Showing papers on "Papillary thyroid cancer published in 2012"
TL;DR: The effects of the BRAFV600E mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified and a comprehensive meta‐analysis was performed.
Abstract: BACKGROUND:
The effects of the BRAFV600E mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified. The authors performed comprehensive meta-analysis to assess the strength of associations between these conditions and the BRAFV600E mutation.
METHODS:
The authors identified the clinical studies that examined the association of the BRAFV600E mutation in surgical specimens with clinicopathologic outcomes between January 2003 and October 2010 using the Medline database. One hundred thirty-one relevant studies were hand-searched. The authors selected 27 studies that included 5655 PTC patients. They calculated the pooled odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) for each study using a random effect model.
RESULTS:
The average prevalence rate of the BRAFV600E mutation was 49.4%. In 26 studies, compared with the patients who had the wild-type BRAF genes, the PTC patients with the BRAFV600E mutation had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI, 1.68-2.73), a lymph node metastasis (OR, 1.54; 95% CI, 1.21-1.97), and an advanced TNM stage (OR, 2.00; 95% CI, 1.61-2.49). In 8 studies, patients with the mutation had 2.14-fold increased risk of recurrent and persistent disease (95% CI, 1.67-2.74). The associations were generally consistent across the different study populations.
CONCLUSIONS:
This meta-analysis demonstrates that the BRAFV600E mutation is closely related to the high-risk clinicopathological factors and poorer outcome of PTC. The results obtained here suggest that the BRAFV600E mutation should be considered as a poor prognostic marker in PTC and may lead to better management for individual patients. Cancer 2012;. © 2011 American Cancer Society.
362 citations
TL;DR: The BRAF mutation in PTC was significantly associated with PTC recurrence, lymph node metastasis, extrathyroidal extension, distant metastasis and American Joint Committee on Cancer (AJCC) stages III/IV.
253 citations
TL;DR: Meta-analysis found that BRAF mutation is associated with LNM, stage, extrathyroidal extension, tumor size, male gender, multifocality, absence of capsule, classic PTC, and tall-cell variant PTC in PTC.
Abstract: Background: There is conflicting literature regarding the association of the BRAF V600E mutation and aggressive clinicopathological features of papillary thyroid cancer (PTC). Nevertheless, some propose that BRAF status be incorporated into the management of patients with PTC, specifically recommendations regarding lymph node dissection. We therefore performed a meta-analysis to examine the relationship between BRAF and clinicopathological features of PTC. Methods: A literature search was performed within PubMed and EMBASE databases using the following Medical Subject Headings (MeSH) and keywords: “braf,” “mutation,” “thyroid,” “neoplasm(s),” “tumor,” “cancer,” and “carcinoma.” Individual study-specific odds ratios and confidence intervals were calculated, as were Mantel-Haenszel pooled odds ratios for the combined studies. Results: Thirty-two studies including 6372 patients were reviewed. BRAF mutation was associated with lymph node metastases (LNM), advanced stage, extrathyroidal extension, tumor size, ...
239 citations
TL;DR: Lateral neck lymph nodes are a significant consideration in the surgical management of patients with DTC and should be considered in the evaluation of the newly diagnosed thyroid cancer patient and for surveillance of the previously treated DTC patient.
Abstract: Background: Cervical lymph node metastases from differentiated thyroid cancer (DTC) are common. Thirty to eighty percent of patients with papillary thyroid cancer harbor lymph node metastases, with the central neck being the most common compartment involved. The goals of this study were to: (1) identify appropriate methods for determining metastatic DTC in the lateral neck and (2) address the extent of lymph node dissection for the lateral neck necessary to control nodal disease balanced against known risks of surgery. Methods: A literature review followed by formulation of a consensus statement was performed. Results: Four proposals regarding management of the lateral neck are made for consideration by organizations developing management guidelines for patients with thyroid nodules and DTC including the next iteration of management guidelines developed by the American Thyroid Association (ATA). Metastases to lateral neck nodes must be considered in the evaluation of the newly diagnosed thyroid cancer pat...
193 citations
TL;DR: DSV and TCV are rare, increasing in incidence, and have a worse prognosis than classic PTC, and patients with these variants should be treated aggressively with thyroidectomy and radioiodine, regardless of tumor size.
Abstract: Background
The diffuse sclerosing (DSV) and tall cell (TCV) variants are considered aggressive subtypes of papillary thyroid cancer (PTC) for which data are limited.
