Prevalence and diagnostic significance of non-invasive follicular thyroid neoplasm with papillary-like nuclear features in Japan-A multi-institutional study.

This multi-institutional study investigated non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) frequency and its diagnostic significance in Japan. We reviewed 4008 thyroid nodules resected in six institutions before NIFTP was proposed. Overall, 26 cases diagnosed as non-invasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) and 145 cases of follicular thyroid adenoma (FTA) were included. Of these nodules, 80.8% and 31.0%, respectively, were NIFTPs. In five institutions, NIFTPs were more commonly found in FTA than in PTC nodules. When NIFTP was included with PTC, the overall prevalence was 2.3%, with rates in five institutions below 5.0% (0.8%-4.4%). One NIFTP case with nuclear score 3 revealed nodal metastasis 2.5 years post-resection, and the carcinoma cells were immunohistochemically positive for BRAF. FTAs or NIFTPs with nuclear score 2 did not metastasize. NIFTP was more common among FTA than among PTC nodules, possibly due to underdiagnosis of PTC on nuclear findings. Considering the clinical findings, molecular pathogenesis, and therapeutic strategy in Japan, NIFTP with nuclear score 2 is not different from FTA, and use of this entity terminology is not meaningful. In contrast, NIFTP with nuclear score 3 has potential for metastasis and BRAFV600E mutation. Therefore, in NIFTP cases, nuclear scores 2 and 3 should be separately reported.

Clinical, cytological, and pathological characteristics of metastatic renal cell carcinoma to the thyroid: A study of 14 cases at a Japanese single institution.

A preoperative diagnosis of metastatic renal cell carcinoma to the thyroid (MRCCT) is important for determining clinical management but is challenging even in cases with a clinical history of renal cell carcinoma (RCC). This study aimed to elucidate the clinical, cytological, and pathological characteristics of MRCCT. Fourteen MRCCT cases extracted from 18 320 malignant thyroid tumors were included in this study. Twelve MRCCT (85.7%) occurred as solitary lesions and the most frequently suspected lesions on ultrasonography were follicular tumors. On cytology, 46.2% of cases were reported as RCC or suspected RCC; a medical history of RCC and immunocytochemistry were helpful in interpretation. RCC metastasized to a follicular adenoma in 50.0% of the solitary lesions. MRCCTs with a long interval from the initial presentation, solitary lesion, and Ki-67 labeling index <10% showed significantly longer disease-free survival. MRCCT is characterized by a long interval from the initial presentation of RCC, appearance as a solitary nodule, ultrasonographic similarity to follicular tumors, sharing cytological findings with primary thyroid tumors, and high frequency of metastasis within follicular adenoma. A long interval from the initial presentation, occurrence as a solitary lesion, and low Ki-67 labeling index may be favorable prognostic factors.

Papillary Thyroid Carcinoma with Honeycomb-Like Growth: Clinicopathological Characteristics and Diagnostic Significance as a Novel Variant.

INTRODUCTION: We aimed to clarify the clinical and pathological characteristics of papillary thyroid carcinoma (PTC) with unique honeycomb-like growth (HLG) and discuss its diagnostic significance. METHODS: Among the 12,745 PTCs that were resected and histologically diagnosed, 28 PTC cases with HLG components (0.2%) were included. RESULTS: PTC-HLG was subclassified into pure (9 cases), which consisted of only HLG components, and mixed (19 cases), which consisted of conventional PTC and HLG components, types. HLG components were histologically characterized by (1) neoplastic cyst aggregation with intervening normal thyroid follicles, (2) the cyst wall composed of single-layered carcinoma cells, (3) low papillary growth, and (4) ball-like granulation tissues. Compared with the mixed type, the pure type occurred in older people (p < 0.05), had a smaller tumor size (p < 0.0001), was more interpreted as being benign by ultrasound (p < 0.05), and had a lower lymph node metastasis rate (p < 0.005). In the mixed type, 44.4% of conventional PTCs showed a Ki-67 labeling index of >5%. All and 10.5% of the mixed type showed lymph node and lung metastases, respectively. CONCLUSION: The pure type could be a nonaggressive variant of PTCs with a unique honeycomb growth pattern and tended to be clinically interpreted as benign. The mixed type is pathogenetically different from the pure type and is slightly aggressive compared with conventional PTCs.

