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Purpose: Multiple punctate echogenic foci (MPEF) on thyroid ultrasonography reflects psammoma bodies in papillary thyroid carcinomas. However, MPEF is also observed in benign thyroid lesions. The aim of this study was to determine the origin of MPEF in patients with benign thyroid lesions., Methods: We enrolled 26 patients with Graves' disease (GD) and 24 with follicular nodular disease (FND) who exhibited MPEF and underwent surgery. As controls, we enrolled 40 patients with GD and 32 with FND, but without MPEF, who underwent surgery., Results: MPEF was observed in both lobes in 80.8% of GDs with MPEF, but was limited to a single lobe in the remaining cases. MPEF was diffusely distributed in 72.3% of the cases and focally distributed in the remaining cases. On ultrasonography, most (92.3%) FNDs with MPEF were solid lesions, and seven nodules (26.9%) were interpreted as intermediate suspicion and their frequencies were higher than in those without MPEF (p < 0.01). Microscopically, calcium oxalate (CaOx) crystals were observed more frequently in GDs and FNDs with MPEF (100% and 88.5%, respectively) than in those without MPEF (p < 0.001). These differences were particularly significant for CaOx crystals > 100 μm. In GD cases, large CaOx crystals were observed more frequently in the lobes with MPEF than in those without (p < 0.05). No psammoma bodies were present in any of the cases., Conclusion: Appearance of MPEF in GDs and FNDs is not because of psammoma bodies; it is attributable to CaOx crystals larger than 100 μm. Therefore, MPEF is not an indicator of malignancy., (© 2024. The Author(s).)

Preoperative flow cytometry is recommended to prove the monoclonality and confirm the diagnosis of thyroid lymphoma. However, lymphoma cases without light chain restriction may also have monoclonality. The aim of our study was to identify a novel marker for thyroid lymphomas using aspirated materials for flow cytometry. We retrospectively analyzed 26 patients with primary thyroid lymphomas and 16 patients with benign lymphoproliferative lesions. The materials for flow cytometry were obtained by fine-needle aspiration cytology using a 22-gauge needle under ultrasound guidance. Light chain restriction was defined as a κ to λ ratio of less than 0.5 or more than 3.0. According to the light chain-positive rate, 25% or less and more than 25% were classified as the low and high light chain-positive rate groups, respectively. B-cell predominance was defined as a CD19 to CD4 ratio (B- to T-cell ratio) of more than 2.0. B-cell predominance was more frequently observed in lymphomas (88.5%) than in benign lymphoproliferative lesions (25.0%; p < 0.001). Light chain restriction based on the κ/λ ratio was detected in 69.2% of lymphomas, but not in benign lymphoproliferative lesions. Among lymphomas belonging to the low light chain-positive rate group, 88.9% did not exhibit light chain restriction and B-cell predominance was present. In contrast, benign lymphoproliferative lesions with B-cell predominance were not detected in the low light chain-positive rate group. B-cell predominance was a useful indicator for diagnosing thyroid lymphoma in the low light chain-positive rate group without light chain restriction.

Objective: Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations., Design and Methods: We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital., Results: Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD., Conclusions: The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Identification of the parathyroid glands during surgery is crucial for preventing postoperative hypoparathyroidism. Kikumori et al. reported that the aspartate aminotransferase (AST)/lactate dehydrogenase (LDH) ratio for the saline suspension of a suspicious tissue can differentiate parathyroid tissue from other tissues. The aim of this study was to evaluate the utility of this method and investigate the appropriate time for measurement. We obtained 465 tissue specimens during thyroidectomy of 102 patients with papillary thyroid carcinoma (PTC), and 422 specimens (129 parathyroid, 92 PTC, and 201 other tissues) with measurable AST and LDH were analyzed. Small pieces of the tissues were immersed in saline and sent for measurement of AST and LDH. The assay was performed immediately after thyroidectomy for 245 specimens (the same-day group) and during the next morning for the remaining 177 specimens (the next-day group). The accuracy of diagnosing parathyroid tissue was significantly better in the same-day group than in the next-day group. A cut-off value of 0.18 gave the best diagnostic precision, with an area under the receiver operating characteristic curve of 0.95 and 88.7% sensitivity and specificity in the same-day group. When the cut-off value was set to 0.20, the specificity for excluding carcinomatous tissues was 100%. When measured on the day of the surgery, the AST/LDH ratio for the saline suspension of the surgical specimens is useful for discriminating parathyroid tissues from other tissues. This method can be utilized at most hospitals where intraoperative frozen sections or rapid parathyroid hormone assays are not available.

Background: There have been no detailed reports on tracheal puncture after thyroid fine-needle aspiration (FNA). This study aimed to discuss the cytological differential diagnoses of tracheal puncture after thyroid FNA and clarify its clinical significance., Methods: Tracheal puncture was defined as aspiration of tracheal components, including ciliated cells, chondrocytes, and goblet cells. A history of air suction or cough during aspiration was also considered tracheal puncture. Among the 18,480 nodules from 13,813 patients that underwent thyroid FNA, 70 (0.38%) nodules with tracheal puncture were retrospectively examined. Eleven thyroglossal duct cysts (TGDCs) and seven bronchial cysts that could exhibit ciliated cells were included in the study to compare the cytological findings., Results: Sixty-six (94.3%) nodules had no clinical evidence of complications during and after FNA. Of the nodules with tracheal puncture, 64.3%, 48.6%, and 51.4% nodules were <1.0 cm in size, located in the isthmus, and associated with calcification. Cytological examination showed that chondrocytes and ciliated cells were present in 94.3% and 32.9% nodules, respectively. Ciliated cells seen in nodules with tracheal puncture and TGDCs were non-degenerative, whereas those in bronchial cysts were degenerative., Conclusion: Tracheal puncture after thyroid FNA is rarely noticed clinically, does not cause serious conditions, and spontaneously resolves. This complication more likely occurs in small-calcified nodules in the isthmus. Chondrocytes are more reliable diagnostic clues than ciliated cells to indicate tracheal puncture cytologically., (© 2021 The Authors. Diagnostic Cytopathology published by Wiley Periodicals LLC.)

Widely invasive follicular thyroid carcinoma (wi-FTC) is regarded as having an aggressive character and a dire prognosis, but it has not been known whether all wi-FTCs have a dire prognosis. Herein we retrospectively analyzed the cases of 133 patients with wi-FTCs to determine the prognostic significance of vascular invasion and cell-proliferation activity based on the Ki-67 labeling index (LI). Of the 119 patients without distant metastasis (M0), 11 (9.2%) showed recurrence during the postoperative follow-up. In a univariate analysis, the recurrence-free survival (RFS) rates of the M0 patients with vascular invasion and those with a Ki-67 LI ≥5% were significantly poorer (p = 0.0013 and p = 0.0268, respectively) than those of the patients without vascular invasion or with a Ki-67 LI <5%. Other clinicopathological factors such as patient age, gender, tumor size, and oxyphilic tumor were not significantly related to the patients' RFS. In a multivariate analysis, positive vascular invasion independently affected the RFS (p = 0.0133), but Ki-67 >5% did not (p = 0.1348). To date, only five patients have died of their thyroid carcinoma; four cases were M1. In conclusion, although M0 wi-FTC generally has a favorable prognosis, cases with positive vascular invasion or a high Ki-67 LI are likely to recur, and careful postoperative follow-up is necessary.

Rapid on-site evaluation of fine-needle aspiration cytology is time-consuming and requires specialized cytopathology staff. Mobile Rose ® is a newly developed device for rapid on-site evaluation of fine-needle aspiration cytology. This study aimed to investigate the potential role of Mobile Rose ® in reducing delayed repeated aspiration of the thyroid. A total of 120 cytological samples were collected and observed using Mobile Rose ® after fine-needle aspiration cytology between September and October 2020, with immediate assessment of minimal or no cell clusters after conventional smear preparation. After qualifying and scoring, needle washout materials were prepared using the BD CytoRich TM method and correlated with cytology results. The average turn-around time of Mobile Rose ® was found to be 1.5 minutes. Sensitivity, specificity, positive predictive value, and negative predictive value were 94.4%, 100%, 100%, and 57.1%, respectively. False-negative results were attributed to small aggregates of cells that were difficult to distinguish from the background and artifacts. Mobile Rose ® may represent an important innovation for rapid on-site evaluation that is fast, has high diagnostic performance, does not require the presence of specialized cytology staff, and can reduce delayed repeated aspiration of the thyroid gland. However, further minor improvements and confirmation are required.

