BRAF V600E mutation and the Bethesda System for Reporting Thyroid Cytopathology of fine-needle aspiration biopsy for distinguishing benign from malignant thyroid nodules

Background:The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) predicts the risk of malignancy for the different categories of the ultrasound-guided fine-needle aspiration biopsy (FNAB). The objective of this study is to investigate the efficiencies of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation test and the TBSRTC categories in distinguishing between benign and malignant thyroid nodules.Methods:In this study, 362 ultrasound-guided fine-needle aspiration (FNA) samples from 344 patients aged from 17 to 76 years old were retrospectively reviewed. The patients were classified into six groups (I–VI) according to the TBSRTC system. The amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used to evaluate the BRAF V600E mutation level in total 362 samples. Among of the 344 patients, 128 patients (131 thyroid nodules) who underwent surgeries were followed by histopathological examination. The predictive values of the BRAF V600E mutation test and TBSRTC categories were evaluated in these 131 thyroid nodules.Results:The median ages of the patients in the TBSRTC IV–VI group were smaller than those in the TBSRTC I–III groups. The proportion of nodules over 1 cm was larger than it in the TBSRTC IV group compared to the other groups. Significant differences in BRAF V600E mutation were observed (P < .001) among these six groups. The sensitivity (89.57%) for the detection of malignant thyroid nodules, negative predictive value (NPV; 45.45%) for the detection of benign nodules, and accuracy (86.26%) for distinguishing between benign and malignant thyroid nodules increased by combining the BRAF V600E mutation test and TBSRTC system when compared with the BRAF V600E mutation test and TBSRTC system respectively. The BRAF V600E mutation test alone demonstrated the increased positive predictive value (PPV; 98.91%) and specificity (93.75%) for the detection of malignant thyroid nodules compared to the TBSRTC method (alone or in combination with the BRAF V600E method).Conclusion:In summary, significant differences in age, nodule diameter, and BRAF V600E mutation were noted among the six categories of the TBSRTC system. The combination of the BRAF V600E mutation test and TBSRTC system demonstrated increases in the NPV, sensitivity, and accuracy, while the BRAF V600E method proved superiority to the TBSRTC system with regard to the PPV and specificity.     

A double mutation of BRAF L597Q and V600E in situ and solitary brain metastasis of occult papillary thyroid carcinoma: A case report

Rationale:The rare BRAF L597Q (c.T1790A) point mutation has been previously reported in childhood acute lymphoblastic leukemia. We present the first rare case of occult papillary thyroid carcinoma with BRAF L597Q mutation in a Tibetan patient.Patient concerns:A 57-year-old male patient presented with a protruding mass on the left forehead for 2 years and numbness in the right limb for 3 weeks.Diagnoses:The patient had a double mutation of BRAF L597Q and V600E in 2 separate lesions at thyroid and brain, the immunohistochemical staining showed that the cytokeratin (CK), thyroglobulin (Tg) and thyroid transforming factor-1 (TTF-1) were immunoreactive. All the findings supported the diagnosis of solitary brain metastasis of occult papillary thyroid carcinoma.Interventions:The patient underwent left frontal lobe metastasis (thyroid cancer) resection that involved craniectomy and artificial skull repair.Outcomes:During the 24-month follow-up, no postoperative complications or recurrence and metastasis were found.Lessons:This is the first case of solitary brain metastasis of occult papillary thyroid carcinoma with double mutation of BRAF L597Q and V600E in 2 separate lesions reported in the literature. Our study extends the disease spectrum of occult papillary thyroid carcinoma and suggests that the BRAF L597Q mutation might play a specific role in inducing the solitary brain metastasis of occult papillary thyroid carcinoma in a Chinese Tibetan patient, but the detailed molecular mechanism remains to be confirmed by a large number of functional experiments and clinical research.     

Association between programmed cell death ligand 1 expression and thyroid cancer: A meta-analysis

