Clinicopathological Features and Molecular Signatures of Lateral Neck Lymph Node Metastasis in Papillary Thyroid Microcarcinoma

Background@#The predictive factors for lateral neck lymph node metastasis (LLNM) in papillary thyroid microcarcinoma (PTMC) remain undetermined. This study investigated the clinicopathological characteristics, transcriptomes, and tumor microenvironment in PTMC according to the LLNM status. We aimed to identify the biomarkers associated with LLNM development. @*Methods@#We retrospectively reviewed the medical records of patients with PTMC from two independent institutions between 2018 and 2022 (n=597 and n=467). We compared clinicopathological features between patients without lymph node metastasis (N0) and those with LLNM (N1b). Additionally, laser capture microdissection and RNA sequencing were performed on primary tumors from both groups, including metastatic lymph nodes from the N1b group (n=30; 20 primary tumors and 10 paired LLNMs). We corroborated the findings using RNA sequencing data from 16 BRAF-like PTMCs from The Cancer Genome Atlas. Transcriptomic analyses were validated by immunohistochemical staining. @*Results@#Clinicopathological characteristics, such as male sex, multifocality, extrathyroidal extension, lymphatic invasion, and central node metastasis showed associations with LLNM in PTMCs. Transcriptomic profiles between the N0 and N1b PTMC groups were similar. However, tumor microenvironment deconvolution from RNA sequencing and immunohistochemistry revealed an increased abundance of tumor-associated macrophages, particularly M2 macrophages, in the N1b group. @*Conclusion@#Patients with PTMC who have a male sex, multifocality, extrathyroidal extension, lymphatic invasion, and central node metastasis exhibited an elevated risk for LLNM. Furthermore, infiltration of M2 macrophages in the tumor microenvironment potentially supports tumor progression and LLNM in PTMCs.

Risk of Subsequent Primary Cancers in Thyroid Cancer Survivors according to the Dose of Levothyroxine: A Nationwide Cohort Study

Background@#Current research has not investigated the effect of thyroid-stimulating hormone suppression therapy with levothyroxine on the risk for developing subsequent primary cancers (SPCs). This study aimed to investigate the association between levothyroxine dosage and the risk for SPCs in thyroid cancer patients. @*Methods@#We conducted a nationwide population-based retrospective cohort study form Korean National Health Insurance database. This cohort included 342,920 thyroid cancer patients between 2004 and 2018. Patients were divided into the non-levothyroxine and the levothyroxine groups, the latter consisting of four dosage subgroups according to quartiles. Cox proportional hazard models were performed to evaluate the risk for SPCs by adjusting for variables including cumulative doses of radioactive iodine (RAI) therapy. @*Results@#A total of 17,410 SPC cases were observed over a median 7.3 years of follow-up. The high-dose levothyroxine subgroups (Q3 and Q4) had a higher risk for SPC (adjusted hazard ratio [HR], 1.14 and 1.27; 95% confidence interval [CI], 1.05–1.24 and 1.17– 1.37; respectively) compared to the non-levothyroxine group. In particular, the adjusted HR of stomach (1.31), colorectal (1.60), liver and biliary tract (1.95), and pancreatic (2.48) cancers were increased in the Q4 subgroup. We consistently observed a positive association between high levothyroxine dosage per body weight and risk of SPCs, even after adjusting for various confounding variables. Moreover, similar results were identified in the stratified analyses according to thyroidectomy type and RAI therapy, as well as in a subgroup analysis of patients with good adherence. @*Conclusion@#High-dose levothyroxine use was associated with increased risk of SPCs among thyroid cancer patients regardless of RAI therapy.