188 citations
TL;DR: Even if the available data are not sufficient to advise LT4 treatment in all patients with nodular goiter with the aim of reducing the risk of papillary thyroid carcinoma, it is proposed that this indication should be reconsidered, taking into account recent evidence reported in the literature.
Abstract: Context: TSH is the main factor involved in the control of proliferation of thyrocytes. Recently, a strong relationship between serum TSH and risk of thyroid malignancy has been reported. Objectives: The aim was to review published papers about the relationship between serum TSH and frequency of differentiated thyroid cancer. Evidence Acquisition: PubMed was used to identify studies focused on the relationship between TSH and differentiated thyroid cancer. Evidence Synthesis: In patients with nodular thyroid disease, the risk of thyroid malignancy increases with serum TSH, and even within normal ranges, higher TSH values are associated with a higher frequency and more advanced stage of thyroid cancer. The likelihood of papillary thyroid carcinoma is reduced when TSH is lower, as in thyroid autonomy, and increased when TSH is higher, as in thyroid autoimmunity. Treatment with l-thyroxine (LT4), which reduces serum TSH, is associated with significantly lower risk of developing clinically detectable thyroid ...
177 citations
Journal Article•
TL;DR: In this article, the most common genetic alternation in thyroid cancer, particularly in papillary thyroid cancer (PTC), was found to play a central role in the tumorigenesis and development of PTC.
Abstract: BRAF mutation is the most common genetic alternation in thyroid cancer, particularly in papillary thyroid cancer (PTC). Excessive activation of BRAF/MAPK signaling pathway due to BRAF mutation plays a central role in the tumorigenesis and development of PTC. The association of BRAF mutation with poor clinicopathological characteristics of PTC further demonstrated the importance of the BRAF mutation alternation in PTC. Detection of BRAF mutation on FNA specimen before surgery is recommended as a useful diagnostic marker and prognostic indicator for PTC, and thus influences surgeon’s decision on management of PTC. Recent studies have focused on inhibition of BRAF activation and several small molecules have been developed as targeting therapy.
159 citations
Georgetown University Medical Center1, University of Texas MD Anderson Cancer Center2, University of Kentucky3, Maine Medical Center4, Johns Hopkins University School of Medicine5, University of Colorado Denver6, Genzyme7, National Institutes of Health8, Harvard University9, University of Cincinnati10
TL;DR: Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes, raising the question of whether an older age cutoff would improve current staging systems.
Abstract: Context: Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr. Objective: The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis. Design: Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS). Participants and Setting: Patients were followed in a prospective registry. Main Outcome Measure: The relationships between gender, age, and PTC outcomes were analyzed. Results: The unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24–0.65]. This female advantage d...
159 citations
TL;DR: The BRAFV600E mutation was associated with high-risk clinicopathologic characteristics in patients with PTC and may be a potential prognostic factor in PTC patients.
Abstract: Background
The BRAFV600E mutation is the most common genetic alteration found in papillary thyroid cancer (PTC). Recent studies show that this mutation occurs more frequently in patients with PTC showing aggressive clinicopathologic features. The aim of the present study was to evaluate the prevalence of the BRAFV600E mutation in tumor samples and its association with high-risk clinicopathologic features prospectively.
140 citations
TL;DR: In most RRA-negative patients, postoperative serum Tg values spontaneously drop to undetectable levels within 5-7 yr after thyroidectomy, thus, in later phases, Tg assays may be a valuable tool for follow-up even in patients who do not undergo RRA.
Abstract: Context: Serum thyroglobulin (Tg) assays are considered fundamental in postoperative surveillance of differentiated thyroid cancer (DTC) patients. However, the postsurgical profile of Tg levels has never been specifically investigated in patients who do not undergo radioiodine remnant ablation (RRA). Objectives: Our objective was to explore the evolution of Tg levels over time in DTC patients treated with total or near-total thyroidectomy without RRA. Design: We retrospectively analyzed 290 consecutively diagnosed cases of low-risk (American Thyroid Association criteria) DTC treated with thyroidectomy alone and followed yearly with neck ultrasonography and serum Tg assays. We compared final Tg values in this group and a matched group of 495 RRA-positive patients. Temporal trends of serial Tg levels were also analyzed in 78 of the RRA-negative patients monitored with a high-sensitivity immunoradiometric assay. Results: After follow-up of 2.5–22 yr (median 5 yr), final Tg levels were undetectable (<1 ng/ml)...
137 citations
TL;DR: A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC) as discussed by the authors.
