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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 -
Seminars in Nuclear Medicine Jul 2023Currently, there is a discrepancy among the available guidelines on the usefulness of nuclear medicine techniques in medullary thyroid cancer (MTC) diagnosis and... (Review)
Review
Currently, there is a discrepancy among the available guidelines on the usefulness of nuclear medicine techniques in medullary thyroid cancer (MTC) diagnosis and treatment. Aim of this review is to provide an update on diagnostic and therapeutic nuclear medicine techniques in this setting. Evidence-based data clearly demonstrates the usefulness of PET/CT with different radiopharmaceuticals in recurrent MTC (in particular when serum calcitonin is higher than 150 pg/mL or calcitonin doubling time is shortened) and F-FDOPA should be the preferred PET radiopharmaceutical. If F-FDOPA PET/CT is negative or unavailable, F-FDG PET/CT or Ga-DOTA-peptides PET/CT could be performed for MTC restaging. There is currently insufficient evidence to recommend PET/CT with several radiopharmaceuticals for MTC staging. Clinical experience on PET/MRI with different radiopharmaceuticals in MTC is still limited. Several investigational nuclear medicine therapeutic options are currently under evaluation in metastatic MTC. More data are needed to evaluate the efficacy, toxicity, and role of these therapeutic options in the management of MTC patients.
Topics: Humans; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Calcitonin; Fluorodeoxyglucose F18; Nuclear Medicine; Neoplasm Recurrence, Local; Carcinoma, Neuroendocrine; Thyroid Neoplasms
PubMed: 36702731
DOI: 10.1053/j.semnuclmed.2023.01.003 -
Acta Endocrinologica (Bucharest,... 2019Calcitonin (CT) is a polypeptidic hormone specifically secreted by the thyroid parafollicular cells (C cells) and tangentially involved in human phosphocalcic and bone...
Calcitonin (CT) is a polypeptidic hormone specifically secreted by the thyroid parafollicular cells (C cells) and tangentially involved in human phosphocalcic and bone metabolism. CT from other species (e.g. salmon) is more potent than human CT and has limited therapeutic applications. The neoplastic proliferation of C cells leads to medullary thyroid carcinoma (MTC) generally characterized by an increase of CT secretion. Serum CT is therefore the ideal marker for MTC and can confirm its presence at an early stage, as well as the follow up of its remission or progression/relapse/survival after surgery. There are, however, controversies such as the necessity of CT screening in patients with thyroid nodules, or particular situations causing false positive or false negative results. Our minireview also deals with an up-to-date of surgical procedures for MTC, as well as with non-surgical therapy.
PubMed: 32377257
DOI: 10.4183/aeb.2019.544 -
Endocrine Pathology Mar 2021Our understanding of the genomics and epigenomics of medullary thyroid carcinoma (MTC) has advanced since the initial recognition of RET as a driver of MTC tumorigenesis... (Review)
Review
Our understanding of the genomics and epigenomics of medullary thyroid carcinoma (MTC) has advanced since the initial recognition of RET as a driver of MTC tumorigenesis in familial MTC. We now have insight into the frequency and prognostic significance of specific RET mutations in sporadic MTC. For example, the most common RET mutation in sporadic MTC is the RET Met918Thr mutation, the same mutation that underlies MEN2B and a poor prognosticator. This mutation is relatively infrequent in medullary thyroid microcarcinomas but is over-represented in advanced-stage disease. RAS mutations are detected in 70% of sporadic, RET wild-type MTC. Although next-generation and whole-exome sequencing studies have shown that tumors that are wild-type for RET and RAS mutations essentially lack other recurrent mutations, additional pathways and epigenetic alterations have been implicated in MTC tumorigenesis. Increased insight into the clinical course of patients with familial MTC with specific RET mutations has guided treatment recommendations for these patients. Finally, an understanding of the genomics has informed treatment for patients with advanced MTC. In this review, we will examine the genomics and epigenomics of sporadic and familial MTC, along with the prognostic significance of molecular alterations, management of patients with germline RET mutations, and treatment strategies for MTC patients.
Topics: Animals; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Epigenesis, Genetic; Epigenomics; Genomics; Humans; Multiple Endocrine Neoplasia Type 2a; Proto-Oncogene Proteins c-ret; Thyroid Neoplasms
PubMed: 33492588
DOI: 10.1007/s12022-021-09664-3 -
Singapore Medical Journal Jul 2022Medullary breast carcinomas (MBCs) are distinguished by circumscribed, high-grade morphology with dense chronic inflammation; they are associated with the basal...
INTRODUCTION
Medullary breast carcinomas (MBCs) are distinguished by circumscribed, high-grade morphology with dense chronic inflammation; they are associated with the basal phenotype but have a relatively good prognosis.
METHODS
This study aimed to review the clinicopathological features of MBCs diagnosed at the Department of Pathology, Singapore General Hospital and correlate them with immunohistochemical expression of hormonal markers and c-erbB-2, the basal markers p53, cytokeratin (CK) 14, epidermal growth factor receptor (EGFR) and 34BE12, and the follow-up outcome.