Background:Programmed cell death ligand 1 (PD-L1), which is highly expressed in a variety of malignant tumors, is closely related to clinicopathological features and prognosis. However, there are few studies on the potential effects of PD-L1 on thyroid carcinoma, the incidence of which has shown an upward trend worldwide. This study aimed to explore the association between PD-L1 expression and clinicopathological features and prognosis of thyroid cancer.Methods:An elaborate retrieval was performed using Medline, PubMed, Cochrane Library, EMBASE, Web of Science, WanFang databases, and China National Knowledge Infrastructure to determine the association between PD-L1 expression and disease-free survival (DFS), overall survival (OS), and clinicopathological features in patients with thyroid cancer. Study selection, data extraction, risk assessment, and data synthesis were performed independently by 2 reviewers. In this meta-analysis, RevMan 5.3 and Stata 15.1 were used for bias risk assessment and data synthesis.Results:After a detailed search, 2546 cases reported in 13 articles were included in this meta-analysis. The outcomes revealed that high expression of PD-L1 in patients with thyroid cancer was associated with poor DFS (hazard ratio [HR] = 3.37, 95% confidence interval [CI] 2.54–4.48, P < .00001) and OS (HR = 2.52, 95% CI: 1.20–5.32, P = .01). High PD-L1 expression was associated with tumor size ≥2 cm, tumor recurrence, extrathyroidal extension, concurrent thyroiditis, unifocal tumor, and absence of psammoma body (P < .05). Subgroup analysis showed that positive expression of PD-L1 was related to poor prognosis for DFS of non-medullary thyroid carcinoma, and the overexpression of PD-L1 in differentiated thyroid carcinoma (DTC) was related to tumor recurrence, concurrent thyroiditis, extrathyroidal extension, unifocal DTC, late stage DTC, and BRAF^V600E mutation in DTC.Conclusion:PD-L1 is a significant predictor of prognosis and malignancy of thyroid cancer (especially DTC), and PD-L1 inhibitors may be a promising therapeutic option for refractory thyroid cancer in the future.     

Pregnancy exacerbated lymph node metastasis of well differentiated thyroid carcinoma: A case report

Introduction:Differentiated thyroid carcinoma is the second most frequently diagnosed cancer during pregnancy, second to breast cancer. Pregnancy can cause an increase in the size of existing thyroid nodules due to the similar structure of placental human chorionic gonadotropin and thyroid stimulating hormone. However, the impact of pregnancy on malignant thyroid tumors is still unclear.Patient concerns:We report a 27-year-old woman with initial thyroid follicular carcinoma was managed with total thyroidectomy and radioiodine therapy. Tumor recurrences with right neck lymph node enlargement were noted during the first and third trimester of pregnancy two years after initial diagnosis.Diagnosis:Right neck lymph node dissection was performed for two episodes of recurrence and the pathology revealed both metastatic papillary thyroid carcinoma, follicular variant but with different pathologic features. And next-generation DNA sequencing of 275 cancer-related genes, which was a commercial set, including common mutations in thyroid cancer revealed only point mutations with unknown clinical correlation.Intervention:For the first recurrence during pregnancy, right neck lymph node dissection was performed at the second trimester of pregnancy. As for the second recurrence in the third trimester of pregnancy, the patient received right neck lymph node dissection with radioiodine therapy one month after uncomplicated delivery.Outcomes:After complete treatment with surgery and radioiodine therapy, the serum thyroglobulin level was 10 ng/ml. During two-year regular follow-ups with serum thyroglobulin and ultrasound, no more recurrence was noted.Conclusion:Pregnancy in differentiated thyroid cancer survivors should be managed and monitored with caution, especially when cancer recurrence is noticed. Further studies are recommended to investigate these previously unreported gene mutations associated with thyroid cancer.     

Graves disease and metastatic hormonal-active Hürthle cell thyroid cancer: A case report

Rationale:A hormone-active metastatic Hürthle cell thyroid carcinoma (HCTC) and Graves disease (GD) present a therapeutic challenge and is rarely reported.Patient concerns:We present a 64-year-old male patient, who had dyspnea and left hip pain lasting 4 months. He had clinical signs of hyperthyroidism and a tumor measuring 9 cm in diameter of the left thyroid lobe, metastatic neck lymph node and metastases in the lungs, mediastinum, and bones.Diagnosis:Laboratory findings confirmed hyperthyroidism and GD. Fine-needle aspiration biopsy and cytological investigation revealed metastases of HCTC in the skull and in the 8th right rib. A CT examination showed a thyroid tumor, metastatic neck lymph node, metastases in the lungs, mediastinum and in the 8th right rib measuring 20 × 5.6 × 4.5 cm, in the left acetabulum measuring 9 × 9 × 3 cm and parietooccipitally in the skull measuring 5 × 4 × 2 cm. Histology after total thyroidectomy and resection of the 8th right rib confirmed metastatic HCTC.Interventions:The region of the left hip had been irradiated with concomitant doxorubicin 20 mg once weekly. When hyperthyroidism was controlled with thiamazole, a total thyroidectomy was performed. Persistent T3 hyperthyroidism, most likely caused by TSH-R-stimulated T3 production in large metastasis in the 8th right rib, was eliminated by rib resection. Thereafter, the patient was treated with 3 radioactive iodine-131 (RAI) therapies (cumulative dose of 515 mCi). Unfortunately, the tumor rapidly progressed after treatment with RAI and progressed 10 months after therapy with sorafenib.Outcomes:Despite treatment, the disease rapidly progressed and patient died due to distant metastases. He survived for 28 months from diagnosis.Lessons:Simultaneous hormone-active HCTC and GD is extremely rare and prognosis is dismal. Concomitant external beam radiotherapy and doxorubicin chemotherapy, followed by RAI therapy, prevented the growth of a large metastasis in the left hip in our patient. However, a large metastasis in the 8th right rib presented an unresolved problem. Treatment with rib resection and RAI did not prevent tumor recurrence. External beam radiotherapy and sorafenib treatment failed to prevent tumor growth.     

