Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Inflammatory rhabdomyoblastic tumors (IRMTs) are newly recognized skeletal muscle tumors with uncertain malignant potential. We investigated 13 IRMTs using clinicopathologic, genetic, and epigenetic methods. The cohort included 7 men and 6 women, aged 23 to 80 years (median, 50 years), of whom 2 had neurofibromatosis type 1. Most tumors occurred in the deep soft tissues of the lower limbs, head/neck, trunk wall, and retroperitoneum/pelvis. Two tumors involved the hypopharyngeal submucosa as polypoid masses. Eight tumors showed conventional histology of predominantly spindled cells with nuclear atypia, low mitotic activity, and massive inflammatory infiltrates. Three tumors showed atypical histology, including uniform epithelioid or plump cells and mitotically active histiocytes. The remaining 2 tumors demonstrated malignant progression to rhabdomyosarcoma; one had additional IRMT histology and the other was a pure sarcoma. All 11 IRMTs without malignant progression exhibited indolent behavior at a median follow-up of 43 months. One of the 2 patients with IRMTs with malignant progression died of lung metastases. All IRMTs were positive for desmin and PAX7, whereas myogenin and MyoD1 were expressed in a subset of cases. Targeted next-generation sequencing identified pathogenic mutations in NF1 (5/8) and TP53 (4/8). All TP53 mutations co-occurred with NF1 mutations. TP53 variant allele frequency was much lower than that of NF1 in 2 cases. These tumors showed geographic (subclonal) strong p53 immunoreactivity, suggesting the secondary emergence of a TP53-mutant clone. DNA methylation-based copy number analysis conducted in 11 tumors revealed characteristic flat patterns with relative gains, including chromosomes 5, 18, 20, 21, and/or 22 in most cases. Widespread loss of heterozygosity with retained biparental copies of these chromosomes was confirmed in 4 tumors analyzed via allele-specific profiling. Based on unsupervised DNA methylation analysis, none of the 11 tumors tested clustered with existing reference entities but formed a coherent group, although its specificity warrants further study.

DOI： 10.1016/j.modpat.2023.100359

PubMed

Language：Japanese   Publisher：(一社)山梨県医師会  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Tumor-stroma ratio (TSR) of invasive breast carcinoma has gained attention in recent years due to its prognostic significance. Previous studies showed TSR is a potential biomarker for indicating the tumor response to neoadjuvant chemotherapy. However, it is not clear how well TSR evaluation in biopsy specimens might reflect the TSR in resection specimens. We conducted a study to investigate whether biopsy evaluation of TSR can be an alternative method. METHOD: We collected cases with invasive breast carcinoma of no special type (IBC-NST) from University of Yamanashi hospital between 2011 and 2017 whose biopsy and resection specimens both had a pathologically diagnosis of IBC-NST (n = 146). We conceptualized a method for evaluating TSR in biopsy specimens within a preliminary cohort (n = 50). Within the studied cohort (n = 96), biopsy-based TSR (b-TSR) and resection-based TSR (r-TSR) were scored by two pathologists. We then evaluated our method's validity and performance by measuring interobserver variability between the two pathologists, Spearman's correlation between b-TSR and r-TSR, and the receiver operating characteristics (ROC) analysis for defining stroma-rich and stroma-poor tumors. RESULTS: Intra-class coefficient between the two pathologists was 0.59. The correlation coefficients between b-TSR and r-TSR in the two pathologists were 0.45 and 0.37. The ROC areas under the curve were 0.7 and 0.67. By considering an r-TSR of < 50% as stroma-rich, the sensitivity and specificity of detecting stroma-rich tumors were 64.1% and 66.7%, respectively, when b-TSR was < 40%. CONCLUSION: Our current b-TSR evaluation method can provide information about r-TSR and facilitate pre-treatment therapy follow-up.

DOI： 10.1007/s10549-022-06768-0

PubMed

Language：Japanese   Publishing type：(MISC) Meeting report etc.  