Many previous studies including ours have reported that athyreotic patients on levothyroxine (LT 4 ) have relatively low serum free triiodothyronine (FT 3 ) levels, whereas patients with large goitrous diseases often have high serum FT 3 levels. Here we investigated Hashimoto thyroiditis (HT) patients on LT 4 to study the relationship between thyroid volume (TV) and thyroid hormone status in hypothyroid patients on LT 4 . We retrospectively studied 408 euthyroid HT patients treated with LT 4 for hypothyroidism; divided them as per TV and compared serum levels of free thyroxine (FT 4 ) and FT 3 and the FT 3 /FT 4 ratio in each patient group with those in euthyroid matched control group. We also evaluated the association between serum FT 3 level and FT 3 /FT 4 ratio and TV among HT patients on LT 4 . In patients with TV <15 mL, serum FT 3 levels were significantly lower than those in controls. In patients with TV 15-80 mL, serum FT 3 levels were equivalent to those in controls. In patients with TV ≥80 mL, the serum FT 3 levels were significantly higher than those in controls. The serum FT 3 level (r = 0.35, p < 0.01) and FT 3 /FT 4 ratio (r = 0.42, p < 0.01) showed a positive correlation with TV. TVs in HT patients on LT 4 caused differences in serum thyroid hormone balance, as increasing volume increases the serum FT 3 level and FT 3 /FT 4 ratio. Serum thyroid hormone balance in HT patients with smaller thyroids was similar to that in athyreotic patients. Mild thyrotropin suppression with LT 4 is needed to achieve normal FT 3 levels in such patients.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and invasive encapsulated follicular variant of papillary thyroid carcinoma (EFV-PTC) are indistinguishable preoperatively. CD26 expression in follicular tumor-uncertain malignant potential (FT-UMP) is reported to be clearly higher than in that without capsular invasion. To verify the diagnostic significance of CD26 immunostaining in EFV-PTC, we examined the expression pattern of CD26 in non-invasive EFV-PTC (NIFTP) and invasive EFV-PTC. We performed immunohistochemical analysis using CD26 antibody for 37 NIFTPs and 54 EFV-PTCs (34 minimally invasive EFV-PTCs and 20 widely invasive EFV-PTCs). Most NIFTP samples showed an apical membranous pattern or a cytoplasmic diffuse pattern of expression. Invasive EFV-PTCs more frequently showed a cytoplasmic dot-like pattern, and the labeling indices of tumor cells with cytoplasmic dot-like patterns were significantly higher than those in NIFTPs. The sizes of dots seen in NIFTPs (mean: 1.12 μm) were significantly smaller than in invasive EFV-PTCs (1.33 μm), minimally invasive EFV-PTC (1.27 μm), and widely invasive EFV-PTC (1.38 μm). We, therefore, conclude that cytoplasmic diffuse and/or cytoplasmic dot-like CD26 expression, particularly the larger CD26-positive dots, could be useful markers for capsular invasion in EFV-PTC. CD26 immunostaining, using cell blocks or cytological specimens, may preoperatively distinguish between NIFTP and invasive EFV-PTC.

Guidelines published by the Japan Association of Endocrine Surgeons (JAES)/Japanese Society of Thyroid Surgery (JSTS) for patients with papillary thyroid carcinoma describe four risk classes (very low-, low-, intermediate- and high-risk) for deciding on therapeutic strategies. Here, we investigate cause-specific survival (CSS) of high- and intermediate-risk patients, taking their age into consideration. CSS of intermediate-risk patients ≥55 years was poorer than that of those <55 years (p < 0.0001) (20-year CSS rates, 96.9% vs. 98.7%). CSS of intermediate-risk patients <55 years was excellent but still poorer (p = 0.0152) than that of low- or very low-risk patients (20-year CSS rates, 100%). CSS of high-risk patients <55 years (20-year CSS rates, 96.0%) was similar (p = 0.7412) to that of intermediate-risk patients ≥55 years, while high-risk patients ≥55 years (20-year CSS rates, 80.6%) showed much poorer prognosis (p < 0.0001) than the others. In high-risk patients <55 years, distant metastasis (M1), extrathyroid extension (Ex), node metastasis ≥3 cm, and extranodal tumor extension, and in those ≥55 years, M1, Ex, and tumor size >4 cm were regarded as prognostic factors on multivariate analysis. We therefore conclude that 1) prognosis of high-risk patients ≥55 years should be carefully treated because of significantly poor prognosis, 2) prognostic factors of high-risk patients vary according to patient age, and 3) overtreatment of intermediate-risk patients and young high-risk patients should be avoided; however, appropriate treatment strategies need to be established, considering that their prognoses are excellent, but still poorer than low- or very low-risk patients.

Background: Primary thyroid Burkitt's lymphoma (BL) is an extremely rare and highly aggressive form of non-Hodgkin's lymphoma; only isolated case reports are available for patients with this disease., Methods: We analyzed the clinicopathological features of thyroid BL by conducting a meta-analysis of 21 known patients (including ours) and compared them to those of extrathyroidal BL., Results: There were 13 men and 8 women with a median age of 39.3 years (range, 6-75 years). The median follow-up was 46.5 months (range, 0.5-361 months). Six patients (28.6%) had stage I disease, 2 (9.5%) had stage II, 2 (9.5%) had stage III, and 11 (52.4%) had stage IV. Five of 7 tested patients with thyroid BL (71.4%) had histological evidence of underlying Hashimoto's thyroiditis. Ki-67 labeling indices exceeding 90% in all 19 patients tested (100%). Fluorescence in situ hybridization performed on 12 patient samples revealed that all (100%) had MYC rearrangement. Among the 16 patients for whom follow-up data were available, 4 died of disease-related causes. Kaplan-Meier analysis revealed that the 12- and 60-month overall survival rates for patients with thyroid BL were 87.5 and 70.7%, respectively., Conclusions: Ours was the largest study of thyroid BL and its detailed clinicopathological features to date. Thyroid BL is not associated with underlying Epstein-Barr virus infection but is closely linked to Hashimoto's thyroiditis; patients generally have good overall survival and respond well to intensive chemotherapy. The correct pathological diagnosis is essential for treatment selection and outcome improvement.

Background: The number of extensive studies focusing on cyst fluid only (CFO) thyroid nodules is limited, and the risk of malignancy (ROM) in CFO nodules has not been well-established. Thus, the purpose of this study was to investigate CFO nodules using cytology and ultrasound. In addition, we sought to define the ROM and determine the recommended clinical management of CFO nodules., Methods: We retrospectively reviewed cytological preparations of 678 nodules that were originally identified as CFO nodules, including conventional specimens in 209 nodules, liquid based cytology (LBC) specimens in 221 nodules, and both conventional and LBC specimens in 248 nodules. Ultrasound reports with representative photographs were also reviewed., Results: Of the 678 CFO nodules, 214 (31.6%) were reclassified into other categories, including non-diagnostic/unsatisfactory (ND/UNS) except for CFO (n = 15), benign (n = 198), and malignant (n = 1). Conventional preparations (33.5%) were more frequently reclassified than LBC preparations (13.6%; P < .0001). Re-aspiration for diagnosis was performed for only one calcified nodule. The rates of surgical resection and malignancy were 3.0% and 0.2%, respectively. Based on American Thyroid Association guidelines and the Kuma Hospital ultrasound classification, worrisome sonographic features were identified in 5.8% and 0% of CFO nodules, respectively., Conclusion: We propose that CFO nodules should be classified as separate from ND/UNS nodules; they should be categorized as a subtype of benign nodules. However, it is essential that fine-needle aspiration cytology be performed under ultrasound-guided real-time visualization of needle placement in the target nodule in all cases., (© 2019 The Authors. Diagnostic Cytopathology published by Wiley Periodicals, Inc.)

While patients with large goitrous thyroid diseases often have a relatively high serum free triiodothyronine (FT 3 )/free thyroxine (FT 4 ) ratio, athyreotic patients have a relatively low FT 3 /FT 4 ratio. Here we investigated the relationship between thyroid hormone status and thyroid volume (TV) among a large number of euthyroid Hashimoto thyroiditis (HT) patients. We retrospectively enrolled 2,603 untreated HT patients who visited the Kuma hospital from 2012 to 2016, and divided them into four groups as per the TV: normal TV (<20 mL), slight goiter (20 ≤ TV < 50 mL), moderate goiter (50 ≤ TV < 80 mL), and the large goiter group (≥80 mL). Baseline characteristics and laboratory data of each group were compared to those of 1,554 control subjects. The association between FT 3 /FT 4 ratio and TV among HT patients was then analyzed. We observed a change in laboratory parameters among 13 patients in the large goiter group who were prescribed levothyroxine (LT 4 ) for reducing TV. Compared to normal subjects, the moderate and large goiter groups exhibited significantly higher serum FT 3 levels, while all HT groups exhibited lower serum FT 4 levels. Serum FT 3 /FT 4 ratios showed a positive correlation with TV (r = 0.35, p < 0.01), which was independent of age, sex, body mass index, and TgAb and TSH levels. LT 4 treatment lowered serum FT 3 levels and FT 3 /FT 4 ratios significantly. Our results indicated that HT patients with increased TV tended to present with high serum FT 3 , low FT 4 , and high FT 3 /FT 4 ratios. The elevation of deiodinase activity may be an important factor affecting thyroid hormonal balance in such patients.