Active Surveillance for Low-Risk Thyroid Cancers: A Review of Current Practice Guidelines

The indolent nature and favorable outcomes associated with papillary thyroid microcarcinoma have prompted numerous prospective studies on active surveillance (AS) and its adoption as an alternative to immediate surgery in managing low-risk thyroid cancer. This article reviews the current status of AS, as outlined in various international practice guidelines. AS is typically recommended for tumors that measure 1 cm or less in diameter and do not exhibit aggressive subtypes on cytology, extrathyroidal extension, lymph node metastasis, or distant metastasis. To determine the most appropriate candidates for AS, factors such as tumor size, location, multiplicity, and ultrasound findings are considered, along with patient characteristics like medical condition, age, and family history. Moreover, shared decision-making, which includes patient-reported outcomes such as quality of life and cost-effectiveness, is essential. During AS, patients undergo regular ultrasound examinations to monitor for signs of disease progression, including tumor growth, extrathyroidal extension, or lymph node metastasis. In conclusion, while AS is a feasible and reliable approach for managing lowrisk thyroid cancer, it requires careful patient selection, effective communication for shared decision-making, standardized follow-up protocols, and a clear definition of disease progression.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part I. Initial Management of Differentiated Thyroid Cancers - Chapter 4. Pathological Diagnosis and Staging after Thyroidectomy 2024

Postoperative pathological diagnosis of differentiated thyroid cancer (DTC) is important to confirm the diagnosis and predict the risk of recurrence and death. Further treatment plans, such as completion thyroidectomy, radioiodine remnant ablation, or external beam radiation therapy, are then opted for to reduce the predicted risk of recurrence or death. The World Health Organization has classified thyroid cancers into seven distinct categories based on the molecular profile and tumor cell origin. Our recommendation is applicable to differentiated follicular cell-derived carcinoma, the most common form of thyroid cancer, and cribriform morular thyroid carcinoma. Postoperative clinical and pathological staging is recommended for all patients with DTC to determine their prognosis and subsequent treatment decisions. In particular, the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system is recommended for staging DTCs for disease mortality prediction and national cancer registries. The information in the pathology report, including histologic features of the tumor that are necessary for AJCC/UICC staging and recurrence prediction, can help assess the patient’s risk.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part IV. Thyroid Cancer during Pregnancy 2024

The prevalence of thyroid cancer in pregnant women is unknown; however, given that thyroid cancer commonly develops in women, especially young women of childbearing age, new cases are often diagnosed during pregnancy. This recommendation summarizes the follow-up and treatment when thyroid cancer is diagnosed during pregnancy and when a woman with thyroid cancer becomes pregnant. If diagnosed in the first trimester, surgery should be postponed until after delivery, and the patient should be monitored with ultrasound. If follow-up before 24–26 weeks of gestation shows that thyroid cancer has progressed, surgery should be considered. If it has not progressed at 24–26 weeks of gestation or if papillary thyroid cancer is diagnosed after 20 weeks of pregnancy, surgery should be considered after delivery.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part I. Initial Management of Differentiated Thyroid Cancers - Chapter 5. Evaluation of Recurrence Risk Postoperatively and Initial Risk Stratification in Differentiated Thyroid Cancer 2024

The American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging classification of thyroid cancer can predict death but cannot determine the type and frequency of follow-up testing. Risk stratification is a concept proposed by the American Thyroid Association that uses additional prognostic factors that are not included in the AJCC/UICC classification, such as number or size of metastatic lymph nodes, genetic mutations, and vascular invasion in follicular cancer, to further refine the prognosis of thyroid cancer. The risk of recurrence was categorized as low, intermediate, and high risk, and the need for total thyroidectomy, radioiodine therapy, or thyroid-stimulating hormone suppression was determined depending on each risk level. This approach has been accepted worldwide, and the previous recommendations of the Korean Thyroid Association followed a similar line of thinking but these have been modified in the revised 2024 guidelines.For the revised initial risk stratification, after careful review of the results of the recent meta-analyses and large observational studies and after a multidisciplinary meeting, four major changes were made: 1) thyroid cancer was reclassified according to the World Health Organization (WHO) 2022 tumor classification system; 2) recurrence risk was stratified by combining encapsulated follicular variant papillary thyroid cancer, follicular thyroid cancer, and oncocytic thyroid cancer, which have similar recurrence risk and associated factors, into follicular-patterned tumor; 3) low-risk groups were defined as those with a known recurrence rate of ≤5%, high-risk groups were upgraded to those with a known recurrence rate of ≥30%, and intermediate-risk groups were those with a recurrence risk of 5–30%; and 4) the intermediate risk group had the recurrence rate presented according to various clinicopathological factors, mainly based on reports from Korea. Thus, it is recommended to evaluate the initial risk group by predicting the recurrence rate by combining each clinical factor in individual patients, rather than applying the recurrence rate caused by single risk factor.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part I. Initial Management of Differentiated Thyroid Cancers - Chapter 1. Preoperative Imaging and Diagnostic Evaluation in Thyroid Cancer 2024

