Inflammatory rhabdomyoblastic tumor (IRMT) is a recently recognized skeletal muscle neoplasm of uncertain malignant potential, characterized by a prominent inflammatory infiltrate. Although its histologic features are increasingly being defined, reports describing its cytologic characteristics remain extremely limited. Herein, we describe the detailed cytologic findings of a case of IRMT across multiple cytologic preparations. A man in his 60s presented with pharyngeal discomfort and was diagnosed with tonsillar diffuse large B-cell lymphoma (DLBCL). Subsequent staging positron emission tomography-computed tomography revealed focal abnormal fluorodeoxyglucose uptake in the left tibialis anterior muscle. Although lymphomatous involvement was considered, ultrasound-guided biopsy suggested IRMT. The patient underwent surgical resection of the soft tissue mass. Imprint, crush, and liquid-based cytology (LBC) preparations were obtained from the resected tumor. Cytologic examination across all preparations revealed a characteristic biphasic pattern: numerous atypical cells with enlarged, variably shaped nuclei, finely granular chromatin, prominent nucleoli, and abundant cytoplasm, admixed with a rich background of reactive lymphocytes and histiocytes. No cross-striations were identified. Mitotic figures and necrosis were absent. On immunocytochemistry, the atypical cells were positive for desmin and MyoD1, while the background histiocytes expressed CD163. The final histopathologic diagnosis was IRMT. Following resection, the patient received R-CHOP chemotherapy for DLBCL. At the most recent follow-up, less than 6 months after resection, there was no evidence of local recurrence or distant metastasis of IRMT. This case highlights the cytologic features of IRMT across conventional and LBC preparations, supported by confirmation of rhabdomyoblastic differentiation by immunocytochemistry. Recognition of atypical rhabdomyoblastic cells within a lymphocyte- and histiocyte-rich background is an important diagnostic clue.

Anaplastic thyroid carcinoma (ATC) is a rare malignancy characterized by an extremely aggressive clinical course, in contrast to the typically indolent behavior of most thyroid carcinomas. Recent advances in high-throughput sequencing technologies have markedly enhanced our understanding of the genetic alterations underlying ATC. These molecular insights have also influenced current clinical management and pathologic classification. In diagnostic pathology, squamous cell carcinoma arising in the thyroid is now recognized as a histologic variant of ATC. The BRAF p.V600E mutation, detected in approximately half of ATCs, represents a clinically significant genetic alteration, as targeted therapies directed against this mutation have been associated with improved clinical outcomes. In addition to advances in molecular pathology, progress has also been made in diagnostic pathology, including expanded recognition of the histologic spectrum of ATC and the development of novel immunohistochemical markers. In this review, we summarize recent advances in the diagnostic and molecular pathology of ATC, aiming to provide both fundamental and practical insights for clinical practice. In diagnostic pathology, ATC often presents significant challenges because of its marked histologic heterogeneity and a broad differential diagnosis. Accordingly, this review provides an overview of both classical knowledge and recent molecular findings related to ATC and integrates these insights to present an updated framework for differential diagnosis and diagnostic approach. In addition, we discuss recent advances in immunohistochemistry, including mutation-specific antibodies and novel diagnostic markers, and highlight their relevance in the context of contemporary diagnostic pathology and evolving therapeutic strategies.

Large B-cell lymphoma (LBCL) frequently affects very elderly patients, and treatment decisions for those aged ≥ 80 years are complicated by heterogeneity in frailty. Evidence focusing specifically on prognostic factors in this age group treated with rituximab-containing chemotherapy remains limited. In this study, we retrospectively analyzed 137 patients aged ≥ 80 years with LBCL who received rituximab-based chemotherapy at our institution to identify prognostic factors. The median age was 83 years. Of 137 patients, 51 (37.2

