Objective: To investigate the clinicopathological features, immunophenotype and gene alterations of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA). Methods: Fifteen case of TL-LGNPPA diagnosed at Zhejiang Cancer Hospital (5 cases) and the First Affiliated Hospital, Zhejiang University School of Medicine (10 cases) from November 2011 to August 2020 were collected. Clinical and pathological examinations, immunohistochemical staining and next-generation sequencing were performed. The clinicopathological and molecular characteristics were summarized, and relevant literature was reviewed. Results: Fifteen patients were identified and included. Their median age was 36 years (range, 20-60 years). The male-female ratio was 1.0∶1.1. The most common symptoms were epistaxis and nasal obstruction. The neoplasms were located on the roof of the nasopharynx or the posterior margin of the nasal septum. The pathological features included complex papillary and glandular structures mainly composed of single or pseudostratified cubic and columnar cells, with mild to moderate cytological atypia. In some cases, spindle cell features, nuclear grooves, ground glass nuclei, squamous metaplasia, or scattered psammoma bodies were identified. In addition, nuclear polar reversal cells, hobnail cells and micropapillary structures were found, but have not been reported in previous literature. Immunohistochemistry showed that the tumor cells were diffusely positive for TTF1, CK7, vimentin and CKpan; focally positive for p40, CK5/6 and p16; and negative for Tg, NapsinA, CK20, CDX2, S-100 and PAX8. The Ki-67 positive rates ranged from 1% to 20% and were≤10% in thirteen cases (13/15). EBER in situ hybridization was negative in all cases. DNA sequencing of 6 specimens was performed and all specimens were found harboring gene mutations (EWSR1, SMAD2, ROS1, JAK3, GRIN2A, ERRCC5, STAT3, and TET2), but no hot spot gene alterations were found. No MSI-H and MMR related gene changes were detected. All tumors showed low tumor mutation burden. All 15 patients underwent endoscopic surgery, and only 1 of them underwent radiotherapy postoperatively. All patients were recurrence free and alive at the end of follow-up periods (range: 23 to 129 months). Conclusions: TL-LGNPPA is a rare indolent tumor of the nasopharynx and exhibits a unique morphology and immunophenotype. Endoscopic resection is an effective treatment for TL-LGNPPA with excellent overall prognosis.
Humans ; Male ; Female ; Adult ; Thyroid Gland/pathology* ; Adenocarcinoma, Papillary/pathology* ; Nasopharyngeal Neoplasms/pathology* ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins ; Nasopharynx/pathology* ; Biomarkers, Tumor

Targeted gene therapy has become a promising approach for lung cancer treatment. In our previous work, we reported that the targeted expression of microRNA-7 (miR-7) operated by thyroid transcription factor-1 (TTF-1) promoter inhibited the growth of human lung cancer cells in vitro and in vivo; however, the intervention efficiency needed to be further improved. In this study, we identified the core promoter of TTF-1 (from -1299 bp to -871 bp) by 5' deletion assay and screened out the putative transcription factors nuclear factor-1 (NF-1) and activator protein-1 (AP-1). Further analysis revealed that the expression level of NF-1, but not AP-1, was positively connected with the activation of TTF-1 core promoter in human non-small-cell lung cancer (NSCLC) cells. Moreover, the silencing of NF-1 could reduce the expression level of miR-7 operated by TTF-1 core promoter. Of note, we optimized four distinct sequences to form additional NF-1-binding sites (TGGCA) in the sequence of TTF-1 core promoter (termed as ^optTTF-1 promoter), and verified the binding efficiency of NF-1 on the ^optTTF-1 promoter by electrophoretic mobility shift assay (EMSA). As expected, the ^optTTF-1 promoter could more effectively drive miR-7 expression and inhibit the growth of human NSCLC cells in vitro, accompanied by a reduced transduction of NADH dehydrogenase (ubiquinone) 1α subcomplex 4 (NDUFA4)/protein kinase B (Akt) pathway. Consistently, ^optTTF-1 promoter-driven miR-7 expression could also effectively abrogate the growth and metastasis of tumor cells in a murine xenograft model of human NSCLC. Finally, no significant changes were detected in the biological indicators or the histology of some important tissues and organs, including heart, liver, and spleen. On the whole, our study revealed that the optimized TTF-1 promoter could more effectively operate miR-7 to influence the growth of human NSCLC cells, providing a new basis for the development of microRNA-based targeting gene therapy against clinical lung cancer.
Animals ; Humans ; Mice ; Carcinoma, Non-Small-Cell Lung/therapy* ; Lung Neoplasms/metabolism* ; MicroRNAs/metabolism* ; Nuclear Proteins/metabolism* ; Thyroid Gland/pathology* ; Thyroid Nuclear Factor 1/genetics* ; Transcription Factors/metabolism*