Language：Japanese   Publishing type：(MISC) Meeting report etc.  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

The risk of distant metastasis in medullary thyroid carcinoma (MTC) has not been well studied. Additional evaluation of MTC metastatic risk can be helpful for improving the quality of medical management. Therefore, we conducted a large population study to develop a method to stratify the risk of metastasis at the initial presentation of MTC patients. We collected 3612 MTC patients from the Surveillance, Epidemiology, and End Results (SEER) database, and included 2526 MTC patients in the study after applying exclusion criteria. We selected the most informative variables from a learning cohort of 2019 patients to obtain 1000 models by repetitive random data splicing into training and regularization cohorts. We selected the optimal model and developed a risk table from that model. Our risk table variables consist of age, gender, tumor size, extrathyroidal extension, and lymph node metastasis. The final model showed good calibration when metastatic risk was < 25% and good performance with areas under the curve (AUCs) of 0.81, 0.84, and 0.84 in the training, regularization, and test cohorts, respectively. We performed K-means clustering analysis on the model's metastatic estimation and determined three risk groups of patients with significant survival differences (p < 0.001). Low-risk patients had 0.88%, 1.3%, and 0.5% while high-risk patients had 19.7%, 15.8%, and 17.8% risk of metastasis in the three cohorts, respectively. The incorporation of our table into the International MTC Grading System (IMTCGS) requires more comprehensive clinicopathological studies.

DOI： 10.1007/s12022-022-09724-2

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Previous studies have not been consistent in the risk of metastasis in follicular thyroid carcinoma (FTC). Therefore, we conducted a large population study to stratify the risk of distant metastasis in FTC patients using only clinical parameters. METHODS: We extracted FTC patients from The Surveillance, Epidemiology, and End Results (SEER) database and divided them into training and validation cohorts. RESULTS: The two cohorts consisted of 4913 and 2391 patients, respectively. We developed a nomogram and risk table based on a logistic regression model using algorithm-selected variables. Receiver Operating Characteristic (ROC) analyses showed high discriminatory power in the training and validation cohorts (Area under the curve [AUC] of 0.85 and 0.84, respectively). Extremely low, low, intermediate, and high-risk groups had 0.3%, 1%, 3.5%, and 16.7% risk of distant metastasis, respectively. CONCLUSIONS: Our risk scoring table can separates patients into four risk groups and efficiently detect patients with almost no risk of metastasis.

DOI： 10.1002/lio2.834

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Squamous dysplasia of the esophagus is an unequivocal neoplastic alteration of the esophageal squamous epithelium without invasion. Esophageal high grade dysplasia (EHGD) is characterized by >50% epithelial involvement or severe cytological atypia. Frequently, lymphocytes accumulate below EHGD lesions even though there is no invasion. If this lymphocytic accumulation is active, a transmitter should exist between the EHGD cells and the lymphocytes. C-X-C motif chemokine ligand (CXCL) 12, CXCL10 and C-C motif chemokine ligand 18 (CCL18) are all lymphocyte chemoattractants in vivo, but there are no reports on the relationship between these chemokines and EHGDs. In this study, we investigated these chemokines and C-X-C motif chemokine receptor 4 (CXCR4) (receptor for CXCL12) in 30 EHGDs using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). For comparison, we enrolled 30 samples of normal esophageal squamous epithelium (NESE). We confirmed CXCL12 expression (H-score≥50 points) in 70% of EHGD and 0% of NESE samples, CXCL10 expression in 3% of EHGD and 3% of NESE samples, CCL18 expression in 3% of EHGD and 0% of NESE samples, and CXCR4 expression in 53% of EHGD and 0% of NESE samples by immunohistochemistry. EHGD and NESE cases were significantly different in their expressions between the tissue types (CXCL12, p<0.001; CXCR4, p<0.001). We examined CXCL12 and CXCR4 mRNA expressions of 3 representative EHGD samples, each having their respective immunostained areas detected by RT-PCR. Finding CXCL12 expression may indicate that this chemokine plays a part in the lymphocyte accumulation that occurs directly under EHGDs.