Abstract: Purpose: A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC). Experimental Design: Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed. Results: Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug. Conclusions: Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome. Clin Cancer Res; 18(7); 2056–65. ©2012 AACR .
TL;DR: The RET protein and mRNA expression level did not show any correlation with the outcome of patients with PTC and no correlation between RET/PTC rearrangements and the expression level of the thyroid differentiation genes was observed, which makes this procedure not applicable at routine level, at least for the moment.
Abstract: Thyroid carcinoma is the most frequent endocrine cancer accounting for 5-10% of thyroid nodules. Papillary hystotype (PTC) is the most prevalent form accounting for 80% of all thyroid carcinoma. Although much is known about its epidemiology, pathogenesis, clinical and biological behaviour, the only documented risk factor for PTC is the ionizing radiation exposure. Rearrangements of the RET proto-oncogene are found in PTC and have been shown to play a pathogenic role. The first RET rearrangement, named RET/PTC, was discovered in 1987. This rearrangement constitutively activates the transcription of the RET tyrosine kinase domain in follicular cell, thus triggering the signalling along the MAPK pathway and an uncontrolled proliferation. Up to now, 13 different types of RET/PTC rearrangements have been reported but the two most common are RET/PTC1 and RET/PTC3. Ionizing radiations are responsible for the generation of RET/PTC rearrangements, as supported by in vitro studies and by the evidence that RET/PTC, and particularly RET/PTC3, are highly prevalent in radiation induced PTC. However, many thyroid tumors without any history of radiation exposure harbour similar RET rearrangements. The overall prevalence of RET/PTC rearrangements varies from 20 to 70% of PTCs and they are more frequent in childhood than in adulthood thyroid cancer. Controversial data have been reported on the relationship between RET/PTC rearrangements and the PTC prognosis. RET/PTC3 is usually associated with a more aggressive phenotype and in particular with a greater tumor size, the solid variant and a more advanced stage at diagnosis which are all poor prognostic factors. In contrast, RET/PTC1 rearrangement does not correlate with any clinical–pathological characteristics of PTC. Moreover, the RET protein and mRNA expression level did not show any correlation with the outcome of patients with PTC and no correlation between RET/PTC rearrangements and the expression level of the thyroid different
TL;DR: The hypothesis that miRNA expression analysis would identify putative markers that could distinguish benign from malignant thyroid neoplasms that are often indeterminate on FNA biopsy was tested.
Abstract: BACKGROUND:
Approximately 30% of fine-needle aspiration (FNA) biopsies of thyroid nodules are indeterminate or nondiagnostic. Recent studies suggest microRNA (miRNA, miR) is differentially expressed in malignant tumors and may have a role in carcinogenesis, including thyroid cancer. The authors therefore tested the hypothesis that miRNA expression analysis would identify putative markers that could distinguish benign from malignant thyroid neoplasms that are often indeterminate on FNA biopsy.
METHODS:
A miRNA array was used to identify differentially expressed genes (5-fold higher or lower) in pooled normal, malignant, and benign thyroid tissue samples. Real-time quantitative polymerase chain reaction was used to confirm miRNA array expression data in 104 tissue samples (7 normal thyroid, 14 hyperplastic nodule, 12 follicular variant of papillary thyroid cancer, 8 papillary thyroid cancer, 15 follicular adenoma, 12 follicular carcinoma, 12 Hurthle cell adenoma, 20 Hurthle cell carcinoma, and 4 anaplastic carcinoma cases), and 125 indeterminate clinical FNA samples. The diagnostic accuracy of differentially expressed genes was determined by analyzing receiver operating characteristics.
RESULTS:
Ten miRNAs showed >5-fold expression difference between benign and malignant thyroid neoplasms on miRNA array analysis. Four of the 10 miRNAs were validated to be significantly differentially expressed between benign and malignant thyroid neoplasms by quantitative polymerase chain reaction (P < .002): miR-100, miR-125b, miR-138, and miR-768-3p were overexpressed in malignant samples of follicular origin (P < .001), and in Hurthle cell carcinoma samples alone (P < .01). Only miR-125b was significantly overexpressed in follicular carcinoma samples (P < .05). The accuracy for distinguishing benign from malignant thyroid neoplasms was 79% overall, 98% for Hurthle cell neoplasms, and 71% for follicular neoplasms. The miR-138 was overexpressed in the FNA samples (P = .04) that were malignant on final pathology with an accuracy of 75%.
