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Thyroid Cancer

Cancer of the thyroid is a disease in which malignant (cancerous) cells are found in the tissues of the thyroid gland. The thyroid gland is located at the base of the throat and produces hormones that help the body function normally. Most patients are between 25 and 65 years old, thyroid cancer is more common in women than in men. It is the most common malignancy of the endocrine (hormone) system. There are four main types of thyroid cancer (depending on the type of cell that the cancer developed in); papillary carcinoma, follicular carcinoma, medullary carcinoma and anaplastic carcinoma. Occasionally other types of cancer (lymphoma, sarcoma and carcinosarcoma) can be found in the thyroid gland. Some thyroid cancers are caused by exposure to radiation and some medullary carcinomas are associated with an inherited condition (multiple endocrine neoplasia). However, in the large majority of cases the cause is unknown

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Molecular Biology of Thyroid Cancers
Multiple Endocrine Neoplasia

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    MeSH term: Thyroid Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Kim SH, Kang JG, Kim CS, et al.
Doxorubicin has a synergistic cytotoxicity with cucurbitacin B in anaplastic thyroid carcinoma cells.
Tumour Biol. 2017; 39(2):1010428317692252 [PubMed] Related Publications
In this study, the combined effect of doxorubicin with cucurbitacin B on survival of anaplastic thyroid carcinoma cells was evaluated. For experiments, 8505C and CAL62 human anaplastic thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, and cytotoxic activity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, multiplexed cytotoxicity assay, and cytotoxicity assay, respectively. Reactive oxygen species production was measured. In experiments, doxorubicin and cucurbitacin B reduced cell viability in a dose- and time-dependent manner. Cotreatment of doxorubicin and cucurbitacin B, compared with treatment of doxorubicin alone, decreased the percentage of viable cells and increased cytotoxic activity. All of the combination index values were lower than 1.0, suggesting the synergism between doxorubicin and cucurbitacin B in induction of cytotoxicity. In cells treated with both doxorubicin and cucurbitacin B, compared with doxorubicin alone, the protein levels of cleaved poly(adenosine diphosphate-ribose) polymerase and cyclooxygenase 2 and reactive oxygen species production were enhanced. In contrast, the protein levels of B-cell chronic lymphocytic leukemia/lymphoma 2 and survivin and B-cell chronic lymphocytic leukemia/lymphoma 2/B-cell chronic lymphocytic leukemia/lymphoma 2-associated x protein ratio were diminished. The protein levels of Janus kinase 2 and signal transducer and activator of transcription 3 were reduced, while phospho-extracellular signal-regulated kinase 1/2 protein levels were elevated without change in total extracellular signal-regulated kinase 1/2 protein levels. These results suggest that doxorubicin synergizes with cucurbitacin B in induction of cytotoxicity in anaplastic thyroid carcinoma cells. Moreover, synergistic cytotoxicity of doxorubicin with cucurbitacin B is mediated by B-cell chronic lymphocytic leukemia/lymphoma 2 family proteins, survivin, and reactive oxygen species and modulated by Janus kinase 2/signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 in anaplastic thyroid carcinoma cells.

Vuong HG, Kondo T, Pham TQ, et al.
Prognostic significance of diffuse sclerosing variant papillary thyroid carcinoma: a systematic review and meta-analysis.
Eur J Endocrinol. 2017; 176(4):431-439 [PubMed] Related Publications
OBJECTIVE: Diffuse sclerosing variant papillary thyroid carcinoma (DSVPTC) is an uncommon variant of papillary thyroid carcinoma (PTC). The biological behaviors and prognostic outcomes of this variant, however, are still controversial. The aim of this systematic review and meta-analysis is to investigate the prognostic significance and outcomes of DSVPTCs in comparison with classical PTCs (cPTCs).
METHODS: An electronic search was performed in five libraries: PubMed, Scopus, ISI, World Health Organization Global Health Library (WHO GHL) and Virtual Health Library (VHL) in June 2016. Published data were extracted and were pooled into odds ratios (OR), mean differences and corresponding 95% confidence intervals (CI) using random-effect model. Publication bias was analyzed using Egger's regression test and funnel plot observation.
RESULTS: From 315 articles, we included 16 articles comprising 732 DSVPTCs for meta-analysis. Overall, DSVPTC manifested more aggressive clinicopathological behaviors than cPTC such as higher rate of vascular invasion (OR: 5.33; 95% CI: 3.08-9.23), extrathyroidal extension (OR: 2.96; 95% CI: 2.04-4.30), lymph node metastasis (OR: 5.40; 95% CI: 2.82-10.35), distant metastasis (OR: 3.61; 95% CI: 1.89-6.88) and were more likely to relapse (OR: 2.83; 95% CI: 1.59-5.05). DSVPTC patients were associated with a worsened overall survival (HR: 1.89; 95% CI: 1.36-2.62).
CONCLUSION: DSVPTCs should be considered high-risk PTCs because of high propensity for tumor invasion, metastasis, relapse and mortality. Aggressiveness of DSVPTCs might be related to a different molecular pathway than that in cPTCs.

Najafian A, Kahan S, Zeiger MA, Olson MT
Unusual findings in thyroid cytology and histology.
Diagn Cytopathol. 2017; 45(3):185-190 [PubMed] Related Publications
INTRODUCTION: Although cytology and histopathology of thyroid lesions generally fall into common, well-defined categories, there are uncommon cases with unusual fine needle aspiration (FNA) findings or histology. Herein, we review the prevalence and characteristics of rare thyroid cytology and histopathology findings at a tertiary hospital.
METHODS: Institutional data from >31,000 patients with a thyroid pathology from 1995 to 2013 were queried. Both cytology and histology were available in 6,693 patients. After exclusion of the common cytological categories detailed by The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and common histopathology categories, 90 patients with either an unusual FNA, histopathology, or both were identified.
RESULTS: A total of 90 cases were included (19: only unusual FNA; 25: only unusual histology; 46: both unusual cytology and histopathology). The positive predictive value of an unusual FNA for discovering an unusual lesion was 71% (95% CI: 58%-81%). The majority (66%) were females and median age was 59 years. On histopathology, 80 (88%) cases were malignant, 72 (90%) of which were initially diagnosed as malignant on FNA. Of the 10 benign lesions, 8 (80%) also had a benign FNA. Patients with unusual malignant lesions were significantly older than those with unusual benign lesions (62 vs. 44 years; P: 0.004).
CONCLUSION: Unusual cytopathological and histopathological findings in thyroid comprise a varied group of tumors that are individually rare but collectively common. A preoperative FNA with an unusual cytopathology is likely to lead to an unusual histopathological diagnosis; however, its diagnostic accuracy in differentiating benign from malignant is lower than the accuracy of cytopathology of conventional TBSRTC. Diagn. Cytopathol. 2017;45:185-190. © 2016 Wiley Periodicals, Inc.

