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Annals of the Royal College of Surgeons... Sep 2006Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy arising from the parafollicular C cells. It accounts for 5-10% of thyroid malignancies and occurs in... (Review)
Review
INTRODUCTION
Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy arising from the parafollicular C cells. It accounts for 5-10% of thyroid malignancies and occurs in sporadic and hereditary forms. There are still many controversial aspects relating to the diagnosis and management of this unusual tumour in its various forms. The present article addresses the more important of these issues.
METHODS
A literature review was performed using Pubmed database combined with additional original papers obtained from citations in those articles identified in the original literature search. Only those articles which related specifically to the controversial issues addressed in this review were included.
RESULTS
Genetically determined tumours constitute approximately 25% of MTC and have special clinical interest because of their association with other endocrinopathies including phaeochromocytoma and hyperparathyroidism in the multiple endocrine neoplasia syndromes (MEN IIa and MEN IIb). Familial medullary thyroid carcinoma (FMTC) is a rare form not associated with any other endocrinopathies. The genetic basis for these familial tumours derives from a series of missense germline mutations in the RET protooncogene. Genetic testing by DNA analysis facilitates identification of family members at risk who can now be offered early 'prophylactic thyroidectomy' with an increased prospect of surgical success and long-term survival. MTC is a tumour which does not take up radioactive iodine, is relatively radioresistant and poorly responsive to chemotherapy. Therefore, surgery is the only treatment which can offer the prospect of cure. Total thyroidectomy with central and lateral nodal dissection can achieve biochemical cure (normocalcitonaemia) in more than 80% of cases. Compartmental orientated microdissection of cervical nodes has significantly improved the results of primary surgery but even so a group of 20% of patients will prove to have recurrent or residual disease. These cases require detailed investigation by a variety of techniques including ultrasound, cross-sectional imaging, nuclear imaging and laparoscopy with liver biopsy to exclude disseminated disease and select those patients who can be offered a prospect of cure by further neck surgery. Such an approach may be associated with successful normalisation of calcitonin levels in about 40%.
CONCLUSIONS
It is hoped that in the near future new medical therapies may become available to treat MTC which still has a 10-year survival of only 60-80% in spite of the application of meticulous surgical techniques.
Topics: Carcinoma, Medullary; Humans; Lymphatic Metastasis; Neoplasm Recurrence, Local; Reoperation; Thyroid Neoplasms; Thyroidectomy
PubMed: 17002842
DOI: 10.1308/003588406X117043 -
Frontiers in Endocrinology 2022Medullary thyroid carcinoma (MTC) is a neuroendocrine malignant tumor originating from parafollicular C-cells producing calcitonin. Most of cases (75%) are sporadic... (Review)
Review
Medullary thyroid carcinoma (MTC) is a neuroendocrine malignant tumor originating from parafollicular C-cells producing calcitonin. Most of cases (75%) are sporadic while the remaining (25%) are hereditary. In these latter cases medullary thyroid carcinoma can be associated (multiple endocrine neoplasia type IIA and IIB) or not (familial medullary thyroid carcinoma), with other endocrine diseases such as pheochromocytoma and/or hyperparathyroidism. RET gene point mutation is the main molecular alteration involved in MTC tumorigenesis, both in sporadic and in hereditary cases. Total thyroidectomy with prophylactic/therapeutic central compartment lymph nodes dissection is the initial treatment of choice. Further treatments are needed according to tumor burden and rate of progression. Surgical treatments and local therapies are advocated in the case of single or few local or distant metastasis and slow rate of progression. Conversely, systemic treatments should be initiated in cases with large metastatic and rapidly progressive disease. In this review, we discuss the details of systemic treatments in advanced and metastatic sporadic MTC, focusing on multikinase inhibitors, both those already used in clinical practice and under investigation, and on emerging treatments such as highly selective RET inhibitors and radionuclide therapy.