The Role of American Thyroid Association Pediatric Thyroid Cancer Risk Stratification and BRAFV600E Mutation in Predicting the Response to Treatment in Papillary Thyroid Cancer Patients ≤18 Years Old

Objective:This study aimed to evaluate the role of risk stratification by the American Thyroid Association (ATA) pediatric thyroid cancer risk levels and BRAF^V600E mutation to predict the response to treatment in papillary thyroid cancer (PTC) patients ≤18 years old.Methods:Clinical outcomes during a median period of 6 (2-21.8) years were assessed in 70 patients, according to ATA pediatric risk stratification, BRAF^V600E mutation status, and dynamic risk stratification (DRS) at final follow-up.Results:Of 70 patients, 44 (63%), 14 (20%), and 12 (17%) were classified initially as low-, intermediate-, and high-risk, respectively. BRAF^V600E mutation analysis data was available in 55 (78.6%) patients, of whom 18 (32.7%) had the BRAF^V600E mutation. According to the final DRS, 61 (87%), two (3%), six (9%), and one (1%) patients were classified as an excellent, incomplete biochemical, incomplete structural, and indeterminate response, respectively. All ATA low-risk patients showed excellent response to treatment, whereas the rate of excellent response was 65.4% in intermediate- and high-risk levels (p<0.001). The rates of excellent response in BRAF^V600E positive and negative patients were 83% and 92%, respectively (p=0.339). The rate of locoregional recurrence was significantly higher in BRAF^V600E positive vs negative patients (33.3% vs 2.7% respectively, p=0.001).Conclusion:ATA pediatric risk stratification is effective in predicting response to treatment in PTC patients ≤18 years old. The presence of BRAF^V600E mutation was highly predictive for recurrence but had no significant impact on the rate of excellent response to treatment at final follow-up.     

p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer

Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf^V600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.Mutations in the v-raf murine sarcoma viral oncogene homolog B (BRAF) kinase occur in ∼60% of papillary thyroid carcinomas (PTCs) (www.cbioportal.org/public-portal/data_sets.jsp). PTC generally exhibits an excellent prognosis with conventional therapy, including surgery and selective use of radioiodine (1). PTC may progress to clinically aggressive forms of thyroid cancer, including poorly differentiated thyroid carcinoma (PDTC), which exhibits more rapid growth and poorer clinical outcome. Less commonly, PTC progresses to undifferentiated (anaplastic) thyroid carcinoma (ATC) that is associated with a grim prognosis with a median survival of 5 mo and a 1-y survival of only 20% (2).Focused sequencing of clinically aggressive subsets of thyroid cancers including PDTC and ATC suggests acquired cooperating mutations drive thyroid cancer progression (3, 4). Mutations in tumor protein p53 (TP53) occur with increasing frequency in more aggressive forms of thyroid cancer, culminating in ATC, which harbors the highest frequency of TP53 mutations (5–7). ATC may progress from well-differentiated thyroid carcinomas and is also believed to arise spontaneously, possibly from clinically undetectable microscopic well-differentiated thyroid tumors. In the former scenario, ATCs frequently harbor mutations in BRAF, and these mutations are concordant between the anaplastic and papillary components. This implicates BRAF mutation as an initiating somatic genetic event and supports the hypothesis that loss of p53 function is important for progression to ATC (3, 8).Mouse models of thyroid cancer have supported the model of acquired mutations driving tumor progression. Although each study has technical limitations, including embryonic oncogene expression and/or elevated circulating thyroid-stimulating hormone (TSH) levels, this work generally supports the notion that BRAF^T1799A is sufficient to initiate PTC (9–12). In addition, deletion of p53 enabled tumor progression to high-grade thyroid carcinomas in a transgenic mouse model of translocations targeting the ret proto-oncogene (RET/PTC) driven PTC, and a model of follicular thyroid carcinoma initiated by tissue-specific phosphatase and tensin homolog (Pten) deletion (13, 14). These studies provide functional evidence of an important tumor suppressive role for p53 during thyroid carcinoma progression, although to date this has not been tested in models of BRAF-mutant PTC.Given the high frequency of BRAF and RAS mutations in thyroid carcinomas and the success of targeted therapy trials for advanced thyroid cancers, the potential utility of small-molecule inhibitors of the MAPK pathway has garnered much recent attention (15). These drugs have also been studied in models of BRAF-mutant thyroid carcinoma. Initial observations using a thyroid-specific doxycycline-inducible BRAF^T1799A allele suggested that BRAF or mapk/Erk kinase (MEK) inhibition induced thyroid carcinoma regression and differentiation (9). However, a recent study from the same laboratory showed a mitigated response to BRAF (PLX4032, vemurafenib) inhibition in human papillary and ATC cell lines and in an endogenous Braf^V600E-driven PTC mouse model. In response to PLX4032/vemurafenib, feedback inhibition of the human epidermal growth factor receptor 3 (HER3) receptor tyrosine kinase was abrogated, leading to reactivation of MAPK signaling (16). In addition, responses in patients treated with the BRAF inhibitor vemurafenib have exhibited modest activity (17).To develop an adult-onset autochthonous model of clinically aggressive thyroid carcinoma, we generate a thyroid-specific CreER transgenic mouse and use conditional Braf^T1799A and Trp53 alleles. We demonstrate that expression of BRAF^V600E is sufficient to initiate tumorigenesis in adult animals, and p53 loss enables progression to bona fide ATC recapitulating the cardinal features of the human disease including intrinsic resistance to BRAF inhibitors.     