B-cell to T-cell ratio as a novel indicator in flow cytometry in the diagnosis of thyroid lymphoma.

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.

Preoperative detection of the TERT promoter mutations in papillary thyroid carcinomas.

OBJECTIVE: Telomerase reverse transcriptase promoter (TERT-p) mutations are strongly associated with tumour aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). Since the TERT-p mutations have been reported to be subclonal, it is unclear how accurately they can be detected by preoperative fine-needle aspiration (FNA). The objective of this study was to analyse the concordance rate of the TERT-p mutations between preoperative FNA and corresponding postoperative surgical specimens. DESIGN AND PATIENTS: Ninety-six cases of PTC aged 55 years or older were studied. The mutational status of TERT-p was detected by droplet digital polymerase chain reaction assay. RESULTS: The mutational status of the TERT-p in FNA samples was highly concordant with that in postoperative formalin-fixed and paraffin-embedded (FFPE) specimens. The TERT-p mutation was significantly associated with age, tumour size, extrathyroidal extension and the Ki-67 labelling index in multivariate analysis in both FNA and FFPE samples. CONCLUSIONS: The detection of the TERT-p mutations using FNA samples has a good ability to predict disease aggressiveness and, therefore, could be clinically useful in the determination of PTC management.

Evaluation of E-Cadherin and ß-Catenin Immunoreactivity for Determining Undifferentiated Cells in Anaplastic Thyroid Carcinoma.

INTRODUCTION: An immunohistochemical study has occasionally been performed to diagnose anaplastic thyroid carcinoma (ATC). However, antibodies to confirm the undifferentiated nature of ATC have not yet been evaluated. The aim of this study was to evaluate E-cadherin and ß-catenin expressions in immunoreactivity to determine undifferentiated carcinoma cells in the diagnosis of ATC. METHODS: We immunohistochemically examined 29 ATCs, 30 poorly differentiated thyroid carcinomas (PDTCs), 22 well-differentiated thyroid carcinomas (WDTCs), and 3 squamous cell carcinomas. Antibodies for thyroid transcription factor-1 (TTF-1), paired-box gene 8 (PAX8), ß-catenin, and E-cadherin were used. RESULTS: All WDTCs tested positive for TTF-1, PAX8, and E-cadherin. The positive rates of TTF-1, PAX8, and E-cadherin were 93.3, 93.3, and 100%, respectively, in PDTCs and 17.2, 51.7, and 10.3%, respectively, in ATCs. WDTC expressed the lateral cell membrane staining for ß-catenin and E-cadherin, whereas PDTC showed circumferential cell membranous expression (fishnet pattern). ß-catenin cell membrane expression in ATCs is lost or discontinuous. Carcinoma cells with ß-catenin nuclear expression without cell membranous expression were scattered in 72.4% of ATCs but were not observed in the other carcinomas. CONCLUSION: We propose 3 immunohistochemical findings to determine undifferentiated carcinoma cells in the diagnosis of ATC: (1) ß-catenin nuclear expression with no or reduced cell membranous expression, (2) the loss or discontinuous pattern of E-cadherin expression, and (3) the loss of PAX8 nuclear expression.

Histological alterations following fine-needle aspiration for parathyroid adenoma: Incidence and diagnostic problems.

This study aimed to clarify the histological alterations following fine-needle aspiration for parathyroid adenoma and discuss the occurrence of diagnostic problems. Among the 392 patients with parathyroid adenoma who underwent resection, fine-needle aspiration was performed for 21 (5.1%) parathyroid adenoma nodules. Histological findings that were significantly more frequent in cases that underwent fine-needle aspiration were considered histological alterations following fine-needle aspiration for parathyroid adenoma, including the following six findings: thick fibrous capsule (71.4%), multilayered fibrous capsules (14.3%), capsular pseudo-invasion (42.9%), fibrous bands (57.1%), hemosiderin deposition (14.3%), and tumor implantation (14.3%). Eighteen parathyroid adenoma nodules (85.7%) exhibited one or more of the six findings. Tumor cells and adipocytes entrapped within the thick fibrous capsule were occasionally observed. The fibrous bands were frequently connected to the thick fibrous capsule. The number of passes, duration between fine-needle aspiration and resection, tumor size, and purpose of fine-needle aspiration were not related to the incidence of histological findings. Because of the histological alterations following fine-needle aspiration for parathyroid adenoma that can be easily mistaken for signs of atypical adenoma or parathyroid carcinoma, we recommend that the six findings be excluded from pathological findings indicating atypical adenoma or parathyroid carcinoma in patients with preoperative fine-needle aspiration.