Background/Aim:Invasive mucinous adenocarcinoma (IMA) of the lung is a rare adenocarcinoma subtype with abundant intracytoplasmic mucin and poor response to standard non-small cell lung cancer chemotherapy. Molecularly targeted therapies may be useful in IMA. Zolbetuximab is a chimeric IgG1 monoclonal antibody against Claudin-18.2 (CLDN18.2) that induces cell death in CLDN18.2-positive gastric and gastro-esophageal junction adenocarcinomas. If lung IMAs also highly express CLDN18.2, they may be candidates for zolbetuximab treatment. This study evaluated CLDN18.2 expression in lung IMAs by immunohistochemistry. Materials and Methods:We analyzed surgically resected samples comprising 30 IMAs, 10 non-mucinous adenocarcinomas (NMAs), 10 squamous cell carcinomas (SqCCs), 10 small cell carcinomas (SmCCs), 9 large cell carcinomas (LCCs), and 10 large cell neuroendocrine carcinomas (LCNECs) of the lung. Results:We confirmed CLDN18.2 expression (H-score ≥50 points) in 77% of IMA samples. Its expression was rarely observed in other histological types of lung cancer. Conclusion:CLDN18.2 is frequently expressed in IMAs but rarely in other major lung cancer subtypes, suggesting that zolbetuximab may represent a promising targeted therapy for IMA.

BACKGROUND:Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic options. Immune checkpoint inhibitors (ICIs) modestly improve outcomes, but predictive biomarkers are lacking. CD73, an ecto-5'-nucleotidase, generates immunosuppressive adenosine and may attenuate ICI efficacy. METHODS:We conducted a single-center, retrospective study of 36 SCLC patients receiving first-line platinum-based chemo-immunotherapy. Tumor CD73 expression was assessed by immunohistochemistry and dichotomized as negative (H-score = 0) or positive (H-score ≥ 1). Molecular subtypes were determined based on dominant transcription factor expression (ASCL1, NEUROD1, POU2F3, YAP1). Associations between CD73 expression, progression-free survival (PFS), overall survival (OS), and transcriptional subtypes were analyzed. Public RNA-sequencing data (GSE69091) were used to contextualize immune-related gene expression patterns. RESULTS:CD73 was positive in 75% of tumors. CD73-positive patients exhibited significantly shorter median PFS compared with CD73-negative patients (4.0 vs. 7.9 months; p = 0.048) and a trend toward reduced OS (8.5 vs. 29.1 months; p = 0.249). CD73 expression was not significantly associated with molecular subtypes. Public dataset analysis revealed CD73-high tumors with elevated T cell and immunosuppressive gene expression, but no OS difference in an ICI-naïve cohort, suggesting that CD73's impact is treatment-specific. CONCLUSIONS:Tumor CD73 expression is associated with inferior PFS in SCLC patients receiving chemo-immunotherapy and may serve as a predictive biomarker for ICI efficacy. Immunohistochemistry-based assessment of CD73 might facilitate treatment stratification, and prospective studies evaluating CD73-targeted therapies in combination with ICIs are warranted.

The purpose of this study was to clarify the clinicopathological features and prognosis of histological subtypes of papillary thyroid carcinoma (PTC) in the pediatric population treated at a single institution. A total of 153 PTC patients ≤18 years of age who underwent initial surgery between 1979 and 2019 were investigated. There were 135 female and 18 male patients, with a mean age at the time of surgery of 16 (range, 8–18) years. The most common subtypes included classic PTC in 124 (81%), solid variant in 16 (10%), diffuse sclerosing variant in 7 (5%) and follicular variant in six (4%) according to the 5th edition of the WHO classification. At initial surgery, 49 patients (32%) had clinical lymph node metastases (cN1), 137 patients (90%) had pathological lymph node metastases (pN1), 73 patients (48%) had number of lymph node metastases (NLNMs) ≥10, 16 (10%) had gross extrathyroidal extension (ETE) and 18 (12%) had lung metastases. During a mean follow-up of 16 years, three (2%) patients died of their disease and 34 (25%) patients had recurrent disease. The 30-year cause-specific survival rate was 97.2%, and the 30-year disease-free survival (DFS) rate was 65.0%. On multivariate analysis, gross ETE, cN1 and NLNMs ≥10 identified as significant factors related to DFS (hazard ratio (HR) 4.13, confidence interval (CI) 1.48–9.96, P = 0.009; HR 2.34, CI 1.09–4.95, P = 0.0293; HR 2.81, CI 1.30–6.59, P = 0.008), but not histological subtype, were associated with disease recurrence. Histological subtypes were not associated with disease recurrence, but long-term follow-up of pediatric patients is necessary to investigate the biological characteristics. Synopsis: This retrospective study investigated the clinicopathological features and clinical outcomes of histological subtypes of PTC in a large series of pediatric patients treated at a single institution. It found that the prognosis of pediatric patients with PTC was excellent, but recurrence was common. In pediatric PTC, histological subtype did not affect survival and recurrence.

