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Adolescent and young adult (AYA, 15-39 years old) patients with papillary thyroid carcinoma (PTC) experience significant psychological distress and place great importance on obtaining information regarding the disease; however, their demands remain unmet. We aimed to investigate clinicopathological and molecular features of PTC in AYA patients and compare them to those of PTC in older patients (≥40 years). This retrospective study enrolled 1,677 patients diagnosed with PTC from January 2018 to December 2022, with 400 AYA patients and 1,277 older adults. At the time of diagnosis, AYA patients with PTC had higher rates of presentation in females, larger tumor size (>2.0 cm), lymphatic vessel invasion, chronic thyroiditis, clinical lymph node metastasis, and pathologic lymph node metastasis, but lower rates of multifocality and extrathyroidal extension compared with PTC in older adults. The two groups had no significant differences regarding surgical method and distant metastasis. The prevalences of BRAF p.V600E and TERT promoter mutations of PTC were significantly lower in AYA patients (69.1% vs. 82.6% and 1.3% vs. 18.8%, respectively; both p < 0.001). In conclusion, PTC in AYA patients differed from PTC in older patients. Particularly, BRAF p.V600E and TERT promoter mutations in AYA with PTC were less frequently observed than in older adults.

Background: The coexistence of v-Raf murine sarcoma viral oncogene homolog B1 ( BRAF V600E ) and telomere reverse transcriptase promoter ( TERT -p) mutations is considerably associated with aggressiveness and poor prognosis in papillary thyroid carcinoma (PTC). However, the association between gross findings and genetic alterations in PTC remains unknown. We aimed to investigate the association between clinicopathologic features, including macroscopic features, and the coexistent BRAF V600E and TERT -p mutations in patients with PTC. Methods: We retrospectively analyzed 375 cases of PTC surgically resected between January 2018 and October 2023 at a single institution, based on the presence of BRAF V600E and TERT -p double mutation. Clinicopathologic features, including gross features on the cut surface of tumors, were evaluated. Subsequently, the association between clinicopathologic features and mutation status was statistically examined. Cox proportional hazard models were used to analyze the impact of molecular pathological features on disease-free survival (DFS). Results: The BRAF V600E and TERT -p double mutation was identified in 78 (20.8%) patients among the PTC cases and was significantly correlated with shorter DFS. Multivariable analysis revealed that factors such as relatively older age (≥55 years) (odds ratio [OR] = 12.083, 95% confidence interval [CI] 4.498-32.456), larger tumor size (>2.0 cm) (OR = 2.722, CI 1.104-6.712), lobulated tumor margins (OR = 16.114, CI 3.155-82.296), papillary excrescences on the cut surface (OR = 17.573, CI 3.462-89.201), solid-cut surface (OR = 4.012, CI 1.084-14.849), minimal extrathyroidal extension (ETE) (OR = 4.156, CI 1.209-14.282), gross ETE (OR = 6.517, CI 1.734-24.490), and Ki-67 labeling index (LI) (≥5%, OR = 12.145, CI 4.354-33.877) were significantly associated with the double mutation. Conclusions: The BRAF V600E and TERT -p double mutation in PTC was significantly associated with relatively old age, larger tumor size, lobulated configuration in tumor margin, papillary excrescences on the cut surface, solid-cut surface, ETE, and high Ki-67 LI. These features are suggestive of the presence of the double mutation and should be analyzed at the molecular level in patients with PTC.

Purpose: This study investigated the effects of ice cream consumption on chyle leakage after left lateral neck dissection in patients with thyroid cancer., Methods: A total of 491 patients with thyroid cancer underwent left lateral neck dissection with identification of the thoracic duct following ice cream consumption. Before closing the wound, the anesthesiologist increased the intrathoracic pressure to observe chyle leakage. If chyle leakage occurred postoperatively, the drain was removed using the drain negative pressure release test., Results: Postoperative chyle leakage was observed in 18 of the 491 patients who underwent left lateral neck dissection. We treated 17 patients conservatively and 1 patient surgically. Drains were removed within five days in all patients. After the drain negative pressure release test had been performed in eight patients, the drainage volume significantly decreased from an average of 175 ml to 31 ml per day. The average number of days until the removal of the drainage tube was 3.2 days. No perioperative complications were associated with ice cream consumption., Conclusions: In left lateral neck dissection for thyroid cancer, performing surgery following ice cream consumption does not completely prevent chyle leakage; however, early drain removal is possible because there is only mild leakage., (© 2023. The Author(s).)