Potential role of mobile rapid on-site evaluation® in thyroid fine-needle aspiration cytology to reduce delayed repeated aspiration.

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 CytoRichTM 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.

Thyroid Tubercle of Zuckerkandl May Not Arise from the Ultimobranchial Body: Results from Histological Analysis.

Thyroid tubercle of Zuckerkandl (TZ) is a nodule arising from the posterolateral thyroid, considered to be a remnant of the ultimobranchial body (UB). Considering that C cells and solid cell nests also arise from the UB, we hypothesized that these would be present in the TZ. We examined the presence of C cells and solid cell nests in the TZ using the histological analyses of 21 patients with grade 2 or 3 TZs following Pelizzo's grading system. Out of 21 TZs, 19 (90.5%) were located in the right lobe of the thyroid. Microscopically, solid cell nests were found within the TZ in 1 case (4.8%), and within the main thyroid tissues in 3 cases (14.3%). Calcitonin-positive C cells were scattered within the TZ in 1 case (4.8%), and within the main thyroid tissue in 15 cases (71.4%). The distribution of C cells within the main thyroid tissue was denser than that within the TZ. The above-mentioned results indicated the lack of C cells and solid cell nests in the TZ. Although the TZ may have an embryological origin different from that of ordinary thyroid tissue, it is unlikely that the remnants of the UB are involved in the formation of the TZ.

Needle Tract Implantation Following Fine-Needle Aspiration of Thyroid Cancer.

BACKGROUND: Needle tract implantation (NTI) can occur after thyroid fine-needle aspiration cytology (FNAC). To date, no studies enrolling a large number of patients and studying the cumulative incidence (CI) of NTI have been published. This study analyzed the clinicopathological features of NTI and calculated the CI. METHODS: A total of 11,745 patients who underwent first FNAC, resection for thyroid carcinomas and related lymph node metastases, and postoperative ultrasonography in Kuma Hospital between 2006 and 2017 were evaluated. NTI was defined as macroscopically visible and/or sonographically detected recurrent tumors at the sites of the previous aspiration. Lymphovascular invasion and/or nodal metastasis were excluded. RESULTS: We found 22 NTI-THY (originated from aspiration of thyroid tumors) and 8 NTI-LN (originating from lymph nodes) cases with CI of 0.15% and 0.37%, and 0.37% and 0.58% at 5 and 10 years after FNAC, respectively. A large percentage (53%) of cases are presented as more aggressive histologic subtypes than their original tumors. Of these NTI patients, 4 (12.1%) died of disease and 10 (33.3%) developed distant metastases but remained alive with stable disease, three (9.1%) developed local recurrences, and the remaining 15 (10%) were free of recurrence. CONCLUSIONS: We demonstrated for the first time the CI and detailed clinicopathological features of thyroid NTI associated with possible histological transformation. Despite the low CI, the risk of death and distant metastases increase manifold in NTI patients than that in patients without recurrence. Therefore, NTI could be an important prognostic variable and impact patient survival.

Prevalence and diagnostic significance of noninvasive follicular thyroid neoplasm with papillary-like nuclear features among tumors previously diagnosed as follicular adenoma: a single-institutional study in Japan.

