Impact of the quality of resected thyroid cancer tissue sample on next-generation sequencing testing.

Activating rearranged during transfection (RET) proto-oncogene alterations can be identified using next-generation sequencing (NGS) of tumor DNA/RNA. We assessed factors associated with NGS (Oncomine Dx Target Test [ODxTT]) success for resected thyroid cancer (TC) specimens, including sample age, processing conditions, and DNA/RNA quality. TC samples were from three Japanese hospitals, with sample age <1-<10 years, fixative 10%/15% neutralized buffered formalin (NBF), and fixation time ≤48 h/>48 h-≤72 h. NGS success rate was defined as the percentage of samples returning validated NGS results (RET fusion-positive/negative [RNA] or RET mutation-positive/negative [DNA], detected using ODxTT). DNA/RNA quality was assessed with indexes based on electrophoresis (DNA/RNA integrity number, DV200 ) and quantitative polymerase chain reaction (DNA/RNA integrity score [ddCq/ΔCq]). NGS success rate (N = 202) was 90%/93% (DNA/RNA) overall, 98%-100% (DNA and RNA) for samples <3 years old, and 91% (DNA and RNA) for samples ≥3-<5 years old fixed in 10% NBF for ≤48 h. Multivariate logistic regression analysis identified ddCq and ΔCq as significant predictors of DNA and RNA NGS success rates, respectively. Quality assessment of nucleic acid extracted from archival tissue samples is important for achieving high NGS success rates in clinical practice, especially for samples ≥3 years old.

Role of the degree of vascular invasion in predicting prognosis of follicular thyroid carcinoma.

OBJECTIVE: The present study investigated the prognostic factors for follicular thyroid carcinoma (FTC) with the incorporation of the histologic subtype and degree of vascular invasion (VI). PATIENTS: The records of 474 patients with FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were reviewed in this retrospective cohort study. The Cox proportional hazard model was used to determine factors associated with disease-free survival (DFS) and distant metastasis-free survival. RESULTS: Of the 474 patients, 140 (30%) had minimally invasive follicular thyroid carcinoma (MI-FTC), 260 (55%) had encapsulated angio-invasive follicular thyroid carcinoma (EA-FTC), and 74 (16%) had widely invasive follicular thyroid carcinoma (WI-FTC). Among the 428 patients with M0 FTC, the 10-year DFS rates of patients with MI-FTC (n = 133), EA-FTC (n = 247), and WI-FTC (n = 48) were 97.3%, 84.2%, and 69.9% (p < 0.001), respectively. A multivariate analysis identified age ≥ 55 years (hazard ration [HR], 2.204; 95% confidence interval [CI], 1.223-3.969; p = 0.009), histologic subtype (HR, 2.068; 95% CI, 1.064-4.021, p = 0.032), number VI of ≥ 2 (HR, 6.814; 95% CI, 3.157-14.710, p < 0.001), and tumor size > 40 mm (HR, 2.014; 95% CI, 1.089-3.727, p = 0.026) as independent negative prognostic factors for DFS. CONCLUSIONS: Our study results may enable us to stratify the prognosis of FTC more accurately by combining the histologic subtype with the degree of VI ≥ 2, age ≥ 55 years, and tumor size > 40 mm.

New Insights on the Importance of the Extent of Vascular Invasion in Widely Invasive Follicular Thyroid Carcinoma.

BACKGROUND: This study aimed to investigate the association between the extent of vascular invasion (VI) and the outcome of widely invasive follicular thyroid carcinoma (WI-FTC). METHODS: The records of 107 patients with WI-FTC confirmed by surgical specimens from January 2005 to December 2016 were retrospectively reviewed. RESULTS: Among the 107 patients with WI-FTC, those with a VI of < 4 (n = 62) and ≥ 4 (n = 45) had a 10 year cause-specific survival (CSS) rate of 97.7% and 89.4% (p = 0.008), respectively. Univariate analysis identified M1 (p = 0.001), and the number of VI of ≥ 4 as significant negative prognostic factors for CSS. Multivariate analysis identified M1 (hazard ratio [HR] = 9.366) as independent negative prognostic factor for CSS. Among the 72 patients with M0 WI-FTC, those with a VI of < 2 (n = 33) and ≥ 2 (n = 39) had a 10-year distant metastasis-free survival (DMFS) rate of 96.8% and 56.8% (p = 0.001), respectively. Univariate analysis identified age ≥ 55 years (p = 0.011), presence of VI, the number of VI of ≥ 2, and resection margin status (p < 0.001) as significant negative prognostic factors for DMFS. Multivariate analysis identified the number of VI ≥ 2 (HR = 9.137), and resection margin status (HR = 5.853) as independent negative prognostic factors for DMFS. CONCLUSIONS: It may be unnecessary that WI-FTC with curative resection margin status and a VI of < 2, especially in capsular invasion only, routinely undergo completion thyroidectomy and postoperative ablation.