Background: Although lenvatinib is the preferred treatment for unresectable radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), this agent exerts considerable toxicities, which can lead to frequent dose interruptions and modifications. The adoption of planned drug holidays has been recently suggested as one means of minimizing or avoiding these severe adverse events. Our retrospective study demonstrated that planned drug holidays appear to be a promising strategy for continuing of lenvatinib. However, the benefits of planned drug holidays in a prospective study have yet to be clarified. Here, we investigated the impact of planned drug holidays on clinical outcomes in patients treated with lenvatinib in the COLLECT study. Methods: In COLLECT, a prospective observational study, patients with RR-DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities was permitted. Furthermore, planned drug holidays were allowed to avoid severe or intolerable toxicities. The present post hoc analysis focused on evaluating the impact of planned drug holidays on clinical outcomes, including overall survival (OS), time to treatment failure (TTF), time to failure strategy (TFS), and progression-free survival (PFS), in patients in the COLLECT study who were treated with lenvatinib. Results: In total, 262 patients were included. Of the 253 patients evaluable for efficacy, 73 undertook a planned drug holiday at the discretion of the attending physician. OS, TTF, TFS, and PFS were significantly longer in patients who used a planned drug holiday than in those who did not. The planned drug holiday group demonstrated notable clinical outcomes, with a 1-year OS of 95.8% and a 1-year PFS of 94.5%. Moreover, planned drug holidays demonstrated a clinically meaningful advantage in clinical outcomes. The planned drug holiday group had a significantly longer duration of administration at a dose of ≥10 mg. Conclusions: Planned drug holidays for lenvatinib were associated with significantly improved clinical outcomes compared to daily oral administration. Further investigation of the optimal treatment schedule for lenvatinib is warranted. Clinical Trial Registration: UMIN000022243.

Nodal metastasis is crucial for determining the stage of well-differentiated thyroid cancer (WTC) in patients older than 55. Well-formed thyroid follicular inclusions (TFIs) are occasionally encountered in the cervical lymph nodes (LNs) of patients with papillary thyroid carcinoma (PTC), and it is difficult to determine whether they are true nodal metastases or ectopic thyroid tissues (ETT). This study aimed to elucidate the impact of the expression of the DNA damage response molecule TP53-binding protein 1 (53BP1) using immunofluorescence (IF) as a biomarker to differentiate TFIs in cervical LN by comparing the mutation analyses of primary thyroid cancers. The data demonstrated the necessity for the differential diagnosis of true metastases from ETT among TFIs in cervical LNs. PTC-like nuclear features using hematoxylin-eosin staining combined with immunohistochemistry for conventional biomarkers of PTC, including BRAF V600E protein, were most helpful in identifying metastatic follicular-patterned carcinomas. In conclusion, IF analysis of 53BP1 expression could be an excellent ancillary technique to distinguish metastatic carcinoma or ETT from TFIs in LNs, particularly in cases other than BRAF V600E -mutated PTC.

Lenvatinib is a molecular-targeting agent that was recently approved in Japan for treatment of curatively unresectable, radioactive iodine-refractory, progressive differentiated thyroid cancer (DTC). Because only a few Japanese patients have received lenvatinib in clinical trials, there are limited domestic data on its safety and efficacy or prognostic factors. Therefore, a prospective observational study has been designed to collect safety and efficacy data in at least 300 patients with curatively unresectable DTC receiving lenvatinib therapy (24 mg/day), in order to find predictors of antitumor activity and survival. Patients with progressive curatively unresectable DTC refractory to radioiodine therapy will be enrolled and the primary endpoint will be overall survival. This study is designed to estimate the 95% confidence intervals of the 1-year and 2-year survival rates with a two-sided width of less than 10%. Secondary endpoints will be the time to treatment failure, time to strategy failure, progression-free survival time with clinical progressive disease, response rate, quality of life, safety, and patient reports. The ultimate goal is to obtain information for developing evidence-based guidelines for treatment of DTC, including recommendations on patient selection, dosages, and duration of treatment. This study has been registered with the UMIN Clinical Trials Registry (UMIN000022243).