Purpose: The serum free triiodothyronine (FT 3 )/free thyroxine (FT 4 ) ratio in patients with huge goitrous Hashimoto's thyroiditis (HG-HT) is relatively high. We investigated the cause of high FT 3 /FT 4 ratios., Methods: We measured the serum FT 3 , FT 4 , and thyrotropin (TSH) levels of seven patients with HG-HT who had undergone a total thyroidectomy. Eleven patients with papillary thyroid carcinoma served as controls. The activities and mRNA levels of type 1 and type 2 iodothyronine deiodinases (D1 and D2, respectively) were measured in the thyroid tissues of HG-HT and perinodular thyroid tissues of papillary thyroid carcinoma., Results: The TSH levels in the HG-HT group were not significantly different from those of the controls. The FT 4 levels in the HG-HT group were significantly lower than those of the controls, whereas the FT 3 levels and FT 3 /FT 4 ratios were significantly higher in the HG-HT group. The FT 3 /FT 4 ratios in the HG-HT group who had undergone total thyroidectomy and received levothyroxine therapy decreased significantly to normal values. Both the D1 and D2 activities in the thyroid tissues of the HG-HT patients were significantly higher than those of the controls. However, the mRNA levels of both D1 and D2 in the HG-HT patients' thyroid tissues were comparable to those of the controls. Interestingly, there were significant correlations between the HG-HT patients' D1 and D2 activities, and their thyroid gland volume or their FT 3 /FT 4 ratios., Conclusions: Our results indicate that increased thyroidal D1 and D2 activities may be responsible for the higher serum FT 3 /FT 4 ratio in patients with HG-HT.

We studied cytological specimens of conventional papillary thyroid carcinoma (PTC), follicular variant papillary thyroid carcinoma (FVPTC), and noninvasive follicular thyroid tumor with papillary-like nuclear features (NIFTP) (formerly noninvasive FVPTC) to identify useful cytological parameters for their differentiation. Cytological findings of invasive FVPTC and NIFTP were very similar to each other but differed from those of conventional PTC. Intranuclear cytoplasmic inclusions, true papillary cell clusters, monolayered cell sheets, ropy colloids, multinucleate giant cells, psammoma bodies, and cystic background were the observed characteristic features of conventional PTC. Microfollicular cell clusters and dense globules of colloids were characteristic features of invasive FVPTC and NIFTP. Scoring the eight parameters (intranuclear cytoplasmic inclusions, nuclear grooves, powdery chromatin, true papillary cell clusters, ropy colloids, multinucleate giant cells, psammoma bodies, and cystic background) readily distinguished NIFTP from conventional PTC, but could not distinguish NIFTP from invasive FVPTC. The average total score of NIFTP, invasive FVPTC, and conventional PTC were 2.60 ± 0.55, 2.63 ± 0.62, and 4.57 ± 0.99, respectively. The difference between conventional PTC and NIFTP or invasive FVPTC was statistically significant (p < 0.001, Student's t-test). Individuals with more than three of the identified parameters likely harbor conventional PTC, rather than NIFTP. In this way, 87.5% (112/128) of conventional PTCs could be differentiated from NIFTP, and definitively diagnosed as malignant by cytology.

The revised Japan Association of Endocrine Surgeons (JAES)/Japanese Society of Thyroid Surgery (JSTS) guidelines for patients with papillary thyroid carcinoma (PTC) describe four risk classes: very-low-risk, low-risk, intermediate-risk, and high-risk. Here we conducted a retrospective analysis to evaluate the appropriateness of these guidelines' risk classification of PTCs. Lymph node recurrence-free, distant recurrence-free and cause-specific survivals at 15-year of high-risk group were significantly poorer than those at 15-year of intermediate-group and these survivals of intermediate-group were poorer than of low- or very-low-risk patients. In the subset analyses based on patient age (≥55 years and <55 years), we obtained the same results in both subsets. Age significantly worsen the whole prognosis of high-risk patients and cause-specific survival of intermediate-risk patients, but not the prognosis of low- or very-low-risk patients. Therefore, the risk classification of the revised JAES/JSTS guidelines is appropriate, and therapeutic strategies should be decided based on the risk class together with the patients' age.

Concerning the needle size for thyroid fine needle aspiration cytology (FNAC), 25-27-gauge needles are generally used in Western countries. However, in Japan, the use of larger needles (21-22-gauge needles) is common. The aim of our study was to determine the optimal needle size for thyroid FNAC. We performed ultrasound-guided FNAC for 200 thyroid nodules in 200 patients using two different-sized needles (22 and 25 gauge). For each nodule, two passes with the different-sized needles were performed. The order of needle sizes was reversed for the second group of 100 nodules. The second aspiration was more painful than the first, regardless of the needle size. An association with more severe blood contamination was more frequently observed with the use of 22-gauge needles (32.0%) than with the use of 25-gauge needles (17.5%) and in the second aspiration (37.5%) than in the initial aspiration (12.0%). The initial aspiration samples were more cellular than the second aspiration samples. Regarding the unsatisfactory and malignancy detection rates, there was no statistical difference between the needles. In three of seven markedly calcified nodules, it was difficult to insert 25-gauge needles into the nodules. In terms of the diagnostic accuracy and pain, either needle size can be used. We recommend using 22-gauge needles for markedly calcified nodules because 25-gauge needles bend more easily in such cases. We demonstrated that the initial aspiration tended to obtain more cellular samples and to be less contaminated. Thus, the initial aspiration is more important and should be closely attended.

The Bethesda System for Reporting Thyroid Cytopathology has recently been revised in 2017 (TBSRTC 2017). This study aimed to evaluate the impact of modifying the diagnostic criteria in TBSRTC 2017 at a single institute. We retrospectively reviewed cytological specimens of 10,399 thyroid nodules submitted for thyroid fine-needle aspiration cytology. Among them, 56 atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) nodules, 16 suspicious for malignancy (SFM) nodules, and 8 malignant nodules were re-categorized into follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN). The incidence of FN/SFN was increased by 0.8%, while that of AUS/FLUS, SFM, and malignant nodule was decreased by 0.5%, 0.2%, and 0.1%, respectively. In nine (60%) of the 15 nodules that were re-classified from AUS/FLUS to FN/SFN nodules and re-aspiration was performed, it was possible to judge whether they were benign or malignant. Of the 24 patients with FN/SFN nodules originally diagnosed with SFM or malignant, 16 were followed up without surgical resection. In conclusion, TBSRTC 2017 only caused minor changes in the incidence of each diagnostic category. TBSRTC 2017 was revised to avoid false positives owing to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) that account for >10% of papillary thyroid carcinomas; however, it is not necessary in low frequency NIFTP institutes or countries. In Japan, we propose active surveillance as an accepted option for clinically managing AUS/FLUS, FN/SFN, SFM, or malignant nodules having favorable benign clinical findings or being part of the low-risk group.

The pathogenesis of thyroid lymphoepithelial cysts is controversial, and two hypotheses have been proposed, namely derivation from branchial-derived remnants or from squamous metaplasia of the follicular cells. The aim of this study was to clarify the pathogenesis of thyroid lymphoepithelial cysts. We performed pathological and immunohistochemical examination of 21 thyroid lymphoepithelial cysts, 13 non-neoplastic squamous metaplasia samples without thyroid carcinoma, 13 solid cell nests, and 14 lateral cervical cysts. On ultrasound, half of thyroid lymphoepithelial cysts were interpreted as calcified nodules regardless of no calcification. Thyroid lymphoepithelial cysts and squamous metaplasia tended to be located in the central and lower portions of the thyroid, while solid cell nests were located in the upper and central portions (p < 0.05). In 95.2% of patients with thyroid lymphoepithelial cysts and all patients with squamous metaplasia, lesions were histologically associated with chronic thyroiditis forming lymph follicles. Hashimoto's disease was serologically confirmed in 18 patients with lymphoepithelial cysts (85.7%) and 10 patients with squamous metaplasia (76.9%). Immunohistochemically, lymphoepithelial cysts showed nuclear positivity for PAX8, thyroid transcription factor 1, and p63. One lateral cervical cyst (7.1%) showed positive staining for PAX8, while solid cell nests were PAX8-negative. In three (14.3%) cases of thyroid lymphoepithelial cysts, squamous cells located on the superficial layer were focally and weakly positive for CEA. We concluded that thyroid lymphoepithelial cysts originate from follicular cells and are unrelated to solid cell nests and lateral cervical cysts arising from branchial-derived remnants.

