Medullary Thyroid Carcinoma (MTC)

• Medullary thyroid carcinoma (MTC) arises from:
  • The neuroendocrine parafollicular C cells or C cells of the thyroid gland
• Sporadic MTC accounts for about 75% to 80% of all cases of the disease:
  • The remaining cases, 20% to 25% consist of inherited tumor syndromes, such as:
    • MEN type 2A (MEN2A):
      • Which is the most common type
    • MEN2B
    • Familial MTC:
      • Is now viewed as a variant of MEN2A
• Sporadic disease:
  • Typically presents in the fifth or sixth decade of life
• Inherited forms of the disease:
  • Tend to present at earlier ages
• The 5-year relative survival for:
  • Stages I to III:
    • 93%
  • Stage IV:
    • 28%
• Because the C cells are predominantly located in the upper portion of each thyroid lobe:
  • Patients with sporadic disease typically present with:
    • Upper pole nodules
• Metastatic cervical adenopathy:
  • Appears in about 50% (50% to 70%) of patients at initial presentation
• Symptoms of upper aerodigestive tract compression or invasion:
  • Are reported by up to 15% of patients with sporadic disease
• Distant metastases:
  • In the lungs or bones cause symptoms:
    • In 5% to 10% of patients
• Many patients with advanced MTC can have:
  • Diarrhea, Cushing syndrome, or facial flushing:
    • Because the tumor can secrete calcitonin and sometimes other hormonally active peptides (ie, adrenocorticotropic hormone [ACTH], calcitonin gene-related peptide [CGRP]):
      • Treatment with somatostatin analogs (eg, octreotide, lanreotide) may be useful in patients with these symptoms
• Patients with unresectable or metastatic disease:
  • May have either slowly progressive or rapidly progressive disease
• Nodule Evaluation and Diagnosis Patients with MTC:
  • Can be identified by using:
    • Pathologic diagnosis or by prospective genetic screening
  • Sporadic MTC Sporadic MTC:
    • Is usually suspected after FNA of a solitary nodule
    • Reports suggest that about:
      • 3% of patients with nodular thyroid disease:
        • Will have an increased serum calcitonin level when measured by a sensitive immunometric assay:
          • 40% of these patients will have MTC at thyroidectomy
      • However, routine measurement of the basal serum calcitonin concentration is not recommended by the NCCN Panel for evaluating a patient with nodular thyroid disease because of:
        • The expense of screening all thyroid nodules and only finding a few cases of MTC
        • The lack of confirmatory pentagastrin stimulation testing
        • The resulting need for thyroidectomy in some patients who have benign thyroid disease
      • The ATA is:
        • Equivocal about routine calcitonin measurement
  • Inherited MTC:
    • For patients in known kindreds with inherited MTC:
      • Prospective family screening with testing for mutant RET genes:
        • Can identify disease carriers long before clinical symptoms or signs are noted
    • The traditional approach of stimulating secretion of calcitonin:
      • By either pentagastrin or calcium infusion to identify patients with MTC:
        • Is no longer recommended:
          • Because elevated calcitonin is not a specific or adequately sensitive marker for MTC and because pentagastrin is no longer available in the United States
    • When MEN2A is suspected, the NCCN Guidelines recommend measurement of:
      • Calcium levels with (or without) serum intact parathyroid hormone levels
    • Compared with sporadic disease, the typical age of presentation for familial disease:
      • Is the third or fourth decade of life, without gender preference
    • In patients with MEN2A:
      • Signs or symptoms of hyperparathyroidism or pheochromocytoma rarely present before those of MTC, even in the absence of screening
  • All familial forms of MTC and MEN2 are:
    • Inherited in an autosomal-dominant fashion
    • Mutations in the RET proto-oncogene:
      • Are found in at least 95% of kindreds with MEN2A and 88% of cases of familial MTC
    • The RET proto-oncogene codes for:
      • A cell membrane-associated tyrosine kinase receptor for a glial, cell line-derived neurotrophic factor
    • Mutations associated with MEN2A and familial MTC:
      • Have been primarily identified in several codons of the cysteine-rich extracellular domains of:
        • Exons 10, 11, and 13
    • MEN2B and some familial MTC mutations are found within the:
      • Intracellular exons 14 to 16
    • Somatic mutations in exons 11, 13, and 16 have also been found:
      • In at least 25% of sporadic MTC tumors:
        • Particularly the codon 918 mutation:
          • That activates the tyrosine kinase function of the receptor and are associated with poorer prognosis of the patient
    • About 6% of patients with clinically sporadic MTC:
      • Carry a germline mutation in RET:
        • Leading to identification of new kindreds with multiple (previously undiagnosed) affected individuals
  • Germline testing for RET proto-oncogene mutations with genetic counseling by a physician or genetic counselor:
    • Is recommended for all patients with newly diagnosed clinically apparent sporadic MTC:
      • If a germline RET mutation is found:
        • Then mutation testing should also be done for family members
  • MTC can involve difficult ethical decisions for clinicians:
    • If parents or guardians refuse screening and/or treatment for children with possible MTC
• The generally accepted preoperative workup includes:
  • Measurement of serum markers:
    • Basal serum calcitonin and serum carcinoembryonic antigen [CEA])
  • Screening of patients with germline RET proto-oncogene mutations for:
    • Pheochromocytoma (MEN2A and MEN2B):
      • Before surgery for MTC:
        • It is important to diagnose and address coexisting pheochromocytoma:To avoid hypertensive crisis during surgery:
          • Pheochromocytoma can be removed using laparoscopic adrenalectomy
    • Hyperparathyroidism (MEN2A)
  • Preoperative thyroid and neck ultrasound (including central and lateral neck compartments) is recommended
  • Contrast-enhanced CT of neck / chest and liver MRI or 3-phase CT of liver can be considered as clinically indicated:
    • Such as in cases of:
      • High burden of disease
      • Calcitonin greater than 400 pg/mL
      • Elevated CEA levels
    • Distant metastasis:
      • Does not contraindicate surgery
    • Liver imaging is rarely needed:
      • If the calcitonin is less than 400 pg/mL
  • Evaluation of vocal cord mobility can also be considered:
    • For patients with:
      • Abnormal voice, surgical history involving the recurrent laryngeal or vagus nerves, invasive disease, or bulky disease of the central neck
• Staging:
  • The NCCN Guidelines for Thyroid Carcinoma:
    • Do not use TNM stages to guide therapy:
      • Instead, many characteristics of the tumor and patient play important roles in these NCCN Guidelines:
        • Many specialists in thyroid cancer also follow this paradigm
    • The TNM criteria for clinicopathologic tumor staging are based on:
      • Tumor size
      • The presence or absence of extrathyroidal invasion
      • Locoregional nodal metastases
      • Distant metastases
    • The 8th edition of the AJCC Cancer Staging Manual separated MTC into its own stand-alone chapter:
      • However, the TNM staging classification lacks other important prognostic factors:
        • Notably absent is the age at diagnosis;
          • Patients younger than 40 years at diagnosis have a:
            • 5- and 10-year disease-specific survival rate of about 95% and 75%, respectively, compared with 65% and 50% for those older than 40 years
          • Controlling for the effect of age at diagnosis:
            • The prognosis of patients with inherited disease (who typically are diagnosed at an earlier age):
              • Is probably similar to those with sporadic disease
        • Despite an even younger typical age at diagnosis, however:
          • Patients with MEN2B who have MTC:
            • Are more likely than those with MEN2A (or familial MTC) to have:
              • Locally aggressive disease
    • Other factors that may be important for predicting a worse prognosis include:
      • The heterogeneity and paucity of calcitonin immunostaining of the tumor
      • A rapidly increasing CEA level:
        • Particularly in the setting of a stable calcitonin level
      • Postoperative residual hypercalcitoninemia
  • A study comparing different staging systems found that a system incorporating:
    • Age, gender, and distant metastases (EORTC):
      • Had the greatest predictive value:
        • However, the AJCC staging system was deemed to be the most appropriate
  • Codon analysis:
    • Is useful for predicting prognosis
    • Presence of an exon 16 mutation:
      • Either within a sporadic tumor or associated with MEN2B:
        • Is associated with more aggressive disease
      • More than 95% of patients with MEN2B:
        • Have a mutation in exon 16 (codon 918)
      • Whereas 2% to 3% have a mutation in:
        • Exon 15 (codon 883)
• Surgical Management:
  • Surgery is the main treatment for MTC
  • While no curative systemic therapy for MTC is available:
    • Vandetanib and cabozantinib are recommended for:
      • Locally advanced and metastatic MTC
  • MTC cells do not concentrate RAI:
    • Therefore, iodine-131 imaging cannot be used, and RAI treatment is not effective in these patients
  • MTC does not respond well to conventional cytotoxic chemotherapy
  • Postoperative levothyroxine is indicated for all patients:
    • However, TSH suppression is not appropriate:
      • Because C cells lack TSH receptors:
        • Thus, TSH should be kept in the normal range by adjusting the levothyroxine dose
  • Patients should be assessed for hyperparathyroidism and pheochromocytoma preoperatively:
    • Even in patients who have apparently sporadic disease:
      • Because the possibility of MEN2 should dictate testing for a germline RET proto-oncogene mutation for all patients with MTC
    • Pheochromocytomas should be removed (eg, laparoscopic adrenalectomy) before surgery on the thyroid:
      • To avoid hypertensive crisis during surgery
    • Patients with pheochromocytomas must be treated preoperatively with:
      • Alpha-adrenergic blockade (phenoxybenzamine) or with alpha-methyltyrosine:
        • To avoid a hypertensive crisis during surgery
      • Forced hydration and alpha-blockade:
        • Are necessary to prevent hypotension after the tumor is removed
      • After institution of alpha-blockade and hydration:
        • Beta-adrenergic blockade may be necessary to treat tachyarrhythmia
  • Total thyroidectomy and bilateral central neck dissection (level VI):
    • Are indicated in all patients with MTC:
      • Whose tumor is 1 cm or larger
      • Who have bilateral thyroid disease
  • Total thyroidectomy is recommended and neck dissection can be considered for:
    • Those whose tumor is smaller than 1 cm
    • For unilateral thyroid disease
  • Given the risks of thyroidectomy in very young children:
    • Referral to a surgeon and team with experience in pediatric thyroid surgery is advised
  • If a patient with inherited disease is diagnosed early enough:
    • The recommendation is to perform a prophylactic total thyroidectomy:
      • By age 5 years or
      • When the mutation is identified (in older patients), especially in patients with:
        • Codon 609, 611, 618, 620, 630, or 634 RET mutations:
          • Note that C634 mutations:
            • Are the most common mutations
    • Total thyroidectomy is recommended in:
      • The first year of life or at diagnosis for patients with:
        • MEN2B who have codon 883 RET mutations, 918 RET mutations, or compound heterozygous (V804M + E805K, V804M + Y806C, or V804M + S904C) RET mutations:
          • Because these RET mutations carry the highest risk for MTC
    • However, for patients with codon 768, 790, 791, 804, and 891 RET (risk level A) mutations:
      • The lethality of MTC may be lower than with other RET mutations:
        • In patients with these less high-risk (ie, lower-risk level A) RET mutations:
          • Annual basal calcitonin testing and annual ultrasound are recommended
          • Total thyroidectomy and central node dissection may be deferred:
            • If these tests are normal
            • There is no family history of aggressive MTC
            • The family agrees to defer surgery
        • Delaying thyroidectomy may also be appropriate for children with lower-risk mutations (ie, level A):
          • Because of the late onset of MTC development
    • A study found no evidence of persistent or recurrent MTC 5 years or more after prophylactic total thyroidectomy;
      • In young patients with RET mutations for MEN2A:
        • Longer follow-up is necessary to determine if these patients are cured
  • Variations in surgical strategy for MTC depend on:
    • The risk for locoregional node metastases and on
    • Whether simultaneous parathyroid resection for hyperparathyroidism is necessary
  • A bilateral central neck dissection (level VI):
    • Can be considered for all patients with MEN2B
  • For those patients with MEN2A who undergo prophylactic thyroidectomy:
    • Therapeutic ipsilateral or bilateral central neck dissection (level VI) is recommended:
      • If patients have an increased calcitonin or CEA test or
      • If ultrasound shows a thyroid or nodal abnormality
  • Similarly, more extensive lymph node dissection (levels II–V) is considered for:
    • These patients with primary tumor(s) 1 cm or larger in diameter (>0.5 cm for patients with MEN2B) or for patients with central compartment lymph node metastases
  • With a concurrent diagnosis of hyperparathyroidism in MEN2A or familial MTC:
    • The surgeon should leave or autotransplant the equivalent mass of one normal parathyroid gland if multiglandular hyperplasia is present
    • Cryopreservation of resected parathyroid tissue should be considered to allow future implantation in the event of iatrogenic hypoparathyroidism
  • Disfiguring radical node dissections:
    • Do not improve prognosis and are not indicated
    • In the presence of grossly invasive disease:
      • More extended procedures with resection of involved neck structures may be appropriate:
        • Function-preserving approaches are preferred
• In some patients, MTC is diagnosed after thyroid surgery:
  • In these patients, additional workup is recommended:
    • To ascertain whether they have RET proto-oncogene mutations (eg, exons 10, 11, 13–16):
      • Which will determine whether they need additional surgery (eg, completion thyroidectomy and/or neck dissection)
• Adjuvant RT EBRT and IMRT:
  • Have not been adequately studied as adjuvant therapy in MTC:
  • Slight improvements in local disease-free survival have been reported after EBRT for selected patients:
    • Such as those with:
      • Extrathyroidal invasion or
      • Extensive locoregional node involvement
    • However, most centers do not have extensive experience with adjuvant EBRT or IMRT for this disease
  • While therapeutic EBRT or IMRT may be considered for grossly incomplete resection:
    • When additional attempts at surgical resection have been ruled out:
      • Adjuvant EBRT or IMRT is rarely recommended
  • EBRT or IMRT can also be given to palliate painful or progressing bone metastases
• Persistently Increased Calcitonin:
  • Basal serum concentrations of calcitonin and CEA:
    • Should be measured 2 or 3 months postoperatively