RESULTS
Using Ridolfi's criteria for histologic reviews, 62 patients previously diagnosed as having 'typical MBC' (n = 26), 'atypical MBC' (n = 32) and 'invasive carcinoma with focal medullary-like features' (n = 4) were re-classified as follows: 'typical MBC' (n = 6; 9.7%), 'atypical MBC' (n = 46; 74.2%), and 'non-medullary infiltrating carcinoma' (n = 10; 16.1%). Clinicopathological parameters, including ethnicity, age, tumour size and concurrent ductal carcinoma in situ (DCIS), showed no statistically significant correlation with review diagnoses and immunohistochemical findings. Presence of lymphovascular invasion and nodal stage were significantly correlated with recurrence and breast cancer-related deaths, respectively. ER negativity was significantly correlated with triple positivity for basal markers CK14, EGFR and 34BE12, which comprised patients who showed a significantly decreased disease-free survival rate within a 10-15-year follow-up period.
CONCLUSIONS
Lymphovascular invasion and high nodal stage as well as triple negativity among typical and atypical MBCs that have basal-like phenotype represent a portion of invasive carcinomas with medullary features that may have poor outcomes in this otherwise relatively good prognostic group.
Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Medullary; Female; Humans; Prognosis; Receptor, ErbB-2; Receptors, Progesterone
PubMed: 33866710
DOI: 10.11622/smedj.2021031 -
Frontiers in Endocrinology 2023
Topics: Humans; Neuroendocrine Tumors; Precision Medicine; Carcinoma, Neuroendocrine; Skin Neoplasms
PubMed: 37564989
DOI: 10.3389/fendo.2023.1253319 -
Frontiers in Endocrinology 2023
Topics: Humans; Thyroid Neoplasms; Endocrinology
PubMed: 37484953
DOI: 10.3389/fendo.2023.1236887 -
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 -
The Journal of Clinical Endocrinology... Sep 2023Management of sporadic medullary thyroid microcarcinoma smaller than 1 cm (micro-MTC) is controversial because of conflicting reports of prognosis. As these cancers are...
CONTEXT
Management of sporadic medullary thyroid microcarcinoma smaller than 1 cm (micro-MTC) is controversial because of conflicting reports of prognosis. As these cancers are often diagnosed incidentally, they pose a management challenge when deciding on further treatment and follow-up.
OBJECTIVE
We report the outcomes of surgically managed sporadic micro-MTC in a specialist endocrine surgery and endocrinology unit and identify associations for recurrence and disease-specific survival in this population.
METHODS
Micro-MTCs were identified from a prospectively maintained surgery database, and slides were reviewed to determine pathological grade. The primary end points were recurrence, time to recurrence and disease-specific survival. Prognostic factors assessed included size, grade, lymph node metastasis (LNM), and postoperative calcitonin.
RESULTS
From 1995 to 2022, 64 patients were diagnosed with micro-MTC with 22 excluded because of hereditary disease. The included patients had a median age of 60 years, tumor size of 4 mm, and 28 (67%) were female. The diagnosis was incidental in 36 (86%) with 4 (10%) being high grade, 5 (12%) having LNM and 9 (21%) having elevated postoperative calcitonin. Over a 6.6-year median follow-up, 5 (12%) developed recurrence and 3 (7%) died of MTC. High grade and LNM were associated with 10-year survival estimates of 75% vs 100% for low grade and no LNM (hazard ratio = 831; P < .01). High grade, LNM, and increased calcitonin were associated with recurrence (P < .01). Tumor size and type of surgery were not statistically significantly associated with recurrence or survival. No patients with low grade micro-MTC and normal postoperative calcitonin developed recurrence.
CONCLUSION
Most sporadic micro-MTCs are detected incidentally and are generally associated with good outcomes. Size is not significantly associated with outcomes. Using grade, LNM, and postoperative calcitonin allows for the identification of patients at risk of recurrence to personalize management.
Topics: Humans; Female; Middle Aged; Male; Calcitonin; Thyroid Neoplasms; Thyroidectomy; Lymph Node Excision; Carcinoma, Medullary; Prognosis; Peptide Hormones; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Retrospective Studies
PubMed: 36964913
DOI: 10.1210/clinem/dgad173 -
Biomarker Research Sep 2023Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine tumour whose diagnosis includes evaluating calcitonin serum levels, which can present fluctuations unrelated...
Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine tumour whose diagnosis includes evaluating calcitonin serum levels, which can present fluctuations unrelated to MTC. Here, we investigated circulating DNA fragmentation and methylation changes as potential biomarkers using ddPCR on cell-free DNA (cfDNA) isolated from the plasma of MTC patients. For cfDNA fragmentation analysis, we investigated the fragment size distribution of a gene family and calculated short fragment fraction (SFF). Methylation analyses evaluated the methylation levels of CG_16698623, a CG dinucleotide in the MGMT gene that we found hypermethylated in MTC tissues by analyzing public databases. The SFF ratio and methylation of CG_16698623 were significantly increased in plasma from MTC patients at diagnosis, and patients with clinical remission or stable disease at follow-up showed no significant SFF difference compared with healthy subjects. Our data support the diagnostic value of cfDNA traits that could enable better management of MTC patients.
PubMed: 37726827
DOI: 10.1186/s40364-023-00522-4