We report three cases of thyroid sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE), which is an extremely rare variant of mucoepidermoid carcinoma (MEC). The aims of this report were to describe the clinicopathological findings, including results from immunohistochemical and fluorescence in situ hybridization analysis of thyroid SMECE, as well as to discuss the distinction between thyroid SMECE and its salivary counterpart. The cases included a 63-year-old female, a 44-year-old male, and a 66-year-old female, with all patients presenting with Hashimoto's thyroiditis. Nodal metastasis was not found in any of the three cases. Neither regional recurrences nor distant metastases were found in any patient during the follow-up, which was 20 years, 3 years, and 18 months, respectively. Histologically, tumors were composed of epidermoid carcinoma cells, intermediate type carcinoma cells, and goblet cell-type mucus-secreting carcinoma cells, with all tumors displaying a sclerotic stroma with eosinophilic and lymphocytic infiltration. The formation of eosinophilic abscess in the tumor nests that might be a novel characteristic finding of SMECE was observed. Immunohistochemically, the carcinoma cells were positive for cytokeratin 34βE12, TTF-1, and PAX8, but negative for thyroglobulin. In two cases, increased IgG4-positive plasma cells were observed. Mastermind-like transcriptional coactivator 2 (MAML2), according to fluorescence in situ hybridization, was intact in all cases. In conclusion, thyroid SMECE has favorable outcomes and seems to be genetically different from salivary MEC. This is the first report to describe the presence of increased IgG4-positive plasma cells in the stroma of SMECE.

Background: Rapid increases in the incidence of thyroid carcinoma with stable mortality rates from thyroid carcinoma have been reported from many countries, and these increases are thought to be due mostly to the increased detection of small papillary thyroid carcinomas (PTCs), including papillary microcarcinomas (PMCs; i.e., PTCs ≤10 mm). Some researchers have suggested that small PTCs have been overdiagnosed and overtreated. In Japan, the active surveillance of patients with low-risk PMCs was initiated by Kuma Hospital (1993) and Tokyo's Cancer Institute Hospital (1995) based on the extremely higher incidences of both latent thyroid carcinomas in autopsy studies and small PTCs detected in mass screening studies using ultrasound examinations compared to the prevalence of clinical thyroid carcinomas., Methods: The above two institutions' data are summarized regarding the active surveillance of low-risk PMCs, and future prospects for their management are discussed., Results: At 10-year observations in the Kuma Hospital series of 1235 patients, only 8% and 3.8% of the PMC patients showed size enlargement by ≥3 mm and the novel appearance of node metastasis, respectively. In contrast to clinical PTC, PMCs are most unlikely to grow in older patients (≥60 years). In the Kuma Hospital series, the 974 patients who underwent immediate surgery had significantly higher incidences of unfavorable events than the 1179 patients who chose active surveillance. The total cost of immediate surgery, including the costs for salvage surgery and postoperative care for 10 years, was 4.1 times the total cost of 10-year management by active surveillance. Only 8% of the 51 PMC patients showed tumor enlargement during pregnancy, and the rescue surgeries after delivery were successful. In the Cancer Institute Hospital series of 230 patients with 300 lesions, only 7% and 1% of the patients showed size enlargement and novel node metastasis, respectively, and that institution's analysis also revealed that macroscopic or rim calcification and poor vascularity were correlated with non-progressing disease. In both series, none of the patients who underwent rescue surgery after progression signs were detected showed significant recurrence or died of PTC., Conclusion: Active surveillance of low-risk PMC can be the first-line management. Interestingly, older patients with low-risk PMCs are the best candidates for active surveillance.

Objective: To identify cytological differences between mucosa-associated lymphoid tissue lymphoma (MALT-L) and nonneoplastic lymphocytes using thyroid liquid-based cytology (LBC)., Study Design: We observed LBC and conventional specimens from 35 MALT-L cases, 3 diffuse large B-cell cell lymphoma (DLBCL) cases, and 44 prominent nonneoplastic lymphocytic infiltration cases., Results: In MALT-L cases, the incidence of lymphoglandular bodies in the LBC specimens was lower than that in the conventional specimens (p < 0.001). Moreover, the nuclear sizes in LBC specimens were larger than those in conventional specimens. In 62.9% of the MALT-L and all DLBCL specimens, large nuclei were present in > 10% of the lymphoid cells in LBC specimens. Two cases with prominent nonneoplastic lymphocytic infiltration also exhibited these findings. In LBC specimens, swollen naked nuclei with less punctate chromatin patterns and thin nuclear margins were observed in 92.1% of lymphoma and 20.5% of prominent nonneoplastic lymphocytic infiltration. Elongated nuclei were significantly more apparent in thyroid lymphoma than in prominent nonneoplastic lymphocytic infiltration (p < 0.001), with a significantly higher incidence in LBC specimens than in conventional specimens (p < 0.001)., Conclusions: Lymphoglandular bodies are not reliable markers for lymphoma diagnosis using LBC specimens. Large, swollen naked, and elongated nuclei are useful in distinguishing thyroid lymphoma from nonneoplastic lymphocytes in LBC specimens., (© 2018 The Author(s) Published by S. Karger AG, Basell.)

Background: We reported that a minority of patients with low-risk papillary microcarcinoma of the thyroid showed disease progression during active surveillance and that older patients had significantly lower disease progression rates than younger patients. Here, we estimated lifetime (≤85 years old) probabilities of disease progression during active surveillance according to the age at presentation based on age decade-specific disease progression rates., Methods: From 1993-2013, 1,211 low-risk papillary microcarcinoma patients aged 20-79 years underwent active surveillance at Kuma Hospital. We calculated the disease progression rate at the 10-year point of active surveillance for each age-decade group (20s to 70s) with the Kaplan-Meier method. The lifetime disease progression probability for each age group was calculated as (1 - cumulative probability of progression-free survival calculated with age decade-specific disease progression rates) until the patients reached their 80s (i.e., 85 years on average)., Results: The age decade-specific disease progression rates at 10 years of active surveillance were 36.9% (20s), 13.5% (30s), 14.5% (40s), 5.6% (50s), 6.6% (60s), and 3.5% (70s); the respective lifetime disease progression probabilities were 60.3%, 37.1%, 27.3%, 14.9%, 9.9% and 3.5% according to the age at presentation., Conclusion: The estimated lifetime disease progression probabilities of papillary microcarcinoma during active surveillance vary greatly according to the age at presentation., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study set out to compare structural and invasive characteristics of sporadic papillary thyroid carcinoma (PTC) in age-matched groups of children and adolescents of Japan and Ukraine to provide detailed histopathological analysis of tumors from different geographical areas with different iodine intake. A total of 348 (160 Japanese and 188 Ukrainian) PTCs from patients without radiation history were analyzed initially as a combined pediatric group and then subdivided into childhood (aged ≤14 years) and adolescent (aged from 15 to ≤18 years) age series. On multivariate comparison, the Japanese pediatric PTC was characterized by a higher sex ratio (p=1.504E-4), and a higher frequency of microcarcinoma (p=0.039), papillary dominant growth pattern (p=0.024), focal oxyphilic cell metaplasia (p=7.644E-6), intrathyroid spread (p=0.010), lymphatic/vascular invasion (p=0.01) and regional lymph node metastases (p=3.540E-6). In the Ukrainian group, multifocal (p=0.004) and non-encapsulated tumors with the solid-trabecular growth pattern (p=0.05) were more frequent. Childhood Japanese PTCs differed from Ukrainian PTCs by more pronounced invasive properties such as lymphatic/vascular invasion and nodal disease, but did not differ by the dominant growth pattern. In adolescents, the differences were detected not only for lymph node metastases, but also for a higher frequency of the papillary dominant pattern in Japanese PTC. Overall, significantly higher frequencies of oxyphilic cell metaplasia and more pronounced invasive features observed in the Japanese PTC in both age-matched series represent the major differences between the tumors from two geographical areas.

Papillary thyroid carcinoma (PTC) with desmoid-type fibromatosis (DTF) is characterized by genetic alterations of the fibroblasts. PTC-DTF is extremely rare, and the reports on such cases have been sporadic. Immunohistochemical staining using the antibody for beta-catenin is useful in diagnosing the variant. This report aims to describe the clinical, pathological, and immunohistochemical findings in 14 cases of PTC-DTF and to clarify the diagnostic significance of the variant. The patients included 9 women and 5 men, with a mean age of 49.3 years. PTCs with focal DTF components and with extensive DTF components included 7 cases each. No significant differences were noted in terms of age, gender, and serum thyroglobulin levels between extensive and focal DTF cases. On aspiration cytology, 12 cases were reported as suspicious for malignancy or malignant, and schwannoma or fibroma was suggested in 1 case each. The DTF components were histologically classified into 4 types, namely, central (4 cases), peripheral (1 case), mixed (7 cases), and diffuse type (2 cases). The stromal components were consistent with those of DTF. Immunohistochemically, fibroblasts in the DTF components showed nuclear and cytoplasmic expression for beta-catenin in 12 cases. The features are observed even in cases in which stromal components focally exist. Neither carcinoma cells nor the fibroblasts with Ki-67 labeling index >5% were found in all cases. We agree that PTC with nodular fasciitis-like stroma should be renamed to PTC-DTF.

