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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.

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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.

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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.

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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.

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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.

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Objectives@#. The mitochondrial ribosomal protein L14 (MRPL14) is encoded by a nuclear gene and participates in mitochondrial protein translation. In this study, we aimed to investigate the role of MRPL14 in thyroid cancer. @*Methods@#. We investigated the association between MRPL14 expression and clinicopathological features using The Cancer Genome Atlas (TCGA) and Chungnam National University Hospital (CNUH) databases. Functional studies of MRPL14, including proliferation, migration, invasion, mitochondrial oxidative phosphorylation and reactive oxygen species (ROS) production, were performed in papillary thyroid cancer (PTC) cell lines (B-CPAP and KTC-1). @*Results@#. Based on the TCGA dataset, PTC tissues lost mitochondrial integrity and showed dysregulated expression of overall mitoribosomal proteins (MRPs) compared with normal thyroid tissues. Of 78 MRPs, MRPL14 was highly expressed in thyroid cancer tissues. MRPL14 overexpression was significantly associated with advanced tumor stage, extrathyroidal extension, and lymph node metastasis. MRPL14 increased cell proliferation of thyroid cancer and promoted cell migration via epithelial-mesenchymal transition-related proteins. Moreover, MRPL14 knockdown reduced the expression of oxidative phosphorylation complex IV (MTCO1) and increased the accumulation of ROS. Cotreatment with a ROS scavenger restored cell proliferation and migration, which had been reduced by MRPL14 knockdown, implying that ROS functions as a key regulator of the oncogenic effects of MRPL14 in thyroid cancer cells. @*Conclusion@#. Our findings indicate that MRPL14 may promote cell growth, migration, and invasion by modulating ROS in thyroid cancer cells.

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The aim of this study was to develop evidence-based recommendations for determining the surgical extent in patients with locally invasive differentiated thyroid cancer (DTC). Locally invasive DTC with gross extrathyroidal extension invading surrounding anatomical structures may lead to several functional deficits and poor oncological outcomes. At present, the optimal extent of surgery in locally invasive DTC remains a matter of debate, and there are no adequate guidelines. On October 8, 2021, four experts searched the PubMed, Embase, and Cochrane Library databases; the identified papers were reviewed by 39 experts in thyroid and head and neck surgery. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence, and to develop and report recommendations. The strength of a recommendation reflects the confidence of a guideline panel that the desirable effects of an intervention outweigh any undesirable effects, across all patients for whom the recommendation is applicable. After completing the draft guidelines, Delphi questionnaires were completed by members of the Korean Society of Head and Neck Surgery. Twenty-seven evidence-based recommendations were made for several factors, including the preoperative workup; surgical extent of thyroidectomy; surgery for cancer invading the strap muscles, recurrent laryngeal nerve, laryngeal framework, trachea, or esophagus; and surgery for patients with central and lateral cervical lymph node involvement. Evidence-based guidelines were devised to help clinicians make safer and more efficient clinical decisions for the optimal surgical treatment of patients with locally invasive DTC.

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Conflicting research results have been reported regarding the influence of lymphovascular invasion as a prognostic factor for recurrence of papillary thyroid cancer, and thus, it is continuously discussed. This systematic review and meta-analysis identified an association between recurrence rate and histological lymphatic or vascular invasion in patients with papillary thyroid carcinoma. Clinical data and outcomes were collected from MEDLINE, Embase, the Cochrane Database of Systematic Reviews and KoreaMed. Selection criteria included studies reporting local or distant recurrence rates according to histological lymphatic or vascular invasion in patients with papillary thyroid carcinoma. Twelve observational studies were included in this study. When vascular invasion was confirmed histologically in patients with papillary thyroid cancer, the local recurrence rate was odds ratio 2.544 (95% confidence interval [CI], 1.469-4.407) compared to the patient group without vascular invasion, and the distant recurrence rate was 5.126 (95% CI, 2.853-9.212). The correlation between lymphatic invasion and recurrence rate could not be analyzed. As a result, this systematic review and meta-analysis confirmed that histological vascular invasion affects the rate of local or distant recurrence in patients with papillary thyroid cancer. Therefore, the presence of histological vascular invasion must be evaluated in patients with papillary thyroid cancer.