Multiple simple cystic metastases in the lateral neck at presentation with papillary thyroid microcarcinoma: A case report

Introduction:Metastasis of a papillary thyroid microcarcinoma (PTMC) in the lateral neck is characterized primarily by solid lymphadenopathy, although some cases may rarely present with a cervical cystic mass. We report a case of lateral cervical lymph node metastases of PTMC that appeared as a cystic lymphangioma of the lateral neck.Patient concerns:A 55-year-old man with a painless egg-sized mass in the right side of the neck that had been present for 1 month underwent physical examination, ultrasonography, computed tomography (CT), fine needle aspiration biopsy (FNAB), and intraoperative fast-frozen pathological examination, which indicated that the cystic masses in the neck were benign. However, the final pathology report identified the lateral neck masses as lymph node metastases of thyroid carcinoma.Diagnosis:The patient was diagnosed with PTMC of the right lobe of the thyroid gland with lateral neck metastases.Interventions:The patient underwent right cervical neck dissection together with a right thyroidectomy, followed by levothyroxine therapy and routine follow-up.Outcomes:No postoperative complications were reported, and the thyroid-stimulating hormone inhibition target was <0.1 mmol/L; there was no detectable tumor recurrence on routine clinical follow-up for up to 16 months.Conclusions:This case report emphasizes the need to consider cervical lymph node metastases of thyroid carcinoma in the differential diagnosis for patients with large, multiple, simple cystic neck masses.     

RAS Mutations in AUS/FLUS Cytology: Does it Have an Additional Role in BRAFV600E Mutation-Negative Nodules?

The object of this study is to evaluate the additional role of RAS mutation in detecting thyroid malignancy among BRAF^V600E mutation-negative nodules diagnosed as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) on cytology.From December 2009 to December 2011, 202 BRAF^V600E mutation-negative thyroid nodules diagnosed as AUS/FLUS cytology in 201 patients were included in this study. RAS mutation analysis was performed using residual material from ultrasonography-guided fine needle aspiration (US-FNA) cytology testing for K-RAS, N-RAS, and H-RAS codons 12/13 and 61 point mutations. The authors evaluated the association between RAS mutation status and cytopathologic characteristics.Of the 202 BRAF^V600E mutation-negative thyroid nodules with AUS/FLUS cytology, 4 were considered insufficient for mutation analysis. Of the 198 thyroid nodules, 148 (74.7%) were confirmed as benign and 50 (25.3%) as malignant. Thirty-one (15.7%) of the 198 thyroid nodules were positive for any RAS mutation, 4 positive for K-RAS 12/13, 26 for N-RAS 61, and 1 positive for H-RAS 61. Seven (22.6%) of the RAS mutation positive nodules were malignant, 1 with K-RAS 12/13, 6 with N-RAS 61. Twenty-four (77.4%) of the 31 nodules positive for K-RAS 12/13 (N = 3), N-RAS 61 (N = 20), or H-RAS 61 (N = 1) mutations were proven benign. None of the 198 thyroid nodules were positive for K-RAS 61, N-RAS 12/13, or H-RAS 12/13 mutations.N-RAS 61 mutation is the most common mutation detected among BRAF^V600E mutation-negative nodules with AUS/FLUS cytology. RAS mutation has limited value in predicting malignancy among BRAF^V600E mutation-negative thyroid nodules with AUS/FLUS cytology and further, investigation is anticipated to evaluate the true role of RAS mutation in thyroid malignancy.     

