Case Report: Solid variant of papillary thyroid carcinoma in a young adult with Turner syndrome with chronic thyroiditis.

Turner syndrome is associated with an increased risk of developing several neoplasms. In particular, a clinical feature of Turner syndrome with chronic thyroiditis implies a relationship with thyroid malignancies. We report a very rare case of a solid variant of papillary thyroid carcinoma that was identified during a follow-up of chronic thyroiditis in a 22-year-old woman with Turner syndrome. The patient had no notable history of radiation exposure. No genetic mutations relating to the occurrence of the solid variant of papillary thyroid carcinoma, including RET/PTC rearrangements and mutations in the BRAF or RAS, were detected by a gene panel test, namely, the Oncomine™ Dx Target test. To the best of our knowledge, this is the first report of a solid variant of papillary thyroid carcinoma in a young adult with Turner syndrome with chronic thyroiditis. Our case suggests that in patients with Turner syndrome, there may be different pathogeneses from those previously reported, including exposure to radiation or known genetic mutations for the development of a solid variant of papillary thyroid carcinoma.

Outpatient ablation treatment with two doses of 30 mCi of radioactive iodine for non-low-risk papillary thyroid cancer.

Outpatient ablation therapy with low-dose radioactive iodine (RAI) is applied to non-low-risk papillary thyroid cancer patients due to a chronic shortage of inpatient RAI treatment wards in Japan. We used the maximum dosage available for outpatient therapy of 30 mCi of RAI for ablation and diagnostic (Dx) whole-body scintigraphy (WBS). This study aimed to examine the significance of the second dose of 30 mCi. DxWBS was performed 6 months after ablation, and assessment of success or failure was performed 12 months after ablation. A second WBS was performed in the remaining RAI accumulation cases in the neck on DxWBS. The criteria for successful ablation was negative cervical accumulation on WBS, thyroid stimulating hormone-suppressed thyroglobulin (sup-Tg) below 1.0 ng?/?mL, and no increase in thyroglobulin antibody (TgAb) level. At the time of DxWBS, 35?/?68 cases met the successful criteria, and 45 cases achieved success at assessment. Sup-Tg values decreased significantly after ablation and decreased further after DxWBS in successful ablation cases, whereas those were not changed in ablation failure cases. Findings indicated that RAI used in DxWBS had therapeutic effects. It makes sense to use 30 mCi for DxWBS, given the current difficulty of inpatient ablation therapy with high-dose RAI. J. Med. Invest. 70 : 17-21, February, 2023.

Surgical strategy of locally advanced differentiated thyroid cancer.

Approximately 20% of patients with differentiated thyroid cancer (DTC) have direct tumor extension with invasion of the surrounding tissues such as the larynx, trachea, esophagus, or recurrent laryngeal nerve. Recent progress of molecular-targeted therapy, such as the use of tyrosine kinase inhibitors, improves survival outcome in patients with advanced DTC. However, induction of tyrosine kinase inhibitors for locally-advanced DTC has presented novel fatal adverse events including fistula in patients with infiltration toward to the trachea, pharynx and esophagus, and fatal bleeding in patients with great vessel invasion. Surgery therefore still has an important role in DTC management, particularly in local control. The surgical strategy for laryngeal/tracheal invasion, which commonly occurs by DTC, is decided according to the extension (depths and area) of the tumor. The "shave procedure" is performed when the tumor has superficially invaded the larynx/trachea. However, intra-luminal extension requires resection and reconstruction of the larynx/trachea wall. Large veins, such as the internal jugular vein and the subclavian vein, are also frequently directly invaded by DTC. Three types of jugular vein reconstruction have been advocated to avoid fatal complications according to bilateral jugular vein ligation. The majority of carotid artery invasion by DTC can be managed with tumor resection of the sub-adventitial layer without reconstruction surgery using an artificial vessel. In this review article, we examine surgery for advanced DTC, showing the surgical strategy toward DTC that has invaded the laryngotracheal, recurrent laryngeal nerve, esophagus/hypopharynx, or great vessels.

Lateral approach contributes to shortened surgical time in video-assisted neck surgery (VANS) for thyroid nodule.

