Medullary Thyroid Carcinoma (MTC)

United States of America

In 2007, the American Thyroid Association (ATA) assembled a group of experts to recommend evidence-based guidelines for the diagnosis and management of medullary thyroid cancer (MTC). In 2015, the ATA Task Force reconvened and updated its recommendations.¹ These are the most comprehensive ATA guidelines currently available, and some important recommendations in the 2015 revision are summarized below. 

Recommendations for MTC as Part of Multiple Endocrine Neoplasia Type 2 Syndrome 

The recommended method of initial testing for multiple endocrine neoplasia type 2A (MEN2A) is either a single or multi-tiered analysis to detect RET gene mutations in exon 10 (codons 609, 611, 618, and 620); exon 11 (codons 630 and 634); and exons 8, 13, 14, 15, and 16.  Patients with presumed sporadic MTC should undergo genetic testing to detect a germline RET mutation. If one is found, the patient should undergo further genetic testing.¹ 

In the very rare cases of families who meet the clinical criteria for MEN2A or MEN2B, even if the results of sequencing the entire RET coding region are negative, the relatives at risk should be periodically screened by conventional methods for MTC, pheochromocytoma (PHEO), and hyperparathyroidism (HPTH). After the initial evaluation, screening should continue at 1- to 3-year intervals.¹

Recommendations for Diagnosis

Clinicians should be aware that falsely high or low serum calcitonin (Ctn) levels may occur in a variety of clinical diseases other than MTC. They should consider this possibility when the serum Ctn levels are out of proportion to the expected clinical findings. In interpreting serum Ctn data, clinicians should be aware that Ctn levels are markedly elevated in children younger than 3 years of age, and especially 6 months of age. Also, Ctn levels are higher in males than in females. Basal serum levels of Ctn and carcinoembryonic antigen (CEA) should be measured concurrently. In patients with advanced MTC, a normal or markedly elevated serum CEA level that is out of proportion to a lower serum Ctn level, or low serum levels of both Ctn and CEA, indicate poorly differentiated MTC.¹

The assessment of a thyroid tumor with any features suggestive of MTC should include immunohistochemical (IHC) analysis to determine the presence of markers such as Ctn, chromogranin, and CEA and the absence of thyroglobulin. Nodules that are 1 cm in size or larger should be evaluated with fine-needle aspiration (FNA), depending on the ultrasound characteristics. When the FNA findings are inconclusive or suggestive of MTC, the Ctn level should be measured in the FNA washout fluid, and IHC staining of the FNA sample should be performed to detect the presence of markers such as Ctn, chromogranin, and CEA and the absence of thyroglobulin. Realizing that the opinions of experts vary regarding the usefulness of measuring serum Ctn levels in patients with nodular goiters, the Task Force recommends that physicians should decide whether the technique is useful in the management of patients in their clinic.¹ 

Patients presenting with a thyroid nodule and a cytological or histological diagnosis of MTC should undergo a physical examination, serum Ctn and CEA measurement, and genetic testing for an RET germline mutation. The presence of a PHEO and of HPTH should be excluded in patients with hereditary MTC. Ultrasound examination of the neck should be performed in all patients with MTC. Contrast-enhanced computed tomography (CT) of the neck and chest, 3-phase contrast-enhanced multidetector CT of the liver or contrast-enhanced magnetic resonance imaging (MRI) of the liver, and axial MRI and bone scintigraphy are recommended for patients with extensive neck disease and signs or symptoms of regional or distant metastases, and for all patients with a serum Ctn level above 500 pg/mL. Neither fluorodeoxyglucose F 18 positron emission tomography/computed tomography (FDG-PET/CT) nor [¹⁸F]DOPA-PET/CT is recommended to detect distant metastases.¹