Protective strategy of parathyroid glands during thyroid lobectomy: A retrospective cohort and case-control study

Parathyroid protection during thyroid lobectomy was not illustrated previously. Aim of this study was to find out the influence of parathyroid glands in situ preservation and autotransplantation on postoperative parathyroid function in thyroid lobectomy.Consecutive patients who underwent primary thyroid lobectomy with unilateral central neck dissection for papillary thyroid carcinoma in our center were included retrospectively. Postoperative hypoparathyroidism was defined as low parathyroid hormone (PTH) levels (<1.6 pmol/L) and keeping over 6 months was defined as permanent. Patients were divided into 3 groups: all identified parathyroid glands preserved in situ (preservation group); at least one parathyroid gland autotransplanted without accidental resection (autotransplantation group); at least one parathyroid gland accidental resected (resection group).A total of 425 patients were included. No permanent hypoparathyroidism was reported, and the rates of transient hypoparathyroidism were similar among all groups. Significantly lower serum PTH levels were found in autotransplantation group versus preservation group at postoperative 1-day (3.77 ± 1.61 vs 4.72 ± 2.31, P < .001). Transient hypoparathyroidism was significantly associated with reduced intraoperative carbon nanoparticles utilization (57.1% vs 77.4%, P = .039).Thyroid lobectomy was a safe surgical method for parathyroid protection no matter the practice to ipsilateral parathyroid glands. However, preservation of all parathyroid glands was still recommended considering relatively stable PTH levels.     

Preoperative neoadjuvant targeted therapy with apatinib for inoperable differentiated thyroid cancer: A case report

Rationale:Though the majority of differentiated thyroid cancer (DTC) patients have a good prognosis after careful and standardized therapy, approximately 13% to 15% of DTC cases show surprisingly aggressive behavior and invasion of the surrounding structures, and a few progress to unresectable diseases. In this study, we report a case of an inoperable locally advanced DTC patient who underwent a curative operation after treatment of preoperative monotherapy of apatinib in a short time.Patient concerns:A 64-year-old woman complained of dysphagia due to large cervical mass, which severely invaded the left esophagus at the junction of the neck and thorax.Diagnoses:The female patient was diagnosed with locally advanced papillary thyroid cancer (PTC) by cytopathology and it was difficult to perform a safe and complete removal.Interventions:Apatinib (500 mg orally once a day) was initially used to treat this patient as a neoadjuvant therapy.Outcomes:Six weeks later, the tumor dramatically shrunk from 56 × 37 mm to 29 × 26 mm with well-controlled mild hypertension. After a 10-day interval of apatinib withdrawal, complete tumor excision was accomplished through cervical incision without esophageal fistula. Postoperative thyroid stimulating hormone suppression and radioiodine ¹³¹I ablation therapy were performed. At the 1-year follow-up evaluation, no tumor recurrence or metastasis was observed.Lessons:Preoperative short term targeted treatment with apatinib for locally advanced inoperable DTC may become a promising neoadjuvant therapy that, can reduce the tumor size and decrease stage, thus making the complete and safe removal of the lesion feasible.     

Ultrasound and cytological characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features compared to papillary carcinomas

IntroductionNIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features, formerly non-invasive encapsulated follicular variant of papillary thyroid carcinoma) has been removed from the carcinoma category because of its indolent character and good prognosis. This change impacts clinical and surgical management, since these tumors no longer require total thyroidectomy, or complementary radioactive iodine therapy for < 4 cm tumor. The aim of the present study was to identify preoperative ultrasound and cytological differences between NIFTP and papillary thyroid carcinoma (PTC).Materials and methodsA retrospective study included 81 patients who underwent total thyroidectomy or thyroid lobectomy with histologic diagnosis of PTC, NIFTP or invasive follicular variant of PTC (IFVPTC) between January 1st, 2016 and May 31st, 2018. Ultrasound and cytological data were analyzed and compared between NIFTP and non-NIFTP (PTC and invasive follicular variant of PTC).ResultsFourteen NIFTPs, 67 PTCs, including 20 IFVPTCs, were included. In comparison with non-NIFTP PTC, nodules in NIFTP were more often isoechoic (69.2% vs. 17.4%; P = 0.0007), with smooth borders (92.3% vs. 31.1%; P = 0.0001) and TI-RADS score 2, 3 or 4a. Cytologically, NIFTPs were mainly in categories AUS/FLUS, FN and SusM of the Bethesda System for Reporting Thyroid Cytopathology. Only nuclear pseudo-inclusions were significantly associated with non-NIFTP (P = 0.0031).ConclusionNIFTP appears non-suspect on preoperative ultrasound and indeterminate on cytology. These differences with respect to PTC can guide diagnosis and surgical treatment.     