Background: Despite endoscopic thyroid surgery contributing to excellent cosmetic outcomes, it requires longer surgical time than open surgery. This study evaluates the factors associated with operative time in video-assisted neck surgery. Methods: We retrospectively reviewed patients who underwent hemithyroidectomy by video-assisted neck surgery at a single hospital between 2017 and 2021. The clinical parameters were evaluated: age, sex, body weight, body mass index, coexistence of Hashimoto thyroiditis, side of operation, surgical approach to thyroid (midline approach or lateral approach), operation time, amount of blood loss during surgery, maximum tumor diameter and tumor volume, and postoperative complications. These parameters were compared to investigate the association of operative time and surgical approach. Results: Seventy consecutive patients were enrolled in this study, the median age at operation was 50 years, and there were 6 (8.6%) men and 64 (91.4%) women. The median body weight and body mass index at operation were 56.6 kg and 21.5, respectively. Coexistence of Hashimoto thyroiditis was found in 17 (24.3%) patients. Significant differences were found between the groups with longer and shorter operation time than median 201 minutes in surgical approaches to the thyroid (P < .001) and the amount of bleeding during surgery (P = .039). There were no differences in other candidates between the groups. Median operation times were 242 minutes in midline approach and 131 minutes in lateral approach (P < .001). Conclusion: The lateral approach of video-assisted neck surgery to the thyroid can contribute to shortened surgical time in the case of benign thyroid nodules.

The Role of Anatomical Imaging and Intraoperative Neuromonitoring (IONM) for Successful Prediction of a Nonrecurrent Laryngeal Nerve.

A nonrecurrent laryngeal nerve (NRLN) is a rare anatomical variant of laryngeal nerves that branches directly from the vagus nerve. The anatomical abnormality makes it difficult to identify the NRLN and results in high incidence of accidental nerve injury during surgery. A 76-year-old woman complained of swelling in the right side of her neck and visited our university hospital for further examination. Ultrasonography showed a right thyroid lobe mass with calcification and fine needle aspiration biopsy was classified as class III. Computed tomography revealed that the right subclavian artery branched directly from the descending aorta without branching from the brachiocephalic artery and ran behind the esophagus. Since it was afraid that the accidental injury of NRLN was likely to occur, a right thyroid lobe dissection using intraoperative neuromonitoring (IONM) was performed. After separating the connective tissue on the thyroid capsule from the right side of the trachea to the inferior pole laterally, the NRLN running across the level of the inferior margin of the cricoid cartilage was identified by using IONM 0.5 mA stimulation. After complete dissection of right thyroid lobe, we again stimulated the NRLN by 0.5 mA and the electromyographic response was confirmed. The pathological analysis confirmed nodular hyperplasia without malignancy; the condition was diagnosed as an adenomatous goiter. There was no vocal cord dysfunction and hoarseness after the surgery. IONM contributed to the prevention of NRLN injury during the surgery. We believe that it is important to confirm the presence or absence of an aberrant subclavian artery on preoperative imaging, and that IONM should be considered to identify the NRLN to prevent vocal cord paralysis if its presence is suspected.

A case of concurrent occurrence of carcinoma showing thymus-like differentiation and follicular variant of papillary thyroid cancer in the same thyroid.

Carcinoma showing thymus-like differentiation (CASTLE) is a rare thyroid cancer. This is the first report of a case of concurrent occurrence of CASTLE with papillary thyroid carcinoma (PTC). A 66-year-old male patient had hoarseness with right vocal cord paralysis. Ultrasonography revealed a hypoechoic nodule in the inferior pole of the right thyroid lobe. Ultrasound-guided fine-needle aspiration cytology suggested differentiated thyroid cancer. The patient underwent total thyroidectomy with neck dissection. Pathological examination revealed two different thyroid cancers: a CASTLE and a follicular variant of PTC. Postoperative radiation therapy was performed. The patient was still alive after 5 year following the initial treatment without evidence of recurrence. The oncological management of patients with concurrent occurrence of different thyroid cancers should consider the biological behavior of both tumors.

Impact of the practical guideline on appropriate usage of antimicrobial treatments for surgical site infections in reconstructive surgery of head and neck cancer.