In 2002, the Japan Thyroid Association (JTA) established the Thyroid Disease Diagnostic Guidelines Development Working Group, which developed diagnostic guidelines for five major diseases: Graves' disease, hypothyroidism, painless thyroiditis, chronic thyroiditis (Hashimoto's thyroiditis), and subacute thyroiditis (acute phase). Since then, the guidelines have been repeatedly revised under the leadership of successive JTA Presidents. Meanwhile, several other diagnostic and treatment guidelines have been established by JTA Working Groups on Important Clinical Issues and published elsewhere. Here, with the launch of Thyroid Science, an English-language medical journal published by the JTA, we have decided to republish the original guidelines for the five diseases in this journal. However, because these guidelines were originally formulated as expert opinions, the papers have been updated to include new references supporting each description. Furthermore, definitions of each disease have been provided, and the format has been adapted to match the latest guidelines.

The latest World Health Organization (WHO) classification of central nervous system tumors (WHO2021/5th) has incorporated molecular information into the diagnosis of each brain tumor type including diffuse glioma. Therefore, an artificial intelligence (AI) framework for learning histological patterns and predicting important genetic events would be useful for future studies and applications. Using the concept of multiple-instance learning, we developed an AI framework named GLioma Image-level and Slide-level gene Predictor (GLISP) to predict nine genetic abnormalities in hematoxylin and eosin sections: IDH1/2, ATRX, TP53 mutations, TERT promoter mutations, CDKN2A/B homozygous deletion (CHD), EGFR amplification (EGFRamp), 7 gain/10 loss (7+/10−), 1p/19q co-deletion, and MGMT promoter methylation. GLISP consists of a pair of patch-level GLISP-P and patient-level GLISP-W models, each pair of which is for a genetic prediction task, providing flexibility in clinical utility. In this study, the Cancer Genome Atlas whole-slide images (WSIs) were used to train the model. A total of 108 WSIs from the Tokyo Women’s Medical University were used as the external dataset. In cross-validation, GLISP yielded patch-level/case-level predictions with top performances in IDH1/2 and 1p/19q co-deletion with average areas under the curve (AUCs) of receiver operating characteristics of 0.75/0.79 and 0.73/0.80, respectively. In external validation, the patch-level/case-level AUCs of IDH1/2 and 1p/19q co-deletion detection were 0.76/0.83 and 0.78/0.88, respectively. The accuracy in diagnosing IDH-mutant astrocytoma, oligodendroglioma, and IDH-wild-type glioblastoma was 0.66, surpassing the human pathologist average of 0.62 (0.54–0.67). In conclusion, GLISP is a two-stage AI framework for histology-based prediction of genetic events in adult gliomas, which is helpful in providing essential information for WHO 2021 molecular diagnoses.