This review emphasizes that the so-called high-risk thyroid carcinoma is not a distinct tumor entity, but a group of tumors with different histologies. High-grade histological features, such as tumor necrosis, increased mitoses, and nuclear pleomorphism, together with high Ki-67 labeling index (more than 10%), are good indicators of high-risk thyroid carcinoma and suggest a possible risk for anaplastic transformation. This review proposes the stratification of patients with thyroid carcinoma into low-, moderate-, and high-risk groups based on Ki-67 labeling index, which should be useful for the clinical management of patients, even after initial surgery. Currently, both the aggressive variant of papillary carcinoma and poorly differentiated carcinoma are aggressively treated by a completion of total thyroidectomy with prophylactic lymph node dissection followed by radioactive iodine treatment. Therefore, patients with moderate-risk or high-risk thyroid carcinoma based on Ki-67 labeling index should also be considered candidates for this treatment strategy.

Introduction: Familial adenomatous polyposis (FAP) is an inherited autosomal dominant syndrome caused by germline mutations in the adenomatous polyposis coli (APC) gene. Papillary thyroid cancer is one of the extracolonic manifestations of FAP. A characteristic histologic feature of this type of thyroid tumor is the cribriform-morula variant of papillary thyroid carcinoma (CMVPTC)., Methods: To investigate roles of the APC and beta-catenin genes in the development of CMVPTC, we examined germline and somatic mutations of these genes in a female patient with CMVPTC and FAP. The patient had undergone total colectomy at the age of 19 years and total thyroidectomy at age 25 years., Results: Numerous tumors were disseminated in both lobes of the thyroid gland, and histopathologic examination revealed typical CMVPTC. DNA was extracted from peripheral blood leukocytes and 12 CMVPTC tumors, and exons 1-15 of the APC gene and exon 3 of the beta-catenin gene were examined. A germline mutation was detected in exon 13 of the APC gene, and this mutation generated a premature stop codon. Six somatic mutations (922delC, 1602delA, 1821delT, 1920delG, 2706del20, 2804insA) were found in the CMVPTC specimens. All mutations were truncating mutations in the N-terminus of the APC protein. Loss of heterozygosity was not observed in the remaining tumor tissues without somatic APC mutations. There were no mutations of the beta-catenin gene in peripheral blood leukocytes or 12 CMVPTC specimens., Conclusions: These results suggest that APC mutations play an important role in the development of CMVPTC and occur predominantly in the 5' side of the APC gene between codons 308 and 935.

Risk factors for distant metastasis were studied in 82 patients with follicular thyroid carcinoma (FTC). Metastases to either the lung or bone existing at the time of presentation were confirmed by I-131 radio-iodine uptake in 10 patients. FTC with an insular component was found in eight patients. Univariate analysis of 14 possible risk factors showed 7 to be statistically significant: insular component, poorly differentiated carcinoma, trabecular component, serum thyroglobulin level before surgery, patient age at the time of presentation, solid component, and vascular invasion (ranked by p values). After further analysis of the interrelation of the factors and of the logistic regression curves, we concluded that presence of an insular component and patient age were the only independent risk factors. Distant metastasis was not detected in any of the 27 patients < or = 49 yr old. Among the 55 older patients (> or = 50 yr old), 5 of the 49 (10%) without an insular component and 5 of the 6 (83%) with an insular component had distant metastasis. The remaining older patient with an insular component but without distant metastasis showed a gradual increase in thyroglobulin levels after total thyroidectomy.

Our standard surgical approach to patients with papillary thyroid cancer is subtotal thyroidectomy with modified radical neck dissection (MRND) on the affected side. MRND preserves the jugular vein, the sternocleidomastoid muscle, and the accessory nerve, effectively conserving function and cosmesis. Knowledge of the anatomy of the neck, precise staging, prognostic evaluation, and experience are needed for a surgeon to perform MRND. Radical neck dissection should not be performed unless the tumor invades the jugular vein and sternocleidomastoid muscle. Berry picking is not indicated for patients with thyroid cancer. The skin incision used is an extended collar incision. If lymph node metastasis is present at the upper bifurcation of the carotid artery, a modified MacFee incision is used. Taping of the carotid artery or sternocleidomastoid muscle is avoided unless the tumor invades these tissues. MRND is a safe procedure when performed by skilled, experienced surgeons.

