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Objective To evaluate the clinical significance and compare the imaging features according to the Thyroid Image Reporting and Data System ( TIRADS) between atypia of undetermined significance/follicular lesion of undetermined significance ( AUS/ FLUS) subcategories. Design & patients A total of 192 thyroid nodules in 188 patients (mean age: 50·2 ± 11·8 years) that had been initially diagnosed as AUS/ FLUS on US-guided fine needle aspiration ( US- FNA) were included. One cytopathologist retrospectively reviewed the cytology slides, subcategorizing cytology results into AUS and FLUS. A TIRADS category was assigned to each thyroid nodule according to the number of suspicious US features. Clinical, US features and malignancy rates were compared between the two subcategories. Results Of the 192 AUS/ FLUS lesions, 149 (77·6%) were subcategorized as AUS and 43 (22·4%) as FLUS. Of the 192 AUS/ FLUS nodules, 82 (42·7%) were malignant. The malignancy rates between AUS and FLUS subcategories were not significantly different, 45·6% to 32·6%, respectively ( P = 0·127). When applying TIRADS, significant differences were seen in TIRADS category between benign and malignant nodules in the AUS subcategory ( P < 0·001), but not in the FLUS subcategory ( P = 0·414). The malignancy rates in TIRADS categories 3, 4a, 4b, 4c and 5 were 15·4%, 22·2%, 33·3%, 57·1% and 80·0% ( P < 0·001) in AUS nodules and 40·0%, 50·0%, 23·5%, 22·2% and 0·0% ( P = 0·414) in FLUS nodules, respectively. Conclusion Suspicious US features are useful in predicting malignancy among AUS subcategories but not in FLUS subcategories. Subcategorization into AUS and FLUS cytology may be helpful in deciding upon treatment or management of thyroid nodules. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the clinical value of additional von Kossa staining on cytology in thyroid nodules with echogenic spots on ultrasound (US). Materials and methods 342 thyroid nodules were analyzed for cytology and von Kossa staining was performed to detect microcalcifications. We compared diagnostic performances and accuracies of FNA and FNA with von Kossa staining to detect malignancy. We evaluated associations of aggressive pathologic features and von Kossa positivity in the surgically confirmed papillary thyroid carcinoma (PTC) group. Results Two hundred and thirty two (67.8%) nodules were malignant and 110 (32.2%) were benign on cytopathology. Compared to cytology alone, additional von Kossa staining slightly improved sensitivity from 89.7% to 90.9% ( P = 0.081). In 207 cases of surgically confirmed PTC, von Kossa positivity was an independent predictor of central lymph node metastasis in PTCs by multivariate analysis (odds ratio, 2.218; P = 0.021). Conclusions Adding von Kossa staining to cytology improved the sensitivity of thyroid nodules with echogenic spots on US. Positive von Kossa stains in PTCs may also be useful in predicting central lymph node metastasis. [ABSTRACT FROM AUTHOR]

Some morphologic parameters have been studied to help predict the BRAF V600E mutation using cytopathologic specimens, which can indicate which nodules should undergo further testing. The aim of this study was to investigate the value of cytomorphologic parameters to predict the BRAF V600E mutation in nodules read as “suspicious for malignancy” on cytology. This study included 142 resected nodules which were diagnosed as “suspicious for malignancy” on cytology in 142 patients. At our institution, BRAF V600E mutation analysis was performed at the request of the referring clinicians based on the clinical features of the patients, or the judgment of the radiologists performing US-FNA because suspicious US features were observed on the targeted nodule during this study period. Cytology smears were re-reviewed to assess the presence and amount of polygonal eosinophilic (plump) cells and microfollicles, and the presence of intranuclear pseudoinclusions, irregular nuclear membranes, nuclear grooves, sickles cells, psammoma bodies, and cystic changes. We evaluated the diagnostic performances of the cytomorphologic features to predict the BRAF V600E mutation. Polygonal eosinophilic (plump) cells, microfollicles, intranuclear pseudoinclusions, sickle cells, and cystic changes were significantly associated with the BRAF V600E mutation. The mutation was not present in all 6 thyroid nodules with microfollicles larger than 20% on cytology. Additionally, polygonal eosinophilic (plump) cells larger than 20%, cystic changes, and sickle cells on cytology had a high specificity of 95%, 96.7%, and 81.7%, respectively. Excluding 6 nodules with microfollicles larger than 20% on cytology, there were 82 (60.3%) nodules with the BRAF V600E mutation among the 136 nodules. Among the 136 nodules, there were 95 nodules with polygonal eosinophilic (plump) cells larger than 20%, cystic changes, or sickle cells on cytology. Of the 95 nodules, 69 (72.6%) had the mutation. Cytomorphologic features can help select nodules for the BRAF V600E mutation test among nodules read as “suspicious for malignancy” on cytology. [ABSTRACT FROM AUTHOR]