Kim J, Cho SG, Kang SR, et al.
Preparation for radioactive iodine therapy is not a risk factor for the development of hyponatremia in thyroid cancer patients.
Medicine (Baltimore). 2017; 96(5):e6004 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to evaluate whether the preparation for radioactive iodine (RAI) therapy by thyroid hormone withdrawal (THW) or a low-iodine diet (LID) can be risk factors for the development of hyponatremia in patients with differentiated thyroid cancer after thyroidectomy.We retrospectively reviewed the medical records and laboratory findings of 326 patients who underwent preparation for RAI therapy after thyroidectomy from 2012 to 2014. Demographic and clinical variables including the method of thyrotropin stimulation and duration of LID were assessed. Serum sodium was measured twice, before operation and before RAI therapy.Hyponatremia was detected in only 3 patients (0.9%) before operation, but in 15 patients (4.6%) before RAI therapy. None of the patients had severe hyponatremia after preparation for RAI therapy. Pre-RAI therapy serum sodium was correlated with the method of thyrotropin stimulation (TWH vs recombinant human thyroid stimulating hormone, P = 0.014) and duration of LID (r = -0.131, P = 0.018); however, the preparation of RAI therapy, THW and LID, did not affect the development of hyponatremia in logistic regression analysis. Preoperative serum sodium was a significant risk factor for hyponatremia during preparation for RAI therapy.Preparation for RAI therapy by THW or LID is not a risk factor for the development of hyponatremia in patients with thyroid cancer. The development of hyponatremia was neither frequent nor severe during preparation for RAI therapy. Physicians should not be greatly concerned about rare life-threatening hyponatremia during preparation for RAI therapy.

Mínguez P, Flux G, Genollá J, et al.
Whole-remnant and maximum-voxel SPECT/CT dosimetry in (131) I-NaI treatments of differentiated thyroid cancer.
Med Phys. 2016; 43(10):5279-5287 [PubMed] Related Publications
PURPOSE: To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC).
METHODS: Eighteen DTC patients were administered 1.11 GBq of (131) I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3-7 days after administration. The activity, the remnant mass, and the maximum-voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimated using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry.
RESULTS: The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2-176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2-145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 ± 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in theS-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients.
CONCLUSIONS: Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.

Liu Y, Li H, Zhang J, Gao X
Potassium Iodate Differently Regulates the Proliferation, Migration, and Invasion of Human Thyroid Cancer Cells via Modulating miR-146a.
Cancer Invest. 2017; 35(2):122-128 [PubMed] Related Publications
The effects of different doses of potassium iodate (KIO3) on the malignancy of thyroid cancer were investigated. Results showed that the proliferation, migration, and invasion of SW579 thyroid cancer cells were improved by 10(-6) M KIO3, which was associated with microRNA(miR)-146a deficit; 10(-2) M KIO3 significantly enhanced miR-146a level and suppressed SW579 cell proliferation, migration, and invasion. The diverse effects of KIO3 on SW579 cells were associated with the expression changes in miR-146a targets, Bcl-2, Bax, and caspase-3. Our study concludes that different doses of KIO3 have counteracting effects on the malignancy of thyroid cancer through modulating miR-146a level.

Grozinsky-Glasberg S, Bloom AI, Lev-Cohain N, et al.
The role of hepatic trans-arterial chemoembolization in metastatic medullary thyroid carcinoma: a specialist center experience and review of the literature.
Eur J Endocrinol. 2017; 176(4):461-468 [PubMed] Related Publications
BACKGROUND: Liver metastases are relatively common in patients with metastatic medullary thyroid carcinoma (MTC), carrying a negative impact on disease prognosis. The options for selective therapy of liver metastases in MTC patients are limited to catheter-guided procedures such as trans-arterial chemoembolization (TACE). Data regarding the effectiveness and safety of this procedure in MTC are limited.
AIM: To explore the clinical outcome, survival and safety profile of TACE for liver metastases in a group of MTC patients.
METHODS: Retrospective case series of patients treated at a single tertiary University Medical Center from 2005 to 2015.
RESULTS: Seven consecutive patients (mean age 64.5 ± 10.9 years, 5 females) with histologically confirmed MTC with liver metastases were included. Metastatic involvement of the liver was less than 50% of the liver volume in all patients. The median size of the largest liver lesion was 40 ± 6.9 mm. The patients underwent in total 20 sessions of TACE. Clinical improvement as well as tumor response (PR) were observed in all patients. The median time to tumor progression was 38 months (range 8-126). Three patients were still alive at the end of the follow-up period (a median overall survival rate of 57 ± 44 months).
CONCLUSION: TACE in MTC patients with hepatic metastases is usually well tolerated and induces both clinical improvement and tumor response for prolonged periods of time in the majority of patients. This therapeutic option should always be considered, irrespective of the presence of extrahepatic metastasis.