CONCLUSIONS:
MicroRNA expression differs for normal, benign, and malignant thyroid tissue. Expression analysis of differentially expressed miRNA could help distinguish benign from malignant thyroid neoplasms that are indeterminate on thyroid FNA biopsy. Cancer 2011. © 2011 American Cancer Society.
TL;DR: Suspicious cervical LN in the lateral neck usually remain stable for long periods of time in properly selected PTC patients and can be safely followed with serial ultrasounds.
Abstract: Context: The risk of loco-regional recurrence in papillary thyroid cancer (PTC) patients ranges from 15–30%. However, the clinical significance of small-volume loco-regional recurrence detected by highly sensitive ultrasonography is unclear. Objective: Our objective was to describe the natural history of abnormal cervical lymph nodes (LN) diagnosed after initial treatment. Design: We conducted a retrospective cohort study. Patients: 166 PTC with patients who had at least one abnormal LN outside the thyroid be on ultrasound and selected for active surveillance were included. Main Outcome Measure: LN growth during a period of active surveillance was the primary outcome. Results: Most patients had classical PTC (85%) and an intermediate risk of recurrence (77%). The median LN size at the start of the observation period was 1.3 cm (range, 0.5–2.7 cm) in largest diameter, with all nodes having at least one abnormal sonographic characteristic (70% of patients had LN with at least two abnormal features). In almo...
TL;DR: The aim of this study was to define the extent of lateral LN involvement and the role of imaging in identification of these metastatic LN in Papillary thyroid cancer.
Abstract: Background Papillary thyroid cancer (PTC) is a common endocrine cancer and frequently presents with lymph node (LN) metastases. The frequency of LN metastases in the lateral compartment and their surgical removal are poorly defined. There are no prospective randomised controlled trials addressing an eventual outcome difference relating to the extent of the initial surgical approach. The aim of this study was to define the extent of lateral LN involvement and the role of imaging in identification of these metastatic LN. Design and methods A systematic review of studies of patients with PTC undergoing either prophylactic or therapeutic lymphadenectomy of the lateral cervical compartment. Studies involving imaging modalities in the detection of lateral cervical LNs in PTC were also analysed. Results Systematic review on the frequency of lateral LN metastases and their detection using various imaging tools identified 19 studies containing data on 5587 patients undergoing prophylactic or imaging-guided removal of the lateral compartment. Imaging-guided surgery retrieved cancerous lateral LNs in 446/3178 or 14% of eligible patients, whilst prophylactic lateral neck dissection yielded histopathological proof of cancer in 1177/204 or 57·5% of patients. The frequency of lateral compartment metastases increased with T stage. The sensitivity of ultrasound and CT was poor as low as 27% when accurately calculated. Conclusion Metastatic cervical LNs were found in more than half of patients when prophylactic lateral LN dissection was performed. Use of conventional imaging for the selection of the surgical approach to the lateral cervical compartment may commonly identify stage N1a instead of N1b and thus lead to false stage assignment as stage III rather than stage IV, concealing the severe prognostic implications of this stage progression in individual patients.
TL;DR: The incidence and prognosis of thyroid cancer associated with hyperthyroidism is a matter of debate, and it seems that Graves' disease is associated with larger, multifocal, and potentially more aggressive thyroid cancer than single hot nodules or multinodular toxic goiter.
Abstract: Thyroid cancer can be associated with thyrotoxicosis caused by Graves’ disease, toxic multinodular goiter, or autonomously functioning thyroid adenoma. The objective of this study was to summarize current evidence regarding the association of thyroid cancer and hyperthyroidism, particularly with respect to the type of hyperthyroidism found in some patients, and whether this affects the outcome of the patient. A PubMed search was performed up to August 2011. Articles were identified using combinations of the following keywords/phrases: thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, hyperthyroidism, Graves’ disease, autonomous adenoma, toxic thyroid nodule, and toxic multinodular goiter. Original research papers, case reports, and review articles were included. We concluded that the incidence, as well as the prognosis of thyroid cancer associated with hyperthyroidism is a matter of debate. It seems that Graves’ disease is associated with larger, multifocal, and potentially more aggressive thyroid cancer than single hot nodules or multinodular toxic goiter. Patients with Graves’ and thyroid nodules are at higher risk to develop thyroid cancer compared to patients with diffuse goiter. Every suspicious nodule associated with hyperthyroidism should be evaluated carefully.
TL;DR: The findings emphasize the ability of US to clinically detect relevant nodal disease and support conservative management of the CNC in the absence of abnormal findings and suggest prophylactic neck dissection of the central compartment does not improve long-term disease control.