BACKGROUND: The absence of thyroid cysts may indicate latent thyroid damage, as demonstrated in our previous study. However, the association between the absence of thyroid cysts and latent functional damage of the thyroid is unknown. At low thyroid hormone productivity, which may be associated with latent functional damage of the thyroid, the association between thyroid-stimulating hormone (TSH) and hypertension might be enhanced. Therefore, we evaluated the association between TSH level and hypertension stratified by thyroid cyst status. METHODS: We conducted a cross-sectional study of 1724 euthyroid Japanese individuals aged 40-74 years who participated in an annual health checkup in 2014. RESULTS: In the study population, 564 and 686 participants had thyroid cysts and hypertension, respectively. A significant positive association was observed between TSH and hypertension in subjects without a thyroid cyst but not in subjects with thyroid cysts. There was a significant positive association between hypertension and TSH in subjects without a thyroid cyst (odds ratio [OR] 1.27; 95% confidence intervals [CI] 1.01, 1.61) but not in subjects with thyroid cysts (OR 0.79; CI 0.57, 1.09) in the model fully adjusted for known confounding factors. The correlation between the TSH and free triiodothyronine (fee T3) levels (simple correlation coefficient [r] = - 0.13, p < 0.01) was stronger in the subjects without thyroid cysts than in those with thyroid cysts (r = - 0.03, p = 0.525). CONCLUSIONS TSH is positively associated with hypertension only in individuals without thyroid cysts. The correlation between the TSH and free T3 levels was stronger in the subjects without thyroid cysts than in those with thyroid cysts. Therefore, the absence of thyroid cysts could be related to the association between TSH level and hypertension, possibly by indicating that the subjects without thyroid cysts had limited thyroid hormone reserves. Therefore, the absence of thyroid cysts could indicate the latent functional damage of the thyroid.
Aged ; Cross-Sectional Studies ; Cysts/etiology* ; Female ; Humans ; Hypertension/metabolism* ; Japan ; Male ; Middle Aged ; Thyroid Diseases/etiology* ; Thyroid Gland/pathology* ; Thyrotropin/metabolism*

PURPOSE: Fine-needle aspiration biopsy (FNAB) can be used to diagnose thyroid cancer and other tumors. Although FNAB without negative pressure (FNAB−P) reduces the risk of blood contamination, FNAB with negative pressure (FNAB+P) increases the sensitivity of the biopsy results. Therefore, we performed a randomized study of FNAB with or without negative pressure to identify the better diagnostic method. METHODS: Between March 2016 and February 2017, 172 consecutive patients were enrolled to investigate >0.5 cm nodules with indeterminate or suspicious malignant features. Patients were randomly assigned to the FNAB+P group (a 50 mL syringe was used to provide negative pressure) or to the FNAB−P group (passive collection of blood in the needle's hub). The 2 methods' diagnostic adequacy and quality were evaluated using an objective scoring system. The study's protocol was registered with the World Health Organization Clinical Research Information Service (http://cris.nih.go.kr/cris, KCT0001857). RESULTS: The patients were randomly assigned to the FNAB+P group (n = 86) or the FNAB−P group (n = 86). There were no significant intergroup differences in nodule position, size, age, consistency, calcification, BRAF mutation, or pathology. Evaluation of diagnostic adequacy parameters revealed no significant differences in background blood/clot (P = 0.728), amount of cellular material (P = 0.052), degree of cellular degeneration (P = 0.622), degree of cellular trauma (P = 0.979), or retention of appropriate architecture (P = 0.487). Furthermore, there was no significant intergroup difference in the diagnostic quality (P = 0.634). CONCLUSION: This prospective randomized study failed to detect significant differences in the diagnostic adequacy and quality of FNAB with or without negative pressure. Therefore, the examiner may select whichever FNAB method they prefer.
Biopsy ; Biopsy, Fine-Needle ; Cytological Techniques ; Humans ; Information Services ; Methods ; Pathology ; Prospective Studies ; Syringes ; Thyroid Gland ; Thyroid Neoplasms ; Thyroid Nodule ; World Health Organization

Adult ; Carcinoma, Adenoid Cystic ; complications ; Female ; Humans ; Thyroid Gland ; pathology ; Thyroid Neoplasms ; secondary ; Ultrasonography