Association between functional polymorphisms in the flanking region of miR-143/145 and risk of papillary thyroid carcinoma: A case-control study

MiR-143 and miR-145 were down-regulated in papillary thyroid carcinoma (PTC) involving in cell proliferation, apoptosis, migration, invasion, and epithelial to mesenchymal transition. In this study, we aimed to investigate the association between 2 functional polymorphisms (ie, rs4705342 and rs353292) in the flanking region of miR-143/145 and risk of PTC.A case-control study including 316 PTC patients and 347 controls was performed. The rs4705342 and rs353292 were genotyped by using the TaqMan allelic discrimination. The results were confirmed by DNA sequencing.For the rs4705342, a reduced risk of PTC was observed in heterozygous comparison, dominant genetic model and allele comparison (CC vs TT: adjusted OR = 0.37, 95% CI = 0.19–0.74, P = .003; CT/CC vs TT: adjusted OR = 0.64, 95% CI = 0.47–0.87, P = .005; C vs T: adjusted OR = 0.66, 95% CI = 0.52–0.85, P = .001, respectively). No significant difference was found in the genotypic distributions of the rs353292 between cases and controls.These findings indicate that the rs4705342 in the flanking region of miR-143/145 may be a protective factor against the occurrence of PTC. Further study is therefore required to investigate the correlation between the genotype and V-raf murine sarcoma viral oncogene homolog B1 V600E, rat sarcoma viral oncogene homolog mutations, rearranged in transformation/PTC1 and rearranged in transformation/PTC3.     

The BRAF(V600E) mutation is associated with malignant ultrasonographic features in thyroid nodules

Context Several ultrasonographic (US) features of thyroid nodules have been reported to predict malignancy. The BRAF^V600E mutation is a useful diagnostic marker for differentiating papillary thyroid carcinoma from benign thyroid nodules, especially in BRAF^V600E‐prevalent populations such as in Korea. Objective To evaluate the association of BRAF^V600E mutation with US features of thyroid nodules in predicting the malignancy of thyroid nodules in Korean patients. Design A total of 991 thyroid nodules from 823 patients in fine‐needle aspiration biopsy (FNAB) specimens were investigated. The relationship between US features and the presence of BRAF^V600E mutation by pyrosequencing method was prospectively analysed. Results The BRAF^V600E mutation was associated with the following US features: solid composition [odds ratio (OR) 20·338; 95% confidence interval (CI): 4·952–83·532; P < 0·001], marked hypoechogenicity (OR 30·744; 95% CI: 15·951–59·255; P < 0·001), irregular margin (OR 9·889; 95% CI: 7·005–13·859; P < 0·001), taller‐than‐wide shape (OR 6·031; 95% CI: 4·343–8·376; P < 0·001) and the presence of microcalcifications (OR 6·664; 95% CI: 4·604–9·648; P < 0·001). The BRAF^V600E mutation with malignant US features in FNAB enhanced the diagnostic accuracy compared with cytologic diagnosis alone (94·3%vs 69·7%). Conclusion The BRAF^V600E mutation is significantly associated with malignant US features, such as solid composition, marked hypoechogenicity, irregular margin, taller‐than‐wide shape and the presence of microcalcifications. The application of BRAF^V600E mutation analysis in US‐guided FNAB can improve the diagnostic accuracy of thyroid nodules.     

Relation Between F-18 FDG Uptake of PET/CT and BRAFV600E Mutation in Papillary Thyroid Cancer

BRAFV600E mutation and F-18 fluorodeoxyglucose (FDG) uptake are potential prognostic factors of papillary thyroid cancer (PTC). This study was performed to investigate the relationship between the BRAFV600E mutation and F-18 FDG uptake in PTC.We retrospectively included 169 PTC patients who underwent F-18 FDG positron emission tomography/computed tomography (PET/CT) before thyroidectomy from May 2009 to August 2012. Subjects were classified into overt PTC (>1 cm, n = 76) and papillary thyroid microcarcinoma (PTMC, n = 93) groups. Univariate and multivariate analyses were performed to assess the relationship between maximum standardized uptake value (SUV_max) of the primary tumors and clinicopathologic variables.The BRAFV600E mutation was detected in 82.2% (139/169). In all subjects, the BRAFV600E mutation and tumor size were independently related to SUV_max by multivariate analysis (P = 0.048 and P < 0.001, respectively). SUV_max was significantly higher in tumors with the BRAFV600E mutation than in those with wild-type BRAF (9.4 ± 10.9 vs 5.0 ± 4.1, P < 0.001). Similarly, in overt PTC group, the BRAFV600E mutation and tumor size were independently correlated with SUV_max (P = 0.032 and P = 0.001, respectively). By contrast, in PTMC group, only tumor size was significantly associated with SUV_max (P = 0.010).The presence of the BRAFV600E mutation is independently associated with high F-18 FDG uptake on preoperative PET/CT in patients with overt PTC, but this relationship was not evident in PTMC. This study provides a better understanding of the relationship between F-18 FDG uptake and BRAFV600E mutation in patients with PTC.     

