Discussion
Medullary thyroid cancers (MTC) originate from the parafollicular cells,
also called the C- cells of the thyroid gland. MTC consists of
approximately 1 to 2% of thyroid cancers in the United States, with the
incidence of sporadic medullary thyroid cancer peaking in the fifth or
sixth decade of life [6]. About 80 % of these cancers are sporadic,
with the remaining 20% hereditary. Hereditary MTC can be isolated or
part of the multiple endocrine neoplasms (MEN) syndromes [7]. MTC
associated with MEN syndromes peaks around the second or third decade of
life. C- cells of the thyroid gland secrete calcitonin; therefore,
elevated serum calcitonin is a good indicator for MTC with high
sensitivity and specificity [8]. Other markers which can aid in
diagnosis include CEA and chromogranin A. There are rare cases of serum
calcitonin-negative MTC. MTC often involves the upper portions of both
thyroid lobes because the C- cells are predominantly found in the upper
lobe of the thyroid gland [9].
Patients with MTC predominantly present with a thyroid nodule in the
upper portion of the thyroid gland; about 70% will have cervical
lymphadenopathy, and patients with T4 tumors and node-positive disease
after surgery predict a higher chance of recurrence [10]. About 5 to
10% of patients will have metastatic disease at the time of
presentation, commonly involving the liver, lung, bone, skin, and brain
[11]. Rarely did patients present with diarrhea and flushing from
very high calcitonin levels, and our patient presented only with
isolated diarrhea.
Fine needle aspiration of the thyroid nodule is an accurate method for
diagnosis, but sometimes the diagnosis can be challenging due to the
morphological heterogeneity of this tumor [12], especially when the
tissue sample is obtained outside the thyroid gland, like in our case.
Although calcitonin levels have high sensitivity, routine calcitonin
screening is controversial due to the risk of false positivity but can
add value in patients with multinodular goiter [13]. Other markers,
such as carcinoembryonic antigen (CEA) and chromogranin, should be
cautiously evaluated as they may be elevated in other malignancies.
Postoperative calcitonin and CEA doubling time provide a sensitive
marker for disease progression.
Neck ultrasound or neck Computed Tomography (CT) is helpful in staging
the disease. Gallium 68 Dotatate PET/CT can identify smaller lesions and
helpful in patients with high calcitonin levels [14], like our
patient, as we identified new bone lesions in the PET/CT. The
pathological analysis is the gold standard for diagnosis and
immunohistochemical expression of calcitonin, chromogranin,
synaptophysin, CEA, and TTF1 [15]. The positivity in chromogranin
and synaptophysin can lead to an alternative diagnosis, especially in
diseases outside the thyroid, as seen in our patient. Approximately 50
to 60 % of MTCs harbor a somatic RET mutation, particularly the M918T
mutation, and it’s associated with an aggressive clinical course
[15]. In patients with germline RET mutation, it is recommended to
screen for hyperparathyroidism and pheochromocytoma.
For locally advanced and metastatic MTC, chemotherapy and radiation have
been largely ineffective. There is no role for radioactive iodine
treatment or thyroid-stimulating hormone suppression. Tyrosine kinase
inhibitors like vandetanib have some promising outcomes in
progression-free survival compared to placebo [16]. Other
multikinase TKIs which has shown responses include cabozantinib and
lenvatinib [17, 18]. Selpercatinib is an ATP-competitive, highly
selective, small-molecule RET kinase inhibitor studied in RET-mutated
MTC. A phase 2 trial studied selpercatinib in patients previously
treated with cabozantinib or vandetanib [19]. The results showed an
objective response rate of 69%, with 9% having a complete response and
60% of patients with a partial response, which led to the FDA approval
for this drug. Pralsetinib was studied in a phase 1/2 Arrow trial and
eventually was FDA-approved in patients with RET mutant MTC patients.
Efficacy for advanced or metastatic RET-mutant MTC was evaluated in 55
patients who received prior cabozantinib or vandetanib. The ORR was 60%
in all patients and 66 % in patients with RET-mutant MTC who did not
receive prior cabozantinib or vandetanib (29 patients). Phase 3 trials
are ongoing for selpercatinib and pralsetinib in advanced medullary
thyroid cancer patients.