An overview of the contemporary diagnosis and management approaches for anaplastic thyroid carcinoma.

Thyroid carcinoma is a complex disease with several types, the most common being well-differentiated and undifferentiated. The latter, "undifferentiated carcinoma", also known as anaplastic thyroid carcinoma (ATC), is a highly aggressive malignant tumor accounting for less than 0.2% of all thyroid carcinomas and carries a poor prognosis with a median survival of 5 months. BRAF gene mutations are the most common molecular factor associated with this type of thyroid carcinoma. Recent advances in targeted biological agents, immunotherapy, stem cell therapy, nanotechnology, the dabrafenib/trametinib combination therapy, immune checkpoint inhibitors (ICI) and artificial intelligence offer novel treatment options. The combination therapy of dabrafenib and trametinib is the current standard treatment for patients with BRAF-V600E gene mutations. Besides, the dabrafenib/trametinib combination therapy, ICI, used alone or in combination with targeted therapies have raised some hopes for improving the prognosis of this deadly disease. Younger age, earlier tumor stage and radiotherapy are all prognostic factors for improved outcomes. Ultimately, therapeutic regimens should be tailored to the individual patient based on surveillance and epidemiological data, and a multidisciplinary approach is essential.

Intra thyroid thymic carcinoma: A case report and literature review.

INTRODUCTION AND IMPORTANCE: Intrathyroid thymic carcinoma (ITC) is a malignant epithelial tumor with thymic differentiation within the thyroid gland. Its frequency is up to 0.15 % of all malignant thyroid tumors. It is frequently a low-grade tumor. The clinical status is often misleading to other more advanced tumors like cervical lymph node metastasis of nonkeratinizing squamous cell carcinoma, undifferentiated variant, dedifferentiated carcinoma, and medullary carcinoma of the thyroid. CASE PREPARATION: The patient came to us with the diagnosis of cervical lymph node metastasis of undifferentiated carcinoma. This patient was first diagnosed with cervical lymph node metastasis in the previous hospital. After having an ITC diagnosis, the patient was operated on the rennet of thyroid glands and had a low dose of radio-chemotherapy for recurrent prevention purposes. It is the first case of such a disease diagnosed at our hospital and also the first case reported in Vietnam. CLINICAL DISCUSSION: ITC is rare and appears similar to all thymic carcinoma variants. The most popular type is squamous carcinoma. Immunohistochemical stains are typical for thymic origin tumors with CD5, CD117 positive. ITC is often negative for monoclonal PAX8 but positive in this case (MRQ-50 clone, Sigma-Aldrich). This finding is an exciting one that should considered. CONCLUSION: Reporting the case increases the awareness of the disease, especially among Vietnam Doctors and patients.

Improvement in Central Neck Dissection Quality in Thyroid Cancer by Use of Tissue Autofluorescence.

BACKGROUND: Risk of postoperative transient or permanent hypoparathyroidism represents one of the most common complications following total thyroidectomy. This risk increases if a cervical lymphadenectomy procedure must also be performed, as is usually the case in thyroid carcinoma patients. Parathyroid autofluorescence (AF) is a non-invasive method that aids intraoperative identification of parathyroid glands. METHODS: In this prospective study, 189 patients with papillary thyroid cancer who underwent total thyroidectomy with central neck dissection were included. Patients were randomly allocated to one of two groups: NAF (no AF, surgery was performed without AF) and the AF group (surgery was performed with AF-Fluobeam LX system, Fluoptics, Grenoble, France). RESULTS: The number of excised lymph nodes was significantly higher in the AF compared to the NAF group, with mean values of 21.3 ± 4.8 and 9.2 ± 4.1, respectively. Furthermore, a significantly higher number of metastatic lymph nodes were observed in the AF group. Transient hypocalcemia recorded significantly lower rates in the AF group with 4.9% compared to 16.8% in the NAF group. CONCLUSIONS: AF use during total thyroidectomy with central neck dissection for papillary thyroid carcinoma patients, decreased the rate of iatrogenic parathyroid gland lesions, and increased the rate of lymphatic clearance.

Anaplastic Transformation in Papillary Thyroid Carcinoma: A Case Report.

