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Endocrine Connections Apr 2021Calcitonin-secreting neuroendocrine neoplasms of the lung are rare, with few cases reported in the literature. Differentiating between medullary thyroid carcinoma and an...
Calcitonin-secreting neuroendocrine neoplasms of the lung are rare, with few cases reported in the literature. Differentiating between medullary thyroid carcinoma and an ectopic source of calcitonin secretion can represent a complex diagnostic conundrum for managing physicians, with cases of unnecessary thyroidectomy reported in the literature. This manuscript reports a case of ectopic hypercalcitonaemia from a metastatic neuroendocrine neoplasm of the lung with concurrent thyroid pathology and summarises the results of a systematic review of the literature. Medical Literature Analysis and Retrieval System Online, Excerpta Medica, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and SCOPUS databases were systematically and critically appraised for all peer reviewed manuscripts that suitably fulfilled the inclusion criteria established a priori. The protocol for this systematic review was developed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols, and followed methods outlined in The Cochrane Handbook for Systematic Reviews of Interventions. This systematic review is registered with PROSPERO. It is vital to consider diagnoses other than medullary thyroid carcinoma when presented with a patient with raised calcitonin, as it is not pathognomonic of medullary thyroid carcinoma. Lung neuroendocrine neoplasms can appear similar to medullary thyroid carcinoma histologically, they can secrete calcitonin and metastasize to the thyroid. Patients with medullary thyroid carcinoma may show stimulated calcitonin values over two or more times above the basal values, whereas calcitonin-secreting neuroendocrine neoplasms may or may not show response to stimulation tests. The present review summarises existing evidence from cases of ectopic hypercalcitonaemia to lung neuroendocrine neoplasms.
PubMed: 33764887
DOI: 10.1530/EC-21-0071 -
Frontiers in Oncology 2021The objective of this study is to summarize the clinical and pathologic characteristics of malignant struma ovarii to facilitate the early diagnosis and treatment of...
The objective of this study is to summarize the clinical and pathologic characteristics of malignant struma ovarii to facilitate the early diagnosis and treatment of this disease. All 144 patients were females from 27 countries. The mean age of the patients at diagnosis was 42.6 years. Overall, 35.71% of the patients underwent unilateral oophorectomy, 58.57% of the patients underwent bilateral oophorectomy, 5.72% of the patients were not ovariectomized, and 38.57% of the patients received radioactive iodine treatment with an average dose of 158.22 mCI each time. "Impure" types accounted for 70.19% of the cases, while pure types accounted for 29.81% of the cases. Among these cases, papillary thyroid carcinoma accounted for 50.00%, follicular thyroid carcinoma accounted for 26.47%, follicular variant of papillary thyroid carcinoma accounted for 18.63%, papillary and follicular mixed thyroid carcinoma accounted for 2.94%, anaplastic carcinoma accounted for 0.98%, and medullary carcinoma accounted for 0.98%. In total, 21 patients (51.22%) had elevated CA125. More than half of the patients (51.94%) had metastasis outside the ovary. The most common metastatic site was the pelvic cavity. The misdiagnosis rate was 17.27%. Mortality was related to metastasis and the cancer type. Gene mutations were found in the NRAS, KRAS, BRAF, and KIT genes and were similar to those in thyroid carcinoma, but some patients (37.5%) did not exhibit any gene mutations. Regardless of the treatment received, the survival rate is high. Treatment could initially include ovariectomy; however, in cases with metastasis and iodine uptake of the metastatic tumor, thyroidectomy, radioactive iodine therapy, and thyroid hormone inhibiting therapy are indicated.