BACKGROUND:Melanoma is a life-threatening skin malignancy, with sentinel lymph node metastasis (SLNM) serving as a critical prognostic factor. While machine and deep learning models using histopathology have focused on melanoma diagnosis, limited efforts have aimed to predict SLNM. OBJECTIVES:This study aimed to develop a collaborative machine and deep learning model that integrates histopathological patches and clinical data to predict SLNM in patients with invasive melanoma, thereby aiding decision-making regarding sentinel lymph node biopsy. METHODS:A total of 78 invasive cutaneous melanoma cases (43 SLNM-positive and 35 SLNM-negative) from the University of Yamanashi Hospital (2007-2022) were divided into training (n = 60) and test (n = 18) datasets. A clustering-constrained attention multiple-instance learning (CLAM) model was developed using haematoxylin and eosin-stained whole-slide images. Among the four CLAM variants, the model using a ResNet50trunc encoder trained on whole-tissue regions (CLAM-R50) demonstrated the best performance and was further integrated with a clinical nomogram. Hybrid modelling was performed using logistic regression, a support vector machine and gradient boosting. RESULTS:CLAM-R50 achieved an area under the receiver operating characteristic curve (AUROC) of 0.875, while the clinical nomogram achieved an AUROC of 0.826 on the test set. The gradient boosting hybrid model, termed the Melanoma Indicative Scorer for Sentinel Lymph node Evaluation (MISSLE), demonstrated the highest AUROC of 0.950 (95% bootstrapped confidence interval (CI): 0.933-1.00) on the test set. CLAM-R50 attention maps identified pale cytoplasm and plasma cell-like tumour cells as predictors of positive SLNM, whereas dense melanin deposition and lymphocyte-like tumour cells predicted negative SLNM. CONCLUSIONS:MISSLE integrates histopathological and clinical data to predict SLNM with high AUROC, surpassing the previous reports and offering a tool for clinical decision-making. Limitations include the single-centre design and predominantly Japanese cohort, limiting generalizability. The code and models are publicly available for external validation.

The Japan Association of Endocrine Surgery published the first edition of the "Clinical guidelines on the management of thyroid tumors" in 2010 and the revised edition in 2018. The guideline presented herein is the English translation of the revised third edition, issued in 2024. The aim is to enhance health outcomes for patients suffering from thyroid tumors by facilitating evidence-based shared decision-making between healthcare providers and patients, as well as standardizing the management of thyroid tumors. The focus is on adult patients with thyroid tumors, addressing clinically significant issues categorized into areas such as an overview of the diagnosis and treatment of thyroid nodules, treatment strategies by histological type, radioactive iodine therapy, treatment of advanced differentiated carcinoma, pharmacotherapy, and complications and safety management associated with thyroid surgery. Thirty-two clinical questions were established in these areas. Following a comprehensive search of the literature and systematic review to evaluate the overall evidence, we aimed to present optimal recommendations by considering the balance of benefits and harms from the patient's perspective. We integrated evidence and clinical experience to determine the "Certainty of evidence" and "Strength of recommendations". Based on these, we illustrated overall flows of care as "Clinical algorithms". Necessary background knowledge of diseases and established clinical procedures for understanding the recommendations are presented in "Notes", while information that may be clinically useful but for which evidence remains insufficient is included in "Columns", based on the current state of evidence. Finally, future challenges for the next revision are presented as "Future research questions".

Introduction:Patients with neurogenic bladder secondary to spinal cord injury are at increased risk of developing bladder urothelial carcinoma due to urinary tract infections. The contribution of HIV infection is unknown in this group of patients. Case Presentation:A spina bifida male patient with macrohematuria and recurrent urinary tract infection was detected with bladder carcinoma covered with soft tissue thickening and was clinically diagnosed cT3N2M1. He was also diagnosed with HIV infection. Despite the treatment with Gemcitabine and Cisplatin, he developed infective endocarditis and a cerebral infarction. He died 3 months after the initiation of chemotherapy. Conclusions:This case highlights a rare case of aggressive bladder carcinoma developed in an HIV-positive male with spina bifida, who had never used an indwelling catheter or intermittent catheterization. HIV-positive men tend to have a higher incidence of bladder cancer at a younger age, and neurogenic bladder might accelerate the progression in this case.