A meta-analysis of the influence of body mass index on the clinicopathologic progression of papillary thyroid carcinoma

Background:Papillary thyroid carcinoma (PTC) incidence has been increasing worldwide. Obesity, that is, having a high body mass index, is associated with the incidence of several cancers including colon, breast, esophageal, and kidney cancer. However, the association between obesity and the clinical features of PTC is still unknown. This study aimed to determine the impact of obesity on the clinical features of PTC.Method:A database search was conducted for articles published up to 2020 on obesity and clinical features of PTC. Data were extracted from articles that met the meta-analysis inclusion criteria.Results:A total of 11 retrospective cohorts and 11,729 patients were included. Obesity was associated with the following variables in PTC patients: older age (difference in means = 1.95, 95% confidence interval [CI] 0.16–3.74, P = .03), male sex (odds ratio [OR] = 3.13, 95%CI 2.24–4.38, P < .00001), tumor size ≥1 cm (OR = 1.34, 95%CI 1.11–1.61, P < .002), multifocality (OR = 1.54, 95%CI 1.27–1.88, P < .0001), extrathyroidal extension (OR = 1.78, 95%CI 1.22–2.59, P = .003) and advanced tumor, node, metastasis stage (OR = 1.68, 95%CI 1.44–1.96, P < .00001). Preoperative serum thyroid-stimulating hormone level (difference in means  = 0.09, 95%CI 0.35–0.52, P = .70), Vascular invasion (OR = 0.84, 95%CI 0.56–1.26, P = .41), lymph node metastasis (OR = 1.07, 95%CI 0.87–1.32, P = .50), distant metastasis (OR = 1.14, 95%CI 0.64–2.04, P = .66), and recurrence (OR = 1.45, 95%CI 0.97–2.15, P = .07) were not associated with obesity.Conclusion:Obesity was associated with several poor clinicopathologic prognostic features: older age, male gender, tumor size ≥1 cm, extrathyroidal extension, multifocality, and advanced tumor/node/metastasis stage. However, thyroid-stimulating hormone level, vascular invasion, lymph node metastasis, distant metastasis, and recurrence were not associated with obesity in PTC.     

Cervical lymph node metastases in papillary thyroid cancer: Preoperative staging with ultrasound and/or computed tomography

Preoperative screening of potential risk of lymph node metastasis is necessary for thyroidectomy plus lymph node dissection. The 2015 American thyroid association management guidelines do not recommend prophylactic cervical lymph node resection without clinical evidence of metastasis. Ultrasound is recommended imaging method and routine computed tomography is not recommended by the 2015 American thyroid association management guidelines for screening of lymph node metastasis. The objective of the study was to compare the diagnostic performance of ultrasound against that of computed tomography for screening cervical lymph node metastasis of patients with papillary thyroid cancer before thyroidectomy plus lymph node dissection.Data regarding preoperative neck ultrasound, neck computed tomography, and physical examination of the head and neck and postoperative pathological results of a total of 185 patients (age > 18 years) with a diagnosis of papillary thyroid cancer who had suspicious lymph nodes on preoperative imaging and treated by thyroidectomy plus lymph node dissection for the therapeutic purpose were collected and analyzed.Sensitivity (78.09% vs 75.28%, P < .0001) and accuracy (77.29% vs 75.13%, P = .0004) of neck computed tomography scanning to detect cervical lymph node metastasis were higher than those of neck ultrasound scanning. Sensitivity, accuracy, positive clinical utility, and negative clinical utility for neck ultrasound scanning plus neck computed tomography scanning to detect cervical lymph node metastasis were higher among all index tests (P < .05 for all) and were statistically the same as those of surgical pathology (P > .05 for all). The working areas for decision-making of thyroidectomy plus lymph node dissection of the physical examination, neck ultrasound, the neck computed tomography, and the neck ultrasound scanning plus the neck computed tomography scanning were 0 to 0.691 diagnostic confidence/lesion, 0 to 0.961 diagnostic confidence/lesion, 0 to 0.944 diagnostic confidence/lesion, and 0 to 0.981 diagnostic confidence/lesion, respectively.Besides the neck ultrasound, the neck computed tomography scanning can be used as a complementary imaging method to detect cervical lymph node metastasis of patients with papillary thyroid cancer before thyroidectomy plus lymph node dissection.Level of evidence: III.Technical efficacy stage: 2.     

Diagnostic and therapeutic use of recombinant human TSH (rhTSH) in differentiated thyroid cancer

The introduction of rhTSH into clinical practice has changed dramatically the monitoring and treatment of differentiated thyroid cancer patients. In particular, the post-surgical thyroid ablation with radio-iodine and the periodical follow-up are more and more routinely based on the use of rhTSH as the method of choice for patient preparation. Therapeutic results and sensitivity of follow-up when using rhTSH are not inferior to conventional thyroid hormone withdrawal and, in some regard, are superior if one considers the preservation of quality of life. The latter aspect is very well exemplified by the constant observation that patients who have experienced rhTSH will never accept going back to thyroid hormone withdrawal.