The selected treatment for a nodule that is diagnosed as thyroid cancer is surgery. Imaging and blood tests are performed prior to surgery to determine the extent of the surgery. An Ultrasound (US) of the thyroid and neck should be performed to evaluate the size of the cancer, whether it is multifocal and has invaded surrounding tissues, and the status of the cervical lymph nodes (LNs). In addition to US, contrast-enhanced computed tomography may help detect cervical LN metastasis and evaluate patients suspected with invasive thyroid cancer.Generally, routine preoperative measurement of serum thyroglobulin and thyroglobulin antibody concentrations is not recommended. Integrated 18F-fluorodeoxyglucose positron-emission/computed tomography may be helpful either in patients with suspected lateral cervical LNs or distant metastasis or in patients with aggressive histology.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part I. Initial Management of Differentiated Thyroid Cancers - Chapter 7. Adjuvant External Beam Radiotherapy and Systemic Chemotherapy Following Thyroidectomy 2024

Surgical resection is typically the primary treatment for differentiated thyroid cancer (DTC), followed by radioactive iodine (RAI) and thyroid-stimulating hormone suppression therapies based on the cancer stage and risk of recurrence. Nevertheless, further treatment may be necessary for patients exhibiting persistent disease following RAI therapy, residual disease refractory to RAI, or unresectable locoregional lesions. This guideline discusses the role of external beam radiotherapy and chemotherapy following surgical resection in patients with DTC. External beam radiotherapy is ineffective if DTC has been entirely excised (Grade 2). Adjuvant external beam radiotherapy may be optionally performed in patients with incomplete surgical resection or frequently recurrent disease (Grade 2). In patients at high risk of recurrence following surgery and RAI therapy, adjuvant external beam radiotherapy may be optionally considered (Grade 3). However, external beam radiotherapy may increase the risk of serious adverse events after tyrosine kinase inhibitor therapy. Therefore, careful consideration is needed when prescribing external beam radiotherapy for patients planning to undergo tyrosine kinase inhibitor therapy. There is no evidence supporting the benefits of the routine use of adjuvant chemotherapy for DTC treatment (Grade 2).

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part III. Management of Advanced Differentiated Thyroid Cancers - Chapter 5.Treatment of Metastatic Lesions in Advanced Differentiated Thyroid Carcinoma 2024

Only a small percentage of patients (2-5%) with differentiated thyroid cancer (DTC) exhibit distant metastasis at the initial diagnosis or during the disease course. The most common metastatic sites of DTC are the lungs, followed by the bones. Radioactive iodine (RAI) therapy is considered the primary treatment for RAI-avid distant metastatic DTC. Depending on the characteristics of metastatic lesions, local treatment such as surgical resection, radiofrequency ablation, and external beam radiation therapy may be considered for some patients with metastatic DTC. Slowly growing and asymptomatic metastases can be monitored with follow-up while receiving thyroid-stimulating hormone (TSH) suppression therapy. In patients with a limited number of lung metastases and good performance status, surgical removal of the metastatic lesions may be considered. Systemic therapy should be considered for patients with progressive RAI refractory DTC. In this clinical guideline, we aim to outline the treatment principles for patients with lung, bone, and brain metastases of DTC.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part III. Management of Advanced Differentiated Thyroid Cancers - Chapter 1-2. Locally Recurred/Persistent Thyroid Cancer Management Strategies 2024