Although, recently observation methods has been proposed as one of the treatment options for non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs), determining treatment strategies may be difficult for small and low-malignant NF-PanNENs; thus, clarifying the significance of lymphatic, microvascular, and perineural invasion in these patients is of great clinical importance. This study aimed to assess the incidence and role of lymphatic, microvascular, and perineural invasion in patients with NF-PanNENs based on tumor size and the 2022 World Health Organization classification. From 2000 to 2023, we retrospectively investigated the incidence of lymphatic, microvascular, and perineural invasion and their impact on recurrence in 80 patients who underwent curative resection and were diagnosed with NF-PanNENs. Of the 80 patients, 14 (18

. Aim. Determining the primary origin of an ovarian mucin-producing carcinoma can be challenging at times because some metastases of primary colorectal origin may exhibit gross, microscopic, and/or immunohistochemical features that overlap with those of primary ovarian mucinous carcinomas (OMCs). We hypothesized that GATA binding protein 4 (GATA4) might be a novel, useful marker for differentiating primary OMCs from metastatic colorectal adenocarcinomas to the ovary. Methodology. For comparison with the usefulness of other markers (special AT-rich sequence-binding protein 2 (SATB2) and caudal type homeobox 2 (CDX2)), we elucidated the expression profiles of GATA4 in OMCs, colorectal non-mucinous adenocarcinomas (CNMACs), and colorectal mucinous adenocarcinomas (CMACs) using immunohistochemistry. Results. We confirmed GATA4 expression (H-score >= 50 points) in 93%, SATB2 in 0%, and CDX2 in 64% of 14 OMCs. GATA4 was expressed in 13%, SATB2 in 90%, and CDX2 in 93% of 30 CNMACs. GATA4 was expressed in 20%, SATB2 in 73%, and CDX2 in 100% of 30 CMACs. Conclusion. The expression of GATA4 in a mucus- producing ovarian tumor strongly supports it being a primary OMC rather than a metastatic colorectal carcinoma: GATA4 expression indicates OMC and SATB2 expression indicates colorectal adenocarcinoma. However, three cases of colorectal adenocarcinoma were GATA4-positive and SATB2-negative, so the GATA4/ SATB2 marker combination is not absolute for determining the primary site. Further research for more markers is necessary to find the ideal combination.

T follicular helper cell lymphoma (TFHL) is a systemic T-cell lymphoma with a phenotype reminiscent of TFH cells and frequent RHOA p.G17V mutation. Here, we report a case of TFHL with spatially multiple and clonally independent B-/plasma cell proliferations (B/PC-Ps), which posed diagnostic difficulties. An 87-year-old female presented with a skin rash, and a skin biopsy from the chest was initially diagnosed as low-grade B-cell lymphoma with plasmacytic differentiation. Three months after rituximab monotherapy, bilateral pleural effusions developed. Cytology of the pleural effusion revealed abnormal lymphocytes and plasma cells. The abnormal T-cells were positive for CD3, CD4, CD10, and PD1, while the neoplastic plasma cells showed kappa-predominant light-chain restriction. Additional cutaneous biopsies from the left forearm and upper arm revealed Epstein-Barr virus-positive and -negative B/PC-Ps, respectively. Polymerase chain reaction identified RHOA p.G17V and the same monoclonal rearrangement of T-cell receptor gamma gene (TRG) in all the four specimens. In addition, three cutaneous lesions showed distinct monoclonal immunoglobulin heavy chain gene (IGH) rearrangements. This case demonstrates phenotypic and clonal diversity of monoclonal B/PC-Ps in TFHL, which can obscure the neoplastic TFH proliferation. In such cases, careful clinicopathological correlation and the integration of immunophenotypic and genetic analyses may aid in the diagnosis.