Abstract: CD9 and CD82, members of the tetraspanin family, act as metastasis suppressors in many human malignant tumors, but the role of these molecules is not well known in clear cell renal cell carcinoma (CCRCC). This study was designed to evaluate the immunohistochemical expression of CD9 and CD82 in 644 cases of CCRCC and to determine the clinicopathologic and prognostic significance of their expression. The percentage of positive tumor cells was evaluated, and the expression was classified into 2 categories: low expression (less than 10% positive cells) or high expression (more than 10% positive cells) for CD9 expression and negative (no positive cells) or positive for CD82 expression. CD9 high expression was found in 303 (47.0%) patients, and CD82 positivity was found in 98 (15.2%) patients. High expression of CD9 was statistically associated with older patients (p =0.003). The cases showing positive immunoreactivity for CD82 exhibited a high stage (p <0.001) and high nuclear grade (p <0.001). The overall, cancer-specific and progression-free survival rates were significantly higher in patients with a CD82-negative profile compared to patients with a CD82-positive profile (p <0.001). Although the biological function of CD82 in CCRCC remains unclear, the CCRCC patients with CD82 positive expression show poor prognosis. [Copyright &y& Elsevier]

ABSTRACT Background and aim: Low gamma-glutamyltranspeptidase (γ-GTP) familial intrahepatic cholestasis is a broad-spectrum condition that ranges from mild to severe. Severe forms of low γ-GTP familial intrahepatic cholestasis, including progressive familial intrahepatic cholestasis type-1 and -2 (PFIC-1 and PFIC-2), present with symptoms of cholestasis early in life and may progress to cirrhosis. Methods: We included five patients with low γ-GTP, cholestasis and hyperbilirubinemia. We analyzed clinicopathological features of these five cases. Results: The age of the patients at diagnosis ranged from 1 month to 1 year old. All patients presented with jaundice, and one experienced pruritus. In contrast to hyperbilirubinemia, serum γ-GTP levels were relatively low, or within normal range. Microscopically, intracanalicular cholestasis, bile duct loss or atrophy and varying degrees of fibrosis were found in all of the cases, whereas giant cell formation of hepatocytes was detected in three cases. Anti-ABCB11 immunostaining revealed loss of expression in three cases with diffuse giant cell transformation of hepatocytes but retained expression in one case with no giant cell transformation. Conclusions: Low γ-GTP familial intrahepatic cholestasis (PFIC-1 and PFIC-2) should be considered a differential diagnosis when pediatric patients with cholestatic liver diseases associated with normal to low serum γ-GTP levels relative to the extent of cholestasis. [ABSTRACT FROM AUTHOR]

Objective: Primary tumour size (PTS) is known to be a significant prognostic factor in patients with papillary thyroid carcinoma (PTC) undergoing thyroidectomy. Although cutoff values of 2 and 4 cm are widely used in surgical extent decision and long‐term outcomes predictions, the effectiveness of arbitrary cutoff values in stratifying patients for target outcomes is questionable. This study aimed to determine new optimal cutoffs of PTS. Design, Patient And Measurements: Patients (n = 529) with PTC who underwent total thyroidectomy were retrospectively reviewed. After risk factor analysis for structural recurrence, the optimal cutoffs of PTS were automatically calculated using restricted cubic spline analysis and X‐tile software. Subgroups were classified based on the newly determined cutoff values. Both the recurrence‐free survival (RFS) and the proportion of patients in each response‐to‐therapy category, using the dynamic risk stratification system (DRS), were compared between the subgroups. Results: PTS was confirmed as an independent risk factor for structural recurrence. The optimal cutoff values were calculated as 1.4 and 3.0 cm. The subgroups stratified using these newly determined cutoffs showed significantly different RFS and DRS based on the response to initial therapy, but the subgroups classified using the cutoffs of 2 and 4 cm did not. Conclusions: The newly determined cutoff values of PTS may be useful in better stratifying patients with PTC undergoing thyroidectomy for target outcomes and can be considered as a new definition in staging and risk stratification systems. [ABSTRACT FROM AUTHOR]