These guidelines aim to establish the standard practice for diagnosing and treating patients with differentiated thyroid cancer (DTC). Based on the Korean Thyroid Association (KTA) Guidelines on DTC management, the “Treatment of Advanced DTC” section was revised in 2024 and has been provided through this chapter. Especially, this chapter covers surgical and nonsurgical treatments for the local (previous surgery site) or regional (cervical lymph node metastasis) recurrences. After drafting the guidelines, it was finalized by collecting opinions from KTA members and related societies. Surgical resection is the preferred treatment for local or regional recurrence of advanced DTC. If surgical resection is not possible, nonsurgical resection treatment under ultrasonography guidance may be considered as an alternative treatment for local or regional recurrence of DTC. Furthermore, if residual lesions are suspected even after surgical resection or respiratory-digestive organ invasion, additional radioactive iodine and external radiation treatments are considered.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part I. Initial Management of Differentiated Thyroid Cancers - Chapter 3. Perioperative Assessment of Surgical Complications 2024

Thyroid surgery complications include voice change, vocal fold paralysis, and hypoparathyroidism. The voice status should be evaluated pre- and post-surgery. In patients with voice change, laryngeal visualization is needed.Intraoperative neuromonitoring helps reduce recurrent laryngeal nerve injury. The measurement of serum calcium, parathyroid hormone, and 25-hydroxyvitamin D levels is recommended to evaluate perioperative parathyroid function and prescribe supplementation preoperatively if necessary. For postoperative hypoparathyroidism, vitamin D and oral calcium supplementation are indicated based on serum parathyroid hormone and calcium levels and the severity of symptoms or signs of hypocalcemia. If long-term treatment is required, the appropriateness of treatment should be evaluated based on the disease itself and the consideration of potential benefits and harms from long-term replacement.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part III. Management of Advanced Differentiated Thyroid Cancers - Chapter 4. Systemic Therapy for Progressive Radioiodine-Refractory Differentiated Thyroid Cancer 2024

The primary treatment for differentiated thyroid cancer (DTC) with distant metastasis is high-dose radioactive iodine (RAI) therapy, which can have various effects depending on the iodine uptake of thyroid cancer cells. The iodine uptake of metastatic lesions decreases over time, and approximately 40-70% of patients eventually develop RAI refractory disease. Although the prognosis of patients with RAI refractory DTC is very poor, clinical outcomes vary depending on the location and progression of metastatic lesions. Therefore, it is crucial to determine which patients should receive active systemic therapy with tyrosine kinase inhibitor (TKI) and how to apply local treatment before or during systemic therapy. This guideline covers the definition, treatment principles, systemic anticancer agents, and complications of progressive RAI-refractory DTC. RAI refractory DTC is defined as (1) the absence of RAI uptake on whole body scan, (2) presence of RAI uptake in some lesions but not in others, or (3) disease progression despite RAI uptake. Treatment options for RAI refractory DTC include surgery, external beam radiation therapy, locoregional therapies such as high-intensity focused ultrasound ablation, and systemic anticancer therapy.In patients with minimal symptoms and progression, active surveillance without specific treatment may be considered. Systemic treatment should be considered for patients with multiple progressive lesions by RECIST criteria. Furthermore, testing for cancer gene mutations, including BRAF, NTRK, and RET genes, is recommended for personalized therapy. Systemic therapy should be decided based on shared decision-making between the patient and specialist, considering anticipated benefits and risks. Regular assessment of treatment responses and evaluation of adverse events is essential, with dose adjustment based on these assessments. The optimal time of use, clinical approaches for the prevention and control of adverse events, and individualized treatment approaches based on patient characteristics will be of great help in the treatment of patients with RAI-refractory DTC.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part I. Initial Management of Differentiated Thyroid Cancers - Chapter 6. Radioactive Iodine Treatment after Thyroidectomy 2024