To evaluate the clinical applicability of galectin-3 and CD44 variant 6 (CD44v6) immunostaining in fine-needle aspiration cytology (FNAC) of thyroid follicular tumors, 79 cytological specimens (35 follicular carcinomas and 44 follicular adenomas) were studied. The positive rates of galectin-3 and CD44v6 were 89 and 74% in follicular carcinoma, respectively, and 25 and 30% in follicular adenoma, respectively. There were no significant correlations between the expression of galectin-3 or CD44v6 in follicular carcinoma and characteristics such as capsular invasion, vascular invasion, metastasis, or tumor size. Positive staining of either galectin-3 or CD44v6 resulted in a diagnostic sensitivity of 97% and a specificity of 52% for follicular carcinoma among follicular tumors. Immunostaining of galectin-3 or CD44v6 using cytological specimens can provide independent information on conventional morphological findings of cytology to distinguish follicular carcinoma from adenoma., (copyright (c) 2004 Wiley-Liss, Inc.)

Mass screening for the purpose of detecting thyroid cancer at its earliest stage may not be recommended at the present time, but screening focused on certain risk groups is advocated. Familial nonmedullary thyroid carcinoma (FNMTC) is a distinct clinical entity with a high incidence of multifocality and association with multiple benign nodules. FNMTC patients have shorter disease-free survival than do sporadic disease patients because of frequent locoregional recurrence. Screening by neck ultrasonography was performed for symptom-free family members of patients with FNMTC. A total of 149 subjects representing 53 FNMTC families were examined in this study. The average age of the patients was 41.0+/-19.0 years (range 3-76 years) with a female/male ratio of 104:45. At least one thyroid nodule was found in 77 (51.7%) of the 149 patients. Surgery was performed in 18 patients, and thyroid cancer was discovered in 15 of them (10.1%; 14 women, 1 man; 32-61 years of age). Papillary thyroid cancer (PTC) was found in 14 and follicular thyroid cancer combined with PTC in 1. The tumors averaged 9.1+/-5.4 mm (3-21 mm) in greatest diameter. Intraglandular metastases were found in 7 (47%) of the 15 patients with thyroid cancer. Lymph node metastases were found in 6 (43%). Ultrasonographic screening for FNMTC family members may enable the discovery of asymptomatic thyroid cancer. Because of the high incidence of intraglandular and lymph node metastases, we recommend screening with ultrasonography for early detection in family members of patients with FNMTC.

We report herein a case of thyroid mucosa-associated lymphoid tissue (MALT) lymphoma in a patient receiving antithyroid drug therapy for Graves' disease. A 75-year-old woman first presented with finger tremor and was diagnosed with Graves' disease on the basis of clinical and laboratory findings. Three years later, she presented with rapid and painless enlargement of the thyroid. Ultrasonography revealed a circumscribed hypoechoic area bilaterally in each lobe of the thyroid, and fine-needle aspiration biopsy showed diffuse monotonous infiltration of small- to medium-sized atypical lymphoid cells. (67)Ga scintigraphy was positive exclusively in the thyroid. After total thyroidectomy, the patient received radiation therapy for treatment of stage IE primary thyroid lymphoma. Results of histological examination, immunohistochemical analysis, and flow cytometric analysis confirmed MALT lymphoma. To our knowledge, there have been few published reports of primary thyroid lymphoma associated with Graves' disease. Our experience with this case, though rare, indicates that an enlarged thyroid in cases of Graves' disease should be examined carefully for primary thyroid lymphoma.

Hypothesis: Dipeptidyl aminopeptidase IV (DPP IV) activity in cytological samples from a follicular thyroid tumor is the most sensitive and specific indicator for the detection of follicular carcinoma of the thyroid gland. Dipeptidyl aminopeptidase IV activity is independent of cytological characteristics and superior to other clinical findings. DESIGN AND PATIENT SELECTION: Among the patients surgically treated for follicular thyroid tumors, we recruited approximately equal numbers of those with true-positive (n = 19), true-negative (n = 26), false-negative (n = 16), and false-positive (n = 18) cytological characteristics., Main Outcome Measures: We examined DPP IV activity using cytological specimens obtained from 35 patients with follicular thyroid carcinomas and 44 patients with follicular adenomas. Tumor size, patient age, serum thyroglobulin level, and ultrasonographic findings were also analyzed., Results: The positive rate of DPP IV activity was 97% in 35 patients with follicular thyroid carcinomas and 5% in 44 patients with follicular adenomas, resulting in a sensitivity of 97%, a specificity of 95%, and an overall accuracy of 96%. This discriminating ability of DPP IV activity was far higher than that of tumor size, patient age, serum thyroglobulin level, or ultrasonographic findings., Conclusions: Positive DPP IV activity in cytological samples is the best discriminatory marker between follicular thyroid carcinoma and follicular adenoma. Its application could alter the clinical management of patients with follicular thyroid tumors.