PubMed: 33763376
DOI: 10.3389/fonc.2021.645156 -
Familial Cancer Oct 2016Multiple endocrine neoplasia type 2A (MEN2A) may be rarely associated with cutaneous lichen amyloidosis (CLA), a skin lesion located in the interescapular region. Here,... (Review)
Review
Multiple endocrine neoplasia type 2A (MEN2A) may be rarely associated with cutaneous lichen amyloidosis (CLA), a skin lesion located in the interescapular region. Here, we describe 3 MEN2A-related CLA kindred and perform a systematic review (SR) of the literature on clinical, biochemical and molecular characteristics of MEN2A-related CLA patients. Thirty-eight patients with MEN2A-related CLA followed at our institution were evaluated. The median age at MEN2A diagnosis in our cohort was 25 (13-41) years, 68 % were women and all harbored codon 634 RET mutations. The literature search resulted in 20 publications that contributed with 25 MEN2A families and 214 individuals. The mean age of MEN2A diagnosis was 31 ± 17 years, with 77 % women. The mean age reported by patients to initial skin lesion suggestive to CLA was 20 ± 13 years. All but two kindred harbored mutations at codon 634: C634R 7 kindred (35 %), C634Y 5 kindred (25 %), C634W 3 kindred (15 %), C634G 1 kindred (5 %), V804M 1 kindred (5 %) and S891A 1 kindred (5 %). Most interesting, the standardized CLA prevalence was higher in women (2.3/1.0, P < 0.005). The overall reported prevalence of medullary thyroid carcinoma, CLA, pheochromocytoma and hyperparathyroidism was 94, 51, 30 and 16 %, respectively. SR of literature indicates that MEN2A-related CLA is more frequent in women and presents a high penetrance, being the second most frequent manifestation of the syndrome, preceded only by MTC.
Topics: Adolescent; Adult; Amyloidosis; Female; Humans; Male; Multiple Endocrine Neoplasia Type 2a; Pedigree; Proto-Oncogene Proteins c-ret; Skin Neoplasms; Young Adult
PubMed: 26920351
DOI: 10.1007/s10689-016-9892-6 -
Health Technology Assessment... Feb 2019Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq; Ipsen, Paris,...
BACKGROUND
Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq; Ipsen, Paris, France) and vandetanib (Caprelsa; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC.
OBJECTIVES
(1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England.
DATA SOURCES
Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers' submissions.
REVIEW METHODS
A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model.
RESULTS
The systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo ( < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower.
LIMITATIONS
The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population.
CONCLUSIONS
The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.
FUTURE RESEARCH PRIORITIES
(1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42016050403.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cost-Benefit Analysis; England; Humans; Models, Economic; Piperidines; Pyridines; Quality-Adjusted Life Years; Quinazolines; Technology Assessment, Biomedical; Thyroid Neoplasms
PubMed: 30821231
DOI: 10.3310/hta23080 -
European Thyroid Journal Jan 2018Positron emission tomography (PET) and PET/CT are functional imaging methods that are widely used in diagnostic procedures in oncology.
BACKGROUND
Positron emission tomography (PET) and PET/CT are functional imaging methods that are widely used in diagnostic procedures in oncology.
OBJECTIVES
The objective of this study was to assess the patient-relevant benefit of PET or PET/CT in patients with thyroid cancer based on a literature review and meta-analysis.
METHODS
A systematic review including studies that had been published until December 2013 was performed. To be included, studies had to prospectively investigate patients with thyroid cancer in a clinical setting of staging, restaging, or diagnosing tumour recurrence.
RESULTS
Out of 3,506 potentially relevant articles, 29 studies were included. No study directly evaluated the benefits of PET. Twenty-eight studies dealt with the diagnostic accuracy of PET or PET/CT, and 1 study evaluated the prognostic value of PET/CT. The authors showed that a positive result of PET/CT in restaging patients with differentiated thyroid cancer yielded a significant decrease in overall survival (hazard ratio, HR 5.01, CI 3.41-6.62). In patients with suspected recurrence of differentiated thyroid cancer, meta-analysis showed higher sensitivity of PET (89.7%, CI 78-99%) and PET/CT (94.3%, CI 87-97%) compared with conventional imaging (65.4%, CI 32-88%) and comparable results for specificity. Due to the low numbers of studies and patients, meta-analyses on medullary carcinoma did not produce meaningful results.
CONCLUSION
The patient-relevant benefits of PET or PET/CT in thyroid cancer could not be evaluated satisfactorily based on the included studies. It remains unclear whether higher diagnostic test accuracy leads to changes in therapeutic strategies and better patient-relevant outcomes.
