Pheochromocytomas: can malignant potential be predicted?.  Urology. 1999;  53 679-683
• 39 Amar L, Servais A, Gimenez-Roqueplo A P, Zinzindohoue F, Chatellier G, Plouin P F. Year of Diagnosis, Features at Presentation, and Risk of Recurrence in Patients with Pheochromocytoma or Secreting Paraganglioma.  J Clin Endocrinol Metab. 2005;  90 2110-2116