eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

Multiple Endocrine Neoplasia, Type 2: Differential Diagnoses & Workup

Author: Melanie L Richards, MD, Associate Professor, Department of Surgery, Mayo Clinic
Coauthor(s): Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine; Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine; Ruth Freeman, MD, Director of Menopause Research and Treatment Center, Professor, Departments of Medicine and Obstetrics and Gynecology, Montefiore Medical Center, Albert Einstein College of Medicine
Contributor Information and Disclosures

Updated: Feb 8, 2008

Differential Diagnoses

Other Problems to Be Considered

Hereditary pheochromocytomas may occur with the following conditions:

Hereditary hyperparathyroidism may occur with the following conditions:

  • MEN 1
  • Familial hyperparathyroidism
  • Familial hypocalciuric hypercalcemia

Workup

Laboratory Studies

  • Perform genetic screening for RET mutations in all index patients. If a mutation is identified, also screen family members who are at risk.
  • For individuals identified with a mutation or for individuals who are at risk, biochemical screening consists of baseline calcitonin levels, urine collection for catecholamines, vanillylmandelic acid and metanephrine concentrations, serum calcium level, and parathyroid hormone (PTH) level. If a patient's calcitonin level is within reference ranges, a pentagastrin and/or Ca++ stimulation test may be used to guide the necessity of a central compartment or modified neck dissection.
    • Screening for medullary thyroid carcinoma is done with the pentagastrin stimulation test, measuring serum calcitonin at baseline and at 2, 5, and 10 minutes. False-positive and false-negative results have been reported.
    • Urinary catecholamines, vanillylmandelic acid, and metanephrines screen for pheochromocytomas. (If elevated, imaging studies of the adrenals are recommended.)
    • Serum calcium level and PTH levels screen for hyperparathyroidism. An inappropriately elevated PTH level in relation to the serum calcium is consistent with primary hyperparathyroidism. If the 24-hour urine calcium level is low, the patient should be considered for familial hypocalciuric hypercalcemic syndrome.

Imaging Studies

  • Perform CT scanning or MRI for imaging of the adrenals. A metaiodobenzylguanidine (MIBG) scan is useful for localizing pheochromocytomas.
  • If calcitonin levels are elevated at either baseline or with provocative testing, evaluate the chest and abdomen for metastatic disease. Available modalities include CT scanning, MRI, octreotide scanning, and, in some instances, laparoscopy.

Other Tests

  • Radionuclide scanning: This modality may reveal the extent of metastasis.
  • OctreoScan: Provides a whole-body examination and is used to examine the spread of medullary thyroid carcinoma. The somatostatin analogue octreotide, which is used for treatment of hormone-related symptoms, is labeled with the isotope indium In 111 and injected intravenously. The next day, the patient is examined with a gamma camera, which can detect accumulation of radioactivity.

Procedures

  • Fine-needle aspiration: Avoid the removal of cells from thyroid masses for cytology in MEN 2 patients who have had their diagnosis previously confirmed by either genetic analysis or elevated calcitonin levels. These patients have an established diagnosis, and a biopsy increases the possibility of tumor spread. A fine-needle aspiration biopsy is primarily used in an index patient who presents with a thyroid nodule when the clinician considers medullary thyroid carcinoma unlikely.

Histologic Findings

In medullary thyroid carcinoma, the tumor is well demarcated, firm, and gray-white. Polygonal cells are uniform, with finely granular eosinophilic cytoplasm with central nuclei. Amyloid formed from calcitonin molecules is often found. C-cell hyperplasia is frequently found and is a precursor in the malignant transformation to medullary thyroid carcinoma. Pheochromocytomas are benign tumors, often bilateral and multifocal, that arise from diffuse hyperplasia of the adrenal medulla. In parathyroid hyperplasia, overgrowth is the most common finding, though adenomatous changes occur in a small percentage of cases.

Staging

The TNM classification is used for postoperative staging. (T = the size of the primary lesion; N = the presence or absence of regional lymph node metastatic involvement; M = the presence or absence of distant metastatic lesions.)

  • Stage 1 is T1 (tumor d1 cm in greatest dimension, limited to the thyroid) at any age. No evidence of lymph node or distant metastases exists.
  • Stage II is T2-T4 (2 = tumor >1 cm but <4 cm and not invading beyond the thyroid capsule; 3 = tumor >4 cm; 4 = extrathyroid extension or invasion through the thyroid capsule). No evidence of lymph node or distant metastases exists.
  • Stage III is any T and N1.
    • N1 means regional lymph node metastasis.
    • N1a means metastasis in ipsilateral cervical lymph node(s).
    • N1b means metastasis in bilateral, midline, or contralateral cervical or mediastinal lymph node(s).
  • Stage IV is any T, any N, and M1 (presence of distant metastatic lesions).

More on Multiple Endocrine Neoplasia, Type 2

Overview: Multiple Endocrine Neoplasia, Type 2
Differential Diagnoses & Workup: Multiple Endocrine Neoplasia, Type 2
Treatment & Medication: Multiple Endocrine Neoplasia, Type 2
Follow-up: Multiple Endocrine Neoplasia, Type 2
References
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References

  1. Calender A. Genetic testing in multiple endocrine neoplasia and related syndromes. Forum (Genova). Apr-Jun 1998;8(2):146-59. [Medline].

  2. Lallier M, St-Vil D, Giroux M, et al. Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg. Jun 1998;33(6):846-8. [Medline].