BACKGROUND: To evaluate the clinical feasibility of radiofrequency ablation (RFA) of benign thyroid nodules along with cytomorphological alteration, and any malignant transformation through biopsy. METHODS: The data were retrospectively collected between April 2008 and June 2013 and core needle biopsy (CNB) was performed on 16 benign thyroid nodules previously treated using RFA. The parameters of the patients were compared, between the time of enrollment and the last follow-up examination, using linear mixed model statistical analysis. RESULTS: No atypical cells or neoplastic transformation were detected in the undertreated peripheral portion of treated benign nodules on the CNB specimen. RFA altered neither the thyroid capsule nor the thyroid tissue adjacent to the treated area. On histopathological examinations, we observed 81.2% acellular hyalinization, which was the most common finding. After a mean follow-up period of over 5 years, the mean volume of thyroid nodule had decreased to 6.4±4.2 mL, with a reduction rate of 81.3%±5.8% (P<0.0001). CONCLUSION: RFA is a technically feasible treatment method for benign thyroid nodules, with no carcinogenic effect or tissue damage of the normal thyroid tissue adjacent to the RFA-treated zone.
Biopsy ; Biopsy, Large-Core Needle ; Catheter Ablation ; Follow-Up Studies ; Humans ; Hyalin ; Methods ; Pathology ; Retrospective Studies ; Thyroid Gland ; Thyroid Nodule ; Ultrasonography

Thyroid nodules are the most common endocrine tumor. Ultrasonography and fine-needle aspiration (FNA) are currently accurate diagnostic tools for evaluating thyroid nodules. However, 10–30% of FNA specimens are cytologically indeterminate. Making an accurate diagnosis between benign and malignant nodules is important so that patients with malignant nodule receive proper treatment and patients with benign nodule can avoid unnecessary treatment. Several genetic changes such as point mutations of the BRAF or RAS and rearrangements of the RET/PTC1, RET/PTC3, PAX8/PPARY are used to adjust to indeterminate FNA. Such a mutational analysis has an excellent positive predictive value (PPV), but there is a weakness in the low negative predictive value (NPV). Gene-expression classifier (GEC) has been found helpful in identify nodules that are benign rather than malignant. GEC has an excellent NPV, but there is a weakness of low PPV. Multiplatform mutational and miRNA test (MPT) and next-generation sequencing assay (NGS) are being studied to compensate for these weaknesses. Molecular tests appear to be a good solution for improving the accuracy of indeterminate FNA cytology specimens and support the clinical management decisions in patients with indeterminate cytologic nodules, but further prospective multicenter trials are required for validation of reported findings and need evaluation of cost-effectiveness. This paper will review recently available molecular diagnostic tools of thyroid nodule.
Biopsy, Fine-Needle ; Diagnosis ; Humans ; MicroRNAs ; Multicenter Studies as Topic ; Pathology, Molecular ; Point Mutation ; Prospective Studies ; Thyroid Gland ; Thyroid Neoplasms ; Thyroid Nodule ; Ultrasonography

BACKGROUND: In the present multi-institutional study, the prevalence and clinicopathologic characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were evaluated among Korean patients who underwent thyroidectomy for papillary thyroid carcinoma (PTC).METHODS: Data from 18,819 patients with PTC from eight university hospitals between January 2012 and February 2018 were retrospectively evaluated. Pathology reports of all PTCs and slides of potential NIFTP cases were reviewed. The strict criterion of no papillae was applied for the diagnosis of NIFTP. Due to assumptions regarding misclassification of NIFTP as non-PTC tumors, the lower boundary of NIFTP prevalence among PTCs was estimated. Mutational analysis for BRAF and three RAS isoforms was performed in 27 randomly selected NIFTP cases.RESULTS: The prevalence of NIFTP was 1.3% (238/18,819) of all PTCs when the same histologic criteria were applied for NIFTP regardless of the tumor size but decreased to 0.8% (152/18,819) when tumors ≥1 cm in size were included. The mean follow-up was 37.7 months and no patient with NIFTP had evidence of lymph node metastasis, distant metastasis, or disease recurrence during the follow-up period. A difference in prevalence of NIFTP before and after NIFTP introduction was not observed. BRAF(V600E) mutation was not found in NIFTP. The mutation rate for the three RAS genes was 55.6% (15/27).CONCLUSIONS: The low prevalence and indolent clinical outcome of NIFTP in Korea was confirmed using the largest number of cases to date. The introduction of NIFTP may have a small overall impact in Korean practice.
Carcinoma, Papillary ; Diagnosis ; Follow-Up Studies ; Genes, ras ; Hospitals, University ; Humans ; Korea ; Lymph Nodes ; Mutation Rate ; Neoplasm Metastasis ; Pathology ; Prevalence ; Protein Isoforms ; Recurrence ; Retrospective Studies ; Thyroid Gland ; Thyroid Neoplasms ; Thyroidectomy