Abstract: Background: Ultrasound (US) of the central neck compartment (CNC) is considered of limited sensitivity for nodal spread in papillary thyroid cancer (PTC); elective neck dissection is commonly advocated even in the absence of sonographic abnormalities. We hypothesized that US is an accurate predictor for long-term disease-free survival, regardless of the use of elective central neck dissection in patients with PTC. Methods: A retrospective chart review of 331 consecutive PTC patients treated with total thyroidectomy at M.D. Anderson Cancer Center between 1996 and 2003 was performed. Information retrieved included preoperative sonographic status of the CNC, surgical treatment of the neck, demographics, cancer staging, histopathological variables and use of adjuvant treatment. The endpoints for the study were nodal recurrence and survival. Results: There were 112 males and 219 females with a median age of 44 years (range 11–87). The median follow-up time for the series was 71.5 months (range 12.7–148.7). The...
TL;DR: The results suggest that a higher proliferation rate in normal thyroid could be related to radiation-induced cancer either as a predisposition or as a consequence of radiation.
Abstract: Papillary thyroid cancer (PTC) incidence increased dramatically in children after the Chernobyl accident, providing a unique opportunity to investigate the molecular features of radiation-induced thyroid cancer. In contrast to the previous studies that included age-related confounding factors, we investigated mRNA expression in PTC and in the normal contralateral tissues of patients exposed and non-exposed to the Chernobyl fallout, using age- and ethnicity-matched non-irradiated cohorts. Forty-five patients were analysed by full-genome mRNA microarrays. Twenty-two patients have been exposed to the Chernobyl fallout; 23 others were age-matched and resident in the same regions of Ukraine, but were born after 1 March 1987, that is, were not exposed to 131I. A gene expression signature of 793 probes corresponding to 403 genes that permitted differentiation between normal tissues from patients exposed and from those who were not exposed to radiation was identified. The differences were confirmed by quantitative RT-PCR. Many deregulated pathways in the exposed normal tissues are related to cell proliferation. Our results suggest that a higher proliferation rate in normal thyroid could be related to radiation-induced cancer either as a predisposition or as a consequence of radiation. The signature allows the identification of radiation-induced thyroid cancers.
TL;DR: Increased Treg and PD-1(+) T cell frequencies in LN may be indicative of aggressive recurrent PTC and further elevated in TILN from patients with recurrent disease.
Abstract: Context: Recurrent metastatic lymph node (LN) disease is common in patients with papillary thyroid cancer (PTC). Novel prognostic markers may be helpful in guiding a therapeutic approach. Our previous studies revealed that immune suppression is evident in PTC and associated with more severe disease. Objective: To characterize the immune response to metastatic PTC, we assessed CD4+ T cell polarization in LN. In addition, we investigated the role of programmed death-1 (PD-1) and T cell exhaustion. Design: Uninvolved (UILN) and tumor-involved lymph nodes (TILN) were sampled ex vivo by fine-needle biopsy. T cell subsets were identified by flow cytometry. In parallel, archived TILN specimens were characterized by immunofluorescence. Setting: The study was conducted at the University of Colorado Hospital. Patients: Data were collected on 94 LN from 19 patients with PTC undergoing neck dissection. Main Outcome: T cell subset frequencies were compared in UILN and TILN and assessed for correlation with recurrent d...
TL;DR: Diffuse FVPTC seems to present and behave in a more aggressive fashion and has a higher rate of central nodal metastasis and BRAF V600E mutation in comparison with EFVPTC and NFVPTC.
Abstract: Objective To examine genotypic and clinical differences between encapsulated, nonencapsulated, and diffuse follicular variant of papillary thyroid carcinoma (EFVPTC, NFVPTC, and diffuse FVPTC, respectively), to characterize the entities and identify predictors of their behavior. Design Retrospective medical chart review and molecular analysis. Setting Referral center of a university hospital. Patients The pathologic characteristics of 484 consecutive patients with differentiated thyroid cancer who underwent surgery by the 3 members of the New York University Endocrine Surgery Associates from January 1, 2007, to August 1, 2010, were reviewed. Forty-five patients with FVPTC and in whom at least 1 central compartment lymph node was removed were included. Main Outcome Measures Patients with FVPTC were compared in terms of age, sex, tumor size, encapsulation, extrathyroid extension, vascular invasion, central nodal metastases, and the presence or absence of mutations in BRAF, H-RAS 12/13, K-RAS 12/13, N-RAS 12/13, H-RAS 61, K-RAS 61, N-RAS 61, and RET/PTC1. Results No patient with EFVPTC had central lymph node metastasis, and in this group, 1 patient (4.5%) had a BRAF V600E mutation and 2 patients (9%) had RAS mutations. Of the patients with NFVPTC, none had central lymph node metastasis (P >> .99) and 2 (11%) had a BRAF V600E mutation (P = .59). Of the patients with diffuse FVPTC, all had central lymph node metastasis (P Conclusions FVPTC consists of several distinct subtypes. Diffuse FVPTC seems to present and behave in a more aggressive fashion. It has a higher rate of central nodal metastasis and BRAF V600E mutation in comparison with EFVPTC and NFVPTC. Both EFVPTC and NFVPTC behave in a similar fashion. The diffuse infiltrative pattern and not just presence or absence of encapsulation seems to determine the tumor phenotype. Understanding the different subtypes of FVPTC will help guide appropriate treatment strategies.