OBJECTIVES: In 2016, Japanese Society of Chemotherapy and Japan Society for Surgical Infection presented the practical guideline for appropriate usage of antimicrobial agents to prevent postoperative infections. This study aims to exhibit the validity of the guideline as a series of effective strategies for prevention of surgical site infections (SSIs) during reconstructive surgery of the head and neck cancer. METHODS: We retrospectively evaluated patients who underwent head and neck reconstructive surgery with free or pedicle flaps in a single institute in Japan between July 2010 and July 2020. We evaluated the incidence of SSIs, patient backgrounds, and microbiological characteristics on the basis of antimicrobial prophylaxis recommended by the guideline. RESULTS: Enrolled in this study were 102 patients in our institution who underwent head and neck reconstructive surgery with free or pedicle flaps between July 2010 and July 2020. In the period between January 2018 to July 2020 after the SSI guideline was advocated (SSI guideline period), the ratio of administration of sulbactam/ampicillin (SBT/ABPC) was significantly higher (P < 0.001) and the duration of prophylactic antimicrobial treatment was significantly shorter than in the period between July 2010 to December 2017 before the SSI guideline was advocated (Pre-SSI guideline period) (P < 0.001). Incidence of SSIs were similar, even when antibiotic use was changed to be short-term single-agent administration in accordance with the practical guideline. CONCLUSIONS: Adherence to the current Japanese practical guideline on appropriate antimicrobial prophylaxis for SSIs can shorten the duration of usage of antimicrobial treatment without increasing the risk for occurrence of SSIs.

Cancer Stem Cells in Oropharyngeal Cancer.

Oropharyngeal cancer (OPC), which is a common type of head and neck squamous cell carcinoma (HNSCC), is associated with tobacco and alcohol use, and human papillomavirus (HPV) infection. Underlying mechanisms and as a result prognosis of the HPV-positive and HPV-negative OPC patients are different. Like stem cells, the ability of self-renewal and differentiate, cancer stem cells (CSCs) have roles in tumor invasion, metastasis, drug resistance, and recurrence after therapy. Research revealed their roles to some extent in all of these processes but there are still many unresolved points to connect to CSC-targeted therapy. In this review, we will focus on what we currently know about CSCs of OPC and limitations of our current knowledge. We will present perspectives that will broaden our understanding and recent literature which may connect to therapy.

A Rare Case of Thyroid Carcinoma Showing Thymus-Like Differentiation in a Young Adult.

Thyroid carcinoma showing thymus-like differentiation (CASTLE) is thought to originate from ectopic thymic tissue or remnants of the developing thymus within or adjacent to the thyroid. This case report describes a mass located on the left thyroid of a 28-year-old man. Fine-needle aspiration cytology revealed a number of lymphoid cells without atypia that were similar to those seen in a malignant lymphoma of the thyroid, and surgery was performed. Based on additional histopathological findings, the tumor was finally diagnosed as a CASTLE. It is difficult to diagnose this neoplasm using fine-needle aspiration cytology. However, it is possible to differentially diagnose CASTLE based on its histological features. CD5 is useful for diagnosing CASTLE with immunohistochemical staining.

Synergistic Effects of Lenvatinib (E7080) and MEK Inhibitors against Anaplastic Thyroid Cancer in Preclinical Models.

E7080, known as lenvatinib, is an oral multitargeted tyrosine kinase inhibitor that has been shown to improve the survival rate of patients with radioiodine-refractory thyroid cancer. However, a majority of patients do not continue lenvatinib intake due to disease progression or significant toxicity. To improve treatment success rates, we propose the combination of lenvatinib with mitogen-activated protein kinase (MEK) inhibitors. To test this hypothesis, we tested the effects of lenvatinib with the MEK inhibitor U0126 in vitro using two human anaplastic thyroid cancer (ATC) cell lines, 8505C and TCO1, and with another MEK inhibitor, selumetinib (AZD6244), in an ATC mouse model. We found that the combination of lenvatinib with MEK inhibitors enhanced the antitumor effects of monotherapy with either agent in vitro and in vivo, and these effects may be through the AKT (Protein Kinase B) and extracellular signal-regulated kinase (ERK) signaling pathways. Furthermore, the combination does not have significant adverse effects in the ATC mouse models in terms of body weight, blood biochemical parameters, and histopathology. In conclusion, the combination of lenvatinib with an MEK inhibitor is a potentially viable therapeutic approach for ATC treatment.