The aims of this report were to clarify the diagnostic significance of ultrasound (US), fine needle aspiration cytology (FNAC), and flow cytometry for primary thyroid lymphoma, and to establish a preoperative diagnostic algorithm of primary thyroid lymphoma. We retrospectively examined US, FNAC, and flow cytometry in 43 patients with benign lymphoproliferative lesions and 32 patients with primary thyroid lymphoma, who underwent US, FNAC, and flow cytometry at Kuma Hospital between May 2012 and December 2015. Primary thyroid lymphomas included 27 mucosa-associated lymphoid tissue lymphomas, 4 diffuse large B-cell lymphomas, and 1 follicular lymphoma. Flow cytometry had the highest specificity (88.4%) and sensitivity (75.0%). The specificity of US was the lowest (32.6%). Both the positive predictive value (90.5%) and negative predictive value (94.7%) were the highest for FNAC. A scoring system was defined as follows: US, low suspicion 0, intermediate suspicion 1, and high suspicion 2; FNAC, benign 0, undetermined 1, malignant 2; and flow cytometry, 0.33< κ/λ ratio <3 0, κ/λ ratio ≤0.33 2, and κ/λ ratio ≥3 2. We propose that a score ≥4 indicates the need for thyroid resection for diagnosing primary thyroid lymphoma. In such a situation, the case of diffuse large B-cell lymphoma, which was aggressive, was not excluded. Approximately one-fifth of mucosa-associated lymphoid tissue lymphomas may be overlooked, but the patients could be followed up with because of an indolent course.

According to the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), cyst fluid only (CFO) cases are classified in the non-diagnostic category. To date, no large study focusing on CFO has been conducted. To reassess the diagnostic significance of CFO, we compared CFO nodules with non-diagnostic nodules excluding CFO (ND-other). We reviewed the conventional thyroid smears of 715 CFO and 766 ND-other nodules. We compared the timing of and findings at re-aspiration, the histology of resected specimens, and the proportion of malignant nodules between the two groups. Re-aspiration was performed in 9.0% of CFO and 23.8% of ND-other cases. In 12.5% of CFO and 49.4% of ND-other cases, the interval between the first and second aspirations was <3 months. Despite this, there were no cases in which cytological interpretation was complicated by the first aspiration. Overall, 77 CFO nodules (10.8%) were surgically resected; 14 were malignant. In all cases in which re-aspiration cytology revealed malignancy, the initial ultrasound interpretation was a high or intermediate suspicion pattern. The proportion of malignancies subsequently diagnosed in nodules initially classified as CFO and ND-other was 2.0% and 5.6%, respectively (p<0.01). As CFO and ND-other thyroid nodules have different clinical management and malignancy rates, we would like to assert that CFO and ND-other nodules should be separated, and that the former should be considered diagnostic. In terms of clinical management, we recommend that only CFO cases with concerning features on ultrasound undergo re-aspiration.

Objectives/hypothesis: Intraoperative neuromonitoring identifies recurrent laryngeal nerve (RLN) injury and gives prognostic information regarding postoperative glottic function. Loss of the neuromonitoring signal (LOS) signifies segmental type 1 or global type 2 RLN injury. This study aimed at identifying risk factors for RLN injury and determining vocal fold (VF) function initially and 6 months after definitive LOS., Study Design: Prospective study encompassing 21 hospitals from 13 countries., Methods: Included in this study were patients with persistent intraoperative LOS., Results: At first postoperative laryngoscopy, early VF palsy was present in 94 of all 115 patients with LOS (81.7%): in 53 of 56 patients (94.6%) with type 1 injury and 41 of 59 patients (69.5%) with type 2 injury. In LOS type 1, women outnumbered men >5-fold. Traction produced LOS type 1 in 38 of 56 patients (67.9%) and LOS type 2 in 54 of 59 patients (91.5%). Course of the RLN posterior and/or anterior to the inferior thyroid artery, extralaryngeal branching, or tuberculum of Zuckerkandl did not increase VF palsy rates. Permanent VF palsy rates were also lower (P = .661) after LOS type 2 than after LOS type 1: 6.8% (four of 59 patients) versus 10.7% (six of 56 patients). Intraoperative administration of steroids did not diminish postoperative VF palsy rates., Conclusions: LOS type 1 entails more severe nerve damage than LOS type 2, affecting women disproportionately. Both LOS types, being primarily associated with traction injury, are unaffected by variant neck anatomy in expert hands and unresponsive to steroids., Level of Evidence: 2b Laryngoscope, 126:1260-1266, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The purpose of this study was to evaluate electromyography (EMG) amplitude and latency changes during tube dislocation in monitored thyroid surgery, which may be observed without recurrent laryngeal nerve injury., Methods: Duroc-Landrace piglets were intubated with the TriVantage EMG tube. We measured EMG changes during both upward and downward tube dislocation (10-20 mm) and rotation (45-90°) with continuous neuromonitoring., Results: The EMG amplitude varied significantly with induced endotracheal tube rotation and depth changes. However, the EMG latency was relatively unaffected by such tube dislocation, just a transient artifactual latency change was observed in the situation of extreme amplitude variation., Conclusion: Amplitude changes without latency changes may be due to changes in tube position alone during surgery, but could still reflect a neurophysiologic event; amplitude changes during neuropraxic injury merit additional investigation. Thus, the combined event (concordant amplitude decrease and latency increase) serves as an appropriate adverse EMG event correlating with impending neural injury. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1004-E1008, 2016., (© 2015 Wiley Periodicals, Inc.)

Objective: We and others recently reported that in total thyroidectomy (TT), serum triiodothyronine (T3) levels during levothyroxine (L-T4) therapy were low compared to the preoperative levels, suggesting that the presence of the thyroid tissue affects the balances of serum thyroid hormone levels. However, the effects of remnant thyroid tissue on these balances in thyroidectomized patients have not been established., Methods: We retrospectively studied 253 euthyroid patients with papillary thyroid carcinoma who underwent a TT or hemithyroidectomy (HT). We divided the cases into the TT+supplemental L-T4 (+L-T4) group (n=103); the HT+L-T4 group (n=56); and the HT-alone group (n=94). We compared the postoperative serum levels of free T4 (FT4) and free T3 (FT3) and the FT3/FT4 ratio in individual patients with those of controls matched by serum TSH levels., Results: The TT+L-T4 group had significantly higher FT4 (P<0.001), lower FT3 (P<0.01) and lower FT3/FT4 (P<0.001) levels compared to the controls. The HT+L-T4 group had FT4, FT3 and FT3/FT4 levels equivalent to those of the controls. The HT-alone group had significantly lower FT4 (P<0.01), equivalent FT3 (P=0.083), and significantly higher FT3/FT4 (P<0.001) ratios than the controls., Conclusions: The presence of the remnant thyroid tissue was associated with different thyroid hormone balances in thyroidectomized patients, suggesting that T3 production by remnant thyroid tissue has a substantial effect on the maintenance of postoperative serum T3 levels., (© 2015 European Society of Endocrinology.)

Infertile women sometimes associated with subclinical hypothyroidism (SCH). The guidelines of the American Endocrine Society, and American Association of Clinical Endocrinologists and American Thyroid Association recommend treatment with thyroxine (T4) for patients with SCH who want to have children. We examined 69 female infertile patients with SCH and the effects of levothyroxine (l-T4) therapy on pregnancy rates and pregnancy outcomes were observed. Fifty-eight (84.1%) patients successfully conceived during the T4 treatment period (Group A), although 17 patients (29.3%) had miscarriage afterward. The remaining 11 patients continued to be infertile (Group B). The median TSH value in Group A before the T4 treatment was 5.46 μIU/mL (range 3.1-13.3) and this significantly decreased to 1.25 μIU/mL (range 0.02-3.75) during the treatment (p<0.001). The estimated duration of infertility before the T4 treatment was 2.8±1.7 years and the duration until pregnancy after the treatment was significantly shorter at 0.9±0.9 years (p<0.001). Shortening of the infertile period after the T4 therapy was observed not only in patients who were treated with assisted reproductive technology (ART) but also in patients who conceived spontaneously in Group A. Administered T4 dose was 54.3±14.2 μg before pregnancy and 68.5±22.8 μg during pregnancy (p<0.001). Anti-thyroid autoantibodies were identified in 42.0% of all patients and no significant difference was observed in positivity between Group A and Group B. High successful pregnancy rate and shorter duration of infertility until pregnancy after T4 treatment strongly suggest that T4 enhanced fertility in infertile patients with SCH.