DOI： 10.14670/HH-18-410

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are associated with various clinicopathological features. Using cytologic specimens for assessing TILs remains to be established. This retrospective study aimed to establish a practical method to assess TILs in cytologic samples. METHODS: The authors found 1101 breast fine-needle aspiration biopsy (FNAB) cytology samples in their hospital, and 214 of them met the inclusion criteria. The TILs score was evaluated using histologic slides, and breast cancers were divided into 2 groups: low- (<60%) and high-TILs (≥60%). Training and validation tests composed of 50 breast cancer samples each were constructed. A cytologic TILs (cTILs) score was introduced to evaluate lymphocytes in FNAB cytology and it was compared with histologically evaluated TILs. The cTILs score was calculated by subtracting the number of neutrophils from the number of lymphocytes surrounding the tumor cells. RESULTS: In the training test, a 2-tier system with low- and high-TILs groups showed a large area under the curve (AUC) (0.943; 95% confidence interval [CI], 0.84-0.99). A cTILs score cutoff value of >8 had 87.5% sensitivity and 90.5% specificity. In the validation test, the AUC was 0.79 (95% CI, 0.6-0.93) whereas sensitivity and specificity were 57% and 89.5%, respectively. When small tumors <0.5 cm were excluded, the AUC improved to 0.93 (95% CI, 0.83-1.0), and sensitivity and specificity were 80% and 88.5%, respectively. CONCLUSIONS: The cTILs scoring system had acceptable reproducibility and concordance with TILs on histologic samples for tumors ≥0.5 cm. Cytologic evaluation can potentially substitute for histologic evaluation of TILs.

DOI： 10.1002/cncy.22551

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1346-8138.16157

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

A 71-year-old woman with a four-year history of chronic lymphocytic leukemia (CLL) received ibrutinib as initial treatment due to progressive anemia and thrombocytopenia. Eleven months after the start of the treatments, although her cytopenia had ameliorated, she developed classic Hodgkin lymphoma, a rare form of Richter's transformation. She was successfully treated with two courses of adriamycin, vinblastin, bleomycin and dacarbazine followed by radiotherapy. In general, several clinical, genetic and molecular factors are associated with Richter's transformation. In addition, our present case suggested that ibrutinib could be a potential risk factor for Richter's transformation in CLL patients.

DOI： 10.2169/internalmedicine.6979-20

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

The Warthin tumor is a benign neoplasm of the salivary glands, histologically, the tumor has an oncocytic epithelial component forming uniform rows of cells surrounded by cystic spaces associated with a lymphoid stroma often showing the presence of germinal centers. The lymphoid stroma is a representative microscopic finding. If this lymphocytic accumulation is active, some sort of transmitter should exist between the Warthin tumor cells and lymphocytes. C-X-C motif chemokine ligand (CXCL12) 12, CXCL10 and C-C motif chemokine ligand 18 (CCL18) are a chemoattractant for lymphocytes in vivo. There is no report on the relationship between these chemokines and Warthin tumors. In this study, we investigated these chemokines expressions in 20 Warthin tumors using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). For comparison, we also enrolled samples of pleomorphic adenoma, which is another benign salivary gland tumor type without prominent lymphocytic infiltration. All Warthin tumors were immunopositive for CXCL12 and CXCL10, and these reactivities were diffuse. Meanwhile, the majority of pleomorphic adenomas were immunonegative for CXCL12 (95%), CXCL10 (80%) and CCL18 (85%). Warthin tumor and pleomorphic adenoma cases were significantly different in these immunostaining expressions (CXCL12, p<0.001; CXCL10, p<0.001; CCL18, p=0.024). We examined CXCL12, CXCL10 and CCL18 mRNA expressions of 3 representative Warthin tumor samples, each having these chemokines immunopositive areas detected by RT-PCR. Finding CXCL12 and CXCL10 expressions indicate that these chemokines may play a part in the formation of a lymphoid stroma within Warthin tumors. In regards to this phenomenon, the participation of CCL18 might be restrictive compared to CXCL12 and CXCL10.