Kwon H, Jeon MJ, Kim WG, et al.
A comparison of lobectomy and total thyroidectomy in patients with papillary thyroid microcarcinoma: a retrospective individual risk factor-matched cohort study.
Eur J Endocrinol. 2017; 176(4):371-378 [PubMed] Related Publications
OBJECTIVE: Papillary thyroid microcarcinoma (PTMC) accounts for most of the increase in thyroid cancer in recent decades. We compared clinical outcomes and surgical complications of lobectomy and total thyroidectomy (TT) in PTMC patients.
DESIGN AND METHODS: In this retrospective individual risk factor-matched cohort study, 2031 patients with PTMC were initially included. Patients who underwent lobectomy or TT were one-to-one matched according to individual risk factors, including age, sex, primary tumor size, extrathyroidal extension, multifocality and cervical lymph node (LN) metastasis.
RESULTS: In total, 688 patients were assigned to each group. During the median 8.5 years of follow-up, 26 patients (3.8%) in the lobectomy group and 11 patients (1.6%) in the TT group had recurrences. The relative risk of recurrence was significantly less in the TT than that in the lobectomy group (hazard ratio (HR) 0.41; 95% confidence interval (CI) 0.21-0.81; P = 0.01). Most recurrences (84.6%) in the lobectomy group occurred in the contralateral lobe, and all patients were disease-free after completion of thyroidectomy. There were no significant differences in recurrence-free survival between the two groups after exclusion of contralateral lobe recurrences (HR, 2.75; 95% CI, 0.08-8.79; P = 0.08). There were significantly more patients with transient and permanent hypoparathyroidism in the TT than that in the lobectomy group (P < 0.001).
CONCLUSIONS: Lobectomy could be appropriate for most patients with PTMC when there is no evidence of extrathyroidal disease in the preoperative work-up. Preoperative and postoperative imaging studies are important for patients who undergo lobectomy for PTMC, because most recurrences are in the contralateral lobe.

Kern B, Coppin L, Romanet P, et al.
Multiple HABP2 variants in familial papillary thyroid carcinoma: Contribution of a group of "thyroid-checked" controls.
Eur J Med Genet. 2017; 60(3):178-184 [PubMed] Related Publications
A heterozygous germline variant in the HABP2 gene c.1601G > A (p.Gly534Glu), which negatively impacts its tumor suppressive activity in vitro, has been described in 4-14% of kindreds of European-American ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European/Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare HABP2 genotypes of patients with fPTC with those of "thyroid-checked" controls. A control group consisting of 136 European patients who were thyroidectomised for medullary thyroid carcinoma and devoid of any histologically detectable PTC or follicular-deriving carcinoma was built. In parallel we recruited 20 patients with fPTC from eleven independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Nucleotide variants were searched for by Snap Shot analysis in the controls. Two variants, c.1601G > A (p.Gly534Glu) and c.364C > T (p.Arg122Trp), were found in 2 and 3 patients at the heterozygous level respectively (minor allele frequency (MAF): 5.0% and 7.5%, respectively). In controls, the MAF was either similar for the c.1601G > A HABP2 variant (2.94%, ns) or significantly lower for the c.364C > T variant (0.73%, p = 0.016). The Arg122 residue lies in the EGF-3 domain of HABP2 which is important for its activation but, however, superposition of the predicted 3D structures of the wild type and mutated proteins suggests that this variant is tolerated at the protein level. In conclusion, our data do not support the pathogenicity of the HABP2 c.1601G > A variant but highlight the existence of a new one that should be more extensively searched for in fPTC patients and its pathogenicity more carefully evaluated.

Ciappuccini R, Blanchard D, Rame JP, et al.
Radioiodine sinus uptake related to mucosal thickening or aspergilloma: a case series of an unrecognized event well evidenced by SPECT/CT.
Cancer Imaging. 2017; 17(1):2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: False-positive radioiodine (RAI) uptake related to chronic sinusitis and mucocele has only rarely been reported in patients with differentiated thyroid cancer (DTC) even with the recent use of single photon emission tomography with computed tomography (SPECT/CT) acquisition. No other etiology of sinus RAI uptake has been mentioned to date.
OBJECTIVES: We report five cases of DTC patients with sinus RAI uptake on post-RAI scintigraphy. SPECT/CT clearly localized RAI uptake either in the sphenoid, the maxillary or the frontal sinus and highly suspected mucosal thickening in four patients and sinus aspergilloma in one patient.
CONCLUSION: These data confirm the possibility of false-positive sinus RAI uptake, provide a new cause of such benign uptake, i.e. sinus aspergilloma, and demonstrate the clinical relevance of head and neck SPECT/CT acquisition in the diagnosis of such uptake. Nuclear medicine physicians should be aware of this pitfall when interpreting post-RAI scintigraphy.

Koukkou EG, Roupas ND, Markou KB
Effect of excess iodine intake on thyroid on human health.
Minerva Med. 2017; 108(2):136-146 [PubMed] Related Publications
The recommended daily intake of iodide, is 150 μg for adolescents and adults, 250 μg for pregnancy and lactation. Thyroid gland is an effective collector of iodine. The active iodine uptake along the basolateral membrane of thyroid cell is followed by its transport to the apical edge of the cell and then to the follicle lumen. TSH acts through cAMP and stimulates NIS gene expression and protein synthesis. The major proportion of iodine in the thyroid gland is bound to Thyroglobulin. The non-organic intrathyroidal iodine is usually low, but significantly greater compared to plasma. Large doses of iodine reduce both the uptake and the organification (Wolff-Chaikoff effect) and cause partial inhibition of Tg proteolysis. The thyroid gland has several protective mechanisms resulting on the maintenance of normal thyroid function despite wide fluctuations of the daily iodine intake. Ingestion of several commonly used drugs and food conservatives results in acute or chronic excessive iodine intake. Failure to escape from the iodine induced organification inhibition can cause hypothyroidism, which is temporary and subsides after iodine exposure ceases. Iodine excess may also establish a status of excessive thyroid hormone synthesis and release, thus inducing autonomic thyroid function in iodopenic areas or can contribute to the development of iodine-induced hyperthyroidism in iodine abundant areas. The anti-arrhythmic Amiodarone, is a benzofuranic product with a very high iodine content, is associated with either hypo- or hyperthyroidism development. In the presence of defective auto-protective mechanisms, excessive iodine ingestion can divert the normal thyroid function.