TL;DR: A validated, histopathology-based prognostic classification can identify patients in need of close follow-up and adjuvant therapy, and should prove valuable to stratify clinical trial cohorts: low-risk patients rarely die from parathyroid cancer, even on long-term follow- up, whereas 5-year mortality in high- risk patients is around 50%.
Abstract: Parathyroid cancer is rare, but often fatal, as preoperative identification of malignancy against the backdrop of benign parathyroid disease is challenging. Advanced genetic, laboratory and imaging techniques can help to identify parathyroid cancer. In patients with clinically suspected parathyroid cancer, malignancy of any individual lesion is established by three criteria: demonstration of metastasis, specific ultrasonographic features, and a ratio >1 for the results of third-generation:second-generation parathyroid hormone assays. Positive findings for all three criteria dictate an oncological surgical approach, as appropriate radical surgery can achieve a cure. Mutation screening pinpoints associated conditions and asymptomatic carriers. Molecular profiling of tumour cells can identify high-risk features, such as differential expression of specific micro-RNAs and proteins, and germ line mutations in CDC73, but is unsuitable for preoperative assessment owing to the potential risks associated with biopsy. A validated, histopathology-based prognostic classification can identify patients in need of close follow-up and adjuvant therapy, and should prove valuable to stratify clinical trial cohorts: low-risk patients rarely die from parathyroid cancer, even on long-term follow-up, whereas 5-year mortality in high-risk patients is around 50%. This insight has improved the approach to parathyroid cancer by enabling risk-adapted surgery and follow-up.
TL;DR: These data provide the first evidence that Src is a central mediator of thyroid cancer growth and metastasis, indicating that SRC inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents.
Abstract: Purpose: There are no effective therapies for patients with poorly differentiated papillary thyroid cancer (PTC) or anaplastic thyroid cancer (ATC), and metastasis to the bone represents a significantly worse prognosis. Src family kinases (SFKs) are overexpressed and activated in numerous tumor types and have emerged as a promising therapeutic target, especially in relation to metastasis. We recently showed that Src is overexpressed and activated in thyroid cancer. We therefore tested whether inhibition of Src with dasatinib (BMS-354825) blocks thyroid cancer growth and metastasis. Experimental Design: The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated in vitro . The therapeutic efficacy of dasatinib was further tested in vivo using an orthotopic and a novel experimental metastasis model. Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using an Src gatekeeper mutant. Results: Dasatinib treatment inhibited Src signaling, decreased growth, and induced cell-cycle arrest and apoptosis in a subset of thyroid cancer cells. Immunoblotting showed that c-Src and Lyn are expressed in thyroid cancer cells and that c-Src is the predominant SFK activated. Treatment with dasatinib blocked PTC tumor growth in an orthotopic model by more than 90% ( P = 0.0014). Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis ( P = 0.016 and P = 0.004, respectively). Conclusion: These data provide the first evidence that Src is a central mediator of thyroid cancer growth and metastasis, indicating that Src inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents. Clin Cancer Res; 18(13); 3580–91. ©2012 AACR .
TL;DR: The role of surgical removal of the central cervical LN compartment is poorly defined and there are no prospective randomized controlled trials addressing the relevance to the extent of the initial surgical approach.
Abstract: Background Papillary thyroid cancer (PTC) is a common endocrine cancer and commonly presents with lymph node (LN) metastases. The role of surgical removal of the central cervical LN compartment is poorly defined. There are no prospective randomized controlled trials addressing the relevance to the extent of the initial surgical approach.