  • About 80% of patients with palpable MTC and 50% of those with nonpalpable but macroscopic MTC:
    • Who undergo supposedly curative resection:
      • Have serum calcitonin values indicative of residual disease:
        • Those patients with residual disease may benefit from further evaluation to detect either residual resectable disease in the neck or the presence of distant metastases
  • Patients with detectable basal calcitonin or elevated CEA:
    • Who have negative imaging and who are asymptomatic:
      • May be followed
  • Patients with a basal serum calcitonin value greater than 1000 pg/mL and with no obvious MTC in the neck and upper mediastinum:
    • Probably have distant metastases:
      • Most likely in the liver
  • However, occasionally patients have relatively low serum CEA and calcitonin levels:
    • But have extensive metastatic disease:
      • Initial postoperative imaging is therefore reasonable despite the absence of very high serum markers
  • The prognosis for patients with postoperative hypercalcitoninemia:
    • Depends primarily on:
      • The extent of disease at the time of initial surgery
    • In a study of 31 patients (10 patients with apparently sporadic disease, 15 patients with MEN2A, and 6 patients with MEN2B):
      • The 5- and 10-year survival rates were 90% and 86%, respectively
      • Two studies have reported higher mortality rates for patients with high postoperative serum calcitonin values:
        • With more than 50% of patients having a recurrence during a mean follow-up of 10 years
      • Routine lymphadenectomy or excision of palpable tumor:
        • Generally fails to normalize the serum calcitonin concentrations in such patients:
          • Therefore, some have focused on detection and eradication of microscopic tumor deposits with a curative intent in patients without distant metastases
      • Extensive dissection to remove all nodal and perinodal tissue from the neck and upper mediastinum:
        • Was first reported to normalize the serum calcitonin levels in 4 of 11 patients at least 2 years postoperatively
      • In subsequent larger studies, 20% to 40% of patients undergoing microdissection of the central and bilateral neck compartments:
        • Were biochemically cured, with minimal perioperative morbidity
    • When repeat surgery is planned for curative intent:
      • Preoperative assessment should include locoregional imaging (ie, ultrasonography of the neck and upper mediastinum) and attempts to exclude patients with distant metastases, which may include:
        • Contrast-enhanced CT or MRI of the neck, chest, and abdomen
• Postoperative Management and Surveillance:
  • Calcitonin is very useful for surveillance:
    • Because this hormone is only produced in the parafollicular cells
  • Thus, measurements of serum calcitonin and CEA levels:
    • Are the cornerstone of postoperative assessment for residual disease
  • For patients with a detectable basal calcitonin or elevated CEA level:
    • Neck ultrasound is recommended
  • Patients with undetectable calcitonin levels and normal CEA levels:
    • Can subsequently be followed with annual measurements of serum markers
  • Additional studies or more frequent testing:
    • Can be done for those with significantly rising calcitonin or CEA
  • Nonetheless, the likelihood of significant residual disease is very low in patients with an undetectable basal calcitonin level in a sensitive assay
  • If the patient has MEN2:
    • Annual screening for pheochromocytoma (MEN2B or MEN2A) and hyperparathyroidism (MEN2A):
      • Should also be performed
  • For some low-risk RET mutations:
    • Examples:
      • Codons 768, 790, 804, or 891:
        • Less frequent screening may be appropriate
  • Patients with detectable serum markers:
    • Calcitonin levels ≥ 150 pg/mL:
      • Should have CT of the neck, chest, and liver
      • Bone scan and MRI of axial skeleton:
        • Should be considered in select patients such as those with very elevated calcitonin levels
  • The NCCN Panel recognizes that many different imaging modalities may be used to examine for residual or metastatic tumor:
    • But there is insufficient evidence to recommend any particular choice or combination of tests
  • For patients with asymptomatic disease and detectable markers in whom imaging fails to identify foci of disease:
    • The NCCN Panel recommends conservative surveillance:
      • With repeat measurement of the serum markers every 6 to 12 months
    • Additional imaging studies (eg, FDG PET/CT, Ga68 DOTATATE, or MRI with contrast of the neck, chest, and abdomen with liver protocol):
      • May be indicated depending on calcitonin / CEA doubling time
  • For patients who are asymptomatic with abnormal markers and repeated negative imaging:
    • Continued disease monitoring or consideration of cervical reoperation is recommended if primary surgery was incomplete
  • For the patient with increasing serum markers:
    • More frequent imaging may be considered
  • Outside of clinical trials:
    • No therapeutic intervention is recommended on the basis of abnormal markers alone

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