Medullary Thyroid Carcinoma Guidelines

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) ^{[30, 2]}
• National Comprehensive Cancer Network (NCCN) ^[7]
• American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME)(diagnosis only) ^[31]
• European Society for Medical Oncology (ESMO) ^[6]
• Japan Associations of Endocrine Surgeons ^[32]

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 ^[2] :

• 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 RET mutation and are at risk for aggressive medullary thyroid carcinoma. ^[2] Japan Associations of Endocrine Surgeons guidelines do not uniformly recommend prophylactic total thyroidectomy for carriers of RET mutations who have not developed MTC; outcomes to consider are the prognosis, surgical complications, and health considerations from the patient's perspective. ^[32]

The original ATA guidelines 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 ^[2] 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)

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

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. ^{[30, 7, 31, 6]}

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 ^{[30, 7, 31]}

• >0.5 cm in diameter (ATA) ^[30]
• ≥1 cm if suspicious sonographic features are present; ≥1.5 cm if no suspicious sonographic features are present (NCCN) ^[7]
• ≥1 cm if high risk; > 2 cm if intermediate risk; > 2 cm if low risk and increasing in size or associated with a risk history and before thyroid surgery or minimally invasive ablation therapy (AACE/ACE/AME) ^[31]
• >1 cm, with the decision to aspirate guided by lesion size and sonographic appearance (ESMO) ^[6]

In its 2016 revised guidelines, AACE/ACE/AME included the following additional recommendations for FNAB for evaluation ^[31] :

• Nodules < 0.5 cm in diameter should be monitored with US, irrespective of their sonographic appearance 
• Nodules 0.5 - 1cm that are associated with suspicious sonographic features, consider either FNA sampling or watchful waiting on the basis of the clinical setting and patient preference
• US-guided FNA is recommended for the following nodules: Subcapsular or paratracheal lesions; suspicious lymph nodes or extrathyroid spread; in patients with a positive personal or family history of thyroid cancer; or, coexistent suspicious clinical findings (e.g., dysphonia)

AACE/ACE/AME, ESMO and NCCN suggest a serum calcitonin assay as an optional test, ^{[7, 31, 6]}  but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence. ^[2] AACE/ACE/AME, ATA and NCCN guidelines recommend radionuclide imaging in patients with a low TSH level. ^{[7, 2, 31]}

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 ^[30] :

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

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. ^[2]

The NCCN recommends the following diagnostic procedures when FNAB results indicate MTC ^[7] :

• Basal serum calcitonin level
• CEA level
• Pheochromocytoma screening
• Serum calcium assay
• Consider genetic counseling
• Screen for germline 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 (ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy)
• Consider contrast-enhanced CT of chest and mediastinum or MRI or 3‑phase CT of live
• if N1 disease or calcitonin >400 pg/mL
•  Consider Ga‑68 DOTATATE PET/CT; if not available, consider bone scan and/or skeletal MRI

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 ^[7] :

• 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

Total thyroidectomy is recommended and neck dissection can be considered for those whose tumor is < 1 cm and for unilateral thyroid disease

ATA guidelines recommend surgical treatments as follows ^[2]

• Total thyroidectomy and dissection of the lymph nodes in the central compartment for patients with MTC and no evidence of lymph node metastases (level VI); 
• Dissection of lymph nodes in the lateral compartments (levels II–V) may be considered based on serum calcitonin (Ctn) levels in patients with MTC and no evidence of neck or distant metastases
• Total thyroidectomy, dissection of the central lymph node compartment (level VI), and dissection of the involved lateral neck compartments (levels II–V) for patient with MTC confined to neck and cervical lymph nodes.
• When preoperative imaging is positive in the ipsilateral lateral neck compartment but negative in the contralateral neck compartment, contralateral neck dissection should be considered if the basal serum calcitonin level is greater than 200 pg/mL

External beam radiation therapy (EBRT) is an option for treatment of incomplete tumor resection when further surgical resection is no longer possible ^[7] . EBRT can also be considered for adjuvant treatment for extrathyroidal extension (T4a or T4b) with positive margins. ^{[7, 2]}

Radioiodine (¹³¹I) therapy is not effective. ^[7]

Suppression of thyroid-stimulating hormone (TSH) is not appropriate; TSH is kept in the normal range by adjusting levothyroxine dose. ^{[2, 7]}

The ATA and NCCN guidelines recommend removal of pheochromocytoma prior to surgery for MTC to prevent a possible hypertensive crisis. ^{[2, 7]}  Pheochromocytoma should be resected by laparoscopic or retroperitoneoscopic adrenalectomy. Subtotal adrenalectomy to preserve adrenal cortical function should be considered as an alternative procedure. Patients with no adrenal glands require glucocorticoid and mineralocorticoid replacement therapy and should be carefully monitored to ensure that their steroid levels are adequate. Patients should be educated regarding the risk of adrenal crisis and wear a bracelet or a necklace indicating that they have no adrenal glands and are on corticosteroid replacement therapy. Glucocorticoid supplementation will be required if they become severely ill or are injured. ^[2]