• the issue of ultrasensitive measures of serum Tg in basal condition versus rhTSH-stimulated serum Tg

• prospective clinical trial of rhTSH-aided RAI therapy for metastatic disease

• definition of the best activity of radio-iodine to be used for post-surgical thyroid remnant ablation

Real-Time PCR Cycle Threshold Values for the BRAFV600E Mutation in Papillary Thyroid Microcarcinoma May Be Associated With Central Lymph Node Metastasis: A Retrospective Study

Papillary thyroid microcarcinoma (PTMC) usually has excellent prognosis, but a small subset shows aggressive behavior. Although the B-Raf proto-oncogene, serine/threonine kinase (BRAF)^V600E mutation is the most common oncogenic alteration in PTMCs, it is frequently heterogeneously distributed within tumors. The aim of this study was to investigate the association of the BRAF^V600E mutation found in fine needle aspirates from PTMCs with known clinicopathologic prognostic factors, based on both its presence and a quantitative approach that uses cycle threshold (Ct) values obtained by a real-time PCR technique.The 460 PTMC patients were included, with 367 patients having the BRAF^V600E mutation. Clinicopathologic variables were compared between patients with and without the BRAF^V600E mutation. BRAF^V600E Ct values were compared according to clinicopathologic prognostic factors. Multivariate analyses were performed to evaluate factors predicting extrathyroidal extension and central and lateral lymph node metastasis (LNM). Each analysis used either the BRAF^V600E mutation status or the Ct value as an independent variable for all the study patients and the 367 BRAF^V600E-positive patients. Receiver-operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of BRAF^V600E Ct values in predicting central and lateral LNM.The BRAF^V600E mutation status was not associated with clinicopathologic prognostic factors among the 460 PTMC patients. Of the 367 BRAF^V600E-positive patients, Ct values were significantly lower in patients with central and lateral LNM (P < 0.001, P = 0.007). The Ct value was the only independent factor to predict central LNM (OR 0.918, P = 0.025). The area under the ROC curve (AUC) for diagnosing central LNM was 0.623 (sensitivity, 50.0%; specificity, 71.9%) and for diagnosing lateral LNM, it was 0.796 (sensitivity, 71.4%; specificity, 94.7%).In conclusion, real-time PCR Ct values for the BRAF^V600E mutation obtained from fine needle aspirates can be associated with central LNM in PTMC patients. Although BRAF^V600E Ct values did not reach statistical significance for predicting lateral LNM in our study, further validation through larger studies can be used to overcome any possible type-II errors. With further studies, Ct values for the BRAF^V600E mutation obtained from fine needle aspirates may have important implications for predicting both central and lateral LNM in patients with PTMCs.     

Clinical outcomes following empiric radioiodine therapy in patients with structurally identifiable metastatic follicular cell-derived thyroid carcinoma with negative diagnostic but positive post-therapy (131)i whole-body scans

Background: While radioiodine (RAI) therapy remains the most effective treatment modality for RAI-avid distant metastatic follicular cell-derived thyroid cancer, the therapeutic utility of empiric RAI therapy in patients with structurally identifiable distant metastases that demonstrate RAI avidity only on the post-therapy scan (negative diagnostic whole-body scan [DxWBS]) remains uncertain. Methods: We report a retrospective assessment of the structural response to RAI therapy in 27 patients (median age 54 years, 59% male) with metastatic thyroid cancer (45% classical papillary thyroid cancer, 21% poorly differentiated, 15% tall-cell variant, 15% follicular variant, and 4% Hurthle cell carcinoma) with structurally identifiable distant metastases (86% pulmonary metastases) in whom a properly conducted DxWBS was negative, and the post-therapy scan showed RAI-avid metastatic lesions at the time of RAI remnant ablation. Results: In response to the initial RAI ablation, none of the selected patients demonstrated structural disease regression, and no patient was rendered free of disease. However, 12 patients (44%) demonstrated stable lesions on serial structural imaging after an RAI ablation. Structural disease progression was seen in the remaining 56% (15/27), a median of 6 months after ablation. Unfortunately, additional RAI therapies given to 12/15 patients with progressive disease and 5/12 patients with stable lesions failed to cause structural disease regression, cure, or conversion from progressive to stable disease in any patient. All of the disease-specific deaths (7/27) were in patients who had structural disease progression (n=15) in response to RAI ablation. None of the patients with persistent but stable lesions on structural imaging (n=12) have died of thyroid cancer over a median follow-up period of 3.7 years. Conclusions: While 44% of patients with the DxWBS-negative/post-therapy scan-positive macroscopic distant metastasis will have stable cross-sectional imaging after RAI remnant ablation, the other 56% will demonstrate structural disease progression that cannot be effectively treated with repeated empiric RAI activities. Furthermore, the high disease-specific mortality rate seen within the first few years of remnant ablation in this small subset of patients with persistent progressive disease despite a positive post-therapy RAI scan argues that treatments other than repeated empiric RAI dosing be strongly considered.