Three-dimensional structural analysis of papillary thyroid carcinoma nuclei with serial block-face scanning electron microscopy (SBF-SEM).

Nuclear morphology of carcinoma cells is critical for the pathological diagnosis of papillary thyroid carcinoma (PTC). However, three-dimensional architecture of PTC nuclei is still elusive. In this study, we analyzed the three-dimensional ultrastructure of PTC nuclei using serial block-face scanning electron microscopy which takes advantage of the high-throughput acquisition of serial electron microscopic images and three-dimensional reconstruction of subcellular structures. En bloc-stained and resin-embedded specimens were prepared from surgically removed PTCs and normal thyroid tissues. We acquired two-dimensional images from serial block-face scanning electron microscopy and reconstructed three-dimensional nuclear structures. Quantitative comparisons showed that the nuclei of carcinoma cells were larger and more complex than those of normal follicular cells. The three-dimensional reconstruction of carcinoma nuclei divided intranuclear cytoplasmic inclusions into "open intranuclear cytoplasmic inclusions" connecting to cytoplasm outside the nucleus and "closed intranuclear cytoplasmic inclusions" without that connection. Cytoplasm with abundant organelles was observed in open inclusions, but closed inclusions contained fewer organelles with or without degeneration. Granules with a dense core were only observed in closed inclusions. Our observations suggested that open inclusions originate from nuclear invaginations, and disconnection from cytoplasm leads to closed inclusions.

Evaluation of factors predicting postoperative recurrence and metastasis of parathyroid cancer: a single-center study.

PURPOSE: The purpose of this study was to examine the postoperative clinical course of parathyroid carcinoma to determine factors that predict postoperative recurrence and distant metastasis. METHODS: In this retrospective study, we included 38 patients with parathyroid carcinoma who received surgical intervention at Itoh Hospital between 1979 and 2020. Clinicopathologic characteristics (age, sex, intact PTH, serum Ca level, operation type, parathyroid weight, parathyroid size, histopathologic findings: vascular invasion, capsular invasion, necrosis, histological type, and Ki-67 staining) were used. The median follow-up observation period was 63.7 months. RESULTS: Postoperatively, 5 patients (13.2%) developed distant metastasis or had localized recurrence, and 3 patients died (7.9%). The results of the univariate analysis revealed three factors affecting distant metastasis and recurrence, which were Ki-67 (p = 0.0041), the presence or absence of necrosis (p = 0.0163), and tumor weight (p = 00,189). Using the cutoff values obtained by ROC analysis, which were 4.1 for Ki-67 (sensitivity of 80% and specificity of 96.9%) and 4890 mg for tumor weight (sensitivity of 100% and specificity of 60.9%), we calculated the cumulative incidence of recurrence and distant metastasis by the three factors retained. We found that the presence of the three factors was associated with a high possibility of distant metastasis or recurrence during the 5-year follow-up period. CONCLUSIONS: Three factors, Ki-67, necrosis, and tumor weight in parathyroid carcinoma, may predict outcomes of postoperative recurrence and distant metastasis.

Adult Thyroid Outcomes of Congenital Hypothyroidism.