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Objectives@#. Thyroid cancer is the most common endocrine tumor, with rapidly increasing incidence worldwide. However, its transcriptomic characteristics associated with immunological signatures, driver fusions, and recurrence markers remain unclear. We aimed to investigate the transcriptomic characteristics of advanced papillary thyroid cancer. @*Methods@#. This study included 282 papillary thyroid cancer tumor samples and 155 normal samples from Chungnam National University Hospital and Seoul National University Hospital. Transcriptomic quantification was determined by high-throughput RNA sequencing. We investigated the associations of clinical parameters and molecular signatures using RNA sequencing. We validated predictive biomarkers using the Cancer Genome Atlas database. @*Results@#. Through a comparison of differentially expressed genes, gene sets, and pathways in papillary thyroid cancer compared to normal tumor-adjacent tissue, we found increased immune signaling associated with cytokines or T cells and decreased thyroid hormone synthetic pathways. In addition, patients with recurrence presented increased CD8+ T-cell and Th1-cell signatures. Interestingly, we found differentially overexpressed genes related to immune-escape signaling such as CTLA4, IDO1, LAG3, and PDCD1 in advanced papillary thyroid cancer with a low thyroid differentiation score. Fusion analysis showed that the PI3K and mitogen-activated protein kinase (MAPK) signaling pathways were regulated differently according to the RET fusion partner genes (CCDC6 or NCOA4). Finally, we identified HOXD9 as a novel molecular biomarker that predicts the recurrence of thyroid cancer in addition to known risk factors (tumor size, lymph node metastasis, and extrathyroidal extension). @*Conclusion@#. We identified a high association with immune-escape signaling in the immune-hot group with aggressive clinical characteristics among Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for advanced papillary thyroid cancer.

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Regional neck metastases in well-differentiated thyroid carcinoma (WDTC) are relatively frequent. The prognostic effects of lymph node (LN) metastases remain controversial. However, it is well known that lateral LN metastasis is related to the recurrence of the disease. In general, when lateral neck LN metastasis is confirmed in WDTC patients, therapeutic lateral neck dissection is recommended. However, the optimal surgical extent of therapeutic lateral neck dissection in WDTC patients with clinical lateral LN metastasis is not clearly presented. Traditional comprehensive neck dissection including level II, III, IV and V even in patients with minimal lateral neck metastases may not be reasonable when considering both oncologic safety and functional aspects. There is controversy whether it is always necessary to perform level II and V LN dissection for all WDTC patients with clinical lateral LN metastasis. This is due to the fact that the likelihood of postoperative complications by the damage of the spinal accessory nerve increases with level II and level V dissection. Therefore, many studies have been reported on the possibility of omitting levels II (especially IIb) and V during therapeutic comprehensive lateral neck dissection.However, there have been no definite conclusions about it, and it is still debate. In this article, we reviewed to find out optimal lateral neck dissection range for WDTC patients with clinical lateral neck metastasis.

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Schwannoma, also known as neurilemmoma, is a benign neoplasm that originates from any nerves wrapped with a sheath made of Schwann cells. Schwannoma occurring in the head and neck region is not rare, but schwannomas of the anterior neck, especially ansa cervicalis, are extremely rare that only 7 cases have been reported to date worldwide. Although rare, it should be considered in differential diagnosis of anterior cervical mass and may be confused with other cervical and thyroid mass. We report a case of intramuscular schwannoma in the sternohyoid muscle. Preoperative diagnosis was established with an ultrasound-guided core needle biopsy. Although it was removed entirely without connection to any other nerves identified or any complication, clinically, the mass was thought to be derived from the nerve. To our knowledge, this is the first case of the intramuscular schwannoma occurring from ansa cervicalis reported in the literature.

