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Advances in Diagnostics and Therapy of Medullary Thyroid Carcinoma (MTC)– A Mini-Review
Michał Miciak1*, Krzysztof Jurkiewicz1
1Department of General, Minimally Invasive and Endocrine Surgery, Faculty of Medicine, Wroclaw Medical University, Wrocław, Poland.
Abstract
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine neoplasm that arises from parafollicular C cells of the thyroid gland. Unlike the typical papillary carcinoma, medullary carcinoma develops more rapidly and causes distant metastases resistant to chemotherapy. The treatment options for MTC are surgery or pharmacotherapy. In recent years, major advances have been made especially in the pharmacological treatment of MTC. This paper aims to review the methods of diagnosis and treatment of MTC, taking into consideration the most recent findings. PubMed, PubMed Central, and Google Scholar databases were searched using keywords related to medullary thyroid carcinoma, its molecular and imaging diagnosis, thyroidectomy, and systemic pharmacotherapy. English-language articles were searched and selected after analyzing abstracts. Types of articles included mainly original articles and meta-analyses. From the initial search, 39 articles were retrieved for final analysis. This mini-review describes diagnostic methods for MTC focusing on testing biomarker levels. The most important, calcitonin, correlates linearly with tumor growth. First-line therapy for MTC is based on total thyroidectomy along with cervical lymphadenectomy. In some cases, systemic therapy based mainly on tyrosine kinase (TK) inhibitors is necessary. Research is also being conducted into gene therapy and blockage of tumor mitochondrial metabolism. MTC is a rapidly growing neuroendocrine tumor requiring radical surgical treatment. In cases where it is not possible, treatments that block the process of tumor carcinogenesis at various stages are used. New substances are being developed constantly to allow more effective treatment.
Keywords: Medullary thyroid carcinoma, Cancer management, Diagnostics, Thyroidectomy, Biomarkers, Neuroendocrine neoplasm
Medullary thyroid cancer (MTC) is a neuroendocrine neoplasm originating from parafollicular C cells of the thyroid gland. It represents less than 5% of all malignancies diagnosed within the thyroid gland making it an extremely rare lesion.[1] The neoplasm is capable of secreting calcitonin and carcinoembryonic antigen (CEA), making it possible to suspect in biochemical test results.[2] The lesions are most often localized in the posterior upper regions of the thyroid lobes where there are larger clusters of neuroendocrine C cells. This cancer can occur sporadically but 25% of cases are associated with an inherited syndrome of other endocrinopathies (MEN2A or MEN2B) or familial without comorbidities. It is characteristically associated with the presence of mutations in the RET proto-oncogene. MTC manifests as a palpable nodule within the thyroid gland, at such a stage metastasis to the cervical lymph nodes (in 70% of patients) and distant metastasis to the liver, lungs, bones, and brain (in 10-15% of patients) are already found. Another fairly common symptom is diarrhea caused by high levels of calcitonin.[1, 3]
Materials and Methods
The mini-review was performed based on PubMed, PubMed Central, and Google Scholar online databases. Papers concerning mostly the last 10 years of MTC management were taken into consideration. Various forms of the following terms: “medullary thyroid cancer”, “MTC diagnosis”, “thyroidectomy”, “calcitonin” and “MTC systematic treatment” were used for research. Original articles and meta-analyses were selected after analyzing abstracts. Of publications from the fields of surgical oncology, clinical oncology, and endocrinology, those that comprehensively described the topic were accepted. Finally, 39 articles have been studied for this mini-review.
Diagnosis of MTC is based on biochemical tests, imaging studies, and analysis of biopsy material. Imaging procedures such as ultrasound and computed tomography help localize a lesion noted on clinical examination. When distant metastases are suspected, multidetector tomography or magnetic resonance imaging of the liver with contrast and bone scintigraphy are additionally recommended. PET scanning with 18F-fluorodeoxyglucose is less sensitive in detecting metastases.[4] Performing fine-needle aspiration (FNA) biopsy is a useful method, but may result in misdiagnosis of MTC as non-neuroendocrine thyroid (papillary) neoplasm or other types of cancer (sarcoma, plasmacytoma). Therefore, such a result should be confirmed by biochemical tests which play the greatest role in the diagnosis of medullary thyroid cancer.[5] A sensitive marker in the diagnosis of MTC is calcitonin. An increase in its serum level correlates with an increase in tumor mass. A level that raises suspicion of MTC oscillates between 60-100 pg/ml, and a level of 500 pg/ml may indicate the existence of distant metastases. However, it should be remembered that calcitonin levels can be falsely elevated by the use of proton pump inhibitors, renal failure, or hypercalcemia.[1, 4] By the fact that MTC is an extremely rare tumor, not all guidelines recommend routine measurement of calcitonin levels in patients diagnosed with thyroid tumors. Therefore, there are other markers in the study to aid in diagnosis.[6] One of these is CEA, which has correlated with the stage of medullary carcinoma in the studies. Compared to calcitonin which has a linear relationship with MTC progression, CEA levels are significantly elevated (approximately >270 ng/ml) in advanced disease. Meanwhile, levels >500 ng/ml are associated with significant patient mortality.[7] Recently the use of Ca19.9 antigen has been proposed as a biomarker of poor prognosis of MTC, which had elevated levels in 16% of patients participating in a clinical trial.[8] It also seems reasonable to study the correlation of procalcitonin levels in medullary carcinoma. There have been found a sensitivity and specificity of 96% and the usefulness of this marker in calcitonin-negative patients with MTC is under consideration.[9] Despite the emergence of more recent studies and attempts to find further markers (e.g., circulating miR-375 micro-RNA), calcitonin and CEA remain the standard diagnostic markers.[1, 10] (Table 1) summarizes the information about MTC markers. Diagnosis requires a broader clinical view due to the possibility of false positives associated with other cancers like pancreatic or colorectal cancer where the relevant markers may also be elevated.
Table 1. Biomarkers used in MTC diagnostics. |
|
Markers |
Notices |
Calcitonin |
increases along with MTC mass, increasing level (from 60-100 pg/ml) arouses MTC suspicion |
CEA |
elevated level (>270 ng/ml) rather in advanced MTC |
Ca19.9 |
appears to be related to poor prognosis in the course of MTC |
Procalcitonin |
helpful in patients with MTC in suspect but with negative calcitonin |
miR-375 micro-RNA |
currently in clinical trials |
|
Figure 1. Management algorithm for patients with MTC. |
MTC is a rare neuroendocrine neoplasm most often associated with genetic mutations, it is more malignant than papillary thyroid carcinoma and its suspicion may be raised by symptoms associated with excessive calcitonin secretion. Measurement of biomarkers (especially calcitonin) plays the greatest role in MTC diagnosis as it should be remembered that FNA is not sensitive in detecting MTC. The therapy of choice for MTC is radical thyroidectomy with cervical lymphadenectomy. MTC distant metastases do not respond to chemotherapy and radiotherapy therefore specialized systemic treatment is required for inoperable lesions or the presence of metastases. Over the past 10 years, significant progress has been made in the discovery of new drug groups based on gene therapy and blocking the MTC carcinogenesis pathway, which provides a hopeful glimpse into the future of MTC therapy.
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