A case report of synchronous bilateral tonsillar carcinoma associated with human papilloma virus.

The case of a 69-year-old man with bilateral synchronous tonsillar carcinoma is reported. The patient complained of nasal closure, strange voice, and discomfort in his pharynx when he was admitted to the Department of Otolaryngology Head and Neck Surgery at Wakayama Medical University, Wakayama, Japan, in March 2017. The palatine tonsils were enlarged and the surface was irregular. Left cervical lymphadenopathy was also evident. Histological examination from both tonsils was performed and bilateral tonsillar squamous cell carcinoma was diagnosed. PCR analysis showed the same HPV-DNA pattern from bilateral tonsils. Concurrent chemoradiotherapy was performed. Total 70 Gy of irradiation (2Gy/day×35 day) was applied to bilateral tonsillar tumours and upper neck. Follow up was conducted every three months and the patient was free of recurrence for three years. Patient's informed consent was taken to publish the case report.

Update of the genotype and phenotype of KMT2D and KDM6A by genetic screening of 100 patients with clinically suspected Kabuki syndrome.

Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000-8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.

MicroRNA 200b promotes mesenchymal-to-epithelial transition in anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) remains a cancer with one of the worst prognoses, despite novel targeted therapies. The median survival rate has not improved for decades. Epithelial-to-mesenchymal transition (EMT) is a crucial step in physiological processes and in cancer progression, but the underlying mechanisms are not yet fully understood. The current study examined the role of microRNA (miR)-200b in mesenchymal-to-epithelial transition in ATC. Total RNA and miR isolation were performed from ATC cell lines transfected with a miR-200b mimic. After miR-200b mimic transfection, expression levels of E-cadherin, vimentin and zinc finger E-box binding homeobox 1 (ZEB1) were confirmed by reverse transcription-quantitative PCR and western blotting. Additionally, cell migration was evaluated using miR-200b mimic and scrambled negative control-transfected cells. A total of 14 human ATC and 15 non-cancerous human thyroid tissues were immunohistochemically stained and scored as controls for E-cadherin, vimentin and ZEB1. In ATC tissues and cell lines, the mesenchymal marker ZEB1 was significantly upregulated and the epithelial marker E-cadherin was significantly downregulated. Additionally, the mesenchymal marker vimentin was significantly upregulated in ATC tissues and in one ATC cell line. MiR-200b mimic transfection significantly increased vimentin and ZEB1 expression, but E-cadherin expression remained below the measurement sensitivity. Furthermore, miR-200b overexpression decreased cell migration. The current study suggested that miR-200b may regulate the expression levels of mesenchymal markers such as vimentin and ZEB1 in ATC and may promote mesenchymal-to-epithelial transition.

Amino Acid Transporters as Potential Therapeutic Targets in Thyroid Cancer.

Thyroid cancer cells have a high amino acid demand for proliferation, invasion, and metastasis. Amino acids are taken up by thyroid cancer cells, both thyroid follicular cell and thyroid parafollicular cells (commonly called "C-cells"), via amino acid transporters. Amino acid transporters up-regulate in many cancers, and their expression level associate with clinical aggressiveness and prognosis. This is the review to discuss the therapeutic potential of amino acid transporters and as molecular targets in thyroid cancer.

False-positive staining of thyroglobulin distinguished from mixed medullary and follicular thyroid carcinoma by duplex in situ hybridization.