Objective: We examined cytological findings for the diagnosis of primary thyroid mucosa-associated lymphoid tissue (MALT) lymphoma by fine needle aspiration., Study Design: During the study period of 4 years, a total of 101 cases including 51 MALT lymphomas, 20 Hashimoto's thyroiditis (HT), and 30 diffuse large-cell B-cell lymphomas were cytologically examined. MALT lymphomas were divided into 44 common MALT and 7 MALT lymphomas with extreme plasmacytic differentiation (MALT-EPCD)., Results: (1) Small- to medium-sized cells displaying irregularly shaped nuclei with prominent nucleoli (ISN-PN) were neoplastic cells. (2) In the case of a frequency of plasma cells (PC) below 15%, the accuracy rate for distinguishing common MALT from HT was 97% for ISN-PN cell frequencies above 20% in combination with the presence of lymphoepithelial lesion clusters (LELC) and mountain range-like clusters (MRLC). The frequency of large-sized cells was below 15% in common MALT. (3) In the case of a frequency of PC above 15%, cases with a sum of PC and ISN-PN cells above 30% were MALT-EPCD. (4) MRLC were cell clusters derived from regions of follicular colonization, and LELC were cell clusters from lymphoepithelial lesions of MALT lymphomas., Conclusion: Useful cytological criteria for the diagnosis of thyroid primary MALT lymphoma, such as neoplastic cells and cell clusters, were defined., (© 2014 S. Karger AG, Basel.)

Most types of thyroid carcinomas express PAX8 transcription factor; however, whether thyroid squamous cell carcinoma (SCC) also expresses PAX8, currently remains unknown. We herein examined the immunoreactivity of PAX8 in SCC of thyroidal and extrathyroidal origin, and discussed the diagnostic significance of PAX8. We immunohistochemically examined specimens from 11 SCC, 22 papillary thyroid carcinoma (PTC), 8 anaplastic thyroid carcinoma (ATC), and 2 mucoepidermoid carcinoma (MEC) cases as well as 5 uterine cervical SCC, 5 esophageal SCC, and 5 pulmonary SCC cases. The rates of PAX8-positive SCC, PTC, ATC, and MEC were 90.9%, 90.9%, 75.0%, and 100%, respectively. Two PAX8-negative PTC cases were cribriform variants. No uterine cervical, esophageal, or pulmonary SCC specimen reacted with PAX8 antibody. Thyroid transcription factor-1 (TTF-1) was positive in 9.1% and 95.5% of SCC and PTC cases, respectively, but negative in all ATC and MEC cases. These results demonstrate that PAX8 staining is useful for distinguishing between primary thyroid SCC and invasion or metastasis from extrathyroidal SCC. We recommend using an immunohistochemical panel of antibodies to PAX8 and TTF-1 to confirm a diagnosis of primary thyroid carcinoma.

Background: Postpartum thyroid dysfunction occurs in approximately 5-10% of women in the general population within one year of delivery. Differentiation of postpartum Graves' thyrotoxicosis (PPGr) from postpartum destructive thyrotoxicosis (PPDT) is essential because of the difference in treatment measures between the two. However, it is sometimes difficult because radioactive iodine uptake is contraindicated when patients are lactating. We examined the usefulness of determining the time of onset postpartum and measurement of antithyrotropin (anti-TSH) receptor antibodies and thyroid blood flow., Methods: Forty-two patients with newly developed thyrotoxicosis after delivery were examined: 18 had Graves' disease and 24 had destructive thyrotoxicosis. Serum free thyroxine (fT4), free triiodothyronine (fT3), and TSH were measured by chemiluminescent immunoassays. Anti-TSH receptor antibodies (TRAb), antithyroglobulin antibodies (TgAb), and antithyroid peroxidase antibodies (TPOAb) were measured by the Elecsys electrochemiluminescence immunoassay. Thyroid volume and blood flow (TBF) were measured quantitatively by color flow Doppler ultrasonography., Results: Onset of thyrotoxicosis was distributed from 2 to 12 months postpartum. Twelve (85.7%) of 14 patients who developed thyrotoxicosis at three months or earlier after delivery had PPDT. On the other hand, all 11 patients who developed thyrotoxicosis at 6.5 months or later had PPGr. All patients with PPGr had positive TRAb (14.9±14.9 IU/L, mean±standard deviation (SD)) and all patients with PPDT had negative TRAb (0.1±0.3 IU/L, p<0.0001). Fifteen (83.3%) of 18 PPGr patients had high TBF of more than 4.0% (8.9±4.4), and all PPDT patients had low TBF of <4.0% (1.6±1.0, p<0.0001). The fT3/fT4 ratio was higher in PPGr (64.0±23.9) than in PPDT (38.9±13.1, p<0.0002), but absolute values overlapped between the two., Conclusion: Early onset of thyrotoxicosis postpartum was associated mainly with PPDT, and a late onset was suggestive of PPGr. Positive TRAb and high TBF >4.0% are indicators of postpartum onset of Graves' disease.

Background: We studied the frequency of thyrotropin (TSH) receptor mutations in hyperthyroid patients with diffuse goiter and negative TSH receptor antibodies (TRAb), and the clinical pictures of the hyperthyroid patients in the presence and absence of mutations., Patients and Methods: From 2003 through 2012, 89 hyperthyroid patients with diffuse goiter and negative TRAb based on a second- or third-generation assay underwent sequence analysis of the TSH receptor gene from peripheral leukocytes. The outcome of hyperthyroidism in patients with a TSH receptor mutation and their affected family members was compared with that in patients without any mutation after a 1-10-year follow-up., Results: Germline mutations of the TSH receptor occurred in 4 of the 89 patients (4.5%), including 3 definitive constitutively activating mutations (L512Q, E575K, and D617Y). The main difference in the clinical outcome of hyperthyroidism was that no patients with a TSH receptor mutation achieved euthyroidism throughout the follow-up, while 23.5% of patients without any mutation entered remission. The progression from subclinical to overt hyperthyroidism was not significantly different between patients with or without a mutation. Meanwhile, 10.3% of TRAb-negative patients without any TSH receptor mutation developed TRAb-positive Graves' hyperthyroidism during the follow-up., Conclusions: The prevalence of nonautoimmune hyperthyroidism with TSH receptor mutations is lower than that of latent Graves' disease in TRAb-negative patients with hyperthyroidism. However, all affected patients with a TSH receptor mutation showed persistent hyperthyroidism regardless of subclinical or overt hyperthyroidism throughout the follow-up.

Background: Papillary thyroid cancer occasionally occurs in women of childbearing age. As papillary thyroid microcarcinoma (PTMC) rarely grows or becomes clinically apparent, observation without surgery is an appropriate strategy for patients with low-risk PTMC. Human chorionic gonadotropin possesses weak thyroid-stimulating activity. The aim of this study was to assess the effect of pregnancy on PTMC., Methods: We studied 9 patients with PTMC who became pregnant between 2005 and 2011. Twenty-seven age-matched nonpregnant female PTMC patients from a database we used in our previous report served as controls. Tumor enlargement was defined as an increase in the diameter of the tumor of 3 mm or more., Results: PTMC enlargement occurred in 44.4% (4/9 patients) of the pregnant subjects, whereas it occurred only in 11.1% (3/27 patients) of the controls (p=0.0497). Three of the pregnant patients who exhibited tumor enlargement underwent surgery after delivery. No relationship was detected between the changes in the serum thyroglobulin level, the serum thyrotropin level, and tumor size during pregnancy. Immunohistochemical examinations did not detect the estrogen receptor in the tumors of the three patients who underwent surgery., Conclusions: This study is an initial report indicating that the risk of PTMC enlargement might increase during pregnancy. PTMC should be carefully followed-up for possible disease aggravation during pregnancy. Even if a PTMC enlarges during pregnancy, the patient's prognosis will probably not worsen.