DOI： 10.14670/HH-18-352

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1007/s10067-020-05453-1

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1007/s12022-021-09674-1

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated tumor with a high incidence in Asian countries. NPC is a type of squamous cell carcinoma originating from the nasopharyngeal mucosa. Although rare, NPCs show some uncommon histologic variants; these variations remain to be understood. We described the cytologic characteristics of a rare NPC variant with abundant intracytoplasmic mucin. A 37-year-old Japanese man presented to our hospital with bilateral ear discomfort and palpable lymph nodes. Nasopharyngeal biopsy showed tumor cells with abundant intracytoplasmic, Alcian blue-PAS-positive mucin. Immunohistochemical analysis demonstrated that the tumor cells were positive for p40 and p53. Epstein-Barr encoding region (EBER) in situ hybridization (ISH) showed EBV infection of the tumor cells. Fluorescence in situ hybridization (FISH) using MAML2 break-apart probes did not show split signals. Fine needle aspiration biopsy (FNAB) cytology of the metastatic lymph nodes was also performed. Smear samples had a necrotic and inflammatory background with both lymphocyte and neutrophil infiltration. Highly cellular tumor clusters and dispersed cells with naked nuclei were observed. The tumor cells showed a clear cytoplasm with distinct cell borders. Intracytoplasmic mucin pushing the nucleus to the periphery was observed in the scattered tumor cells in a liquid-based cytology sample. Given these findings, the final diagnosis was advanced nasopharyngeal carcinoma; cisplatin-based chemoradiation therapy was performed as the first-line treatment. The tumor recurred 8 months after completing the treatment. The recurrent nasopharyngeal tumor was a typical non-keratinizing NPC and lacked intracytoplasmic mucin.

DOI： 10.1002/dc.24934

PubMed

Language：Japanese   Publishing type：(MISC) Meeting report etc.  

Language：Japanese   Publishing type：(MISC) Meeting report etc.  

Language：Japanese   Publishing type：(MISC) Meeting report etc.  

Language：English   Publishing type：Research paper (scientific journal)  

In endometrioid carcinomas (ECs) of the uterine corpus, neutrophil accumulation within the carcinoma cell clusters is a representative microscopic finding. Because this accumulation is active, some sort of transmitter ought to exist between the EC cells and neutrophils. Interleukin-8 (IL-8) and C-X-C motif chemokine ligand 5 (CXCL5) is a cytokine that attracts neutrophils in vivo. In this study, we investigated IL-8, CXCL5 and C-X-C motif chemokine receptor 2 (CXCR2) (their chemokine receptor) expressions in ECs by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). There are few reports on the relationship between these chemokines and ECs. For comparison, we enrolled samples of colorectal adenocarcinoma (CRAC), it is another representative tumor with neutrophil infiltration. We analyzed 30 ECs and 30 CRACs. We confirmed IL-8 expression (H-score ≥50 points) in 40% of EC and 7% of CRAC samples; CXCL5 expression in 7% of EC and 10% of CRAC samples; CXCR2 expression in 83% of EC and 53% of CRAC samples by immunohistochemistry. We examined each mRNA (IL-8 and CXCL5) expression of 3 representative EC and 3 CRAC samples. Finding IL-8 expression might indicate that this cytokine is important for the process of neutrophil accumulation, particularly within ECs. The participation of CXCL5 regarding neutrophil accumulation within their carcinoma cell clusters might be restrictive compared to IL-8.

DOI： 10.14670/HH-18-281

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.21037/gs-20-356

Language：English   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1111/pin.12937

Language：English  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.21873/anticanres.13061