Topics: Carcinoma, Neuroendocrine; Humans; Multiple Endocrine Neoplasia Type 2a; Precision Medicine; Proto-Oncogene Proteins c-ret; Thyroid Neoplasms
PubMed: 35422765
DOI: 10.3389/fendo.2022.864253 -
Thyroid : Official Journal of the... Oct 2020
Topics: Animals; Carcinoma; Carcinoma, Neuroendocrine; Drug Approval; Glucagon-Like Peptide-1 Receptor; Humans; Incidence; Product Surveillance, Postmarketing; Registries; Thyroid Neoplasms; United States
PubMed: 32316860
DOI: 10.1089/thy.2019.0591 -
Endocrine-related Cancer May 2022Medullary thyroid carcinoma (MTC) is a rare malignancy comprising 1-2% of all thyroid cancers in the United States. Approximately 20% of cases are familial, secondary to... (Review)
Review
Medullary thyroid carcinoma (MTC) is a rare malignancy comprising 1-2% of all thyroid cancers in the United States. Approximately 20% of cases are familial, secondary to a germline RET mutation, while the remaining 80% are sporadic and also harbour a somatic RET mutation in more than half of all cases. Up to 15-20% of patients will present with distant metastatic disease, and retrospective series report a 10-year survival of 10-40% from time of first metastasis. Historically, systemic therapies for metastatic MTC have been limited, and cytotoxic chemotherapy has demonstrated poor objective response rates. However, in the last decade, targeted therapies, particularly multitargeted tyrosine kinase inhibitors (TKIs), have demonstrated prolonged progression-free survival in advanced and progressive MTC. Both cabozantinib and vandetanib have been approved as first-line treatment options in many countries; nevertheless, their use is limited by high toxicity rates and dose reductions are often necessary. New generation TKIs, such as selpercatinib or pralsetinib, that exhibit selective activity against RET, have recently been approved as a second-line treatment option, and they exhibit a more favourable side-effect profile. Peptide receptor radionuclide therapy or immune checkpoint inhibitors may also constitute potential therapeutic options in specific clinical settings. In this review, we aim to present all current therapeutic options available for patients with progressive MTC, as well as new or as yet experimental treatments.
Topics: Carcinoma, Neuroendocrine; Humans; Progression-Free Survival; Retrospective Studies; Thyroid Neoplasms
PubMed: 35521769
DOI: 10.1530/ERC-21-0368 -
The Journal of Clinical Endocrinology... Aug 2013Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has... (Review)
Review
CONTEXT
Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients.
EVIDENCE ACQUISITION
We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin.
EVIDENCE SYNTHESIS
Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confounded decisions about the timing of prophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. A distinct advance has been the demonstration through phase II and phase III clinical trials that molecular targeted therapeutics are effective in the treatment of patients with locally advanced or metastatic MTC.
CONCLUSIONS
The effective management of patients with MEN2A, MEN2A, and FMTC depends on an understanding of the variable behavior of disease expression in patients with a specific RET mutation. Information gained from molecular testing, biochemical analysis, and clinical evaluation is important in providing effective management of patients with either early or advanced-stage MTC.
Topics: Calcitonin; Carcinoma, Medullary; Genotype; Humans; Multiple Endocrine Neoplasia Type 2a; Mutation; Phenotype; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Sequence Analysis, DNA; Thyroid Neoplasms; Thyroidectomy
PubMed: 23744408
DOI: 10.1210/jc.2013-1204 -
The Surgical Clinics of North America Oct 2009Medullary thyroid cancer (MTC) accounts for 5% to 10% of all thyroid cancers. The high frequency of familial cases mandates screening and genetic testing. The... (Review)
Review
Medullary thyroid cancer (MTC) accounts for 5% to 10% of all thyroid cancers. The high frequency of familial cases mandates screening and genetic testing. The aggressiveness and age of onset of familial MTC differs depending on the specific genetic mutation, and this should determine the timing and extent of surgery. Sporadic MTC can present at any age, and it is usually associated with a palpable mass and the presence of nodal metastases. Surgery is standard treatment for any patient presenting with resectable MTC. Further studies are needed to investigate the role of radiation therapy in the palliation and local control of postresection and advanced-stage MTC. New systemic therapies for metastatic disease are being investigated. Targeted molecular therapies, based on knowledge of the pathways affected by RET mutations, are being tested in multiple clinical trials.
Topics: Biomarkers, Tumor; Carcinoma, Medullary; Combined Modality Therapy; Diagnosis, Differential; Diagnostic Imaging; Genetic Predisposition to Disease; Genotype; Humans; Multiple Endocrine Neoplasia Type 2a; Multiple Endocrine Neoplasia Type 2b; Phenotype; Prognosis; Thyroid Neoplasms
PubMed: 19836492
DOI: 10.1016/j.suc.2009.06.021 -
Archives of Pathology & Laboratory... Aug 2015Thyroid paragangliomas are rare tumors that arise from the inferior laryngeal paraganglia. Most patients are female and present with an asymptomatic thyroid nodule.... (Review)
Review
Thyroid paragangliomas are rare tumors that arise from the inferior laryngeal paraganglia. Most patients are female and present with an asymptomatic thyroid nodule. Histologically, the tumor is composed of cells arranged in a well-defined nest (zellballen) pattern surrounded by a thin fibrovascular stroma. It is a diagnostic pitfall and is occasionally misdiagnosed as follicular neoplasm, medullary thyroid carcinoma, intrathyroid parathyroid proliferation, and especially secondary neuroendocrine tumors. Immunohistochemical stains (cytokeratin, parathyroid hormone, thyroid transcription factor 1, tyrosine hydroxylase, chromogranin A, synaptophysin, S100, calcitonin, carcinoembryonic antigen) are essential in establishing the diagnosis. Loss of succinate dehydrogenase complex, subunit B (SDHB), immunoexpression can be used to triage genetic testing because some mutations are associated with a higher risk for developing metastasis. Total thyroidectomy or lobectomy for solitary lesion is the preferred treatment. Elective lymph node dissection is usually not indicated. Postoperatively, patients should receive hormonal evaluation for functional disease and imaging for evaluation of multifocal or metastatic disease.