Anaplastic thyroid cancer (ATC), a rare thyroid malignancy, accounts for only 5% of all thyroid cancers. However, it is the most aggressive form and has a very poor prognosis. Increasing evidence suggests that ATC arises from papillary thyroid carcinoma (PTC). However, the exact mechanism underlying this transformation remains unclear. In almost all cases, ATC originates within, but rarely outside, the thyroid gland. Transformation of metastatic PTC into ATC within the cervical lymph nodes is extremely rare. In this report, we present a rare case in a 63-year-old male patient who was initially diagnosed with PTC at his first hospital visit, which underwent anaplastic transformation in lymph node metastasis, and was subsequently diagnosed during the follow-up visit.

The BRAFV600E mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia.

Although disorders of primary cilia (PCs) were first reported in human papillary thyroid cancer (PTC) tissues in 1987, their precise role in PTC remains unclear. PCs sense the thyroid follicle colloid environment and act as a cell signaling hub. The present study investigated whether PCs are needed for BRAFV600E-driven PTC. We assessed whether BRAFV600E protein expression correlates with papillary histological architecture and clinicopathological features of PTC. We found that expression of ciliary intraflagellar transport 88 (IFT88) and PC formation were reduced in BRAFV600E-driven PTCs and that loss of cilia may be associated with lymph node metastasis. In PTC cells, the BRAFV600E mutation maintained the aggressiveness of PTC, which was partially related to loss of PCs. Our work confirms that BRAFV600E mutation-driven PC downregulation contributes to maintaining the aggressiveness of PTCs and that manipulating PC can potentially reduce the adverse incidence of PTC in a range of conditions.

Genomic profiling of primary and metastatic thyroid cancers.

The genetic repertoire of primary thyroid cancers (TCs) is well documented, but there is a considerable lack of molecular profiling in metastatic TCs. Here, we retrieved and analyzed the molecular and clinical features of 475 primary and metastatic TCs subjected to targeted DNA sequencing, from the cBioPortal database. The cohort included primary and metastatic samples from 276 papillary thyroid carcinomas (PTCs), 5 follicular thyroid carcinomas, 22 Hürthle cell carcinomas (HCCs), 127 poorly differentiated thyroid carcinomas (PDTCs), 30 anaplastic thyroid carcinomas (ATCs) and 15 medullary thyroid carcinomas. The ATCs had the highest tumor mutational burden and the HCCs the highest fraction of the genome altered. Compared to primary PTCs, the metastases had a significantly higher frequency of genetic alterations affecting TERT (51% vs 77%, P < 0.001), CDKN2A (2% vs 10%, P < 0.01), RET (2% vs 7%, P < 0.05), CDKN2B (1% vs 6%, P < 0.05) and BCOR (0% vs 4%, P < 0.05). The distant metastases had a significantly lower frequency of BRAF (64% vs 85%, P < 0.01) and a significantly higher frequency of NRAS (13% vs 3%, P < 0.05) hotspot mutations than the lymph node metastases. Metastases from HCCs and PDTCs were found to be enriched for NF1 (29%) and TP53 (18%) biallelic alterations, respectively. The frequency of subclonal mutations in ATCs was significantly higher than in PTCs (43% vs 25%, P < 0.01) and PDTCs (43% vs 22%, P < 0.01). Metastatic TCs are enriched in clinically informative genetic alterations such as RET translocations, BRAF hotspot mutations and NF1 biallelic losses that may be explored therapeutically.

Clinical Outcomes of Radioactive Iodine Redifferentiation Therapy in Previously Iodine Refractory Differentiated Thyroid Cancers.