Recommendations for Management

Patients with MTC and no evidence of neck lymph node metastases on ultrasound examination and no evidence of distant metastases should undergo a total thyroidectomy and dissection of the lymph nodes in the central compartment (level VI). Patients with MTC confined to the neck and cervical lymph nodes should have a total thyroidectomy, dissection of the central lymph node compartment (level VI), and dissection of the involved lateral neck compartments (levels II-V).¹

In the presence of extensive regional or metastatic disease, less aggressive surgery in the central and lateral regions of the neck may be appropriate to preserve speech, swallowing, parathyroid function, and shoulder mobility. External beam radiotherapy (EBRT), systemic medical therapy, and other nonsurgical therapies should be considered to achieve local tumor control.¹ 

Following unilateral thyroidectomy for presumed sporadic MTC, completion thyroidectomy is recommended in patients with an RET germline mutation, an elevated postoperative serum Ctn level, or imaging studies indicating residual MTC.¹

The serum thyroid-stimulating hormone (TSH) should be measured within 4 to 6 weeks postoperatively. Replacement therapy with levothyroxine should be administered with the goal of maintaining serum TSH levels in the euthyroid range. Serum calcium levels should be monitored postoperatively. Oral calcium and vitamin D should be administered to patients in whom symptomatic hypocalcemia develops. Long-term replacement therapy is indicated for patients who cannot be weaned from medication.¹

Children with an M918T RET mutation or MEN2B should undergo a thyroidectomy in the first year of life, perhaps even in the first months of life. Experienced physicians and surgeons in tertiary care centers should be responsible for the management of children with MEN2A or MEN2B.¹

United Kingdom and Japan

The United Kingdom National Multidisciplinary Guidelines (UKNMGs) specify 6 clear goals for the treatment of differentiated thyroid cancer. These are to remove the primary tumor and involved lymph nodes, minimize treatment-related morbidity, allow accurate staging of the disease, facilitate postoperative treatment with radioactive iodine in appropriate patients, enable long-term surveillance for disease recurrence, and minimize the risk for disease recurrence and distant metastases.² 

The Japan Society of Thyroid Surgery, along with the Japan Association of Endocrine Surgeons (JSTS/JAES), published a set of revised clinical practice guidelines for the treatment of thyroid cancer in 2020. They outline 2 main goals to improve health-related outcomes in patients with thyroid cancer. Firstly, clinical decision making should involve both patients and physicians and should be evidence-based. Secondly, the guidelines should facilitate physician implementation of standardized clinical practices for the management of thyroid tumors.³ These guidelines are very similar to the ATA guidelines.

The UKNMGs recognize that the ATA guidelines are comprehensive and agree with most of the ATA recommendations, with some minor differences. The JSTS/JAES guidelines are also very similar. Two differences are outlined below: 

1. The UKNMGs recommend that prophylactic thyroidectomy be offered to all MTC patient family members with an RET mutation.² The ATA guidelines offer prophylactic thyroidectomy only to children with MEN2B syndrome.¹ The Japanese guidelines do not recommend routine prophylactic thyroidectomy for RET carriers.³ 

2. The UKNMGs recommend that all patients with proven MTC larger than 5 mm undergo total thyroidectomy and central compartment neck dissection.² The ATA does not use tumor size as a threshold for total thyroidectomy and recommends the procedure for all patients with MTC and RET germline mutations.¹ The JSTS/JAES guidelines recommend subtotal thyroidectomy for patients with sporadic MTC confined to 1 lobe.³ 

References

1. Wells SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. doi:10.1089/thy.2014.0335

2. Mitchell AL, Gandhi A, Scott-Coombes D, Perros P. Management of thyroid cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016;130(S2):S150-S160. doi:10.1017/S0022215116000578

3. Ito Y, Onoda N, Okamoto T. The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: core questions and recommendations for treatments of thyroid cancer. Endocr J. 2020;67(7):669-717. doi:10.1507/endocrj.EJ20-0025

Article reviewed by Harshi Dhingra, MD, on July 1, 2021.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.