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Background@#Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. @*Methods@#This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. @*Conclusion@#The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

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Background@#Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. @*Methods@#This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. @*Conclusion@#The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

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BACKGROUND: Macrophages have been known to have diverse roles either after tissue damage or during the wound healing process; however, their roles in flap wound healing are poorly understood. In this study, we aimed to evaluate how macrophages contribute to the flap wound regeneration.METHODS: A murine model of a pedicled flap was generated, and the time-course of the wound healing process was determined. Especially, the interface between the flap and the residual tissue was histopathologically evaluated. Using clodronate liposome, a macrophage-depleting agent, the functional role of macrophages in flap wound healing was investigated. Coculture of human keratinocyte cell line HaCaT and monocytic cell line THP-1 was performed to unveil relationship between the two cell types.RESULTS: Macrophage depletion significantly impaired flap wound healing process showing increased necrotic area after clodronate liposome administration. Interestingly, microscopic evaluation revealed that epithelial remodeling between the flap tissue and residual normal tissue did not occurred under the lack of macrophage infiltration. Coculture and scratch wound healing assays indicated that macrophages significantly affected the migration of keratinocytes.CONCLUSION: Macrophages play a critical role in the flap wound regeneration. Especially, epithelial remodeling at the flap margin is dependent on proper macrophage infiltration. These results implicate to support the cellular mechanisms of impaired flap wound healing.

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PURPOSE: An enhanced recovery after surgery (ERAS) protocol incorporates up-to-date perioperative care principles; the primary aim in using an ERAS protocol is to reduce issues that delay the recovery and cause the complications. The aim of this study was to compare outcomes associated with head and neck cancer surgery with free-flap reconstruction before and after implementation of an ERAS protocol. METHODS: Outcomes were analyzed by dividing patients into 2 groups: 29 patients in the non-ERAS group and 60 patients in the ERAS group. The ERAS group performed a prospective observational cohort study of patients who underwent a head and neck cancer surgery with free-flap reconstruction in Ajou University Hospital from August 2015 to December 2017. The non-ERAS group retrospectively reviewed the medical records of patients who had undergone the same surgery from August 2012 to July 2015. RESULTS: Demographics, comorbidities, hospital length of stay (LOS), postoperative complications, starting time of rehabilitation, and postoperative periods before radiotherapy for the non-ERAS and ERAS groups were compared. Hospital LOS was significantly lower for patients whose care followed the ERAS protocol than for patients in the non-ERAS group (30.87 ± 20.72 days vs. 59.66 ± 40.43 days, P < 0.0001). CONCLUSION: In this study, hospital LOS was reduced through fast recovery after the implementation of the ERAS protocol. Therefore, the ERAS protocol appeared feasible and safe in head and neck cancer surgery with free-flap reconstruction.

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Osseous choristoma is a rare, benign proliferative osseous lesion, which is defined as the growth of normal tissue in an abnormal location. The etiopathogenesis for its formation is unknown, but various hypotheses have been proposed. Treatment of choice is en-bloc resection, and no recurrence has been reported. Here, we report the two cases of osseous choristoma, presented with a mass on the base of the tongue with/without globus symptom and were treated with surgical excision.

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Malakoplakia is usually found in the genitourinary tract; however, it occurs uncommonly as a chronic inflammatory disease and rarely in the head and neck area, having been reported in the literature only few times. Here, we report, with a review of the related literature, a case of malakoplakia on the posterior neck. A 76-year-old male patient visited our institution presenting a rapidly growing neck mass that had invaded the overlying skin for several weeks. The results of imaging studies strongly indicated a malignant tumor, but an accurate diagnosis was not made until after a fine needle aspiration biopsy was undertaken twice. The lesion was completely excised with an extended radical neck dissection including the overlying skin and scalene muscle upon consent of the patient. The pathological diagnosis was made with various immunohistochemical staining methods including Von Kossa, Periodic acid-Schiff-diastase, CD-68 and CD163. During the 24 months follow-up after the surgery, there was no sign of recurrence.