Background: More than 40 years have passed since the introduction of newborn screening (NBS) for congenital hypothyroidism (CH), and many early diagnosed patients have reached adulthood. Their thyroid morphology and function have been little studied. This cross-sectional, observational study was conducted to characterize the thyroid morphology and function of adult CH patients diagnosed in the framework of NBS for CH. Methods: A total of 103 adult CH patients born after 1979 were enrolled at Ito Hospital, Tokyo, Japan, and were classified into Goiter, Normal gland, and Dysgenesis groups based on ultrasonographic findings. For 60 patients, genetic analysis was performed. Thyroid function test results and the proportion of patients with thyroid nodules were compared among the three groups and between 56 female CH patients and 168 non-CH women matched for thyrotropin levels. Results: A significantly low serum free triiodothyronine/free thyroxine ratio (0.22) was observed in the Dysgenesis group. Thyroid nodules were detected in 14.3% (8/56) of female CH patients, more frequently than in non-CH women. Thyroid nodules were detected most frequently in the Goiter group (71%, 10/14). Genetic defects were identified in 89% (8/9) of patients belonging to the Goiter group, including thyroglobulin defect (33%, 3/9), thyroid peroxidase defect (33%, 3/9), and dual oxidase 2 defect (22%, 2/9). Conclusions: Our results suggest that adults with thyroid dysgenesis on levothyroxine replacement therapy have relative triiodothyronine deficiency. Most adults with goitrous CH have genetic dyshormonogenesis. They are at high risk of developing thyroid nodules. Our findings support the current guideline recommendation that CH patients with dyshormonogenesis should undergo periodic thyroid ultrasonography.

Primary Thyroid Mucoepidermoid Carcinoma (MEC) Is Clinically, Prognostically, and Molecularly Different from Sclerosing MEC with Eosinophilia: A Multicenter and Integrated Study.

Mucoepidermoid carcinoma (MEC) and sclerosing MEC with eosinophilia (SMECE) are rare primary thyroid carcinomas. In this study, we aimed to present our multicenter series of MEC and SMECE and integrated our data with published literature to further investigate the clinicopathological characteristics and prognoses of these tumors. We found 2 MECs and 4 SMECEs in our multicenter archives. We performed fluorescence in situ hybridization (FISH) to determine the MAML2 gene rearrangement. We screened for mutations in BRAF, TERT promoter, and RAS mutations using Sanger sequencing and digital polymerase chain reaction. Histopathologically, MECs and SMECEs were composed of two main cell types including epidermoid and mucin-secreting cells, arranged in cords, nests, and tubules. SMECEs were characterized by a densely sclerotic stroma with abundant eosinophils. We did not detect any MAML2 fusion in any of our cases. Two MEC cases harbored concomitant BRAF p.V600E and TERT C228T mutations. RAS mutations were absent in all cases. Concurrent foci of another thyroid malignancy were more commonly seen in MECs (p < 0.001), whereas SMECEs were associated with chronic lymphocytic thyroiditis (p < 0.001). MECs and SMECEs had equivalent recurrence-free survival (RFS) but MECs conferred significantly dismal disease-specific survival (DSS) as compared to SMECEs (p = 0.007). In conclusion, MECs and SMECEs not only shared some similarities but also demonstrated differences in clinicopathological characteristics, prognoses, and molecular profiles. SMECEs had a superior DSS in comparison to MECs, suggesting that they are low-grade cancers. This could help clinicians better evaluate patient outcomes and decide appropriate treatment plans.

Response to neoadjuvant paclitaxel predicts survival in anaplastic thyroid carcinoma.

The clinical utilities of paclitaxel in anaplastic thyroid carcinoma (ATC) have been reported. The current study investigated the outcomes in ATC patients treated by paclitaxel as neoadjuvant setting. Furthermore, the prognostic factor for overall survival (OS) and predictive marker for response to paclitaxel were investigated. Records of ATC patients treated by paclitaxel as neoadjuvant setting in our hospital were reviewed. The median OS for the patients with (n = 43) and without (n = 23) resection were 14.7 (95% CI, 11.0-21.7) and 4.2 (95% CI, 3.0-5.4) months, respectively (p < 0.001). Univariate analysis identified the factors of stage (p = 0.028), prognostic index (PI) ≥2 (p < 0.001), response to paclitaxel (p = 0.007), resection (p < 0.001), and radiotherapy (p < 0.001) to be associated with OS, and multivariate analysis revealed that the factors of PI ≥2 [hazard ratio (HR), 2.406 (95% CI, 1.096-5.281), p = 0.029], response to paclitaxel [HR, 0.423 (95% CI, 0.193-0.930), p = 0.032], resection [HR, 0.316 (95% CI, 0.129-0.773), p = 0.012], and radiotherapy [HR, 0.229 (95% CI, 0.100-0.526), p < 0.001] were independent prognostic factors of OS. There were no significant predictive factors for response to paclitaxel in baseline characteristics. PI ≥2, response to paclitaxel, resection, and radiotherapy were independent prognostic factors in ATC patients treated with paclitaxel as neoadjuvant setting. It is important to investigate predictor for response to paclitaxel for improving resectability and prognosis in ATC.