Follicular thyroid carcinoma (FTC) is the second most common malignancy arising from follicular cells. It is classified into two categories based on the degree of invasion: widely and minimally invasive FTC. Here we focused on the prognostic value of patient age in FTC. We enrolled 292 minimally invasive and 79 widely invasive FTC patients who underwent initial surgery between 1983 and 2007. We classified these patients into three groups based on patient age: < 20 years (children and adolescents), 20-44 years (young adults) and ≥ 45 years (middle-aged or older), and compared their prognoses disease-free survival (DFS) and cause-specific survival (CSS). Among the minimally invasive FTC patients, those aged ≥ 45 years showed a poorer DFS and CSS than those < 45 years. In the subset of patients < 45 years, the DFS of patients < 20 years tended to be poorer than those aged 20-44 years, but none of the patients < 20 years died of FTC. Among the patients with widely invasive FTC, only three were younger than 20 years old. Two patients showed carcinoma recurrence, but neither died of FTC. In minimally invasive FTC, the DFS showed a biphasic pattern, but the CSS became poorer with increasing age. In widely invasive FTC, similar to minimally invasive FTC, patients < 20 years might be likely to show recurrence but are unlikely to die of FTC, although studies using larger number of patients are necessary before drawing any conclusions.

The Japan Thyroid Association (JTA) recently published new guidelines for clinical management of thyroid nodules. This paper introduces their diagnostic system for reporting thyroid fine-needle aspiration cytology. There are two points where the new reporting system that differs from existing internationally-accepted ones. The first is the subclassification of the so-called indeterminate category, which is divided into 'follicular neoplasm' and 'others'. The second is the subclassification of follicular neoplasm into 'favor benign', 'borderline' and 'favor malignant'. It is characterized by self-explanatory terminologies as to histological type and probability of malignancy to establish further risk stratification as well as to facilitate communication between clinicians and cytopathologists. The different treatment strategies adopted for thyroid nodules is deeply influenced by the particular diagnostic system used for thyroid cytology. In Western countries all patients with follicular neoplasms are advised to have immediate diagnostic surgery while patients in Japan often undergo further risk stratification without immediate surgery. The JTA diagnostic system of reporting thyroid cytology is designed for further risk stratification of patients with indeterminate cytology. If a surgeon applies diagnostic lobectomy to all patients with follicular neoplasm unselectively, this subclassification of follicular neoplasm has no practical meaning and is unnecessary. Cytological risk stratification of follicular neoplasms is optional and cytopathologists can choose either a simple 6-tier system without stratification of follicular neoplasm or a complicated 8-tier system depending on their experience in thyroid cytology and clinical management.

Objective: 3,5,3'-Triiodothyronine (T(3))-predominant Graves' disease is characterized by the increasing volume of thyroid goiter resulting in poor prognosis. Although type 1 and type 2 iodothyronine deiodinases (DIO1 and DIO2 respectively) are known to be overexpressed in the thyroid tissues of T(3)-predominant Graves' disease, the pathogenesis of this disease is still unclear. The aim of our study is to identify genes that characterize T(3)-predominant Graves' disease tissue in order to clarify the molecular mechanism of this disease., Design and Methods: mRNAs from two thyroid tissues of both typical T(3)-predominant and common-type Graves' disease were analyzed with DNA microarrays with probes for 28 869 genes. Genes identified to be differentially expressed between the two groups were further analyzed in the second and third screenings using 70 Graves' thyroid tissues by real-time quantitative RT-PCR., Results: Twenty-three candidate genes were selected as being differentially expressed in the first screening with microarrays. Among these, seven genes, leucine-rich repeat neuronal 1 (LRRN1), bone morphogenetic protein 8a (BMP8A), N-cadherin (CDH2), phosphodiesterase 1A (PDE1A), creatine kinase mitochondrial 2 (CKMT2), integrin beta-3 (ITGB3), and protein tyrosine phosphatase non-receptor type 4 (PTPN4), were confirmed to be differentially expressed in DIO1 or DIO2 over- and underexpressing Graves' tissues., Conclusions: These genes are related to the characteristics of T(3)-predominant Graves' disease, such as high titer level of serum anti-TSH receptor antibody, high free T(3) to free thyroxine ratio, and a large goiter size. They might play a role in the pathogenesis of T(3)-predominant Graves' disease.

Follicular thyroid carcinoma (FTC) is divided into two categories: minimally and widely invasive FTC. Generally, the prognosis of minimally invasive FTC is excellent, but patients showing certain characteristics have a dire prognosis. In this study, we investigated the prognostic factors of minimally invasive FTC using a series of 292 patients. On multivariate analysis, extensive (4 or more) vascular invasion, age ≥ 45 years, and tumor size > 4 cm were independent prognostic factors of patient disease-free survival (DFS). Distant metastasis at diagnosis (M1) was the strongest prognostic factor of cause-specific survival (CSS). Extensive vascular invasion and tumor size > 4 cm also independently affected patient carcinoma death. Capsular invasion was not related to patient prognosis. The ten-year DFS rate of patients with extensive vascular invasion was 80%, which was poorer than that of those having tumor size > 4 cm (91%) and aged 45 years or older (90%). These findings suggest that 1) M1 most strongly affects the CSS of patients, and 2) M0 patients with extensive vascular invasion may be candidates for completion total thyroidectomy and radioactive iodine ablation.

Recent reports on Hashimoto's thyroiditis (HT) with increased numbers of IgG4-positive plasma cells suggest that this type of HT may have a close relationship to IgG4-related disease (IgG4-RD). This unique subgroup of HT is termed as IgG4 thyroiditis and reveals distinct clinical, serological, and sonographic features from the non-IgG4 thyroiditis group. On the basis of immunostaining for IgG4, HT was divided into an IgG4 thyroiditis group and a non-IgG4 thyroiditis group. Clinically, IgG4 thyroiditis was associated with younger age group, lower female-male ratio, higher levels of thyroid autoantibodies, diffuse low echogenicity, more rapid progress requiring surgical treatment and more subclinical hypothyroidism. Serum IgG4 concentrations elevated in IgG4 thyroiditis and decreased significantly after a thyroidectomy. Histopathologically, IgG4 thyroiditis showed a higher grade of stromal fibrosis, lymphoplasmacytic infiltration, and follicular cell degeneration than non-IgG4 thyroiditis. IgG4 thyroiditis may represent IgG4-RD of thyroid gland, because it shares common histopathological characteristics with IgG4-RD in other organs. The identification of IgG4-RD of the thyroid gland opens new insights not only for patient's treatment with HT but also for the development of new therapeutic approaches for this rapidly progressive destructive subtype of HT. This article mainly focuses on reviewing the unique histopathological, clinical, and serological features of IgG4 thyroiditis group of HT. The etiology and genetic changes of HT are also discussed.

Background: Pyriform sinus fistulae are the major routes of infection in acute suppurative thyroiditis (AST). There have been only a few reports describing imaging studies in AST. We reviewed our imaging studies in patients with AST to elucidate its features so as to facilitate its diagnosis and treatment., Methods: We reviewed ultrasonography (US) examinations, computed tomography (CT) scans, and barium swallow studies performed on 60 patients with the AST who were seen for medical care between 1998 and 2008 and were retrospectively reviewed. All of these patients had pyriform sinus fistulae., Results: In the acute inflammatory stage, US showed a hypoechoic lesion spreading in and around the affected thyroid lobe, destruction of the lobe, and abscess formation in the neck. CT scans demonstrated similar features with clearer anatomical involvement and edema in the ipsilateral hypopharynx. These findings allowed easy diagnosis of AST. However, in the early inflammatory stage US showed an unclear hypoechoic area in the affected lobe and CT scans showed a nonspecific low-density area. These findings often led to erroneous diagnoses of subacute thyroiditis. A careful review of the US studies demonstrated that the following findings are characteristic of acute suppurative thyroidits: a perithyroidal hypoechoic space, effacement of the plane between the thyroid and perithyroid tissues, and the hypoechoic lesions being unifocal. The former two are not seen in subacute thyroiditis, and hypoechoic lesions in subacute thyroiditis are usually multiple and often bilateral. In the late inflammatory stage, US and CT scans often showed atrophy and an unclear hypoechoic or low-density area in and around the affected lobe. To detect pyriform sinus fistulae, barium swallow studies are more sensitive than US or CT scans., Conclusion: During the acute inflammatory stage of AST, both US and CT scans showed inflammatory processes in and around the affected thyroid lobe, although the CT scans more clearly demonstrate the anatomical locations involved. In the early inflammatory stage, these features may lead to an erroneous diagnosis of subacute thyroiditis. Careful US studies should indicate the correct diagnosis, which can then be proven by a barium swallow study or fine-needle aspiration followed by cytological examination and bacterial culturing.