Topics: Adult; Female; Humans; Male; Middle Aged; Paraganglioma; Thyroid Neoplasms
PubMed: 26230601
DOI: 10.5858/arpa.2013-0703-RS -
Annals of Oncology : Official Journal... Jul 1998Medullary thyroid carcinoma (MTC) originates in the thyroid C cells, accounting for 5% to 10% of all thyroid malignancies. Approximately 75% of cases are sporadic.... (Review)
Review
BACKGROUND
Medullary thyroid carcinoma (MTC) originates in the thyroid C cells, accounting for 5% to 10% of all thyroid malignancies. Approximately 75% of cases are sporadic. Significant advances have been made in the molecular biology of MTC, but some aspects of diagnosis and management still remain controversial.
DESIGN
We reviewed relevant articles published in major English-language medical journals. We used the MEDLINE database, selected bibliographies, and articles available in our personal files.
RESULTS
Mutations of the RET proto-oncogene have been identified in the germline DNA of patients with familial MTC syndromes. Genetic testing can identify patients affected by multiple endocrine neoplasia types IIA and IIB and familial MTC, allowing early diagnosis and possible cure. Surgical treatment is total thyroidectomy. Plasma calcitonin measurements are excellent markers for postoperative follow-up. Adjunctive therapy includes radiotherapy and chemotherapy. The overall prognosis is worse than papillary thyroid carcinoma.
CONCLUSIONS
Recent advances in genetic testing allow early diagnosis and treatment of familial MTC syndromes. Despite some advances in treatment, optimal management remains controversial.
Topics: Carcinoma, Medullary; Combined Modality Therapy; Genetic Testing; Humans; Proto-Oncogene Mas; Thyroid Neoplasms; Thyroidectomy
PubMed: 9739433
DOI: 10.1023/a:1008242302749 -
The Quarterly Journal of Nuclear... Dec 2008Medullary thyroid carcinoma (MTC) is a relatively rare neuroendocrine tumour originating from the parafollicular C cells and releases calcitonin (hCt), carcinoembryonic... (Review)
Review
Medullary thyroid carcinoma (MTC) is a relatively rare neuroendocrine tumour originating from the parafollicular C cells and releases calcitonin (hCt), carcinoembryonic antigen (CEA) and occasionally other substances. In 20-30% of cases MTC presents a germline mutation of the RET proto-oncogene and occurs in 3 different hereditary forms: familial MTC, multiple endocrine neoplasia (MEN) 2A and MEN 2B syndrome. Prognosis of MTC is largely related to tumour extension at disease onset. Surgery remains the most effective therapy for potential cure. Overall survival is strictly linked to the occurrence of relapse. After surgery, serum hCt remains the most sensitive test for occult disease. Diagnostic imaging work-up includes ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, as the more frequent sites of recurrence or metastases are cervical and mediastinal lymph nodes, lungs, liver and bone. Nuclear medicine procedures include (111)In-labelled somatostatin analogs, radioiodinated metaiodobenzylguanidine (MIBG), and several PET radiopharmaceuticals. Experience with radionuclide therapy in MTC is restricted to few patients treated with (131)I-MIBG or (90)Y-DOTATOC. Since 1987, 1 027 diagnostic MIBG scans were performed in the Department Department of Diagnostic Imaging and Therapy of the Istituto Nazionale Tumori IRCCS Foundation (Milan, Italy), 85 of which for MTC, with a sensitivity of 38.7% in patients with evidence of disease and 30.7 % if all patients were considered. Since 1994, 13 MTC patients were treated with MIBG with 4 partial responses and 4 stable diseases. Patients with liver or bone involvement responded to therapy and showed long-term partial remission of disease, others showed stability of disease, which was apparently unrelated to therapy. Improvement of efficacy can be achieved through dosimetric calculation of administered activity.
Topics: 3-Iodobenzylguanidine; Carcinoma, Medullary; Humans; Neoplasm Metastasis; Neoplasm, Residual; Proto-Oncogene Mas; Recurrence; Thyroid Neoplasms
PubMed: 19088696
DOI: No ID Found -
Journal of Internal Medicine Jul 2009The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term... (Review)
Review
The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.
Topics: Biomarkers, Tumor; Carcinoma, Medullary; Humans; Medical Oncology; Positron-Emission Tomography; Prognosis; Thyroid Neoplasms
PubMed: 19522831
DOI: 10.1111/j.1365-2796.2009.02106.x