Medullary Thyroid Carcinoma Guidelines

Updated: Feb 09, 2017
  • Author: Anastasios K Konstantakos, MD; Chief Editor: Neetu Radhakrishnan, MD  more...
  • Print
Guidelines

Guidelines Summary

Guidelines Contributor:  Kemp M Anderson Medical University of South Carolina College of Medicine

The following organizations have released guidelines for the diagnosis and/or management of thyroid cancer:

  • American Thyroid Association (ATA) [1, 19, 20]
  • National Comprehensive Cancer Network (NCCN) [21]
  • American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA)(diagnosis only) [22]

Prevention

The familial medullary thyroid carcinoma (MTC) syndromes consist of multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC. They are inherited in an autosomal dominant fashion. Children inheriting any of these syndromes have a 100% risk of developing MTC.

MEN 2A (Sipple syndrome) consists of MTC, pheochromocytoma (in 50% of patients), and hyperparathyroidism (10-20% of patients). MEN 2B consists of MTC, pheochromocytoma (in 50% of patients), marfanoid habitus, and ganglioneuromatosis. FMTC consists of MTC alone.

MTC in MEN 2B has the most aggressive biologic features. In this situation, MTC usually develops around 10 years of age, and it has a high propensity for rapid growth and metastasis. MTC in MEN 2A can appear in the first decade of life, and it almost always develops by the second decade. MTC in FMTC usually develops during adulthood.

Genetic testing is now the mainstay in the diagnosis of the familial MTC syndromes. Germline RET proto-oncogene mutations (on chromosome arm 10q) discovered in these syndromes include the following [1] :

  • MEN 2A – Majority of cases show substitutions of conserved cysteine residues in exons 10 and 11
  • MEN 2B – 95% of cases show threonine-for-methionine substitution in codon 918 of exon 16.
  • Familial MTC - Most commonly seen with mutations in exons 10, 13 & 14

Guidelines from the American Thyroid Association (ATA) recommend prophylactic thyroidectomy for individuals that have a documented RETmutation and are at risk for aggressive medullary thyroid carcinoma. [1]

The original ATA guidelines [1] stratified risk level of RET carriers into four categories, A through D, based upon the increasing aggressiveness of the particular mutation. Due to some confusion and lack of uniformity with other staging guidelines, the revised ATA guidelines [20] transition category D to “highest risk” (HST), transition category C to “high risk” (H), and combine categories B and A into “moderate risk”. The risk stratification, screening schedules, and prophylactic thyroidectomy schedules are described in the table below.

Table. Revised ATA MTC Risk Levels and Pediatric Recommendations (Open Table in a new window)

Risk Level

RETcodon Mutation

Possible Diagnoses

Prophylactic Thyroidectomy

Recommendations

Follow-up

Highest Risk (HST)

M918T+All MEN2B

MEN2B

Within the first year of life or the first months of life based upon specialist and parental discussions. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection.

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually; begin screening for pheochromocytoma at age 11 yr

High Risk (H)

C634, A883F

MEN2A

At or before age 5 yr, to be determined on the basis of serum Ctn

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually. Begin screening for pheochromocytoma at age 11.

Moderate Risk (MOD)

All other mutations

MEN2A

When serum Ctn becomes elevated or in childhood to avoid lengthy evaluation period.

Evaluate every 6 months for 1 year. Annual follow-ups thereafter if serum Ctn is normal or undetectable. Begin screening for pheochromocytoma at age 16 yr

CEA=carcinoembryonic antigen;  Ctn=calcitonin; MEN=multiple endocrine neoplasia; US=ultrasound

Next:

Diagnosis

All the guidelines advocate ultrasound evaluation of thyroid nodules along with measurement of serum thyroid-stimulating hormone (TSH) levels to determine whether a fine needle aspiration biopsy (FNAB) is indicated. A routine measurement of serum thyroglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended because Tg levels are elevated in most benign thyroid conditions. [19, 21, 22]

Although all the guidelines recommend FNAB as the procedure of choice in the evaluation of solid thyroid nodules, there is variance in the size of the nodule as an indication for FNAB, as follows [19, 21, 22] :

  • >0.5 cm in diameter (ATA) [19]
  • >1 cm, in the absence of suspicious sonographic features (AACE/AME/ETA) [22]
  • >1 cm if suspicious sonographic features are present; >1.5 cm if no suspicious sonographic features are present (NCCN) [21]

AACE/AME/ETA and NCCN suggest a serum calcitonin assay as an optional test, 56 but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence. 1 All three guidelines recommend radionuclide imaging in patients with a low TSH level. [19, 21, 22]

Patients with medullary thyroid carcinoma (MTC) can be identified by pathologic diagnosis or by prospective genetic screening. According to the revised ATA guidelines, an FNAB result suspicious for MTC should prompt the following [19] :

  • Ultrasound of the neck
  • Serum calcitonin assay
  • Serum carcinoembryonic antigen (CEA) measurement
  • DNA analysis for  RET germline mutation

According to 2009 ATA guidelines, a calcitonin level >100 pg/mL should be considered suspicious of MTC  [1] . Although calcitonin is a valuable tumor marker in patients with MTC, the 2015 Revised ATA guidelines note that clinical judgment should be exercised in the interpretation of calcitonin test results. Serum levels can be falsely high or low in a variety of clinical diseases, can be elevated in children under 3 years of age, and can be higher in males than females. [20]

The NCCN recommends the following diagnostic procedures when FNAB results indicate MTC5:

  • Basal serum calcitonin level
  • CEA level
  • Pheochromocytoma screening
  • Serum calcium assay
  • Consider genetic counseling
  • Screen for  RET proto-oncogene mutations (exons 10, 11, 13-16)
  • Thyroid and neck ultrasound (including central and lateral compartments), if not previously done
  • Consider evaluation of vocal cord mobility
  • Consider contrast-enhanced CT of chest and mediastinum or MRI if N1 disease or calcitonin >400 pg/mL
Previous
Next:

Treatment

The National Comprehensive Cancer Network (NCCN) guidelines recommend total thyroidectomy and bilateral central neck dissection (level VI) for all patients with medullary thyroid carcinoma (MTC) whose tumor is ≥1 cm or who have bilateral thyroid disease, as well as the following [21] :

  • Therapeutic ipsilateral or bilateral modified neck dissection for clinically or radiologically identifiable disease (levels II–V)
  • Prophylactic ipsilateral modified neck dissection for high volume or gross disease in the adjacent central neck may be considered

External beam radiation therapy (EBRT) is an option for treatment of incomplete tumor resection when further surgical resection is no longer possible. EBRT can also be considered for adjuvant treatment for extrathyroidal extension (T4a or T4b) with positive margins

Other therapy considerations are as follows:

  • Total thyroidectomy is recommended and neck dissection can be considered for those whose tumor is <1 cm and for unilateral thyroid disease
  • Radioiodine (131I) therapy is not effective

Suppression of thyroid-stimulating hormone (TSH) is not appropriate; TSH is kept in the normal range by adjusting levothyroxine dose.

  • Pheochromocytoma removal prior to thyroid surgery by laparoscopic adrenalectomy, and treatment preoperatively with alpha-adrenergic blockade (phenoxybenzamine) or with alpha-methyltyrosine to avoid a hypertensive crisis during surgery
Previous