Objective: 3,5,3'-triiodothyronine-predominant Graves' disease (T(3)-P-GD) is characterized by a persistently high serum T(3) level and normal or even lower serum thyroxine (T(4)) level during antithyroid drug therapy. The source of this high serum T(3) level has not been clarified. Our objective was to evaluate the contribution of type 1 and type 2 iodothyronine deiodinase (D1 (or DIO1) and D2 (or DIO2) respectively) in the thyroid gland to the high serum T(3) level in T(3)-P-GD., Methods: We measured the activity and mRNA level of both D1 and D2 in the thyroid tissues of patients with T(3)-P-GD (n=13) and common-type GD (CT-GD) (n=18) who had been treated with methimazole up until thyroidectomy., Results: Thyroidal D1 activity in patients with T(3)-P-GD (492.7±201.3 pmol/mg prot per h) was significantly higher (P<0.05) than that in patients with CT-GD (320.7±151.9 pmol/mg prot per h). On the other hand, thyroidal D2 activity in patients with T(3)-P-GD (823.9±596.4 fmol/mg prot per h) was markedly higher (P<0.005) than that in patients with CT-GD (194.8±131.6 fmol/mg prot per h). There was a significant correlation between the thyroidal D1 activity in patients with T(3)-P-GD and CT-GD and the serum FT(3)-to-FT(4) ratio (r=0.370, P<0.05). Moreover, there was a strong correlation between the thyroidal D2 activity in those patients and the serum FT(3)-to-FT(4) ratio (r=0.676, P<0.001)., Conclusions: Our results suggest that the increment of thyroidal deiodinase activity, namely D1 and especially D2 activities, may be responsible for the higher serum FT(3)-to-FT(4) ratio in T(3)-P-GD.

Recent advances in ultrasonography and fine needle aspiration biopsy (FNAB) have facilitated accurate diagnosis of thyroid carcinomas that require treatment. However, we often encounter nodules evaluated as malignant on ultrasonography but diagnosed as benign on cytology, for which the optimal treatment strategy remains uncertain. A 28-year-old female had solitary and solid thyroid nodule measuring 6 cm in maximal diameter in February 1994. The lesion was cytologically diagnosed as benign. From September 1998, the nodule spontaneously decreased in size but ultrasonographic findings suspicious of malignancy such as peripheral and intra-tumoral calcification, low internal echo and irregular border gradually appeared. In July 2010, the volume of her nodule showed 97% decrease but was evaluated as papillary carcinoma on ultrasonography. FNAB was performed again and the nodule was diagnosed as benign. When we encounter a nodule showing ultrasonographic findings suggestive of malignancy with negative cytology, we should consider the possibility of a benign nodule degenerating over time.

Context: IgG4-related sclerosing disease is a new syndrome characterized by high serum IgG4 levels and increased IgG4-positive plasma cells in the involved organs. Recently the first description was made by our group of a subsection of Hashimoto's autoimmune thyroiditis (HT) patients showing indistinguishable histopathological features with IgG4-related sclerosing disease, which was termed as IgG4 thyroiditis., Objective: The objective of the study was analysis of the immunophenotypic features of IgG4 in 70 cases of HT patients and to clarify the histopathological and clinical characteristics of the patients with IgG4 thyroiditis., Design: Thyroid tissue samples were obtained from 70 patients with HT who were treated surgically. Quantitative analyses of the expression of IgG4 and IgG were performed. Statistical analyses of clinical and histopathological parameters were also conducted., Results: On the basis of immunohistochemistry of IgG4 and IgG4/IgG ratio, the 70 patients with HT were divided into two groups: IgG4 thyroiditis (19 cases) and non-IgG4 thyroiditis (51 cases). Histopathologically, IgG4 thyroiditis showed higher grade of stromal fibrosis, lymphoplasmacytic infiltration, and follicular cell degeneration than non-IgG4 thyroiditis. Moreover, these two groups were also demonstrated to be related with different clinical features, with IgG4 thyroiditis associated more with male gender, rapid progress, subclinical hypothyroidism, more diffuse low echogenicity, and higher level of circulating antibodies., Conclusions: From both clinical and histopathological aspects, IgG4 thyroiditis and non-IgG4 thyroiditis were demonstrated to be distinct entities. Measuring serum IgG4 concentration provides a useful method of distinguishing IgG4 thyroiditis from non-IgG4 thyroiditis.

Background and Study Aim: Recently, immunohistochemistry has shown numerous IgG4-positive plasma cells in a subset of Hashimoto's thyroiditis (HT), and this type of HT (IgG4 HT) appears to be a subtype of IgG4-related sclerosing disease. However, little is known about the distribution pattern of plasma cells in IgG4 thyroiditis. To clarify the distribution pattern of IgG4-positive plasma cells, 33 cases of HT demonstrating abundant lymphoplasmacytic infiltrate were studied., Methods: Using formalin-fixed paraffin-embedded sections, histological, immunohistochemistry and polymerase chain reaction were performed., Results: Fourteen cases were classified as IgG4 HT and 19 cases were non-IgG4 HT. Histologically, there was no significant difference between the 2 groups with regard to the degree of stromal fibrosis, lymphoid follicle formation, or the presence of phlebitis or fibrous thyroiditis. The present study demonstrated 2 distribution patterns of IgG4- and/or IgG-positive plasma cells, namely the interfollicular (n = 31) and intrafollicular + interfollicular patterns (n = 2). Interfollicular plasma cells were always polytypic intracytoplasmic immunoglobulin in all 33 cases. However, intrafollicular plasma cells in 2 lesions had monotypic kappa light chain by immunohistochemistry., Conclusion: The present study demonstrated that the majority of IgG4 HT and non-IgG HT cases showed an interfollicular distribution pattern of IgG4- and/or IgG-positive plasma cells., (Copyright © 2010 S. Karger AG, Basel.)

Somatic mutations of the thyrotropin receptor (TSHR) gene and the gene encoding the alpha subunit of the stimulatory GTP-binding protein (Gsalpha) are the main cause for autonomously functioning thyroid nodules (AFTN) in iodine-deficient regions of the world. In iodine-sufficient regions, including Japan, the genetic relevance of AFTN is unclear. In a series of 45 Japanese subjects with AFTN, exons 9 and 10 of the TSHR and exons 7-10 of Gsalpha , where the activating mutations have been found, were analyzed using direct sequencing. We found 29 somatic mutations: 22 in the TSHR gene and 7 in the Gsalpha gene. The most frequent mutation in TSHR was Met453Thr (10 cases), followed by clustered residues from codons 630 through 633 on TSHR (7 cases). Mutations of Gsalpha were detected at codon 201 in 5 cases and at codon 227 in 2 cases. No patients had coexistent TSHR and Gsalpha mutations in the same nodule. All mutated residues but one, which was deleted at codon 403 on the TSHR gene, are constitutively active. The prevalences of a germline polymorphism of Asp727Glu on the TSHR gene and incidental papillary thyroid carcinoma in thyroid surgical specimens were similar to those reported in other studies. In the present study, more than half of the cases with AFTN had a somatic activating mutation either of the TSHR or Gsalpha gene, despite their high iodine intake.

Preoperative excess iodide administration for patients with Graves' disease has been widely adopted by surgeons to perform surgery safely, because it decreases blood flow in the thyroid. However, surgeons often encounter the enlargement of thyroid volume after iodide administration, which makes surgery even more difficult. In this study, we retrospectively investigated the change in thyroid volume in Graves' disease that was evaluated on ultrasonography between before and after iodide administration. Eighty-nine patients who received iodide administered (KI(+) patients) and 24 in whom iodide was not administrated (KI(-) patients) before surgery for Graves' disease were enrolled in the study. The level of free T4 (FT4) significantly decreased and that of thyroid stimulating hormone (TSH) significantly increased after iodide administration. Average thyroid volume also significantly increased for KI(+) patients after iodide administration and 17% of these patients showed a 30% or more increase in thyroid volume. In KI(-) patients who were preoperatively treated only by anti-thyroid drugs, thyroid volume did not change before surgery. Preoperative TSH levels remained below measurement sensitivity in 37 of KI(+) patients, but the average thyroid volume also significantly increased after iodide administration. These findings suggest that thyroid volume in Graves' disease can increase with iodide administration not only due to TSH stimulation but also due to reasons other than TSH. Surgeons should be careful when preoperatively iodide administering to patients with Graves' disease, especially when the goiter is large.

Background: The relative expression level of trefoil factor 3 (TFF3) mRNA to galectin-3 (LGALS3) mRNA (T/G ratio) is a useful marker to distinguish thyroid follicular carcinomas from adenomas. However, because of the interference by the simultaneously aspirated peripheral blood cells or infiltrating lymphocytes, the precise measurement of the T/G ratio in aspirates is difficult., Methods: We tested 2 methods of selecting thyroid tumor cells and removing blood cells from the aspirates. One method was selection with magnetic beads coated with Ber-EP4 antibody and the other was filtration through a nylon mesh., Results: After selection with Ber-EP4 antibody, T/G ratios in aspirates showed varied degrees of difference from those in the corresponding tissues. After mesh filtration, differences in T/G ratios between the aspirates and the corresponding tissues were less than 200% in all 8 cases., Conclusion: Mesh filtration of aspirates proved superior results for the measurement of T/G ratio.