Impact of Local Control on Clinical Course in Stage IVC Anaplastic Thyroid Carcinoma.

BACKGROUND: The present study investigated the association between local resection and cause of death in anaplastic thyroid carcinoma (ATC) patients with stage IVC disease. METHODS: A total of 54 ATC patients with stage IVC disease were included in the study. Information including patient characteristics, laboratory data including complete blood count, treatment, and death were collected for analysis. RESULTS: The median overall survival (OS) for patients with or without resection was 8.4 [95% confidence interval (CI) 5.9-14.4)] and 4.2 (95% CI 2.5-6.2) months, respectively (p < 0.001). No patients survived without resection at 1 year. Univariate analysis revealed that resection (p < 0.001) and radiotherapy (p = 0.018) were significantly associated with OS. Multivariate analysis revealed that resection (hazard ratio 0.257; 95% CI 0.115-0.575; p < 0.001) was the only independent prognostic factor of OS. In ATC patients with known resection status, the median OS for the patients with a resection status of R0/1 (n = 28) and R2 (n = 7) were 13.0 (95% CI 7.5-18.7) and 1.7 (95% CI 0.1-6.2) months, respectively (p < 0.001). The most common specific cause of death was respiratory insufficiency (35%), followed by airway obstruction (25%) and cerebral cardiovascular-related death (5%). The frequency of airway obstruction was significantly lower in patients with resection (p = 0.018). CONCLUSIONS: Resection probably impacts on clinical course in ATC patients despite the presence of distant metastasis. However, R2 resection is likely to be harmful and surgeons should carefully consider the resectability of thyroid tumors.

The Mediation Role of Thyrotropin Receptor Antibody in the Relationship Between Age and Severity of Hyperthyroidism in Graves' Disease.

Background: The severity of hyperthyroidism in Graves' disease (GD) has been reported to be worse in younger patients and to gradually improve with advancing age, accompanied by declining thyrotropin (TSH) receptor antibody (TRAb) values. This study was conducted to explore the extent to which the declining TRAb production may contribute to a decrease in severe hyperthyroidism with advancing age in patients with GD. Methods: This study was a cross-sectional analysis of retrospectively reviewed data. The medical records of patients newly diagnosed with GD at Ito Hospital, between January 2005 and June 2019, were examined. Patients were divided into age-stratified groups for evaluation. Multivariable logistic regression was performed to estimate the odds ratio (OR) of severe hyperthyroidism by increasing age. Mediation analyses were also conducted to quantify the association between age and declining severity of hyperthyroidism mediated through decreased TRAb productivity. Results: A total of 21,018 patients with newly diagnosed GD (3848 male and 17,170 female) were included. A correlation was observed between TRAb value and thyroid hormone values in each age-stratified group, which became weaker with an increase in age. Patients aged <40 years had a higher risk of severe hyperthyroidism (free thyroxine [fT4] level >7.0 ng/dL [n = 5616], OR [confidence interval, CI] = 1.80 [1.68-1.92]; free triiodothyronine [fT3] level >25 pg/mL [n = 4501], OR [CI] = 2.06 [1.92-2.23]) than those aged ≧40 years. In examining the relationship between age and severe hyperthyroidism, the proportion mediated through TRAb productivity was 8.5% and 8.4% using fT4 and fT3 as an outcome index, respectively. Conclusions: Declining TRAb value mediated only 8.5% of the negative association between age and severity of hyperthyroidism. The presence of other underlying mechanisms, such as the decline in the reactivity of thyrocytes to TSH stimulation, requires further investigation.

Expression of T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT) in anaplastic thyroid carcinoma.