The initial treatment for differentiated thyroid cancer includes appropriate surgery and radioactive iodine (RAI) therapy, followed by thyroid-stimulating hormone (TSH) suppression therapy as long-term management to prevent recurrence. RAI therapy following thyroidectomy has the three main purposes: remnant ablation, adjuvant therapy, and therapy for known disease. To optimize the goals and targets of RAI therapy, postoperative disease assessment, determination of recurrence risk, and consideration of various individual factors are necessary. The objectives of RAI therapy are determined based on the individual’s recurrence risk, and the administered activity of RAI is then determined according to these treatment objectives. Adequate stimulation of serum TSH is necessary before RAI therapy, and recombinant human TSH is widely used because of its advantage in reducing the risk of exacerbation of comorbidities associated with levothyroxine discontinuation and improving patients’ quality of life. Additionally, reducing iodine intake through appropriate low-iodine diet is necessary. Whole-body scans are conducted to assess the disease status after RAI therapy. If planar whole-body scans are inconclusive, additional single-photon emission computed tomography (SPECT)/CT imaging is recommended. Over the past decade, prospective randomized or retrospective clinical studies on the selection of candidates for RAI therapy, administered activity, methods of TSH stimulation, and advantages of SPECT/CT have been published. Based on these latest clinical research findings and recommendations from relevant overseas medical societies, this clinical practice guideline presents the indications and methods for administering RAI therapy after thyroidectomy.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part II. Follow-up Surveillance after Initial Treatment 2024

Based on the clinical, histopathological, and perioperative data of a patient with differentiated thyroid cancer (DTC), risk stratification based on their initial recurrence risk is a crucial follow-up (FU) strategy during the first 1–2 years after initial therapy. However, restratifiying the recurrence risk on the basis of current clinical data that becomes available after considering the response to treatment (ongoing risk stratification, ORS) provides a more accurate prediction of the status at the final FU and a more tailored management approach. Since the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and DTC, the latest guidelines that include the National Comprehensive Cancer Network clinical practice and European Association for Medical Oncology guidelines have been updated to reflect several recent evidence in ORS and thyroid-stimulating hormone (TSH) suppression of DTC. The current clinical practice guideline was developed by extracting FU surveillance after the initial treatment section from the previous version of guidelines and updating it to reflect recent evidence. The current revised guideline includes recommendations for recent ORS, TSH target level based on risk stratification, FU tools for detection of recurrence and assessment of disease status, and long-term FU strategy for consideration of the disease status. These evidence-based recommendations are expected to avoid overtreatment and intensive FU of the majority of patients who will have a very good prognosis after the initial treatment of DTC patients, thereby ensuring that patients receive the most appropriate and effective treatment and FU options.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part III. Management of Advanced Differentiated Thyroid Cancers - Chapter 3.Radioactive Iodine Therapy in Advanced Thyroid Cancer 2024

Radioactive iodine (RAI) therapy can effectively eliminate persistent or recurrent disease in patients with advanced differentiated thyroid cancer (DTC), potentially improving progression-free, disease-specific, and overall survival rates. Repeated administration of RAI along with thyroid-stimulating hormone (TSH) suppression is the mainstay of treatment for patients with distant metastases. Remarkably, one in three patients with distant metastases can be cured using RAI therapy and experience a near-normal life expectancy. Patients with elevated serum thyroglobulin and a negative post-RAI scan may be considered for empiric RAI therapy in the absence of structurally evident disease. However, in some patients, the iodine uptake capacity of advanced lesions decreases over time, potentially resulting in RAI-refractory disease. RAI-administered dose can be either empirically fixed high activities or dosimetry-based individualized activities for treatment of known diseases. The preparation method (levothyroxine withdrawal vs. recombinant human TSH administration) should be individualized for each patient.RAI therapy is a reasonable and safe treatment for patients with advanced DTC. Despite the risk of radiation exposure, administration of low-activity RAI has not been associated with an increased risk of a secondary primary cancer (SPM), leukemia, infertility, adverse pregnancy outcomes, etc. However, depending on the cumulative dose, there is a risk of acute or delayed-onset adverse effects including salivary gland damage, dental caries, nasolacrimal duct obstruction, and SPM. Therefore, as with any treatment, the expected benefit must justify the use of RAI in patients with advanced DTC.