Crescenzi A, Fulciniti F, Bongiovanni M, et al.
Detecting N-RAS Q61R Mutated Thyroid Neoplasias by Immunohistochemistry.
Endocr Pathol. 2017; 28(1):71-74 [PubMed] Related Publications
Recently, the immunohistochemistry (IHC) for N-RAS Q61R has been developed and commercialized for clinical practice. Here, we investigated the reliability of IHC to identify N-RAS Q61R mutated thyroid neoplasia. A series of 24 consecutive thyroid lesions undergone surgery following indeterminate cytology were enrolled. Paraffin sections were stained for IHC using the rabbit monoclonal anti-human N-RAS Q61R, clone SP174. N-RAS mutations in codon 61 were also investigated by automated sequencing. At histology, 12 cases of follicular carcinoma, cytologically defined as follicular lesions, 1 papillary cancer, 7 follicular adenomas, and 4 hyperplastic nodules were found. Of these, 4 showed a positive IHC for anti N-RAS antibody where N-RAS expression was detected mainly at cytoplasmic level with similar intensity of reaction. The remaining cases had negative IHC. A 100% concordance between IHC and molecular analysis for N-RAS Q61R was observed. In conclusion, this study shows high reliability of IHC to identify N-RAS Q61R mutated thyroid lesions with high cost-effectiveness. These data indicate the reliability of IHC to identify N-RAS Q61R mutated thyroid neoplasia and suggest to adopt this approach for a more accurate management of patients, when indicated.

Kluijfhout WP, Drake FT, Pasternak JD, et al.
De novo thyroid cancer following solid organ transplantation-A 25-year experience at a high-volume institution with a review of the literature.
J Surg Oncol. 2017; 115(2):105-108 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: We investigated the rate, stage, and prognosis of thyroid cancer in patients after solid-organ transplantations, and compared this to the general population.
METHODS: We performed a retrospective review of patients who developed thyroid cancer after a solid-organ transplantation between January 1988 and December 2013 at a high volume transplant center. Standardized Incidence Ratio's (SIR) were calculated. Additionally, a systematic review of the literature was performed.
RESULTS: A total of 10,428 patients underwent solid organ transplantation. Eleven patients (11.4 per 100,000 person-years) developed thyroid cancer: six men and five women with a mean age at diagnosis of thyroid cancer of 58 years. Ten patients underwent surgery and had stage I thyroid cancer. One patient had recurrent disease after a mean follow-up time of 78 months. The SIR varied between 0.75 and 2.3. Seventeen studies were included in the systematic review with a SIR ranging from 2.5 to 35.
CONCLUSION: Rate of thyroid cancer is not significantly higher in patients who underwent solid organ transplantation compared to general population. Stage at presentation and prognosis also appear to be similar to that of the general population. Post-transplant screening for thyroid cancer remains debatable; however, when thyroid cancer is discovered, treatment should be similar to that of non-transplant patients. J. Surg. Oncol. 2017;115:105-108. © 2017 Wiley Periodicals, Inc.

Nakayama M, Okizaki A, Takahashi K
A Randomized Controlled Trial for the Effectiveness of Aromatherapy in Decreasing Salivary Gland Damage following Radioactive Iodine Therapy for Differentiated Thyroid Cancer.
Biomed Res Int. 2016; 2016:9509810 [PubMed] Free Access to Full Article Related Publications
Objective. The aim of this study was to investigate effects of aromatherapy in decreasing salivary gland damage for patients undergoing radioactive iodine (RAI) therapy with differentiated thyroid cancer (DTC). Materials and Methods. The subjects were 71 patients with DTC. They were divided into aromatherapy group (group A, n = 35) and a control group (group B, n = 36). We blended 1.0 mL of lemon and 0.5 mL of ginger essential oils. The patients in the inhalation aromatherapy group inhaled this blend oil and those in the control group inhaled distilled water as placebo for 10 min during admission. We statistically compared salivary gland function before and after treatment between groups A and B. Results. In comparison with group B, the rate of change of the accumulation rate was significantly higher in the parotid glands and submandibular glands of group A (P < 0.05). In comparison with group B, a significant increase in rate of secretion change before and after treatment was noted in the bilateral parotid glands in group A (P < 0.05). Conclusion. Because an amelioration of salivary gland function was observed in the present study, our results suggest the efficacy of aromatherapy in the prevention of treatment-related salivary gland disorder. This trial is registered with UMIN Clinical Trial Registry: UMIN000013968.

Yin DT, Yu K, Lu RQ, et al.
Prognostic impact of minimal extrathyroidal extension in papillary thyroid carcinoma.
Medicine (Baltimore). 2016; 95(52):e5794 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It is widely accepted that maximal extrathyroidal extension (ETE) plays a vital role in the prognosis of papillary thyroid carcinoma (PTC). However, there is no consensus among researchers about the meaning of minimal ETE (mETE) in PTC. Herein, we conducted a systematic review and meta-analysis to examine the role of mETE in the prognosis of PTC.
METHODS: We searched PubMed, EMBASE, and Cochrane search trials databases in English to identify studies comparing data on disease recurrence in PTC patients with mETE and those with no ETE. To summarize the data related to mETE status, risk ratios and hazard ratios adjusted for potential confounders were used to assess the number of recurrence and time-dependent risks related to mETE status, respectively.
RESULTS: According to the inclusion criteria, a total of 7951 patients from 9 studies were included. The recurrence rate in patients with mETE is significantly higher when compared with those with no ETE (risk ratio = 1.70, 95% confidence interval: 1.26-2.28, I = 56%). According to the data summarized with hazard ratios, PTC patients with mETE showed a significantly increased risk of disease recurrence.
CONCLUSION: mETE is a risk factor for poor prognosis in patients with PTC. Our innovative classification of ETE has its value in assessing the prognosis of PTC.

