Medullary Thyroid Carcinoma Generalities

Is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland:
- MTC accounts for:
  - Approximately 1% to 2% of all thyroid cancers in the United States:
    - The production of calcitonin:
      - Is a characteristic feature of this tumor
- Most medullary thyroid carcinomas:
  - Are sporadic (75% to 80%):
    - However:
      - Approximately 20% to 25% are familial:
        As part of the multiple endocrine neoplasia type 2 (MEN2) syndrome

Clinical Presentation:
- Sporadic MTC:
  - Sporadic medullary thyroid cancer (MTC):
    - Accounts for approximately 75% of all cases of the disease:
      - The typical age of presentation:
        Is in the fourth and sixth decades of life
- Symptoms and signs:
  - The most common presentation of sporadic MTC:
    - Is that of a solitary thyroid nodule:
      - Which occurs in 75% to 95% percent of patients
  - The C cells or parafoliccular cells are predominantly located in the upper portion of each thyroid lobe:
    - Thus:
      - Most tumors are located in this region
  - In most patients with MTC:
    - The disease has already metastasized at the time of diagnosis:
      - Approximately 70% of patients have clinically detectable cervical lymph node involvement
    - Up to 15% of patients with MTC:
      - Have symptoms of upper aerodigestive tract compression or invasion:
        Such as dysphagia or hoarseness
    - Approximately 5% to 10%:
      - Have distant metastatic disease:
        Distant metastases may occur in the:
        Liver, lung, bones, and, less often, brain and skin
        Nodal metastases:
        Are more common in patients with multifocal disease:
        However, as calcitonin screening results in the identification of more “micro” medullary cancers:
        The number of patients with metastases at presentation appears to be decreasing
        Calcitonin screening for MTC in patients with thyroid nodules is controversial
- Systemic symptoms may occur due to hormonal secretion by the tumor:
  - Tumor secretion of calcitonin, calcitonin gene-related peptide, or other substance:
    - Can cause diarrhea or facial flushing in patients with advanced disease
  - In addition, occasional tumors secrete corticotropin (ACTH):
    - Causing ectopic Cushing’s syndrome
Biochemical tests:
- Basal serum calcitonin concentrations:
  - Usually correlate with tumor mass but also reflect tumor differentiation, and they are almost always high in patients with a palpable tumor
- Most MTCs also secrete carcinoembryonic antigen (CEA):
  - Which, like calcitonin, can be used as a tumor marker
  - In addition, the expression of CEA on MTC cells has led to the use of anti-CEA antibodies for immunotherapy
- Thyroid function tests are normal in patients with MTC
Imaging:
- There are several ultrasound features of thyroid nodules (eg, hypoechoic, microcalcifications) that are associated with thyroid cancer risk:
  - However, there are no ultrasound features that are pathognomonic for thyroid cancer.
  - Furthermore, the majority of studies evaluating suspicious ultrasound characteristics of nodules focused on papillary thyroid cancer
  - In a small retrospective study examining the ultrasound characteristic of nodules that were histologically proven to be MTC and papillary thyroid cancer
    - 50% of MTCs were solid and hypoechoic
    - 16% showed microcalcifications
      - Compared with 69.2% and 69.2%:
        Respectively, for papillary thyroid cancers
      - The presence of at least one suspicious ultrasound feature was almost equal in patients with MTC (58.3%) and controls with benign nodules (55.5%), whereas it was significantly more frequent in patients with papillary thyroid cancer (100%)
  - In other series
    - Hypoechogenicity was present in 50% to 89% and microcalcifications in 30% to 70%:
      - There was no difference in echogenicity or the presence or type of calcifications between MTC and papillary thyroid cancer .
    - Large areas of calcification (macrocalcification) were noted in 16% to 30%:
      - Rarely:
        The diagnosis of MTC is suggested by the presence of dense calcifications seen on radiographs or imaging of the anterior neck.
Inherited MTC:
- Multiple endocrine neoplasia type 2 (MEN2):
  - Is subclassified into two distinct syndromes (MEN2A and MEN2B):
    - Each of which is transmitted in an autosomal dominant fashion and is associated with MTC
  - These syndromes result from:
    - Different mutations in the RET proto-oncogene
  - In the past:
    - Familial MTC (FMTC):
      - An inherited syndrome characterized by the presence of only MTC without hyperparathyroidism or pheochromocytoma:
        Was considered a separate entity but is now considered a variant of MEN2A
- Hereditary MTC is:
  - Typically bilateral and multicentric:
    - Classical MEN2A is associated with:
      - MTC
      - Pheochromocytoma
      - Primary parathyroid hyperplasia
        While the penetrance of MTC is nearly 100%:
        There is inter- and intrafamily variability in the specific pattern of the other disease manifestations
  - MEN2B shares the inherited predisposition to MTC and pheochromocytoma present in classical MEN2A:
    - But does not include hyperparathyroidism
    - MTC occurs in almost all patients
    - The tumor develops at:
      - An earlier age and may be more aggressive than in MEN2A
    - Patients typically have:
      - A marfanoid habitus (but do not have Marfan syndrome),
      - Mucosal neuromas
      - Intestinal ganglioneuromatosis
  - In the index case:
    - The clinical presentation and manifestations of MEN2-associated MTC are similar to those of sporadic MTC:
      - The most common presentation is that of:;
        A solitary thyroid nodule or cervical lymphadenopathy
    - Early diagnosis (prior to any clinical manifestations) by screening of “at-risk” family members in MEN2 kindreds is important because MTC is a life-threatening disease that can be cured or prevented by early thyroidectomy

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