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

#Arrangoiz #ThyroidSurgeon #ThyroidExpert #MedullaryThyroidCarcinoma #MTC #HeadandNeckSurgeon #CancerSurgeon #CASO #Miami #CenterforAdvancedSurgicalOncology

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