BACKGROUND: Immune checkpoint proteins have not been fully examined in follicular cell-derived thyroid carcinoma and medullary thyroid carcinoma (MTC). Anaplastic thyroid carcinoma (ATC) is one of the most aggressive carcinomas. Even multimodal treatment does not result in favorable clinical outcomes for patients with ATC. Anti-tumor immunity has therefore been highlighted as having therapeutic promise for ATC. METHODS: We examined a novel immune checkpoint receptor, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT), in variable thyroid lesions: adenomatous goiter, follicular adenoma, and thyroid carcinoma (TC) using immunohistochemistry (IHC). RESULTS: Our IHC results showed that TIGIT expression was detected in cancer cells of MTC and high-grade TC: poorly differentiated thyroid carcinoma (PDTC) and ATC. Neoplastic cells were positive for TIGIT in four of five MTCs (80.0%), 17 of 31 ATCs (54.8%) and in 3 of 12 PDTCs (25.0%). TIGIT was not detected in any adenomatous goiters, thyroid benign tumors, or differentiated thyroid carcinoma (DTCs). Intriguingly, ATC cells showing pleomorphic/giant cell features were positive for TIGIT, while ATC cells with other cell morphologies lacked the immunoreactivity. Intra-tumoral immune cell was inclined to be enriched in TIGI-positive ATC. Although coexisting papillary thyroid carcinoma (PTC) components demonstrated high-grade microscopic features, neither the PTC nor follicular thyroid carcinoma (FTC) components expressed TIGT in any composite ATCs. CONCLUSION: TIGIT was immunohistochemically found in MTC with high frequency and partially in high-grade TC. TIGIT expression in cancer cells may be beneficial for a potential utility in MTC and a subset of high-grade TC, especially ATC therapy.

Preoperative inflammatory markers for predicting parathyroid carcinoma.

Objective: Parathyroid carcinoma is a rare tumor among parathyroid tumors. Aspiration cytology and needle biopsy are generally not recommended for diagnostic purposes because they cause dissemination. Therefore, it is commonly diagnosed by postoperative histopathological examination. In this study, we investigated whether preoperative inflammatory markers can be used as predictors of cancer in patients with primary hyperparathyroidism. Design: This was a retrospective study. Methods: Thirty-six cases of parathyroid carcinoma and 50 cases of parathyroid adenoma (PA) operated with the diagnosis of primary hyperparathyroidism and confirmed histopathologically at Ito Hospital were included in this study. Preoperative clinical characteristics and inflammatory markers (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio (LMR)) were compared and their values in preoperative prediction were evaluated and analyzed. Results: Preoperative intact-parathyroid hormone (P = 0.0003), serum calcium (P = 0.0048), and tumor diameter (P = 0.0002) were significantly higher in parathyroid carcinoma than in PA. LMR showed a significant decrease in parathyroid carcinoma (P = 0.0062). In multivariate analysis, LMR and tumor length diameter were independent predictors. In the receiver operating characteristics analysis, the cut-off values for LMR and tumor length diameter were 4.85 and 28.0 mm, respectively, for parathyroid cancer prediction. When the two extracted factors were stratified by the number of factors held, the predictive ability improved as the number of factors increased. Conclusion: In the preoperative evaluation, a combination of tumor length diameter of more than 28 mm and LMR of less than 4.85 was considered to have a high probability of cancer.

Substantial improvement of histopathological diagnosis by whole-slide image-based remote consultation.

Consultation by subspecialty experts is the most common mode of rendering diagnosis in challenging cases in pathological practice. Our study aimed to highlight the diagnostic benefits of whole-slide image (WSI)-based remote consultation. We obtained diagnostically challenging cases from two institutions from the years 2010 and 2013, with histological diagnoses that contained keywords "probable," "suggestive," "suspicious," "inconclusive," and "uncertain." A total of 270 cases were selected for remote consultation using WSIs scanned at 40 × . The consultation process consisted of three rounds: the first and second rounds each with 12 subspecialty experts and the third round with six multi-expertise senior pathologists. The first consultation yielded 44% concordance, and a change in diagnosis occurred in 56% of cases. The most frequent change was from inconclusive to definite diagnosis (30%), followed by minor discordance (14%), and major discordance (12%). Out of the 70 cases which reached the second round, 31 cases showed discrepancy between the two consultants. For these 31 cases, a consensus diagnosis was provided by six multi-expertise senior pathologists. Combining all WSI-based consultation rounds, the original inconclusive diagnosis was changed in 140 (52%) out of 266 cases. Among these cases, 80 cases (30%) upgraded the inconclusive diagnosis to a definite diagnosis, and 60 cases (22%) changed the diagnosis with major or minor discordance, accounting for 28 cases (10%) and 32 cases (12%), respectively. We observed significant improvement in the pathological diagnosis of difficult cases by remote consultation using WSIs, which can further assist in patient healthcare. A post-study survey highlighted various benefits of WSI-based consults.

The Relationship Between Primary Thyroid Lymphoma and Various Types of Thyroid Autoimmunity: A Retrospective Cohort Study of 498 Cases, Including 9 Cases with Graves' Disease.