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: CD10 is an endopeptidase that degrades various bioactive peptides in the extracellular matrix. In addition to enzymatic degradation, it affects multiple intracellular signal transduction pathways. CD10 expression has been extensively studied in human epithelial cancers of numerous organs and sites. However, its presence in thyroid carcinomas, especially in anaplastic thyroid carcinoma (ATC), has not been fully determined. An actual CD10 expression in thyroid lesions including a large series of ATC was evaluated. METHODS AND RESULTS: We examined CD10 by immunohistochemistry (IHC) in 152 thyroid lesions: nine adenomatous goitres (AGs) and 143 tumours, including 47 anaplastic carcinomas. IHC showed diffuse and strong positivity for CD10 in the epithelial components of almost all ATCs. However, epithelia with squamous metaplasia and oncocytic change from AGs, follicular adenomas and differentiated carcinomas had focal CD10 reactivity. Some papillary thyroid carcinomas (PTCs), along with the PTC components of some ATCs, showed CD10 positivity in fibroblast-like stromal cells and fibrous material. CONCLUSION: Our results imply that the CD10 expression pattern depended on the histotypes of thyroid lesions. When possible metastatic tumours and non-epithelial tumours are excluded, high CD10 expression may be useful in determining whether a primary thyroid carcinoma includes an anaplastic component.

DOI： 10.1111/his.13657

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Solid variant papillary thyroid carcinoma (SVPTC) is a rare variant of papillary thyroid cancer (PTC) and its prognostic value is still unclear. The purpose of this systematic clinical review and meta-analysis is to investigate the prognostic value of SVPTC in comparison with classical PTC (cPTC). METHODS: Four electronic databases, including PubMed, Scopus, Web of Science, and Virtual Health Library, were searched in June 2017. Extracted data were pooled into odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence interval (CI) using the random-effect model. RESULTS: From 1439 articles, we finally included 11 studies with 205 SVPTCs for meta-analysis. Overall, SVPTC manifested a significantly higher risk for vascular invasion, tumor recurrence, and cancer mortality as compared to cPTC. The genetic profile of SVPTC was also distinct from that of cPTC. CONCLUSION: A case of SVPTC should be regarded as an aggressive variant of PTC because of a higher risk for tumor recurrence and mortality.

DOI： 10.1002/hed.25123

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

There are ongoing debates with respect to the prognostic roles of molecular biomarkers in sporadic medullary thyroid carcinoma (MTC). In this study, we aimed at investigating the prognostic value of RET and RAS mutations - the two most common mutations in sporadic MTCs. A search was conducted in four electronic databases. Relevant data were extracted and pooled into odds ratios (OR), mean differences (MD) and corresponding 95% confidence intervals (CI) using the random-effect model. We used Egger's regression test and visual of funnel plots to assess the publication bias. From 2581 studies, we included 23 studies with 964 MTCs for meta-analysis. Overall, the presence of RET mutation was associated with an elevated risk for lymph node metastasis (OR = 3.61; 95% CI = 2.33-5.60), distant metastasis (OR = 2.85; 95% CI = 1.64-4.94), advanced tumor stage (OR = 3.25; 95% CI = 2.02-5.25), tumor recurrence (OR = 3.01; 95% CI = 1.65-5.48) and patient mortality (OR = 2.43; 95% CI = 1.06-5.57). RAS mutation had no significant prognostic value in predicting tumor aggressiveness. To summarize, our results affirmed that RET mutation is a reliable molecular biomarker to identify a group of highly aggressive sporadic MTCs. It can help clinicians better assess patient prognosis and select appropriate treatment decisions.

DOI： 10.1530/ERC-18-0056

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(一社)山梨県医師会  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

The initial determination of left-right asymmetry is an essential process in embryonic development. In mouse embryo, cilia in the node play an important role generating the nodal flow that subsequently triggers left-right determination in the embryo. Although nodal cilia have historically been thought to have a 9 + 0 axonemal configuration, the existence of 9 + 2 cilia has been reported so far. Because the distribution of those two types of cilia within the node has not yet been reported, we assessed the arrangement of 9 + 0 and 9 + 2 cilia in the node. In this study, we concluded that most of the nodal cilia were 9 + 0 in structure and there were much fewer 9 + 2 cilia than 9 + 0 cilia. Furthermore, the two types of cilia were randomly distributed in the node with no regularity. In addition, we studied the embryonic origin of the crown cells surrounding the node to better understand their identity.

DOI： 10.1093/jmicro/dfv352

PubMed

Language：Japanese  

J-GLOBAL

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Presentation type：Oral presentation(general)  

Language：Japanese  

Language：Japanese  

Language：Japanese