Medullary carcinoma
Medullary thyroid carcinoma (MTC)
Synonym
solid carcinoma
solid carcinoma with amyloid stroma
solid amyloidotic carcinoma
C-cell carcinoma
Compact cell carcinoma
neuroendocrine carcinoma of thyroid
Definition
Malignant epithelial cell tumor of C-cell origin of thyroid gland
Etiology/Pathogenesis
Genetic cases
Strong genetic correlation with multiple endocrine neoplasia syndrome (MEN)
MEN2A (Sipple): parathyroid hyperplasia (hyperparathyroidism), medullary thyroid cancer, adrenal pheochromocytoma and endocrine tumors of the pancreas
MEN2B (Wagenmann-Froboese syndrome) includes, in addition to the above, soft tissue tumors (usually sarcomas)
Autosomal dominant, highly aggressive and various manifestations
Germ cell mutations (usually point mutations) occurring on 10q11.2 that result in enhanced function of the RET gene
RET is a fusion gene containing a gene encoding a tyrosine kinase fragment (RET, Rearranged during Transfection contraction)
……
RET is also associated with papillary thyroid carcinoma (chromosomal remap also known as RET/PTC)
Familial medullary thyroid carcinoma (FMTC) is not associated with extrathyroidal disease but is still associated with RET proto-oncogene mutations in germ cells.
Sporadic cases
More than 2/3 of sporadic cases have somatic RET mutations
Other genetic or epigenetic alterations are also seen
Pathogenesis
C-type cells of posterior parotid origin are the primary cells of the tumor
Type C (parafollicular) cells develop embryologically from the fourth parotid/pharyngeal bursa
They are found in the upper middle part of the thyroid lobe
Medullary carcinoma does not originate in the thyroid headland
Calcitonin is a peptide hormone secreted by C-type cells to maintain calcium homeostasis in the body
In hereditary cases, C-cell hyperplasia is the precursor of medullary carcinoma
Epidemiology
Incidence
Approximately 5-8% of thyroid malignancies in the United States
Predominantly disseminated (80%), with the remainder (20%) being hereditary (familial)
Age
Sporadic cases: 50-60 years
Familial cases: 30 years old
MEN2A: late adolescence or early adulthood
MEN2B: infancy or early childhood
Gender.
Sporadic cases: female > male (1.1:1)
Location
Upper middle thyroid lobe
Site of C cells and/or posterior parotid body
The thyroid headland is not affected
Description
Sporadic cases
Painless, unilateral, isolated thyroid swelling
Approximately 50% of patients have enlarged cervical lymph nodes
Hoarseness, wheezing, upper airway obstruction, or dysphagia in about 10-15% of patients
Hereditary/familial cases
Thyroid/neck presentation is the same as in disseminated cases, except that patients are younger than in disseminated cases
More than 30% of patients have diarrhea and facial flushing, which are associated with increased plasma calcitonin levels
Multicentric or bilateral thyroid involvement
Clinical symptoms of other non-thyroidal organs may be predominant
Calcium disorders due to hyperparathyroidism
excessive sweating, headache, paroxysmal hypertension, palpitations, syncope and vertigo due to pheochromocytoma
Cushing’s syndrome caused by ACTH or pituitary adenoma peptide products produced by the tumor
Gastrointestinal symptoms caused by peptide secretion from pancreatic endocrine tumors
Mucosal neuromas (oral, lip, tongue and gastrointestinal tract)
In some familial cases, can be detected before the onset of clinical symptoms
Parathyroid, adrenal, pituitary, pancreatic, and gastrointestinal manifestations
Incidental finding of thyroid disease during evaluation for MEN syndrome
Laboratory tests
Serum calcitonin levels are elevated to varying degrees
Elevated CEA levels
Calcium dysregulation (triggered by calcitonin and parathyroid hormone abnormalities)
Treatment
Treatment strategies, risks and complications
Prophylactic thyroidectomy for patients with germ cell RET mutations (RET phenotype specific)
Thyroidectomy at the recommended age for patients with specific RET mutations
Thyroidectomy before 12 months for patients with codon 883, 918 and 922 mutations
For patients with codon 611, 618, 620 and 634 mutations, thyroidectomy before 5 years of age
For patients with other codon mutations: thyroidectomy after abnormal pentagastrin-stimulated calcitonin response
Surgical procedures
Total thyroidectomy
Neck dissection
Central zone (zone VI)
If the central zone lymph nodes are positive or the tumor size is more than 1 cm, an ipsilateral neck dissection should be performed
If bilateral tumors are present, bilateral radical neck dissection should be performed
Parathyroidectomy in some hereditary cases
Adjuvant treatment
Chemotherapy, growth inhibitor analogues, anti-CEA radioimmunotherapy may be indicated for some patients
Radiotherapy
For cases with large residual masses or distant metastases, external particle beam radiation therapy is indicated.
Additional treatment
Radiofrequency ablation
Molecular targeted therapy (tyrosine kinase inhibitors targeting RET kinase)
Prognosis
Clinical stage and genetic type dependent
Overall 10-year survival rate 70%-80%
Good prognosis for those cases with smaller tumors still confined to the thyroid, incidental findings, and no lymph node metastases (100%)
Prognosis: familial non-MEN> disseminated cases>MEN2A>MEN2B
Best prognosis for prophylactic thyroidectomy cases, worst for cases with lymph node metastasis
Tumor stage is the most important prognostic factor (invasive extra-thyroidal and metastatic)
Stage I: 100 % survival rate at 10 years
Stage III: 10-year survival rate 65%-85%
Stage IV: 10-year survival rate 20%-50%
Younger patients (less than 45 years old) have a better prognosis than older patients
Women have a slightly worse prognosis (this result is still controversial)
Lymph node metastases are more common (about 50%)
Distant metastases are rare (about 15)
Liver, lung, bone
Prognosis is better in patients with amyloid-rich material and more than 75% cytocalcitonin positive
If somatic RET mutations are present, with codon 918 mutations being the most malignant
If preoperative serum calcitonin and CEA levels are high, they can be used as a test for follow-up