Purpose. We report a rare case of severe hypercalcemia that was ultimately diagnosed as primary bone marrow diffuse large B-cell lymphoma (BCL). Case Report. A 74-year-old male patient visited our hospital complaining of tenderness and swelling of the left knee caused by supracondylar fracture of the left distal femur. His initial blood tests showed a serum calcium level of 13.9 mg/dL, inorganic phosphorus of 4.34 mg/dL, and a serum creatinine level of 1.54 mg/dL. A serum assay of intact parathyroid hormone showed 5.24 pg/mL, and the patient’s serum 25(OH)D level was 22.33 ng/mL. To exclude malignancy, we performed imaging studies, including abdomen or chest computed tomography and positron emission tomography-computed tomography; however, no suspicious lesion was found, although the serum PTH-related peptide level was elevated at 4.0 pmol/L. A bone marrow biopsy was performed to identify any hidden hematologic malignancy. As a result, the pathology of bone marrow confirmed the presence of atypical lymphocytes that stained positive for the CD20 marker, which is consistent with BCL involving the bone marrow. Conclusion. This case highlights the importance of pursuing a thorough workup for rare underlying causes of hypercalcemia when parathyroid-related etiologies can be excluded. [ABSTRACT FROM AUTHOR]

Simple Summary: The analytic appropriateness and general applicability of lymph node-related risk factors used to predict long-term outcomes in patients with papillary thyroid carcinoma need to be validated. This study aimed to assess detailed lymph node-related risk factors and suggest new risk categories. In the present study, using the K-means clustering algorithm, we determined new cutoffs for lymph node variables besides extranodal extension: 0.2 cm and 1.1 cm for the maximal diameter of metastatic lymph node foci, 4 and 13 for the number of metastatic lymph nodes, and 0.28 and 0.58 for the metastatic lymph node ratio; new lymph node risk categories were suggested. The recurrence-free survival curves of each subgroup classified by these newly determined cutoffs showed significant differences. These newly developed risk categories might be considered when redefining risk stratification or staging systems. Background: Lymph node (LN)-related risk factors have been updated to predict long-term outcomes in patients with papillary thyroid carcinoma (PTC). However, those factors' analytic appropriateness and general applicability must be validated. This study aimed to assess LN-related risk factors, and suggest new LN-related risk categories. Methods: This multicenter observational cohort study included 1232 patients with PTC with N1 disease treated with a total thyroidectomy and neck dissection followed by radioactive iodine remnant ablation. Results: The median follow-up duration was 117 months. In the follow-up period, structural recurrence occurred in 225 patients (18.3%). Among LN-related variables, the presence of extranodal extension (p < 0.001), the maximal diameter of metastatic LN foci (p = 0.029), the number of retrieved LNs (p = 0.003), the number of metastatic LNs (p = 0.003), and the metastatic LN ratio (p < 0.001) were independent risk factors for structural recurrence. Since these factors showed a nonlinear association with the hazard ratio of recurrence-free survival (RFS) rates, we calculated their optimal cutoff values using the K-means clustering algorithm, selecting 0.2 cm and 1.1 cm for the maximal diameter of metastatic LN foci, 4 and 13 for the number of metastatic LN, and 0.28 and 0.58 for the metastatic LN ratio. The RFS curves of each subgroup classified by these newly determined cutoff values showed significant differences (p < 0.001). Each LN risk group also showed significantly different RFS rates from the others (p < 0.001). Conclusions: In PTC patients with an N1 classification, our novel LN-related risk estimates may help predict long-term outcomes and design postoperative management and follow-up strategies. After further validation studies based on independent datasets, these risk categories might be considered when redefining risk stratification or staging systems. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and aim: The three-panel marker, glypican-3, HSP70 and glutamine synthetase, is helpful for making a diagnosis of early hepatocellular carcinoma. To further characterize the diagnostic values of these three markers, we performed immunostaining studies in non-neoplastic hepatocytes (chronic hepatitis B) and hepatocellular carcinoma. Methods: Immunostaining was performed for all three markers. The cases were 60 needle biopsies of chronic hepatitis B (30 with low-grade activity and 30 with high-grade activity) and 40 hepatocellular carcinomas (HCCs). Results: Glypican-3 staining was detected in only one of the 60 chronic hepatitis B cases, and this case expressed moderate immunoreactivity for glypican-3 and showed high-grade inflammatory activity. HSP70 expression was not observed in any cases. Glutamine synthetase was strongly immunoreactive at peri-venular hepatocytes with cytoplasmic staining in all cases. These findings reflected a normal expression pattern. On the other hand, all three markers were positive in 15 (37.5%) HCCs. At least two of three markers were positive in 26 (65.0%). Moreover, all three markers were negative in 2 (5.0%) HCCs. Conclusions: The combination of these three markers is highly specific for detecting hepatocellular carcinoma. However, caution should be exercised because non-neoplastic hepatocytes in chronic hepatitis B with high necro-inflammatory activity tend to show focal positivity for glypican-3. Also we emphasize that all three markers can show negative immunoreactivity in HCC. [ABSTRACT FROM AUTHOR]