Background: Primary thyroid lymphoma (PTL) is known to develop mostly in patients with Hashimoto's thyroiditis (HT), and it is rare for it to develop in patients with Graves' disease (GD). The objective of this study was to investigate the clinical features, pathological findings, and long-term outcomes of PTL patients, grouped according to the presence of GD, HT, or no autoimmune thyroid disease (AITDs). The GD group was of major interest due to limited knowledge of the relationship with PTL. Methods: In this single-center retrospective cohort study, we reviewed the medical records of all patients diagnosed with PTL between August 1979 and October 2021, and we characterized the patients according to the presence of HT, GD, or no AITDs. Pathological specimens were classified according to the World Health Organization classification. Staging was performed in accordance with the Ann Arbor classification. Results: During the 42-year period, 498 participants were diagnosed with PTL. The median age was 68 (interquartile range 61-76) years, and 221 patients were stage IE, whereas the remaining 277 patients were stage IIE. Of the PTL patients, 431 (86.6%) were diagnosed with HT, 9 (1.8%) were diagnosed with GD, and 58 (11.6%) did not have AITDs. All nine patients with GD were positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. All patients with GD were treated with anti-thyroid medication. There were no significant differences in the proportions of each subtype of PTL between the PTL patients with GD and all subjects with PTL (p = 0.51), PTL patients with HT (p = 0.51), or PTL patients without AITDs (p = 0.48). The median follow-up time was 6.2 (interquartile range 3.0-10.7) years after the diagnosis of PTL. The Kaplan-Meier curve analyses showed no significant differences in overall survival and event-free survival between PTL patients with GD and those with HT (p = 0.37), or between PTL patients with GD and those without AITDs (p = 0.43). Conclusions: The PTL was observed with HT in a majority of cases, and rarely with GD (1.8%). The proportions of each pathological subtype of PTL and the prognosis of PTL were not different between the patients with GD and those with HT or those without AITDs.

Encapsulated Angioinvasive Follicular Thyroid Carcinoma: Prognostic Impact of the Extent of Vascular Invasion.

BACKGROUND: Previous studies have reported an association between four or more foci of vascular invasion (VI) and thyroid cancer prognosis, while the current study aimed to investigate the association between extent of VI and outcome of encapsulated angioinvasive follicular thyroid carcinoma (FTC). METHODS: The records of 303 patients with encapsulated angioinvasive FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were retrospectively reviewed. Thirteen patients had distant metastasis at diagnosis and were classified as M1. RESULTS: Among the 290 patients with M0 encapsulated angioinvasive FTC, the 10-year disease-free survival (DFS) rate was 85.6%. Those with a VI of 1 (n = 131) or ≥ 2 (n = 159) had a 10-year DFS rate of 94.9% and 77.9% (p < 0.001), respectively, and those with a VI of 1-3 (n = 211) or ≥ 4 (n = 79) had a 10-year DFS rate of 86.3% and 83.3% (p = 0.311), respectively. Multivariate analysis identified age ≥ 55 years (p = 0.031) and VI ≥ 2 (p = 0.002) as independent negative prognostic factors for DFS. Patients with M0 encapsulated angioinvasive FTC aged ≥ 55 years and VI ≥ 2 had significantly poorer prognosis and a 10-year DFS rate of 66.4% (p < 0.001). CONCLUSIONS: Patients with encapsulated angioinvasive FTC who had two or more foci of VI, especially patients aged ≥ 55 years, should be carefully followed-up.

Clinical course and outcome of differentiated thyroid cancer patients with pregnancy after diagnosis of distant metastasis.

PURPOSE: There is no sufficient data about the clinical course and outcome in thyroid cancer patients who become pregnant after diagnosis of distant metastasis (DM). The current study was conducted to collect information regarding the clinical and reproductive characteristics, and outcomes in thyroid cancer patients who became pregnant after being diagnosed with DM. METHODS: Records of 125 differentiated thyroid cancer (DTC) patients with age ≤45 years at DM diagnosis who had visited Ito Hospital from January 2005 to June 2021 were retrospectively reviewed. Among those 125 patients, 28 who became pregnant after DM diagnosis were classified as pregnancy group, and the remained 97 patients were classified as comparator group. RESULTS: In pregnancy group, the median age at malignancy diagnosis, DM diagnosis, and first pregnancy after DM diagnosis was 25 years (range, 4-41 years), 27 years (range, 11-41 years), and 32 years (range, 25-45 years), respectively. Fifty-five pregnancies and 40 live births were reported. Other pregnancy outcomes were miscarriage (n = 14) and induced abortion (n = 1). The 10-year progression-free survival (PFS) rates of pregnant and comparator group were 92.1% and 74.4%, respectively (p = 0.018). The multivariate analysis showed that multiple 131I treatment was independent negative prognostic factor for PFS (p = 0.046). CONCLUSIONS: DTC patients with age ≤45 years at DM diagnosis had good survival even though they became pregnant. Our results add to the information required for counseling thyroid cancer patients who have concerns about their fertility in the future.