Although anaplastic thyroid carcinomas (ATCs) typically arise from papillary thyroid carcinomas (PTCs), follicular thyroid carcinomas (FTCs) can also progress to ATCs; however, histologically confirmed FTC-derived ATCs are relatively uncommon and remain poorly characterized. To clarify this phenomenon, we analyzed eight FTC-derived ATCs and compared them with 11 PTC-derived ATCs. Whole-exome sequencing (WES) was conducted on the differentiated thyroid carcinoma (DTC) and ATC components within the same tumors to examine mutational profiles; three additional cases underwent FoundationOne® testing. The demographic features were similar between FTC- and PTC-derived ATCs. Histologically, spindle-cell morphology was more common in FTC-derived ATCs (3/8), whereas PTC-derived ATCs exhibited squamoid (5/11) and giant cell features (5/11), including osteoclast-like cells. WES was successfully performed on both the ATC and FTC components in seven of the eight FTC-derived ATCs. Common alterations included TERT promoter (5/7), NRAS (4/7), and HRAS (2/7) mutations in both components. TP53 mutations were observed only in the ATC component (5/7). EIF1AX mutations co-occurred with TERT and HRAS mutations in two cases. PTEN mutations were found in two FTCs with solid/trabecular patterns but were absent in the corresponding ATC components. One tumor harbored a DGCR8 p.E518K mutation that was retained during progression. By contrast, PTC-derived ATCs consistently showed concurrent BRAF and TERT promoter mutations (11/11). Immunohistochemistry for BRAF V600E, RAS Q61R, p53, PTEN, and MTAP showed high concordance with the corresponding mutation status. These findings revealed significant histological and genetic differences between FTC- and PTC-derived ATCs, providing new insights into the molecular basis of FTC dedifferentiation into ATC.

BACKGROUND/AIM:Aquaporins (AQPs) were initially discovered as water channel proteins that facilitate transcellular water movements. Recent studies have shown that AQPs are expressed and play an oncogenic role in various cancers. However, the expression and role of Aquaporin 4 (AQP4) in colon cancer have not been investigated. This study aimed to examine the clinical and pathophysiologic significance of AQP4 in colon cancer.PATIENTS AND METHODS:Immunohistochemistry (IHC) of AQP4 for 145 primary tumor samples obtained from patients with stage II or III colon cancer was performed, and the relationship between AQP4 expression and patients' prognoses was analyzed. Knockdown experiments with AQP4 small interfering RNA using human colon cancer cells were conducted to analyze the effects on cell invasiveness.RESULTS:IHC revealed that AQP4 was scarcely expressed in the noncancerous colonic mucosa. Of the 145 patients who enrolled in this study, 109 (75.2%) and 36 (24.8%) patients were classified as negative and positive for AQP4 expression, respectively. A high level of AQP4 expression is significantly associated with deeper tumors with lymph node metastasis and venous invasion. A 5-year progression-free survival rate of AQP4-positive patients was significantly worse than that of AQP-4 negative patients (70.7% vs. 87.0%, p=0.049). Furthermore, AQP4 knockdown significantly inhibited cell migration and invasion in HCT116 cells.CONCLUSION:AQP4 may be a novel biomarker and therapeutic target for colon cancer.

The Japan Association of Endocrine Surgeons and the Japanese Society of Thyroid Pathology developed the Japanese General Rules for the Description of Thyroid Cancer (JRTC) in accordance with actual medical practice in Japan to describe clinical findings and unify the pathological diagnosis of thyroid tumors. The 9th Japanese edition of the JRTC was published in 2023 based on the revision of the TNM classification (AJCC) and the WHO tumor classification. In the clinical portion, subclassification of N factor according to the size and extranodal extension of metastatic nodes, subclassification of surgical Ex according to the organs to which carcinoma invades, and the abolishment of preoperative and pathological Ex were major changes from the last edition. In the pathological portion, the tumor classification was rearranged according to the differentiation and malignancy based on the genetic alterations. Adenomatous goiter was classified as a tumor-like lesion. Low-risk neoplasms were placed between benign and malignant tumors, scoring the nuclear findings of papillary carcinoma, and clearly indicating the findings for capsular and vascular invasion of follicular tumors. High-grade differentiated carcinoma was added as a reference to poorly differentiated carcinoma. Oncocytic adenoma and carcinoma were classified independently. The cytology reporting system was partly modified from the Bethesda 2023 system. This translated edition facilitates the submission of Japanese clinicopathological studies of thyroid tumors to international journals and is expected to contribute to the improvement and standardization of the description of the surgical treatment and pathological diagnosis of thyroid tumors. (242 words)