We describe our modification of the reversed T-shaped sternotomy. The conventional technique consists of a limited upper sternotomy with transverse division of the sternum. Our modification involves shifting the transverse division lines one costal space between the right and left sides for perfect apposition of the divided upper and lower sternum. This technique can be used for patients with thyroid cancer and mediastinal lymph node metastasis and for those with a mediastinal tumor or certain cardiac disorders.

First-degree relatives of persons with thyroid cancer are known to be at relatively high risk for the disease. To better understand the clinicopathologic characteristics of familial nonmedullary thyroid carcinoma (FNMTC), we carried out a retrospective study in which we identified individuals treated at our institution who had at least one first-degree relative with the disease. We used data obtained from our patient records to compare the features of 258 cases of the disease with the features of sporadic papillary or follicular thyroid carcinoma in another group of patients. The 258 patients represented 154 families and were selected from among 6458 patients with papillary or follicular thyroid carcinoma who underwent thyroidectomy between 1946 and 2000. Compared to the patients with sporadic disease, the FNMTC patients were more likely to have intraglandular dissemination (28.5% vs. 40.7%; p < 0.0001) and multiple benign nodules (29.8% vs. 41.5%; p <0.0001). There were no significant differences between the two types of patients in terms of gender, age, tumor diameter, adhesion to or invasion of the surrounding tissues, macroscopic metastasis observed at surgery, histology, presence of single benign nodules, presence of chronic thyroiditis, microscopic metastasis, or rate of lymph node metastasis. Recurrence was statistically frequent in the FNMTC patients compared with that in the sporadic disease patients (16.3% vs. 9.6%; p = 0.0005), and the disease-free survival rate was significantly poorer in the FNMTC patients (p = 0.0041 by the Wilcoxon test and p <0.0001 by the log-rank test). No significant difference in the overall survival rate was found between the two groups. Multivariate analysis by Cox's proportional hazards method showed FNMTC to be an independent predictor of shorter disease-free survival (risk ratio 1.88; confidence interval 1.35-2.54; p = 0.0003). Locoregional recurrence in the ipsilateral or contralateral lymph nodes and contralateral thyroid lobe was significantly more frequent in the FNMTC patients than in the sporadic disease patients, whereas no difference was found regarding distant metastases. We conclude that FNMTC is a clinically distinct entity with an aggressive nature. Because of the frequent presence of benign nodules, multifocality, and high rate of locoregional recurrence, total or near-total thyroidectomy with modified radical neck dissection in FNMTC patients is recommended.

Differentiated thyroid cancer sometimes shows microscopic vascular invasion but rarely causes a tumor thrombus in a great vein. A preoperative diagnosis of the latter condition is difficult if a patient does not have any overt symptoms, but it is important for operative planning. We encountered a 26-year-old woman with papillary thyroid cancer and a tumor thrombus extending from the brachiocephalic vein to the superior vena cava. The tumor was successfully treated by surgical resection. To our knowledge only 19 such cases have so far been reported. We herein report our case, review the literature, and discuss the associated diagnostic problems and treatments including such areas as age, gender, symptoms, pathology, extension, and outcome.

Purpose: We previously reported a poor prognosis in papillary thyroid carcinoma patients with recurrence in the contralateral cervical lymph nodes after thyroidectomy and ipsilateral modified radical neck dissection (MRND) with a curative intent. The aim of this study was to investigate whether bilateral MRND improved prognosis in patients at risk for contralateral nodal recurrence., Methods: We retrospectively reviewed the cases of 86 patients with contralateral nodal metastasis who underwent a thyroidectomy with bilateral MRND (group 1) and the cases of 32 patients who suffered contralateral nodal recurrence after a thyroidectomy with ipsilateral MRND (group 2)., Results: Although tumor progression was considered similar in patients from groups 1 and 2, group 1 developed fewer distant metastases than group 2 (6.8% vs 31.1%), thus resulting in a lower cancer death rate (5.8% vs 28.1%). Group 1 had a better 10-year survival rate than of group 2 (97.1% vs 83.7%)., Conclusion: Bilateral MRND during initial surgical management is thus considered to improve the prognosis of some papillary carcinoma patients at risk for recurrence in the contralateral cervical lymph nodes.