Medullary thyroid carcinoma (MTC) may mimic mixed medullary and follicular thyroid carcinoma (MMFTC). MTC originates from para-follicular cells, while MMFTC is an uncommon tumor characterized by coexistence of follicular and para-follicular cell-derived tumor populations. A 35-year-old woman was diagnosed with MTC but showed a hot nodule in thyroid scintigraphy. The tumor included diffusely-spread follicular lesions within it, which were immunostained with thyroglobulin and calcitonin. Immunofluorescence showed the presence of several tumor cells that were double-stained with thyroglobulin and calcitonin. To clarify whether or not the tumor was MMFTC, we used duplex in situ hybridization (ISH). Thyroglobulin and calcitonin-related polypeptide alpha mRNA were not expressed together in a single cell, so we suspected false-positive staining of tumor cells with thyroglobulin. To make comparisons with other follicular lesions in MTC, we searched our hospital database. Five cases within a ten-year period had been pathologically diagnosed as MTC. All had follicular lesions in the tumor, but unlike the other case, they were peripherally localized. Dual differentiation into follicular or para-follicular tumor cells was not indicated by either immunofluorescence or duplex ISH. Compared with the case suspected to be MMFTC, there was only mild invasion of tumor cells into the follicular epithelium. The extent of follicular lesions and invasiveness of tumor cells may be associated with pseudo-staining of thyroglobulin in MTC. Duplex ISH can distinguish MTC that are stained with thyroglobulin from MMFTC.

A rare case of the recurrent surgery for cribriform-morular variant of papillary thyroid carcinoma.

INTRODUCTION: The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is an uncommon subtype of PTC, and it is associated with familial adenomatous polyposis (FAP). PRESENTATION OF CASE: We describe a 32-year-old female who presented recurrent CMV-PTC with FAP. Surgery performed after the recurrent disease resulted in left recurrent laryngeal nerve palsy due to formation of strong scar after initial operation. The histopathological examination revealed the recurrent CMV-PTC without thyroid capsular invasion in remnant thyroid tissue of berry ligament. In addition, the immunohistochemical analysis showed that ß-Catenin was diffusely positive in both cytoplasm and nucleus in CMV-PTC tissue. CONCLUSION: Total thyroidectomy in CMV-PTC with FAP should be performed at initial surgery due to high recurrence.

Identification and chemoresistance of cancer stem cells in HPV-negative oropharyngeal cancer.

The underlying mechanisms of resistance to chemoradiotherapy of human papilloma virus (HPV)-negative patients with oropharyngeal cancer (OPC) remain unclear. The present study aimed to characterize cancer stem cells (CSC) of the HPV-negative OPC cell line in terms of chemotherapy resistance. CSCs were isolated through magnetic activated cell sorting using the CSC specific marker aldehyde dehydrogenase 1 antibody, and characterized by sphere formation capacity, immunofluorescence staining, and CSC marker expression. CSC response to cisplatin treatment was evaluated via XTT-assays. Spheres of CSCs of the HPV-negative UTSCC-60A cell line were highly dark holospheres. RNA expression levels of CSC markers OCT4, SOX2, Kruppel-like factor 4 and BMI1 were significantly higher in CSC. CSCs were significantly resistant to cisplatin treatment at various dosages compared with nonCSC. The present study suggested that the proportion of CSCs is very low in the tumor bulk, CSCs are resistant to cisplatin in HPV-negative OPC, which requires further investigation to define their mechanism.

A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1.

A novel therapeutic approach is urgently needed for patients with anaplastic thyroid cancer (ATC) due to its fatal and rapid progress. We recently reported that ATC highly expressed MYC protein and blocking of MYC through its selective inhibitor, JQ1, decreased ATC growth and improved survival in preclinical models. One of the important roles of MYC is regulation of L-neutral amino acid transporter 1 (LAT1) protein and inhibition of LAT1 would provide similar anti-tumor effect. We first identified that while the human ATC expresses LAT1 protein, it is little or not detected in non-cancerous thyroidal tissue, further supporting LAT1 as a good target. Then we evaluated the efficacy of JPH203, a LAT1 inhibitor, against ATC by using the in vitro cell-based studies and in vivo xenograft model bearing human ATC cells. JPH203 markedly inhibited proliferation of three ATC cell lines through suppression of mTOR signals and blocked cell cycle progression from the G0/G1 phase to the S phase. The tumor growth inhibition and decrease in size by JPH203 via inhibition of mTOR signaling and G0/G1 cell cycle associated proteins were further confirmed in xenograft models. These preclinical findings suggest that LAT1 inhibitors are strong candidates to control ATC, for which current treatment options are highly limited.

Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer.

Context: Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated. Objective: To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models. Design: We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells. Results: JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling. Conclusions: These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.

Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model.

PURPOSE: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer. EXPERIMENTAL DESIGN: We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. RESULTS: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. CONCLUSIONS: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430-40. ©2016 AACR.