Progression of Papillary Thyroid Carcinoma to Anaplastic Carcinoma in Metastatic Lymph Nodes: Solid/Insular Growth and Hobnail Cell Change in Lymph Nodes Are Predictors of Subsequent Anaplastic Transformation.

Most anaplastic thyroid carcinomas (ATCs) arise from papillary thyroid carcinoma (PTC). This process is also called anaplastic transformation, and the morphological harbingers of this phenomenon in nodal recurrence have not been assessed systematically. For this reason, the current study focused on features of 10 PTCs with regional lymph node recurrence that was accompanied with disease progression due to anaplastic transformation in at least one of the nodal recurrences. The findings of additional 19 PTCs which recurred without anaplastic transformation after ≥ 10 years of follow-up served as the control group. There were no clinicopathological differences between the two groups at initial surgery including age, gender, tumor size, lymph node metastasis, distant metastasis, extrathyroidal extension, histologic subtype, and treatment. The median time from the initial thyroid surgery to anaplastic transformation in the nodal recurrence was 106 months (range 6 to 437 months). Mutational analyses showed recurrent PTCs with anaplastic transformation had a high prevalence of BRAFV600E mutation (8/9) and TERT promoter mutation (9/9), both of which were detected in primary tumors. PIK3CAH1047R mutation was detected in one case. No case had RAS mutation. Nineteen recurrent PTCs without anaplastic transformation harbored BRAFV600E mutation and seventeen of these had TERT promoter mutation. Unlike primary tumors with subsequent nodal anaplastic transformation, TERT promoter mutation was only present in the metastatic nodal recurrence from 4 patients without transformation. No patients had neither high-grade features (necrosis and increased mitotic activity) nor solid/insular growth or hobnail cell features in their primary tumors. In the group of patients with transformation, 3 had solid/insular growth in the lymph node metastasis at the time of primary tumor resection (one displaying nuclear features of PTC and solid growth with increased mitotic activity, one with insular component consistent with poorly differentiated carcinoma component, and one displaying nuclear features of PTC and solid growth), and additional 2 patients had solid/insular growth with no high-grade features or poorly differentiated carcinoma component at the time of subsequent nodal recurrence prior to anaplastic transformation. Hobnail cell features were exclusively seen in subsequent metastatic lymph nodes prior to anaplastic transformation. The control group lacked solid/insular growth and hobnail cell features in the metastatic nodal disease. Aberrant p53 expression and loss of TTF-1 featured tumor components with anaplastic transformation. This series identified a subset of recurrent PTCs with TERT promoter mutation was prone to undergo anaplastic transformation, and that solid/insular growth and hobnail cell features were morphological predictors of anaplastic transformation in the nodal recurrence.

Application of the Bethesda System for Reporting Thyroid Cytopathology in the Pediatric Population.

OBJECTIVES: We aimed to provide the Asian experience with the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) in pediatric thyroid nodules. METHODS: Consecutive thyroid fine-needle aspirates (patient age, ≤18 years) were retrospectively collected from 7 tertiary centers in 5 Asian countries. RESULTS: Of 194,364 thyroid aspirates, 0.6% were pediatric cases (mean age, 15.0 years). Among 827 nodules with accessible follow-up, the resection rate and risk of malignancy (ROM) were 36.3% and 59.0%, respectively. Malignant nodules (n = 179) accounted for 59.7% of resected nodules and 21.6% of all thyroid nodules with available follow-up. Compared with the published adult series, pediatric nodules had a higher resection rate and ROM, particularly in the indeterminate categories. CONCLUSIONS: Our study demonstrates that Asian pediatric thyroid nodules had higher ROM than those from adults. The prototypic outputs of TBSRTC may need to be adjusted in the pediatric population.