Zacho HD, Nielsen JB, Dettmann K, et al.
Incidental Detection of Thyroid Metastases From Renal Cell Carcinoma Using 68Ga-PSMA PET/CT to Assess Prostate Cancer Recurrence.
Clin Nucl Med. 2017; 42(3):221-222 [PubMed] Related Publications
Ga-PSMA PET/CT is increasingly used to assess prostate cancer. Avid Ga-PSMA uptake by thyroid cancer and renal cell carcinoma (RCC) has been reported in few cases. A 75-year-old man who received a diagnosis of RCC in 2006 and prostate cancer in 2009 presented with elevated prostate-specific antigen levels (0.7 ng/mL) following prostatectomy. Ga-PSMA PET/CT showed avid Ga-PSMA uptake in 1 pelvic and 1 retroperitoneal lymph node and focal Ga-PSMA accumulation in the thyroid. Excised retroperitoneal lymph node and thyroid tissues showed metastases from RCC, whereas the pelvic lymph node exhibited metastasis from prostate cancer.

Trimboli P, Fulciniti F, Zilioli V, et al.
Accuracy of international ultrasound risk stratification systems in thyroid lesions cytologically classified as indeterminate.
Diagn Cytopathol. 2017; 45(2):113-117 [PubMed] Related Publications
BACKGROUND: Eminent international societies have published their thyroid ultrasound risk stratification system (US-RSS) to give a friendly tool for thyroidologists. In particular, American Thyroid Association (ATA), American Association Clinical Endocrinologists/American College of Endocrinologists and Associazione Medici Endocrinologi (AACE/ACE/AME), British Thyroid Association (BTA), and Thyroid Imaging Reporting and Data System (TIRADS) are often adopted for clinical practice. The reliability of these US-RSS has not been evaluated in discriminating cancers from benignancy in nodules with indeterminate FNA.
METHODS: Indeterminate thyroid lesions were searched in our database and only those with histology were finally included. The matching of US and histologic data of nodule's location and size were verified. All US images and clips were re-evaluated and nodules classified according to the above US-RSS.
RESULTS: A series of 101 indeterminate lesions, diagnosed by FNA were included (mean size 2.4 cm) and a 21% of cancers was found at histology. When all lesions were classified by US-RSS, poor accuracy (up to 54%) and specificity (up to 19%) were recorded. Highest sensitivity (91%) and NPV (94%) was obtained by BTA. Of relevance, the rate of nodules with indeterminate US risk recorded by BTA was significantly lower than the other (P < 0.001). At nodule's size analysis, cancers had significantly higher estimated volume (P < 0.05). When we considered the size thresholds proposed by guidelines, ATA system reached the highest sensitivity in detecting cancers (95%).
CONCLUSIONS: Even if international US-RSS have suboptimal accuracy in indeterminate thyroid nodules, high sensitivity can be obtained using ATA system with specific dimensional cut-offs. Diagn. Cytopathol. 2017;45:113-117. © 2016 Wiley Periodicals, Inc.

Megwalu UC
Observation versus thyroidectomy for papillary thyroid microcarcinoma in the elderly.
J Laryngol Otol. 2017; 131(2):173-176 [PubMed] Related Publications
OBJECTIVE: To compare the effectiveness of non-surgical versus surgical therapy in elderly patients with papillary thyroid microcarcinoma.
METHODS: The study cohort included 2323 elderly patients (aged 65 years and over) diagnosed with papillary thyroid microcarcinoma between 1988 and 2009, identified in the Surveillance, Epidemiology, and End Results 18 database of the National Cancer Institute.
RESULTS: The five-year overall survival rate was 23 per cent for non-surgical patients compared with 91 per cent for surgical patients (p < 0.0001). Unadjusted analysis revealed significantly improved survival in surgical patients compared with non-surgical patients (hazard ratio = 0.06; p < 0.0001). Propensity score analysis also revealed significantly improved survival in surgical patients compared with non-surgical patients (hazard ratio = 0.11; p < 0.0001).
CONCLUSION: Thyroidectomy appears to provide a survival benefit for elderly patients with papillary thyroid microcarcinoma. High-quality prospective studies are needed to better evaluate the comparative effectiveness of immediate thyroidectomy versus observation for elderly patients with papillary thyroid microcarcinoma.

Wang YL, Gong WG, Yuan QL
Effects of miR-27a upregulation on thyroid cancer cells migration, invasion, and angiogenesis.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Thyroid cancer is the most common type of endocrine tumor. MicroRNAs (miRNAs) play a critical role in a variety of diseases, especially cancer occurrence and progression. However, the specific mechanism by which miRNAs trigger disease states has not been fully elucidated. This study aims to investigate the role of miR-27a in thyroid cancer cells. A wound healing assay was adopted to examine cell migration. A transwell assay was applied to assess cell invasion. A thyroid cancer xenograft model was established using BALB/c nude mice. Western blot was performed to quantify iNOS expression. Tumor tissue blood vessel density was evaluated via immunohistochemistry assays. The results indicated that miR-27a downregulation inhibited thyroid cancer cell migration, while upregulation of miR-27a promoted thyroid cancer cell migration (P < 0.05). Furthermore, reduction in miR-27a expression suppressed thyroid cancer cell invasion (P < 0.05). In the nude mouse model of thyroid cancer xenograft, upregulation of miR-27 induced iNOS expression in pathological tumor tissues, whereas miR-27a inhibition resulted in the opposite effect (P < 0.05). CD105 level was also significantly increased during miR-27a upregulation, and was declined when miR-27a was inhibited (P < 0.05). In conclusion, miR-27a upregulation in thyroid cancer cells affects tumor cell migration, invasion, and angiogenesis by targeting downstream genes. Therefore, miR27a may act as a biomarker of thyroid cancer.