PubMed: 29594049
DOI: 10.1159/000481707 -
Experimental Cell Research Aug 2016In this review, we discuss the molecular mechanisms and prognostic implications of the protein kinase A (PKA) signaling pathway in human tumors, with special emphasis on... (Meta-Analysis)
Meta-Analysis Review
In this review, we discuss the molecular mechanisms and prognostic implications of the protein kinase A (PKA) signaling pathway in human tumors, with special emphasis on the malignant thyroid. The PKA signaling pathway is differentially activated by the expression of regulatory subunits 1 (R1) and 2 (R2), whose levels change during development, differentiation, and neoplastic transformation. Following the identification of gene mutations within the PKA regulatory subunit R1A (PRKAR1A) that cause Carney complex-associated neoplasms, several investigators have studied PRKAR1A expression in sporadic thyroid tumors. The PKA regulatory subunit R2B (PRKAR2B) is highly expressed in benign, as well as in malignant differentiated and undifferentiated lesions. PRKAR1A is highly expressed in follicular adenomas and malignant lesions with a statistically significant gradient between benign and malignant tumors; however, it is not expressed in hyperplastic nodules. Although the importance of PKA in human malignancy outcomes is not completely understood, PRKAR1A expression correlates with tumor dimension in malignant lesions. Additional studies are needed to determine whether a relationship exists between PKA subunit expression and clinical outcomes, particularly in undifferentiated tumors. In conclusion, the R1A subunit might be a good molecular candidate for the targeted treatment of malignant thyroid tumors.
Topics: Adult; Aged; Aged, 80 and over; Cell Differentiation; Cyclic AMP-Dependent Protein Kinases; Female; Humans; Hyperplasia; Male; Middle Aged; Prognosis; Protein Subunits; Thyroid Gland; Thyroid Neoplasms
PubMed: 27321957
DOI: 10.1016/j.yexcr.2016.06.004 -
American Journal of Clinical Oncology Apr 2018Primary paraganglioma (PG) of the thyroid gland is an extremely rare neuroendocrine tumor with potential for misdiagnosis. We describe 2 cases of thyroid PG, suggest a...
INTRODUCTION
Primary paraganglioma (PG) of the thyroid gland is an extremely rare neuroendocrine tumor with potential for misdiagnosis. We describe 2 cases of thyroid PG, suggest a possible diagnostic and therapeutic management strategy, and present a systematic review of the literature.
CASE REPORTS
Two 67-year-old women presented similarly with asymptomatic but rapidly growing thyroid nodules in which malignancy was suspected after fine needle aspiration biopsy, "THY 4" according to the 2014 SIAPEC classification, both undergoing total thyroidectomy. Unexpectedly, immunohistochemistry showed neuroendocrine cellular architecture that was negative for common markers of well-differentiated follicular neoplasms, thyroglobulin, thyroid transcription factor 1, cytokeratins and medullary thyroid cancer, calcitonin, carcinoembryonic antigen, whereas neuron-specific enolase, synaptophysin, chromogranin A, and S-100 protein were highly expressed, confirming the diagnosis of primary thyroid PG. The patients were both discharged on postoperative day 2, without any other therapy and are currently well without evidence of local recurrence of metastatic disease, after 4 years and 3 months of follow-up, respectively.
DISCUSSION
These are the only 2 cases of thyroid PG experienced in our center which specializes in thyroid surgery. Thyroid PG is a rare neuroendocrine neoplasm first described by Van Miert in 1964 with just over 50 cases reported in the literature. Our experience is concordant with the literature that the diagnosis of the primary PG of the thyroid is challenging, due to its low prevalence and the cytologic and histopathologic similarities with other more frequently diagnosed benign and malignant thyroid tumors. Immunohistochemistry is required for definitive diagnosis but gross tumor characteristics are also helpful for diagnosis. Surgical resection is the recommended standard treatment.
Topics: Aged; Disease Management; Female; Humans; Paraganglioma; Prognosis; Thyroid Neoplasms; Thyroidectomy
PubMed: 27163832
DOI: 10.1097/COC.0000000000000295 -
Endocrine-related Cancer Jun 2018There are ongoing debates with respect to the prognostic roles of molecular biomarkers in sporadic medullary thyroid carcinoma (MTC). In this study, we aimed at... (Meta-Analysis)
Meta-Analysis
There are ongoing debates with respect to the prognostic roles of molecular biomarkers in sporadic medullary thyroid carcinoma (MTC). In this study, we aimed at investigating the prognostic value of and mutations - the two most common mutations in sporadic MTCs. A search was conducted in four electronic databases. Relevant data were extracted and pooled into odds ratios (OR), mean differences (MD) and corresponding 95% confidence intervals (CI) using the random-effect model. We used Egger's regression test and visual of funnel plots to assess the publication bias. From 2581 studies, we included 23 studies with 964 MTCs for meta-analysis. Overall, the presence of mutation was associated with an elevated risk for lymph node metastasis (OR = 3.61; 95% CI = 2.33-5.60), distant metastasis (OR = 2.85; 95% CI = 1.64-4.94), advanced tumor stage (OR = 3.25; 95% CI = 2.02-5.25), tumor recurrence (OR = 3.01; 95% CI = 1.65-5.48) and patient mortality (OR = 2.43; 95% CI = 1.06-5.57). mutation had no significant prognostic value in predicting tumor aggressiveness. To summarize, our results affirmed that mutation is a reliable molecular biomarker to identify a group of highly aggressive sporadic MTCs. It can help clinicians better assess patient prognosis and select appropriate treatment decisions.