We investigated the clinicopathological implications of leptin-signaling proteins and Epstein-Barr virus (EBV)-infection status in gastric carcinomas. Immunohistochemistry for leptin signalling-related proteins (leptin, leptin-receptor, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha), and in situ hybridization for EBV-encoded small RNAs was performed in 343 cases of gastric carcinomas. The siRNA against leptin-receptor was transfected into three stomach cancer cell lines, and western blot for caspase 3 was performed. The TNM stage was a prognostic factor in all 343 patients, and was negatively correlated with expression of leptin, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha (P < 0.05). Leptin-receptor expression was correlated with poor survival in 207 patients of the advanced gastric cancer (AGC) subgroup, 139 of the Lauren diffuse group, and in 160 patients with lymph node metastasis (P < 0.05, respectively). Additionally, in stomach cancer cells, cleaved caspase 3 level increased by leptin-receptor inhibition, that is, apoptosis increased. Interestingly, EBV-positive AGC (n = 29) tended to show better survival of patients than EBV-negative AGC (n = 178) (P = 0.06). pAkt expression was related with a good survival of 32 patients (9%) in the EBV-positive subgroup, but was not an independent prognostic factor. Among, leptin signaling-related proteins, expressions of leptin-receptor and mTOR were different between EBV-positive subgroup and EBV-negative subgroup (P < 0.05, respectively). In conclusion, leptin-signaling proteins and EBV status show different significance on patient survival, according to subsets of gastric carcinomas. The leptin-receptor may predict poor patient prognosis in the AGC, Lauren diffuse and lymph node metastasis subgroups, while EBV-positive status can show a good prognosis in the AGC. Each leptin signaling-related protein may be differently involved in carcinogenesis of EBV-negative and EBV-positive subsets. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the diagnostic utility of PAI at detecting thyroid microcalcifications at 700 nm laser wavelengths. Methods: This study included 36 resected samples in 18 patients. To evaluate the PA manifestation of microcalcifications in PAI, gray level histogram and co-occurrence matrix (COM) texture parameters were extracted from the 3 fixed ROI US and PA images, respectively, per sample. We compared the textural parameters obtained from specimen PAIs between samples with punctate microcalcifications on specimen radiography and those without microcalcifications. Results: On specimen US, the mean value (2748.4±862.5) of samples with microcalcifications on specimen radiography was higher than that (1961.9±780.2) of those without microcalcifications (P = 0.007). However, there were no significant differences in textural parameters obtained from specimen PAIs between samples with punctate microcalcifications on specimen radiography and those without when applying both the mean value of the three slices of thyroid specimens and the value of the thyroid specimen slice which had the highest value of the mean values in specimen US. Conclusion: PAI did not show significant PA contrast on thyroid microcalcifications indicating that the experimental setup and protocols should be enhanced, e.g., method of complete blood rejection from ex vivo specimens, the multi-wavelength spectroscopic PA imaging method which can solely extract the PA signal from microcalcifications even with high spectral interferences, or PA imaging with narrower slice thickness using 2-dimensional array transducer, etc. [ABSTRACT FROM AUTHOR]