  3. van Heurn LW, Schaap C, Sie G, et al. Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children. J Pediatr Surg. Apr 1999;34(4):568-71. [Medline].

  4. de Graaf JS, Lips CJ, Rutter JE, van Vroonhoven TJ. Subtotal adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2A. Eur J Surg. Jun 1999;165(6):535-8. [Medline].

  5. Edstrom E, Grondal S, Norstrom F, et al. Long term experience after subtotal adrenalectomy for multiple endocrine neoplasia type IIa. Eur J Surg. May 1999;165(5):431-5. [Medline].

  6. Gagel RF, Levy ML, Donovan DT, et al. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. Nov 15 1989;111(10):802-6. [Medline].

  7. Calmettes C, Ponder BA, Fischer JA, Raue F. Early diagnosis of the multiple endocrine neoplasia type 2 syndrome: consensus statement. European Community Concerted Action: Medullary Thyroid Carcinoma. Eur J Clin Invest. Nov 1992;22(11):755-60. [Medline].

  8. Carling T. Multiple endocrine neoplasia syndrome: genetic basis for clinical management. Curr Opin Oncol. Jan 2005;17(1):7-12. [Medline].

  9. Chi DD, Moley JF. Medullary thyroid carcinoma: genetic advances, treatment recommendations, and the approach to the patient with persistent hypercalcitoninemia. Surg Oncol Clin N Am. Oct 1998;7(4):681-706. [Medline].

  10. Evans DB, Fleming JB, Lee JE, et al. The surgical treatment of medullary thyroid carcinoma. Semin Surg Oncol. Jan-Feb 1999;16(1):50-63. [Medline].

  11. Frank-Raue K, Rondot S, Hoeppner W, Goretzki P, Raue F, Meng W. Coincidence of multiple endocrine neoplasia types 1 and 2: mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism. J Clin Endocrinol Metab. Jul 2005;90(7):4063-7. [Medline].

  12. Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med. Feb 25 1988;318(8):478-84. [Medline].

  13. Goretzki PE, Hoppner W, Dotzenrath C, et al. Genetic and biochemical screening for endocrine disease. World J Surg. Dec 1998;22(12):1202-7. [Medline].

  14. Iler MA, King DR, Ginn-Pease ME, et al. Multiple endocrine neoplasia type 2A: a 25-year review. J Pediatr Surg. Jan 1999;34(1):92-6; discussion 96-7. [Medline].

  15. Johnston LB, Chew SL, Trainer PJ, et al. Screening children at risk of developing inherited endocrine neoplasia syndromes. Clin Endocrinol (Oxf). Feb 2000;52(2):127-36. [Medline].

  16. Koch CA. Molecular pathogenesis of MEN2-associated tumors. Fam Cancer. 2005;4(1):3-7. [Medline].

  17. Lips CJ. Clinical management of the multiple endocrine neoplasia syndromes: results of a computerized opinion poll at the Sixth International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau disease. J Intern Med. Jun 1998;243(6):589-94. [Medline].

  18. Moore SW, Appfelstaedt J, Zaahl MG. Familial medullary carcinoma prevention, risk evaluation, and RET in children of families with MEN2. J Pediatr Surg. 2007;42:326-32. [Medline].

  19. Neumann HP, Bausch B, McWhinney SR. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. May 9 2002;346(19):1459-66. [Medline].

  20. Romeo G, Ceccherini I, Celli J, et al. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med. Jun 1998;243(6):515-20. [Medline].

  21. Wick MJ. Clinical and molecular aspects of multiple endocrine neoplasia. Clin Lab Med. Mar 1997;17(1):39-57. [Medline].

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Further Reading

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Keywords

Sipple syndrome, MEN 2, MEN2, MEN II, MENII, thyroid cancer, pheochromocytomas, benign tumors of the adrenal medulla, stromal amyloid, parathyroid hyperplasia, mucosal neuromas, marfanoid habitus, familial cancer syndromes, autosomal dominant disorders, familial medullary thyroid carcinoma-only, FMTC-only, primary hyperparathyroidism, thyroidectomy, adrenalectomy, cutaneous lichen amyloidosis, RET proto-oncogene

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Contributor Information and Disclosures

Author

Melanie L Richards, MD, Associate Professor, Department of Surgery, Mayo Clinic
Melanie L Richards, MD is a member of the following medical societies: American Association of Endocrine Surgeons, American College of Surgeons, International Association of Endocrine Surgeons, Southwestern Surgical Congress, and Western Surgical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine
Suzanne M Carter, MS is a member of the following medical societies: American Bar Association
Disclosure: Nothing to disclose.

Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine
Susan J Gross, MD, FRCS(C), FACOG, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, American Society of Human Genetics, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Ruth Freeman, MD, Director of Menopause Research and Treatment Center, Professor, Departments of Medicine and Obstetrics and Gynecology, Montefiore Medical Center, Albert Einstein College of Medicine
Ruth Freeman, MD is a member of the following medical societies: American College of Clinical Endocrinologists
Disclosure: Nothing to disclose.

Medical Editor

Ghassem Pourmotabbed, MD †, Former Associate Professor, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Tennessee School of Medicine and Health Science Center
Ghassem Pourmotabbed, MD † is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Romesh Khardori, MD, Chief, Division of Endocrinology, Metabolism and Molecular Medicine, Professor, Department of Internal Medicine, Southern Illinois University School of Medicine
Romesh Khardori, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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