TL;DR: It is hypothesised that long-term HT leads to elevated serum TSH, which is the real risk factor for thyroid cancer.
Abstract: Background
The goal of this study was to identify the clinicopathological factors of co-existing papillary thyroid cancer (PTC) in patients with Hashimoto’s thyroiditis (HT) and provide information to aid in the diagnosis of such patients.
TL;DR: The genetic profile of PTC changed over the last 15 yr, with a significant decrease in the prevalence of RET/PTC rearrangements and an increase in BRAF(V600E) mutations.
Abstract: Background: Evidence for an increased prevalence of BRAFV600E mutations has been documented in recent decades. The aim of this study was to evaluate the prevalence of both RET/PTC rearrangements and BRAFV600E mutations in an Italian cohort of papillary thyroid carcinoma (PTC) patients followed at the Endocrine Units of Pisa, Milano, and Perugia from 1996–2010. Patients and Methods: In total, 401 PTC patients were examined and grouped according to the time of surgery: group 1, 1996–2000; group 2, 2001–2005; and group 3, 2006–2010. Patients were analyzed for clinical, pathological, and molecular features. In parallel, the molecular characteristics of 459 PTC from Sicily were studied. Results: The genetic profiles of the three groups were significantly different (P < 0.0001). In particular, the frequency of RET/PTC rearrangements decreased from 1996–2010, occurring in 33 of 100 (33%) of the patients in group 1, 26 of 148 (17%) in group 2, and 15 of 153 (9.8%) in group 3. The incidence of BRAFV600E mutations ...
TL;DR: Select low- and intermediate-risk group patients who have undetectable Tg after total thyroidectomy for PTC can be managed safely without adjuvant RAI with no increase in risk of recurrence.
TL;DR: It is not clear that the BRAF(V600E) mutation is useful for prediction of poor prognosis of PTC, but a high-risk Metastasis, Patient Age, Completeness of resection, local Invasion and Tumor Size and lymph node metastasis were not significantly associated with the BRAFs.
Abstract: Objective Recent studies have shown that a BRAF V600E reflects poor prognosis, mainly in Western countries. However, some clinicians in Japan have suggested that the BRAF V600E mutation is not associated with a poor prognosis. Therefore, we investigated a relationship between BRAF V600E mutation and clinicopathologic factors. Methods From September 2008 to December 2009, we performed routine analysis of the BRAF V600E mutation using thyroid cancer tissue from 424 patients who underwent thyroidectomy with cervical lymph node dissection. Results The BRAF V600E mutation was found in 335 of 424 cases (79%) and was higher in classic papillary thyroid carcinoma (PTC) (79.7%) than in the follicular variant of PTC (62.5%) ( P = .019). On univariate analysis, the BRAF V600E mutation was associated with extrathyroidal extension ( P = .009) and variants of PTC ( P = .019), but a high-risk Metastasis, Patient Age, Completeness of resection, local Invasion and Tumor Size (MACIS) score (≥ 6) ( P = .146) and lymph node metastasis ( P = .628) were not significantly associated with the BRAF V600E mutation. Multivariate analysis showed that extrathyroidal extension is independently associated with the BRAF V600E mutation (relative ratio: 2.466; 95% confidence interval, 1.213–5.011; P Conclusion It is not clear that the BRAF V600E mutation is useful for prediction of poor prognosis of PTC.
TL;DR: Tregs and NK cells may be important regulators of thyroid cancer progression and positively correlated with advanced disease stage.
Abstract: Context: The immune system seems to play a key role in preventing metastasis and recurrence of thyroid cancer. T regulatory lymphocytes (Tregs) and natural killer (NK) cells play an important role in the dysfunction of the host immune system in cancer patients. Objective: We investigated thyroid gland infiltration by Tregs and NK cells in patients with papillary thyroid cancer (PTC) and thyroid nodular goiter (TNG). The correlation between the extent of the disease and the lymphocytic infiltration of Tregs and NK cells was examined. Design, Setting, and Participants: A total of 65 patients with PTC, 25 with TNG, and 50 healthy controls were studied. Blood and tissue samples from 28 patients with PTC and 13 with TNG and blood samples from the healthy controls were analyzed for T4 (CD3+CD4+), T8 (CD3+CD8+), NK (CD3−CD16+CD56+), and CD4+CD25+CD127−/low Tregs by flow cytometry (FC). Tissue samples were also analyzed for Foxp3+ Tregs by immunohistochemistry. Results: Tregs showed greater infiltration in thyroi...