Ma S, Zhou P, Wu X, et al.
Detection of the Single-Session Complete Ablation Rate by Contrast-Enhanced Ultrasound during Ultrasound-Guided Laser Ablation for Benign Thyroid Nodules: A Prospective Study.
Biomed Res Int. 2016; 2016:9565364 [PubMed] Free Access to Full Article Related Publications
This study aimed to investigate the single-session complete ablation rate of ultrasound-guided percutaneous laser ablation (LA) for benign thyroid nodules. LA was performed in 90 patients with 118 benign thyroid nodules. Contrast-enhanced ultrasound (CEUS) was used to evaluate complete nodule ablation one day after ablation. Thyroid nodule volumes, thyroid functions, clinical symptoms and complications were evaluated 1, 3, 6, 12, and 18 months after ablation. Results showed that all benign thyroid nodules successfully underwent LA. The single-session complete ablation rates for nodules with maximum diameters ≤2 cm, 2-3 cm and ≥3 cm were 93.4%, 70.3% and 61.1%, respectively. All nodule volumes significantly decreased than that one day after ablation (P < 0.05); at the final evaluation, the volume decreased from 6.16 ± 5.21 mL to 0.05 ± 0.01 mL. Thyroid functions did not show significant differences at one month after ablation compared with that before (P > 0.05). Three patients had obvious pain during ablation; one (1.1%) had recurrent laryngeal nerve injury, but the voice returned to normal within 6 months after treatment. Thus, ultrasound-guided LA can effectively inactivate benign thyroid nodules. LA is a potentially viable minimally invasive treatment that offers good cosmetic effects.

Qiu ZL, Shen CT, Sun ZK, et al.
Circulating Long Non-Coding RNAs Act as Biomarkers for Predicting 131I Uptake and Mortality in Papillary Thyroid Cancer Patients with Lung Metastases.
Cell Physiol Biochem. 2016; 40(6):1377-1390 [PubMed] Related Publications
PURPOSE: The aims of the current study were to explore plasma lncRNAs as a novel biomarker panel for the diagnosis of non-131I-avid lung metastases of PTC and to investigate the plasma lncRNA expression levels associated with survival in PTC patients with lung metastases.
METHODS: The expression of lncRNAs was examined using an lncRNA microarray chip. The lncRNAs with the most significant difference in expression between PTC patients with non-131I-avid lung metastases and PTC patients with 131I-avid lung metastases were verified by quantitative reverse-transcription polymerase chain reaction. The Kaplan-Meier method was used to determine whether the plasma lncRNA levels might be indicative of patient prognosis.
RESULTS: Compared with 131I-avid lung metastases, we discovered that two lncRNAs (ENST00000462717 andENST00000415582) were upregulated and two (TCONS_00024700 and NR_028494) were downregulated in the non-131I-avid lung metastases of PTC. Receiver operating characteristic curve (ROC) analyses indicated that the use of these four lncRNAs had high diagnostic sensitivity and specificity for predicting non-131I-avid lung metastases of PTC. The merged areas under the curve for ENST00000462717, ENST00000415582, TCONS_00024700,and NR_028494 in the training and validation sets were 0.890, 0.936, 0.975, and 0.918, respectively. Low (ENST00000462717 and ENST00000415582) and high plasma lncRNA levels(TCONS_00024700and NR_028494) were also found to be associated with better prognosis of PTC patients with lung metastases(P<0.001).
CONCLUSIONS: ENST00000462717, ENST00000415582, TCONS_00024700, and NR_028494 may be used as novel and minimally invasive markers for the diagnosis and prognostic assessment of non-131I-avid lung metastases from PTC.

Rossi ED, Bizzarro T, Martini M, et al.
Cytopathology of Follicular Cell Nodules.
Adv Anat Pathol. 2017; 24(1):45-55 [PubMed] Related Publications
The detection of thyroid nodules, consisting of different diseases, represents a common finding in population. Their evaluation and diagnosis are mostly achieved with fine-needle aspiration cytology (FNAC). Even though the majority of thyroid nodules are correctly diagnosed, a total of 25% to 30% of them are classified "indeterminate" comprising lesions with varying risk of malignancy and different types of management. Although the number of thyroid FNACs, including small lesions, is increasing due to the reliance upon sonographic and cytologic interpretations, there are issues concerning cytomorphologic interpretation and interobserver reproducibility. Different classification systems have tried to better define the criteria for inclusion in specific categories and to therefore reduce the rate of indeterminate diagnoses such as atypia of undetermined significance, follicular neoplasms, and suspicious for malignancy. However, the support of ancillary techniques (eg, immunocytochemistry and molecular analysis) are reshaping morphologic diagnoses made on materials obtained from FNAC.

Lai X, Liu M, Xia Y, et al.
Hypervascularity is more frequent in medullary thyroid carcinoma: Compared with papillary thyroid carcinoma.
Medicine (Baltimore). 2016; 95(49):e5502 [PubMed] Free Access to Full Article Related Publications
This study was designed to retrospectively compare the sonographic features of medullary thyroid carcinoma (MTC) and the features of papillary thyroid carcinoma (PTC).A total of 97 patients with 127 MTCs between January 2000 and January 2016 and 107 consecutive patients with 132 PTCs were included in this study. Two radiologists retrospectively determined the sonographic features and compared the findings of MTCs and PTCs.Compared with the patients with PTCs, the patients with MTCs were older (46.9 years vs 42.9 years, P = 0.016) and the male proportion was higher (53.6% vs 33.6%, P = 0.005). Most of the MTCs had an irregular shape (72.4%), a length/width ratio <1 (75.6%), an unclear boundary (63.8%), no peripheral halo ring (93.7%), hypoechogenicity (96.9%), heterogeneous echotexture (76.4%), no cystic change (78.7%), calcification (63.8%), and hypervascularity (72.4%). There was no significant difference in the boundary, peripheral halo ring, echogenicity, and calcification between the MTCs and PTCs. However, compared with the PTCs, a larger size (2.2 vs 1.2 cm, P <0.001), a regular shape (27.6% vs 7.6%, P <0.001), a length/width ratio <1 (75.6% vs 51.5%, P<0.001), heterogeneous echotexture (76.4% vs 54.5%, P <0.001), cystic change (21.3 vs 8.3%, P = 0.005), and hypervascularity (72.4% vs 47.7%, P <0.001) were more frequent in the MTCs.The sonographic features with a higher likelihood of malignancy are common in MTCs, including a shape taller than the width, irregular infiltrative margins, an absent halo, hypoechogenicity, the presence of microcalcifications, and increased intranodular vascularity. However, MTCs tend to possess these suspicious sonographic features less often than PTCs, with the exception of hypervascularity, which was more frequent in MTCs.