Topics: Carcinoma, Neuroendocrine; Humans; Lymphatic Metastasis; Mutation; Neoplasm Recurrence, Local; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Thyroid Neoplasms
PubMed: 29615431
DOI: 10.1530/ERC-18-0056 -
Radiotherapy and Oncology : Journal of... Jul 2019In order to clarify the role of external beam radiotherapy in the management of medullary thyroid cancer (MTC), a systematic review was undertaken.
OBJECTIVE
In order to clarify the role of external beam radiotherapy in the management of medullary thyroid cancer (MTC), a systematic review was undertaken.
PATIENTS AND INTERVENTIONS
Patients with MTC of any stage receiving radiotherapy, either as adjuvant postoperative treatment or as primary treatment for unresectable disease.
DESIGN
Electronic searching Medline and ProQuest databases for randomised or non-randomised studies. A risk of bias assessment (ROBINS-I) was carried out for each study.
MAIN OUTCOME MEASURES
Overall survival, rates of locoregional recurrence, locoregional relapse-free survival.
RESULTS
There were no randomised studies. Twenty-seven non-randomised studies were identified. Within four cohort studies, radiotherapy had no significant effect on overall survival. Within one prospective and 22 retrospective studies (of approximately 1200 patients), radiotherapy similarly had no consistent effect on overall survival but there was evidence that radiotherapy reduces the risk of locoregional relapse, particularly in those with nodal involvement, extrathyroidal extension or residual disease. In a meta-analysis of patients within four studies, radiotherapy reduced the risk of locoregional relapse by at least 38%. Evidence supports the use of doses of 60 Gy or greater and an interval between surgery and radiotherapy of less than two months. Thirteen of 63 patients (21%) treated for unresectable disease achieved a complete response. Acute morbidity was observed in relation to difficulty swallowing, xerostomia and skin reactions. Late morbidity was infrequent with a low incidence of xerostomia.
CONCLUSIONS
Radiotherapy should be considered for those at high risk of locoregional relapse, in particular those with nodal involvement, extrathyroidal extension or residual disease (microscopic or macroscopic).
Topics: Carcinoma, Neuroendocrine; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Radiotherapy; Thyroid Neoplasms; Xerostomia
PubMed: 31015112
DOI: 10.1016/j.radonc.2019.03.033 -
Endocrine Journal Dec 2020The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in... (Meta-Analysis)
Meta-Analysis
The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in their clinical efficacy and toxicity remain unclear. This meta-analysis assessed the efficacy and toxicity of these four TKIs based on 34 studies. The pooled incidence of partial response (PR), stable disease (SD), TKI-related adverse events (AEs), and pooled median progression-free survival (PFS) were calculated with 95% confidence intervals (CI). Complete response to TKIs was extremely rare (0.3%). The highest PR rate and longest PFS were observed for lenvatinib in differentiated thyroid cancer (69%, 95% CI: 57-81 and 19 months, 95% CI: 9-29, respectively) and vandetanib in medullary thyroid cancer (40%, 95% CI: 25-56 and 31 months, 95% CI: 19-43, respectively). Although the discontinuation rate due to AEs was similar for each TKI, there was a difference in the most frequently observed AE for each TKI (hand-foot syndrome for sorafenib, hypertension and proteinuria for lenvatinib, and QTc prolongation for vandetanib). The identified differences in the TKI efficacy and AE profiles may provide a better understanding of thyroid cancer treatment. Although TKIs are promising agents for thyroid cancer treatment, they are unlikely to lead to a cure. Thus, even in the TKI era, a multimodal treatment including surgery, radioiodine therapy, external beam radiotherapy, and TKIs is required to optimize patient chances of improved survival.
Topics: Antineoplastic Agents; Humans; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms; Treatment Outcome
PubMed: 32814730
DOI: 10.1507/endocrj.EJ20-0171