TL;DR: It is shown that HMGB1 increases the expression of miR-221 andMiR-222 in primary papillary lesions and in an established papillary cancer cell, which is associated with an increase in malignancy scores, namely cell growth and motility.
Abstract: Experimental and epidemiological studies have revealed that chronic inflammation contributes to cancer progression and even predisposes to cellular transformation. Inflammatory infiltrates in papillary thyroid cancer include lymphocytes, macrophages and cytokines. High-mobility group box 1 protein (HMGB1) is a late inflammatory cytokine that signals danger to the immune system through the receptor for advanced glycation end-products (RAGE) and Toll-like receptor. The activation of the above receptors results in the secretion of growth, chemotactic and angiogenic factors that contribute to chronic inflammation. In this study, we suggest that apart from the activation of signal transduction pathways by the activation of RAGE, the indirect inhibition of cell cycle regulators [such as phosphatase and tensin homolog (PTEN)] may also cause an increase in cell growth and motility. MicroRNAs (miRNAs) have increasingly been implicated in regulating the malignant progression of cancer. MiR-221 and miR-222 have been found to be deregulated in human papillary thyroid carcinomas. They are involved in cell proliferation through the inhibition of the cell cycle regulator, p27kip1, in human papillary carcinomas. In this study, we show that HMGB1 increases the expression of miR-221 and miR-222 in primary cultures of excised papillary lesions and in an established papillary cancer cell line (BC PAP). The overexpression of oncogenic miR-221 and miR-222 caused by HMGB1 is associated with an increase in malignancy scores, namely cell growth and motility.
TL;DR: The aim of this study was to present the experience with reoperative central compartment dissection (RCCD) for recurrent/persistent papillary thyroid cancer (PTC) and explore the association between the BRAF mutation status and the clinicopathologic characteristics and outcomes of a large cohort of PTC patients who have undergone RCCD.
Abstract: Objectives/Hypothesis:
The aims of this study were to present our experience with reoperative central compartment dissection (RCCD) for recurrent/persistent papillary thyroid cancer (PTC), and to explore the association between the BRAF mutation status and the clinicopathologic characteristics and outcomes of a large cohort of PTC patients who have undergone RCCD.
Study Design:
Case series with chart review.
Methods:
This is a retrospective study. One hundred twenty consecutive patients between July 2001 and June 2010 who underwent RCCD for recurrent/persistent PTC performed by a single surgeon (r.p.t.) were reviewed. Data reviewed included demographic information; records from previous operations, RCCD, and any other concurrent procedures; pre- and postoperative serum and ionized calcium levels; pre- and postoperative fiberoptic laryngoscopic examination reports; postoperative notes; and pathology reports. V600E mutations in the BRAF gene were detected by performing pyrosequencing for the 107 patients deemed evaluable for the BRAF mutation.
Results:
The median time to tumor recurrence (TTR) was 36 months (range, 6–791 months). All recurrent laryngeal nerves (RLNs; 161/161) that were at risk were successfully identified. There were seven new findings of abnormal post-RCCD vocal fold (VF) motion that were the result of intentional RLN resection. Among them, six were because of the need for resection of a local recurrence, and one was because of bulky lymph nodes circumferentially involving the RLN. There were no findings of unexpected RLN injury or VF paralysis. Fifteen patients developed hypocalcemia as a result of RCCD that improved with oral calcium and vitamin D supplementation. Among them, 12 cases developed only post-RCCD transient hypocalcemia (≤6 months), and three patients developed permanent hypocalcemia. No patient exhibited central compartment recurrent/persistent PTC in the post-RCCD period based on semiannual high-resolution neck ultrasound examination with a median follow-up of 41.5 months (range, 6–123 months). Eighty (74.8%) of 107 cases demonstrated the BRAF V600E mutation. The presence of the BRAF mutation was significantly associated with a shorter TTR (P = .015) compared with the BRAF mutation-negative group. The BRAF mutation-positive group had a higher incidence of concurrent lateral lymph node metastases (P = .0064) than the BRAF mutation-negative group.
Conclusions:
Recurrent/persistent PTC in the central compartment typically harbors the BRAF mutation. The time to central neck recurrence from initial treatment is significantly shorter in the BRAF-positive population of patients compared to the BRAF-negative group, making it more likely that a recurrence will be identified early in the surveillance period. Although we have demonstrated that RCCD can be performed safely and effectively for nodal metastases, there is still risk involved, and this must be carefully weighed by the multidisciplinary team and the patient in optimizing a tailored plan for management. Laryngoscope, 2012