Korean Thyroid Association Management Guidelines for Patients with Thyroid Nodules 2024

Thyroid nodules represent a prevalent condition that is detectable via palpation or ultrasound. In recent years, there has been a paradigm shift toward enhanced diagnostic precision and less aggressive therapeutic approaches, highlighting the growing necessity for tailored clinical recommendations to optimize patient outcomes. The Korean Thyroid Association (KTA) has developed guidelines for managing patients with thyroid nodules, following a comprehensive review by task force members of the relevant literature identified via electronic database searches. The recommendations are provided with a level of recommendation for each section. The guidelines encompass thyroid cancer screening in high-risk groups, appropriate diagnostic methods for thyroid nodules, role of pathologic and molecular marker testing in making a diagnosis, long-term follow-up and treatment of benign thyroid nodules, and special considerations for pregnant women. The major revisions that were made in the 2023 guidelines were the definition of high-risk groups for thyroid cancer screening, application of the revised Korean Thyroid Imaging Reporting and Data System (K-TIRADS), addition of the role of core needle biopsy and molecular marker tests, application of active surveillance in patients with low-risk papillary thyroid microcarcinoma, and updated indications for nonsurgical treatment of benign thyroid nodules. In the 2024 revision of the KTA guidelines for thyroid cancer, the evidence for some recommendations has been updated to address the tumor size in the context of active surveillance in patients with low-risk thyroid cancer and the surgical size cutoff. These evidence-based recommendations serve to inform clinical decision-making in the management of thyroid nodules, thereby facilitating the delivery of optimal and efficacious treatments to patients.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part V. Pediatric Differentiated Thyroid Cancer 2024

Pediatric differentiated thyroid cancers (DTCs), mostly papillary thyroid cancer (PTC, 80-90%), are diagnosed at more advanced stages with larger tumor sizes and higher rates of locoregional and/or lung metastasis. Despite the higher recurrence rates of pediatric cancers than of adult thyroid cancers, pediatric patients demonstrate a lower mortality rate and more favorable prognosis. Considering the more advanced stage at diagnosis in pediatric patients, preoperative evaluation is crucial to determine the extent of surgery required. Furthermore, if hereditary tumor syndrome is suspected, genetic testing is required. Recommendations for pediatric DTCs focus on the surgical principles, radioiodine therapy according to the postoperative risk level, treatment and follow-up of recurrent or persistent diseases, and treatment of patients with radioiodine-refractory PTCs on the basis of genetic drivers that are unique to pediatric patients.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Overview and Summary 2024

Differentiated thyroid cancer demonstrates a wide range of clinical presentations, from very indolent cases to those with an aggressive prognosis. Therefore, diagnosing and treating each cancer appropriately based on its risk status is important. The Korean Thyroid Association (KTA) has provided and amended the clinical guidelines for thyroid cancer management since 2007. The main changes in this revised 2024 guideline include 1) individualization of surgical extent according to pathological tests and clinical findings, 2) application of active surveillance in low-risk papillary thyroid microcarcinoma, 3) indications for minimally invasive surgery, 4) adoption of World Health Organization pathological diagnostic criteria and definition of terminology in Korean, 5) update on literature evidence of recurrence risk for initial risk stratification, 6) addition of the role of molecular testing, 7) addition of definition of initial risk stratification and targeting thyroid stimulating hormone (TSH) concentrations according to ongoing risk stratification (ORS), 8) addition of treatment of perioperative hypoparathyroidism, 9) update on systemic chemotherapy, and 10) addition of treatment for pediatric patients with thyroid cancer.

Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part I. Initial Management of Differentiated Thyroid Cancers - Chapter 2. Surgical Management of Thyroid Cancer 2024

The primary objective of initial treatment for thyroid cancer is minimizing treatment-related side effects and unnecessary interventions while improving patients’ overall and disease-specific survival rates, reducing the risk of disease persistence or recurrence, and conducting accurate staging and recurrence risk analysis. Appropriate surgical treatment is the most important requirement for this purpose, and additional treatments including radioactive iodine therapy and thyroid-stimulating hormone suppression therapy are performed depending on the patients’ staging and recurrence risk. Diagnostic surgery may be considered when repeated pathologic tests yield nondiagnostic results (Bethesda category 1) or atypia of unknown significance (Bethesda category 3), depending on clinical risk factors, nodule size, ultrasound findings, and patient preference. If a follicular neoplasm (Bethesda category 4) is diagnosed pathologically, surgery is the preferred option. For suspicious papillary carcinoma (suspicious for malignancy, Bethesda category 5), surgery is considered similar to a diagnosis of malignancy (Bethesda category 6). As for the extent of surgery, if the cancer is ≤1 cm in size and clinically free of extrathyroidal extension (ETE) (cT1a), without evidence of cervical lymph node (LN) metastasis (cN0), and without obvious reason to resect the contralateral lobe, a lobectomy can be performed. If the cancer is 1-2 cm in size, clinically free of ETE (cT1b), and without evidence of cervical LN metastasis (cN0), lobectomy is the preferred option. For patients with clinically evident ETE to major organs (cT4) or with cervical LN metastasis (cN1) or distant metastasis (M1), regardless of the cancer size, total thyroidectomy and complete cancer removal should be performed at the time of initial surgery. Active surveillance may be considered for adult patients diagnosed with low-risk thyroid papillary microcarcinoma. Endoscopic and robotic thyroidectomy may be performed for low-risk differentiated thyroid cancer when indicated, based on patient preference.

Different Molecular Phenotypes of Progression in BRAF- and RAS-Like Papillary Thyroid Carcinoma

Background@#Papillary thyroid carcinoma (PTC) can be classified into two distinct molecular subtypes, BRAF-like (BL) and RASlike (RL). However, the molecular characteristics of each subtype according to clinicopathological factors have not yet been determined. We aimed to investigate the gene signatures and tumor microenvironment according to clinicopathological factors, and to identify the mechanism of progression in BL-PTCs and RL-PTCs. @*Methods@#We analyzed RNA sequencing data and corresponding clinicopathological information of 503 patients with PTC from The Cancer Genome Atlas database. We performed differentially expressed gene (DEG), Gene Ontology, and molecular pathway enrichment analyses according to clinicopathological factors in each molecular subtype. EcoTyper and CIBERSORTx were used to deconvolve the tumor cell types and their surrounding microenvironment. @*Results@#Even for the same clinicopathological factors, overlapping DEGs between the two molecular subtypes were uncommon, indicating that BL-PTCs and RL-PTCs have different progression mechanisms. Genes related to the extracellular matrix were commonly upregulated in BL-PTCs with aggressive clinicopathological factors, such as old age (≥55 years), presence of extrathyroidal extension, lymph node metastasis, advanced tumor-node-metastasis (TNM) stage, and high metastasis-age-completeness of resection- invasion-size (MACIS) scores (≥6). Furthermore, in the deconvolution analysis of tumor microenvironment, cancer-associated fibroblasts were significantly enriched. In contrast, in RL-PTCs, downregulation of immune response and immunoglobulin-related genes was significantly associated with aggressive characteristics, even after adjusting for thyroiditis status. @*Conclusion@#The molecular phenotypes of cancer progression differed between BL-PTC and RL-PTC. In particular, extracellular matrix and cancer-associated fibroblasts, which constitute the tumor microenvironment, would play an important role in the progression of BL-PTC that accounts for the majority of advanced PTCs.