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Malakoplakia is usually found in the genitourinary tract; however, it occurs uncommonly as a chronic inflammatory disease and rarely in the head and neck area, having been reported in the literature only few times. Here, we report, with a review of the related literature, a case of malakoplakia on the posterior neck. A 76-year-old male patient visited our institution presenting a rapidly growing neck mass that had invaded the overlying skin for several weeks. The results of imaging studies strongly indicated a malignant tumor, but an accurate diagnosis was not made until after a fine needle aspiration biopsy was undertaken twice. The lesion was completely excised with an extended radical neck dissection including the overlying skin and scalene muscle upon consent of the patient. The pathological diagnosis was made with various immunohistochemical staining methods including Von Kossa, Periodic acid-Schiff-diastase, CD-68 and CD163. During the 24 months follow-up after the surgery, there was no sign of recurrence.

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Althoughmany graftmaterials have been used for augmentation rhinoplasty, an ideal graft has not yet been developed.As the field of tissue engineering has been developing, it has been applied to the reconstruction of many organs, but its application in the rhinoplasty field is still limited. This study evaluated the utility of allogenic chondrocytes with fibrin/hyaluronic acid (HA)–poly(L-lactic-co-glycolic acid) (PLGA) constructs in augmentation rhinoplasty. Chondrocytes from rabbit auricular cartilage were isolated and cultured with fibrin/HA hydrogels and implanted into PLGA scaffolds. After 8 weeks of in vitro culture, the scaffolds were implanted in the nasal dorsum of six rabbits. Eight weeks postoperatively, the implanted siteswere evaluated with gross, radiologic, and histologic analysis. In vitro, more than 90% of the seeded chondrocytes in the PLGA scaffolds survived for 2 weeks, and they produced a large amount of extracellular matrix and were well differentiated. The grafts maintained their initial shape for 8 weeks after implantation. Radiological and histological evaluations showed that the structure was well maintained with minimal inflammatory response and appropriate elevation levels. However, the formation of neo-chondrocytes was not observed. PLGA scaffolds seeded with fibrin/HA and allogenic chondrocytes can be a biocompatible augmentation material in rhinoplasty in the future.

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BACKGROUND AND OBJECTIVES: The reconstruction of surgical defects in head and neck cancer patients requires thorough anatomical knowledge and considerable clinical experiences, hence it is a demanding job for un-experienced reconstructive surgeons. We evaluated the appropriateness and the surgical outcome of a one-year experience of head and neck reconstruction carried out in a tertiary hospital setting. SUBJECTS AND METHOD: We performed a retrospective review of the medical records of 73 patients who underwent reconstructive surgery at the Otolaryngology Department and Plastic Surgery from January, 2012 to September, 2016. RESULTS: Twenty-eight of 42 patients underwent free-flap reconstruction, including anterolateral thigh, radial forearm, or fibula free-flap by a head and neck surgeon. The rest of the patients underwent pedicled-flap surgery including pectoralis major or latissimus dorsi myocutanous flap. The mean operation time was 209.5 minutes and an average of 1.2 days intensive care unit- and 37.2 days of hospital stay were required in the free-flap cases. The flap failure happened in three patients, two in free-flap and one in pedicled flap. These surgical outcomes were comparable to those of the plastic surgery patient group. CONCLUSION: The technical appropriacy and acceptable outcome of head and neck reconstruction by head and neck surgeons was proven in this investigation. We propose that reconstructive surgery should be performed by head and neck surgeons as they could reduce operation time or complications because of their familiarity with complex surgical anatomy and early decision making competency.

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