The incidence of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in papillary thyroid carcinoma (PTC) is significantly lower in Asian countries than Western countries; however, the difference remains unexplained. This study aimed to evaluate the incidence of NIFTP in tumors diagnosed as follicular adenoma (FA) in a Japanese institution and discuss the significance of NIFTP. In this study, 44 tumors were investigated, which were histologically diagnosed as FA at the Kuma Hospital in 2008. Of the 44 tumors, 13 (29.5%) were revised as NIFTP. In the remaining 31 tumors, the FA diagnosis was reconfirmed. On aspiration cytology, most of the NIFTPs were categorized into follicular neoplasm or suspicious for a follicular neoplasm. On histological examination, 9 (29.0%) of 31 FA nodules showed a nuclear score of 1. Twelve (92.3%) of 13 NIFTP nodules showed a nuclear score of 2, and the remaining nodule had a nuclear score of 3. No metastasis of FA or NIFTP was detected. There were no evidences of distant metastasis during follow-up. This is the first study to describe that NIFTP is more frequently included in tumors diagnosed as FA rather than PTC in Japan. As clinical management of FA and NIFTP is the same, in Japan, there is no reason to distinguish between FA and NIFTP. Conclusively, the necessity of using the disease entity "NIFTP" is not found in Japan.

Diagnostic significance of apical membranous and cytoplasmic dot-like CD26 expression in encapsulated follicular variant of papillary thyroid carcinoma: a useful marker for capsular invasion.

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.

Cribriform-Morular Variant of Papillary Thyroid Carcinoma Shows High Ki-67 Labeling Indices, despite Its Excellent Prognosis.

OBJECTIVE: This study aimed to demonstrate that the cribriform-morular variant (CMV) of papillary thyroid carcinoma (PTC) has high Ki-67 labeling indices, despite its excellent prognosis. METHODS: We examined 21 CMV-PTCs and 5 conventional PTCs (C-PTCs) resected at Kuma Hospital between 2008 and 2018. All of the patients with CMV-PTC were women. Their ages ranged from 17 to 35 years, with a mean of 25.2 years. An immunohistochemical study using ß-catenin, estrogen receptor (ER), and Ki-67 was performed. For apoptotic analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was performed. RESULTS: All CMV-PTCs were encapsulated with thick fibrous connective tissue. Eleven and one CMV-PTCs exhibited capsular invasion and extrathyroidal invasion, respectively. Two patients showed regional nodal metastasis. The Ki-67 labeling index ranged from 4.8 to 36.4% (mean 15.2%). Apoptotic cells were counted, which showed 2-52 positive cells (mean 12.6) per 10 high-power fields. The Ki-67 labeling index was positively correlated with the apoptotic cell count (r = 0.48, p = 0.030). Ki-67 labeling indices of CMV-PTCs were significantly higher than those of C-PTCs (p = 0.0027). Ages and tumor sizes did not have significant correlations with Ki-67 labeling indices or apoptotic cell counts. CONCLUSION: This study is the first to demonstrate disproportionally high Ki-67 labeling indexes in a large number of CMV-PTC cases, despite the fact that these cases had favorable prognoses. The favorable prognosis of CMV-PTC may be attributable to encapsulation and nuclear ER expression.

Optimal needle size for thyroid fine needle aspiration cytology.

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.

Important cytological findings for distinction between follicular variant and conventional papillary thyroid carcinoma, including noninvasive follicular thyroid tumors with papillary-like nuclear features.

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.

Stromal tiny black dots, like "sugar-coated", of von Kossa stain is a diagnostic clue to hyalinizing trabecular tumor of the thyroid gland.

Hyalinizing trabecular tumor (HTT) is a rare low-grade tumor, and a prominent feature is the basement membranous stroma. We assume that such characteristic stromal findings of HTT are related to calcium deposition, and examined HTT samples by von Kossa special staining. There has been no report describing von Kossa special staining for such stroma. We collected 12 cases of HTT and 30 cases of papillary thyroid carcinoma (PTC) that had matched age, gender, tumor size, and surgical procedure characteristics as a control group. We compared the staining pattern and degree of von Kossa positivity between HTT and PTC, and a grading system of von Kossa stain was adopted to highlight differences between them. On von Kossa staining, all HTT revealed many tiny black dots around vessels in the hyalinized stroma, like "sugar-coated", and a high degree of calcium deposition in most cases, whereas PTC showed sparse stromal calcification in some cases. The degree of von Kossa staining was significantly different between the two groups. This is the first report describing abundant tiny black dots, like a "sugar-coated" appearance, of von Kossa stain in HTT. Here, we propose this finding can be a useful diagnostic clue to HTT.

