1. DIAGNOSTIC EVALUATION
2. BIOPSY
3. TREATMENT
4. ADJUVANT TREATMENT
5. FOLLOW UP
6. FAMILY SCREENING 
7. BIBLIOGRAPHY

I.DIAGNOSTIC EVALUATION:

Clinical Evaluation:

• Complete history and physical examination
  
  The history should document presence/absence and duration of symptoms referable to hypercalcitonemia (diarrhea and flushing), pheochromocytoma (headache, palpitations/tachycardia, hypertension, diaphoresis, nausea/vomiting, tremulousness/anxiety), or hyperparathyroidism (renal stones, bone abnormalities, etc.) as well as the presence or absence of hoarseness, dysphagia and stridor. The history should also indicate whether or not there is a family history of non-MEN Medullary carcinoma (FMTC), multiple endocrine neoplasia (MEN) 2A or 2B. History of previous or current mucosal neuromata of the oral cavity or GI tract should be noted.
  
  
• Complete head and neck exam
  
  Consists of inspection and palpation of the head and neck; the presence or absence of neuromata of the tongue, thickened lips or marfanoid facies should be documented. Attention should focus on the characteristics of the palpable thyroid mass such as size, consistency, number and fixation to trachea or larynx Extrathyroidal extension to involve soft tissues in the central compartment of the neck or the skin should also be documented. The larynx should be visualized and vocal cord function documented. 
  
   If enlarged lymph nodes are present, their location (Group or Level I - VI), number, size, mobility, relationship to adjacent structures and staging should be documented.

Imaging Studies:

• Chest radiograph
  To evaluate for metastatic disease

• CT scan of neck with contrast or MRI
  It is indicated when there is suspicion of tumor extending into the larynx or trachea or into the mediastinum. MRI is preferable if well-differentiated thyroid neoplasm remains in the differential at this point (The iodine contrast used for CT scanning may delay postoperative radioactive iodine therapy.

Laboratory Tests:

Should include:

• Serum calcitonin levels Serum calcium (If elevated, obtain parathyroid hormone level).
• Serum albumin levels
• Alkaline Phosphatase 24-hour urine catecholamine (especially if symptoms suspicious for pheochromocytoma or if known familial MTC).
• Preoperative laboratory tests as required by institutional guidelines

Consultations:

• Endocrinology consult
• Anesthesia If pheochromocytoma previously resected or present work-up equivocal.
• General Surgery If pheochromocytoma present

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Fine needle aspiration has likely preceded suspicion of medullary carcinoma if sporadic MTC. If sporadic MTC suspected from elevated calcitonin alone, FNA optional depending on clinical presentation. (Increased calcitonin is present occasionally in other malignancies, bone disorders, renal failure, hemorrhagic disorders or thyroiditis.)

FNA of thyroid not necessary when there is a family history of MTC and ret gene mutation or increased pentagastrin stimulated calcitonin level have been documented.

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Primary tumor:

• Surgery
  Total thyroidectomy recommended in all cases.

• Radiation
  Not indicated as primary treatment.

• Chemotherapy
  Not indicated

Neck:

• Surgery

N0: Medial compartment neck dissection should be performed in all cases; it includes lymph nodes from the level of the hyoid bone to the innominate vein and from one carotid sheath to the other. In addition, all cases merit intraoperative palpation of the jugular nodes and neck dissection if palpable nodes are present. N+: In cases with clinical or radiologic suspicion of nodal metastases, a neck dissection should be performed which includes levels II-V and may preserve uninvolved structures (e.g., spinal accessory nerve). It should be recognized during the course of neck treatment that no effective adjunctive treatment has been established for medullary carcinoma

• Chemotherapy
  No role established

Other:

In MEN 2A parathyroid hyperplasia occurs in 10-20% of the cases and subtotal parathyroidectomy or total parathyroidectomy and autotransplantation should be considered at the time of primary operation to avoid the potential risk of recurrent laryngeal nerve injury in reoperation of the central compartment. Cryopreservation of one or more removed parathyroid glands may be considered for later reimplantation should hypoparathyroidism result from the initial surgery.

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Preoperative

Pheochromocytoma discovered during pre-operative work-up should be resected prior to treatment of MTC.

Postoperative

Radiation therapy: 

Extracapsular extension of tumor has been associated with poor prognosis in MTC. There is limited information in the literature suggesting that radiation therapy may be beneficial in patients with multiple, large nodal metastases with extracapsular extension. It may also be beneficial when there is gross or microscopic residual tumor. 

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V.FOLLOW UP:

The follow up schedule depends on the patient's clinical course and individual risk for recurrence. In general, patients should be examined every 3 to 6 months for three years, thereafter every 6 - 12 months for up to ten years, then once a year for life.

Follow up evaluations should include:

• Examination of the head and neck area.

• Chest x-ray, yearly.

• Calcitonin levels, yearly, in all patients

• Serum calcium levels and urine catecholamines, yearly, in patients with familial MTC.

• Serum Carcinoembryonic antigen (CEA) may be useful as a secondary tumor marker.

• CT scan of the neck and upper mediastinum after completion of treatment may be useful as a baseline study.

• When calcitonin levels are elevated following treatment, the following modalities may be useful in localizing residual disease: CT scans, octreotide scintigraphy, and selective venous catheterization.

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A sporadic case of MTC may represent the index case of a familial MTC kindred. Bilateral tumors or evidence of C-cell hyperplasia may indicate such a situation. Family history of thyroid surgery, a poorly differentiated carcinoma or sudden death may also indicate a familial MTC. Available members of familial MTC kindreds should be screened for MTC. For FMTC and MEN 2A, assessment of peripheral blood for evidence of ret gene mutation can be performed. No such gene mutation has been defined for MEN 2B and these kindreds must be screened using baseline and pentagastrin stimulated serum calcitonin measurements.

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Brierley J, Tsang R, Simpson WJ, Gospodarowicz M, Sutcliffe S, Panzarella T. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 1996 Aug;6(4):305-10.

Donovan, DT, Gagel, FT.  Medullary thyroid carcinoma and the multiple endocrine neoplasia syndromes in Thyroid Disease:  Endocrinology, Surgery, Nuclear Medicine and Radiotherapy.  SA Falk, ed, Raven Press, New York, 1990.

Evans DB, Fleming JB, Lee JE, Cote G, Gagel RF. The surgical treatment of medullary thyroid carcinoma. Semin Surg Oncol 1999 Jan-Feb;16(1):50-63.

Giuffrida D, Gharib H. Current diagnosis and management of medullary thyroid carcinoma. Ann Oncol 1998 Jul;9(7):695-701.

Moley JF, Dilley WG, DeBenedetti MK. Improved results of cervical reoperation for medullary thyroid carcinoma. Ann Surg 1997 Jun;225(6):734-40; discussion 740-3.

Tisell LE, Ahlman H, Wangberg B, et. al. Somatostatin receptor scintigraphy in medullary thyroid carcinoma. Br J Surg 1997 Apr;84(4):543-7.

Wells, SA, Chi, DD, Toshima, K et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Annals of Surgery 1994; 220: 237-250.

Van Heerden, JA, Grant, CS, Gharib, H, Hay, ID and Ilstrup, DM. Long-term course of patients with persistent hypercalcitonemia after apparent curative primary surgery for medullary thyroid carcinoma. Annals Surgery 1990; 212: 395-401.