Objective: To compare clinical characteristics and prognosis between patients with primary (PTL) and secondary thyroid lymphoma (STL) . Methods: A retrospective analysis was performed on 46 patients with thyroid lymphoma (PTL 19, STL 27) from January 2002 to October 2018. Results: ①PTL group included 4 males and 15 females, with a median age of 57 years. The STL group included 10 males and 17 females, with a median age of 61 years. Diffuse large B-cell lymphoma (DLBCL) was the main pathological subtype in both PTL and STL groups, with 14 cases (73.7%) and 20 cases (74.1%) respectively. In terms of clinical manifestations, goiter was the most common symptom in PTL patients 100.0% (19/19) , while 29.6% (8/27) STL had goiter (P<0.001) . The incidences of increased thyroglobulin antibody (TRAb) /thyroid peroxidase antibody (TPO) were 81.3% (13/16) in PTL group and 43.8% (7/16) in STL group (P=0.028) respectively. Concerning the clinical features of patients, only two PTL patients (10.5%) with advanced Ann Arbor stage (Ⅲ/Ⅳ) , while 21 (77.8%) STL experienced advanced Ann Arbor stage (P<0.001) . Elevated serum β(2)-MG were appeared in 1 (7.1%) PTL and 9 (47.4%) STL patients (P=0.013) , and advanced IPI score (3-5) was more common in STL than PTL (59.3% vs 5.3%, P<0.001) . ②Among the 17 PTL patients who received treatments, 15 (88.2%) achieved remission; as for STL patients received treatments, 23/25 (92.0%) were in remission. The 5-year overall survival (OS) rates of PTL (n=17) and STL groups (n=25) were (87.4±8.4) % and (70.0±13.1) % (P=0.433) respectively. ③The 5-year OS rate in 41 patients with B-cell thyroid lymphoma was (81.1±7.5) %. Univariate analysis showed that IPI score of 3-5 (P=0.040) and high level of serum IL-8 (P=0.022) were significantly associated with poor outcome. Conclusion: DLBCL was the most common subtype in both PTL and STL, and goiter was the major symptom in PTL. IPI score of 3-5 and high level of serum IL-8 were unfavorable prognostic factors for patients with B-cell thyroid lymphoma.
Autoantibodies/blood* ; Female ; Goiter/etiology* ; Humans ; Interleukin-8/blood* ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Male ; Middle Aged ; Prognosis ; Retrospective Studies ; Survival Rate ; Thyroid Gland/pathology* ; Thyroid Neoplasms/secondary*

To investigate the effect of serine/threonine-protein kinase B-Raf (BRAF)-activated long-chain non-coding RNA (lncRNA-BANCR) on apoptosis and autophagy in thyroid carcinoma cells and the underlying mechanisms.
 Methods: RT-PCR was used to detect the expression of lncRNA-BANCR in thyroid carcinoma and normal thyroid tissues. The association between lncRNA-BANCR and clinicopathological data was analyzed in patients with thyroid cancer. Cell counting kit-8 (CCK-8) was used to detect the effect of lncRNA-BANCR on the proliferation of thyroid cancer cells. The effect of lncRNA-BANCR on the apoptosis of thyroid carcinoma cells was detected by flow cytometry. Transwell invasion assay was used to detect the effect of lncRNA-BANCR on the invasive ability of thyroid cancer cells. Western blot was used to detect the changes of autophagy proteins LC3-I and LC3-II after the lncRNA-BANCR expression was suppressed.
 Results: Compared with normal thyroid tissues, the expression level of lncRNA-BANCR in thyroid carcinoma tissues was elevated (P<0.05). The expression of lncRNA-BANCR was positively related to the pathological stage of thyroid carcinoma and the lymph node metastasis. Inhibition of lncRNA-BANCR expression attenuated the proliferation and invasion ability of thyroid cancer cells (both P<0.05); but the apoptosis was enhanced (P<0.05); the expression levels of autophagy protein LC3-I and LC3-II were also increased (P<0.05).
 Conclusion: The expression level of lncRNA-BANCR affects the proliferation, invasion and apoptosis of thyroid cancer cells through modulation of autophagy behavior.
Apoptosis ; Autophagy ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Invasiveness ; Proto-Oncogene Proteins B-raf ; metabolism ; RNA, Long Noncoding ; metabolism ; Serine ; metabolism ; Threonine ; metabolism ; Thyroid Gland ; cytology ; metabolism ; Thyroid Neoplasms ; metabolism ; pathology