Warthin-like papillary thyroid carcinoma with immunoglobulin G4-positive plasma cells possibly related to Hashimoto's thyroiditis.

Hashimoto's thyroiditis with heavy lymphoplasmacytic infiltration is a common comorbidity of immunoglobulin G4 (IgG4)-related thyroiditis and Warthin-like papillary thyroid carcinoma (WL-PTC). We hypothesized that WL-PTC may have a strong association with IgG4-related thyroiditis. To validate this hypothesis, we clinically and immunohistochemically studied 17 WL-PTC cases. Fourteen patients (82.4%) had anti-thyroglobulin antibody and were confirmed to have Hashimoto's thyroiditis through microscopic analysis. Among them, five (29.4%) had disease consistent with IgG4-related thyroiditis but did not exhibit a "storiform" pattern or obliterative phlebitis. IgG4-related diseases were not found in other organs. No cases with serum IgG4 level of >135 mg/dL were noted. A total of 94.1% of WL-PTC cases had IgG4-positive plasma cells (+PCs) in the stroma, and cases with rich IgG4+PCs were more frequently associated with Hashimoto's thyroiditis than those with poor IgG4+PCs. In this study, all three cases without Hashimoto's thyroiditis had poor IgG4+PCs, and one of them did not exhibit IgG4+PCs in the stroma of WL-PTC and Hashimoto's thyroiditis. Nodal metastatic lesions were seen in eight cases, all of which were not WL-PTC. As such, we should consider that the Hashimoto's disease with rich IgG4+PCs seen in our cases is representative of non-IgG4-related disease and not IgG4-related disease involving multiple organs. This study is the first to demonstrate the presence of IgG4+PCs in the stroma of WL-PTC. We concluded that the appearance of IgG4+PCs in the stroma of WL-PTC may be related to Hashimoto's thyroiditis with rich IgG4+PC.

Impact of the modification of the diagnostic criteria in the 2017 Bethesda System for Reporting Thyroid Cytopathology: a report of a single institution in Japan.

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.

Derivation of thyroid lymphoepithelial cysts from follicular cells.

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.

Utility of monoclonal PAX8 antibody for distinguishing intrathyroid thymic carcinoma from follicular cell-derived thyroid carcinoma.

Follicular cell-derived thyroid carcinomas, including thyroid squamous cell carcinomas (SCCs) and anaplastic carcinomas, are immunoreactive for paired-box gene 8 (PAX8), while non-follicular cell-derived thyroid carcinomas stain negative for the PAX8 antibody. Intrathyroid thymic carcinoma (ITTC) arising from the intrathyroidal ectopic thymus exhibits moderate-to-strong nuclear reactivity for polyclonal PAX8. This is difficult to understand given that PAX8 is not associated with embryonic thymic development. We aimed to determine the diagnostic significance of monoclonal PAX8 antibody in distinguishing ITTCs from follicular cell-derived thyroid carcinomas. Ten ITTCs, 14 poorly differentiated thyroid carcinomas (PDTCs), 14 thyroid SCCs, 7 thymic tissue specimens, 7 thymomas, and 1 thymic carcinoma were analyzed using antibodies against polyclonal and monoclonal PAX8, thyroid transcription factor-1, p63, and CD5. Four ITTCs (40.0%) stained positive for polyclonal PAX8; none stained positive for monoclonal PAX8. All PDTCs and 92.9% of SCCs were immunoreactive for both polyclonal and monoclonal PAX8. All PDTCs, 46.2% of SCCs, and none of the ITTCs were immunoreactive for thyroid transcription factor-1. Eight ITTCs (80.0%), but none of the PDTCs and SCCs, were immunoreactive for CD5. We are the first to show that ITTCs stain negative for monoclonal PAX8. Monoclonal PAX8 is a more reliable marker than polyclonal PAX8 for determining follicular cell origin. We conclude that monoclonal PAX8 is a useful marker for distinguishing ITTCs from PDTCs and SCCs. Monoclonal PAX8 negativity is additional evidence in support of ITTCs not being follicular cell-derived thyroid carcinomas, but having a thymic origin.