Becker-Weidman DJ, Malhotra N, Reilly DF, et al.
Imaging Surveillance in Patients After a Benign Fine-Needle Aspiration Biopsy of the Thyroid: Associated Cost and Incidence of Subsequent Cancer.
AJR Am J Roentgenol. 2017; 208(2):358-361 [PubMed] Related Publications
OBJECTIVE: The objective of our study was to determine patterns and cost of imaging tumor surveillance in patients after a benign fine-needle aspiration (FNA) biopsy of the thyroid in a large teaching hospital as well as the rate of subsequent cancer detection.
MATERIALS AND METHODS: This cohort study was approved by the appropriate institutional review board and complied with HIPAA. All patients who had a benign thyroid FNA biopsy between January 1, 1999, and December 31, 2003, were identified from an institutional pathology database. We gathered information from electronic medical records on imaging tumor surveillance and subsequent cancer detection. Cost was determined using the facility total relative value unit and the 2014 Hospital Outpatient Prospective Payment System conversion factor.
RESULTS: Between January 1, 1999, and December 31, 2003, 1685 patients had a benign thyroid FNA biopsy, 800 (47.5%) of whom underwent follow-up imaging. These patients underwent 2223 thyroid ultrasound examinations, 606 ultrasound-guided thyroid FNA biopsies, 78 thyroid scintigraphy examinations, 168 neck CTs, and 53 neck MRIs at a cost of $529,874, $176,157, $39,622, $80,580, and $53,114, respectively, for a total cost of $879,347 or $1099 per patient. The mean length of follow-up was 7.3 years, during which time 19 (2.4%) patients were diagnosed with thyroid cancer at a cost of $46,281 per cancer. Seventeen (89.5%) were diagnosed with papillary carcinoma and two (10.5%) with Hurthle cell carcinoma.
CONCLUSION: Over a 5-year period, about half of the patients who had a benign thyroid FNA biopsy underwent follow-up imaging at considerable cost with a small rate of subsequent malignancy.

Wendler J, Kroiss M, Gast K, et al.
Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany.
Eur J Endocrinol. 2016; 175(6):521-529 [PubMed] Related Publications
CONTEXT: Anaplastic thyroid carcinoma (ATC) is an orphan disease and confers a dismal prognosis. Standard treatment is not established.
OBJECTIVE: The aim of this study is to describe clinical characteristics, current treatment regimens and outcome of ATC and to identify clinical prognostic markers and treatment factors associated with improved prognosis.
DESIGN: Retrospective cohort study at five German tertiary care centers.
PATIENTS AND METHODS: Totally 100 ATC patients diagnosed between 2000 and 2015 were included in the analysis. Disease-specific overall survival (OS) was compared with the Kaplan-Meier method and log-rank test; Cox proportional hazard model was used to identify risk factors.
RESULTS: The 6-month, 1-year and 5-year disease-specific OS rates were 37, 28 and 5%, respectively. Stage-dependent OS at 6 months was 78, 54 and 18% for stage IVA, B and C, respectively. 29% patients survived >1 year. Multivariate analysis of OS identified age ≥70 years, incomplete local resection status and the presence of distant metastasis as significant risk factors associated with shorter survival. Radical surgery (hazard ratio [HR] 2.20, 95% confidence interval (CI) 1.19-4.09, P = 0.012), external beam radiation therapy (EBRT) ≥40 Gy (HR = 0.34, 0.15-0.76, P = 0.008) and any kind of chemotherapy (CTX) (HR = 11.64, 2.42-60.39, P = 0.003) were associated with longer survival in multivariate analyses adjusted for age and tumor stage. A multimodal treatment regimen was significantly associated with a survival benefit (HR = 1.04, 1.01-1.08, P < 0.0001) only in IVC patients.
CONCLUSION: Disease-specific OS is still poor in ATC. Treatment factors associated with improved OS provide a rationale to devise treatment pathways for routine care. Collaborative research structures should be aimed to advance treatment of ATC.

Megwalu UC, Saini AT
Racial disparities in papillary thyroid microcarcinoma survival.
J Laryngol Otol. 2017; 131(1):83-87 [PubMed] Related Publications
OBJECTIVE: To evaluate the impact of race on survival in patients with papillary thyroid microcarcinoma.
METHODS: The study cohort included 17 668 patients diagnosed with papillary thyroid microcarcinoma between 1988 and 2009, identified in the Surveillance, Epidemiology, and End Results 18 database of the National Cancer Institute.
RESULTS: Black patients had lower overall survival than other racial groups (p < 0.001). Black patients had significantly worse overall survival (hazard ratio = 2.59) after adjusting for sex, marital status, age, year of diagnosis, multifocal disease and type of surgery. A subset analysis of Black patients revealed no significant difference in overall survival for total thyroidectomy versus lobectomy (p = 0.15).
CONCLUSION: Black race is a negative prognostic factor in thyroid cancer, which cannot be explained by advanced disease stage. Further research on mechanisms by which race affects survival is needed to reveal areas of opportunity for interventions aimed at reducing health disparities in cancer care.