Objective: Redifferentiation therapy (RDT) can restore radioactive iodine (RAI) uptake in differentiated thyroid cancer (DTC) cells to enable salvage 131I therapy for previously RAI refractory (RAIR) disease. This study evaluated the clinical outcomes of patients who underwent RDT and identified clinicopathologic characteristics predictive of RAI restoration following RDT. Methods: This is a retrospective case series of 33 patients with response evaluation criteria in solid tumors (RECIST)-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic (Rochester, MN). All patients underwent genomic profiling and received MEK, RET or ALK inhibitors alone, or combination BRAF-MEK inhibitors for 4 weeks. At week 3, those with increased RAI avidity in metastatic foci received high-dose 131I therapy. Baseline and clinicopathologic outcomes were comprehensively reviewed. Results: Of the 33 patients, 57.6% had restored RAI uptake following RDT (Redifferentiated subgroup). 42.1% (8/19) with papillary thyroid cancers (PTC), 100% (4/4) with invasive encapsulated follicular variant PTCs (IEFV-PTCs), and 100% (7/7) with follicular thyroid cancers (FTC) redifferentiated. All (11/11) RAS mutant tumors redifferentiated compared with 38.9% (7/18) with BRAF mutant disease (6 PTC and 1 IEFV-PTC). 76.5% (13/17) of redifferentiated and 66.7% (8/12) of non-redifferentiated patients achieved a best overall RECIST response of stable disease (SD) or non-complete response/non-progressive disease. Both subgroups had a median 12% tumor shrinkage at 3 weeks on drug(s) alone. The redifferentiated subgroup, following high-dose 131I therapy, achieved an additional median 20% tumor reduction at 6 months after RDT. There were no statistically significant differences between both groups in progression free survival (PFS), time to initiation of systemic therapy, and time to any additional therapy. Of the entire cohort, 6.1% (2/33) experienced histologic transformation to anaplastic thyroid cancer, 15.1% (5/33) died, and all had redifferentiated following RDT and received 131I therapy. Conclusion: RDT has the potential to restore RAI avidity and induce RECIST responses following 131I therapy in select patients with RAIR-DTC, particularly those with RAS-driven "follicular" phenotypes. In patients with PTC, none of the evaluated clinical outcomes differed statistically between the redifferentiated and non-redifferentiated subgroups. Further studies are needed to better characterize the long-term survival and/or safety outcomes of high-dose RAI following RDT, particularly whether it could be associated with histologic anaplastic transformation.

CTC, ctDNA, and Exosome in Thyroid Cancers: A Review.

Thyroid cancer has become more common in recent years all around the world. Many issues still need to be urgently addressed in the diagnosis, treatment, and prognosis of thyroid cancer. Liquid biopsy (mainly circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and circulating exosomes) may provide a novel and ideal approach to solve these issues, allows us to assess the features of diseases more comprehensively, and has a function in a variety of malignancies. Recently, liquid biopsy has been shown to be critical in thyroid cancer diagnosis, treatment, and prognosis in numerous previous studies. In this review, by testing CTCs, ctDNA, and exosomes, we focus on the possible clinical role of liquid biopsy in thyroid cancer, including diagnostic and prognostic biomarkers and response to therapy. We briefly review how liquid biopsy components have progressed in thyroid cancer by consulting the existing public information. We also discuss the clinical potential of liquid biopsy in thyroid cancer and provide a reference for liquid biopsy research. Liquid biopsy has the potential to be a useful tool in the early detection, monitoring, or prediction of response to therapies and prognosis in thyroid cancer, with promising clinical applications.

Challenges in diagnosis and biomarker testing for RET-altered lung and thyroid cancer care: an international mixed-method study.

BACKGROUND: The introduction of new targeted therapies for RET-altered lung and thyroid cancers (LC/TC) has impacted pathologists' practice by making genomic testing more relevant. Variations in health systems and treatment access result in distinct clinical challenges and barriers. This study aimed to assess practice gaps and challenges experienced by pathologists involved in the diagnosis of RET-altered LC/TC, including biomarker testing, to inform educational solutions. METHODS: Pathologists in Germany, Japan, the UK, and US participated in this ethics-approved mixed-methods study, which included interviews and surveys (data collected January-March 2020). Qualitative data was thematically analysed, quantitative data was analysed with chi-square and Kruskal-Wallis H-tests, and both were triangulated. RESULTS: A total of 107 pathologists took part in this study. Knowledge gaps were reported regarding genomic testing for LC/TC in Japan (79/60%), the UK (73/66%), and the US (53/30%). Skill gaps were reported when selecting genomic biomarker tests to diagnose TC in Japan (79%), the UK (73%) and US (57%) and when performing specific biomarker tests, especially in Japan (82% for RET) and in the UK (75% for RET). Japanese participants (80%) reported uncertainty about what information to share with the multidisciplinary team to ensure optimal patient-centered care. At the time of data collection, pathologists in Japan faced access barriers to using RET biomarker tests: only 28% agreed that there are relevant RET genomic biomarker tests available in Japan, versus 67% to 90% in other countries. CONCLUSIONS: This study identified areas where pathologists need additional continuing professional development opportunities to enhance their competencies and better support delivery of care to patients with RET-altered lung or thyroid tumours. Addressing identified gaps and improving competencies of pathologists in this field should be emphasised in continuing medical education curricula and through quality improvement initiatives. Strategies deployed on an institutional and health system level should aim to improve interprofessional communication and genetic biomarker testing expertise.