ESMO guidelines recommend preoperative ulltrasound (US) for all patients with MTC. ^[6] In US-positive patients, total thyroidectomy and bilateral central neck dissection plus therapeutic neck dissection of involved levels is recommended, plus contalateral lateral neck dissection if the serum Ctn level is > 200 pg/mL. In US-negative patients, treatment recommendations vary according to Ctn levels, as follows:

• Ctn < 20 pg/mL - Total thyroidectomy
• Ctn 20-50 pg/mL - Total thyroidectomy with or without bilateral central neck dissection
• Ctn 50-200 pg/mL - Total thyroidectomy with bilateral central neck dissection and ispilateral lateral neck dissection (at least IIA-III-IV)
• Ctn 200-500 pg/mL - Total thyroidectomy with bilateral central neck dissection and bilateral lateral neck dissection (at least IIA-III-IV)
• Ctn > 500 pg/mL - Work up for distant metastasis: If M0, total thyroidectomy with bilateral central neck dissection and bilateral lateral neck dissection (at least IIA-III-IV); if M1, neck surgery based on disease progression and symptoms

Vandetanib and cabozantinib have been approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of patients with locally advanced/metastatic MTC. ESMO guidelines recommend vandetanib and cabozantinib as the first-line systemic treatments for progressive metastatic MTC. ^[6] Similarly, ATA guidelines recommend using vandetanib or cabozantinib as single-agent first-line systemic therapy in patients with advanced progressive MTC. ^[2]

For asymptomatic recurrent or metastatic MTC, the NCCN recommends the following treatment options ^[7] :

• Active surveillance
• Resection, if possible or ablation or vandetanib (category 1) or cabozantinib (category 1), if not resectable and progressing

For symptomatic or progressing recurrent or metatstaic MTC, NCCN recommends the following treatment options ^[7] :

• Vandetanib (category 1) or cabozantinib (category 1) or clinical trial orother small-molecule kinase inhibitors or Decarbazine (DTIC)-based chemotherapy 
• External beam radiation therapy (EBRT)/Intensity modulated radiation therapy (IMRT) for local symptoms

For bone metastases, NCCN and ATA guidelines recommend  bisphosphonate or denosumab therapy. ^{[7, 2]}

ATA guidelines recommend performing brain imaging in patients with metastatic MTC who have neurologic symptoms, including patients who are candidates for systemic therapy. Patients with isolated brain metastases are candidates for surgical resection or EBRT (including stereotactic radiosurgery). Whole-brain EBRT is indicated for multiple brain metastasis. ^[2]   

If, in the 2-3 months postoperatively, the basal calcitonin level remains undetectable and the CEA level remains within the reference range, NCCN guidelines recommend the following for active surveillance ^[7] :

• Annual serum calcitonin and CEA testing
• Consider ultrasound of the central and lateral neck compartments
• Perform additional studies or more frequent testing if the calcitonin or CEA rises significantly
• No additional imaging is required if the calcitonin and CEA levels remain stable
• For MEN2B or MEN2A, perform annual biochemical screenings for pheochromocytoma and hyperparathyroidism (MEN2A)

ESMO guidelines recommend pstoperative assessment 30–60 days after surgery with serum Ctn and CEA and neck ultrasound (US), with use of other imaging modalities depending on the stage and serum Ctn and CEA levels. ^[6] The subsequent surveillance protocol depends on the results of that assessment, as follows:

• Excellent response (Ctn and CEA undetectable or within normal range, no structural evidence of disease) - Serum Ctn every 6 months for 1 year, then annually; repeat neck US depending on Ctn levels (abnormal values should prompt imaging studies)
• Biochemical incomplete response (detectable Ctn and abnormal CEA, but no structural evidence of disease) - Serum Ctn and CEA every 3 to 6 months to determine doubling times (doubling times < 24 months are associ-ated with progressive diseasec); neck US every 6-12 months depending on Ctn and CEA doubling times; other imaging modalitiesa depending on Ctn and CEA levels and doubling times
• Structural incomplete response (structural evidence of disease, regardless Ctn and CEA levels) - If disease is stable, serum Ctn and CEA every 3-6 months to determine doubling times; neck US every 6-12 months, depending on Ctn and CEA doubling times; other imaging modalities, depending on Ctn and CEA levels and their doubling times; in progressive symptomatic disease, locoregional therapy if single lesion, systemic therapy with cabozantinib or vandetanib if multiple lesions