Louvet C, De Bellis A, Pereira B, et al.
Time course of Graves' orbitopathy after total thyroidectomy and radioiodine therapy for thyroid cancer.
Medicine (Baltimore). 2016; 95(48):e5474 [PubMed] Free Access to Full Article Related Publications
The risk of cancer is relatively higher in Graves' patients presenting simultaneously with thyroid nodules. Radioiodine (RAI) therapy recommended in high-risk differentiated thyroid carcinoma may be associated with worsening of a pre-existing Graves' orbitopathy (GO) or developing a new onset. The impact of RAI therapy in patients with differentiated thyroid cancer on the course of a pre-exisiting GO has not been specifically investigated.The aim of this study is to assess the influence of RAI treatment administered for differentiated thyroid cancer on the course of a pre-existing GO.This is a retrospective multicenter study including 35 patients from the University Hospital of Clermont-Ferrand (7 patients) and Lyon-Est (6 patients) in France and from a literature review published as case reports or studies (22 patients).Seven patients exhibited a worsened pre-existing GO after total thyroidectomy followed by RAI treatment for thyroid cancer. Older men, those who initially presented with a lower clinical score of GO before RAI therapy, received higher doses of I especially when prepared with recombinant thyroid-stimulating hormone, and/or not prepared with glucocorticoids during RAI are at a higher risk to worsen their GO.This study is the first and complete study collection. We describe worsening of GO in 20% of patients after RAI treatment for thyroid cancer and determine a pool of predictive factors.

Zane M, Parello C, Pennelli G, et al.
Estrogen and thyroid cancer is a stem affair: A preliminary study.
Biomed Pharmacother. 2017; 85:399-411 [PubMed] Free Access to Full Article Related Publications
Gender influences Papillary Thyroid Cancer (PTC) with an incidence of 3:1 when comparing women to men with different aggressiveness. This gender discrepancy suggests some role of sex hormones in favoring the malignant progression of thyroid tissue to cancer. Estrogens are known to promote Stem Cell self-renewal and, therefore, may be involved in tumor initiation. The goals of these studies are to investigate the underlying causes of gender differences in PTC by studying the specific role of estrogens on tumor cells and their involvement within the Cancer Stem Cell (CSC) compartment. Exposure to 1nmoll(-1) Estradiol for 24h promotes growth and maintenance of PTC Stem Cells, while inducing dose-dependent cellular proliferation and differentiation following Estradiol administration. Whereas mimicking a condition of hormonal imbalance led to an opposite phenotype compared to a continuous treatment. In vivo we find that Estradiol promotes motility and tumorigenicity of CSCs. Estradiol-treated mice inoculated with Thyroid Cancer Stem Cell-enriched cells developed larger tumor masses than control mice. Furthermore, Estradiol-pretreated Cancer Stem cells migrated to distant organs, while untreated cells remained circumscribed. We also find that the biological response elicited by estrogens on Papillary Thyroid Cancer in women differed from men in pathways mediated. This could explain the gender imbalance in tumor incidence and development and could be useful to develop gender specific treatment of (PTC).

Chereau N, Trésallet C, Noullet S, et al.
Prognosis of papillary thyroid carcinoma in elderly patients after thyroid resection: A retrospective cohort analysis.
Medicine (Baltimore). 2016; 95(47):e5450 [PubMed] Free Access to Full Article Related Publications
The size of the elderly population and the incidence of papillary thyroid carcinoma (PTC) in this group appear to be rapidly increasing, although published information based on more detailed older age groupings are lacking.This study aimed to determine the clinical features and outcomes of elderly patients in PTC.All consecutive patients who received surgery for PTC in our Department from 1978 to 2014 were included. We compared 3 patient groups: young (<65 years), older (65-75 years), and very old patients (>75 years). Total thyroidectomy was performed with lymph node (LN) dissection in most cases, and radioiodine therapy was administered as needed.A total of 3835 patients (3257 young patients, 450 older patients, and 128 very old patients) were identified. Very old patients were more likely to have advanced (III/IV) tumor, nodes, metastases (TNM) stage, greater tumor size, number of tumors, and extracapsular invasion compared with young and older patients. For the 2289 patients with LN dissection (60%), metastatic LNs were more frequent in the very old group (44%) than in the other groups (34% young and 33% older patients) (P = 0.01). Very old patients had more frequent distant metastases (5%) than the older (2%) and young groups (1%) (P < 0.001). The overall postoperative morbidity was not significantly different between the 3 age groups. Recurrence was documented in 202 (6.2%) young, 29 (6.4%) older, and 15 (11.7%) very old PTC patients (P = 0.04). The 5-year disease-free survival was 81.3% for very old, 92.9% for older, and 94.7% for young group (P < 0.001).Very old patients should be considered high-risk PTC patients and their therapeutic strategy may benefit from aggressive treatment.

Pyo JY, Kim J, Choi SE, et al.
Extremely Well-Differentiated Papillary Thyroid Carcinoma Resembling Adenomatous Hyperplasia Can Metastasize to the Skull: A Case Report.
Yonsei Med J. 2017; 58(1):255-258 [PubMed] Free Access to Full Article Related Publications
We describe herein histologic, immunohistochemical, and molecular findings and clinical manifestations of a rare case of an extremely well differentiated papillary thyroid carcinoma (EWD-PTC). Similarly, it is also difficult to diagnose follicular variant papillary thyroid carcinoma (FVPTC), whose diagnosis is still met with controversy. A recently reported entity of well-differentiated tumor of uncertain malignant potential (WDT-UMP) is added to the diagnostic spectrum harboring EWD-PTC and FVPTC. We report this case, because EWD-PTC is different from FVPTC in its papillary architecture, and also from WDT-UMP in its recurrence and metastatic pattern. These morphologically deceptive entities harbored diagnostic difficulties in the past because the diagnosis depended solely on histology. However, they are now diagnosed with more certainty by virtue of immunohistochemical and molecular studies. We experienced a case of EWD-PTC, which had been diagnosed as adenomatous hyperplasia 20 years ago and manifested recurrence with lymph node (LN) metastasis 7 years later. After another 7 years of follow-up, a new thyroid lesion had developed, diagnosed as FVPTC, with LN metastasis of EWD-PTC. One year later, the patient developed metastatic FVPTC in the skull. Immunohistochemically, the EWD-PTC was focally positive for CK19, negative for galectin-3, and focally negative for CD56. Molecular studies revealed BRAF-positivity and K-RAS negativity. The FVPTC in the left thyroid showed both BRAF and K-RAS negativity. In conclusion, EWD-PTC and FVPTC share similar histologic features, but they are different tumors with different molecular biologic and clinical manifestations. A large cohort of EWD-PTC should be included in further study.

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