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Background: Plasmonic core-shell nanostructures with embedded internal markers used as Raman probes have attracted great attention in surface-enhanced Raman scattering (SERS) immunoassay for cancer biomarkers due to their excellent uniform enhancement. However, current core-shell nanostructures typically exhibit a spherical shape and are coated with a gold shell, resulting in constrained local field enhancement., Results: In this work, we prepared a core-shell AuNR@BDT@Ag structure by depositing silver on the surface of Raman reporter-modified gold nanorods (AuNR). With cysteamine-driven specific deposition of Ag atoms, the internal standard nanoprobes with an ortho-tetrahedral morphology were obtained. Owing to its tetrahedral morphology and the effective plasmon coupling at the Ag-Au interface, this internal standard Raman probe exhibited excellent Raman enhancement. Also, with embedded Raman reporter, the probes of Au nanorod in Ag tetrahedron avoided the desorption of Raman reporter and competitive adsorption of interfering molecule, which greatly improved the stability and reproducibility of SERS signal and addressed the drawbacks of low reproducibility existing in SERS immunoassay. The feasibility of the AuNR@BDT@Ag probe was demonstrated by the sensitive detection of the liver cancer biomarker alpha-fetoprotein (AFP) in Eppendorf (EP) tubes and microfluidic chips. The results in EP tubes revealed a linear range of 1 fg/mL-1 ng/mL and a detection limit of 0.631 fg/mL. When the detection was performed in microfluidic chips, the linear range was 10 pg/mL to 0.1 μg/mL, with a limit detection of 8.29 pg/mL., Significance: The performance of AFP detection in EP tubes and microfluidic chips demonstrates that the tetrahedral core-shell AuNR@BDT@Ag nanostructures used as internal standard Raman probes have the potential to detect biomarkers in blood samples for cancer screening., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

The National Cancer Institute's Clinical Proteomics Tumor Analysis Consortium (CPTAC) was established to address the need for improved design, standardization, and validation of proteomics assays to enable better translation of biomarkers from the analytical lab to the clinic. Here, we applied CPTAC guidelines to characterize quantitative mass spectrometry (MS) assays in a new multiple reaction monitoring (MRM) proteomics panel. The panel of 50 proteins was developed in response to a previous study that identified a proteomic profile of altered translational control associated with response to a new cancer drug. MRM-MS assays for 53 peptides of interest were developed, optimized, and characterized on a UPLC system coupled to a triple-quadrupole mass spectrometer (QQQ-MS) using synthetic proteotypic peptides and corresponding stable-isotope labeled internal standard (SIS) peptides. Most of the assays were found to be fit-for-purpose for biomarker verification in that they precisely and reproducibly quantify the peptides at levels corresponding to the endogenous concentration in the desired cancer cell lines. Of these, 28 peptide assays represent to proteins that previously had no associated assays published in the CPTAC database. The targeted proteins in this publicly deposited validated multiplexed panel may be of use for research applications in cancer, cellular stress, neurology, cardiology, and metabolism.

Lung adenocarcinoma (LUAD) is the most common histological subtype of nonsmall-cell lung cancer. Herein, a multiomics method, which combined proteomic and N-glycoproteomic analyses, was developed to analyze the normal and cancerous bronchoalveolar lavage fluids (BALFs) from six LUAD patients to identify potential biomarkers of LUAD. The data-independent acquisition proteomic analysis was first used to analyze BALFs, which identified 59 differentially expressed proteins (DEPs). The bioinformatic analyses of 59 DEPs have shown that a potential marker protein, beta-1,4-galactosyltransferase 1 (B4GALT1), was consistently downregulated in all cancerous lung lobes (CLLs). As the downregulation of B4GALT1 may indicate changes in protein N-glycosylation, site-specific N-glycoproteome analysis of BALFs from the normal lung lobes (NLLs) and CLLs was further performed by using a fully automated glycopeptide enrichment and separation system. Comparing the glycan structures containing free GlcNAc in BALFs between NLLs and CLLs qualitatively, the percentage of unique glycan structure for free GlcNAc existing only in NLLs was 52.8%, which was significantly higher than the 46.3% existing only in CLLs. Furthermore, the sequential proteomic and N-glycoproteomic analyses allowed us to identify a panel of functionally related potential biomarkers consisting of one protein (B4GALT1) and four glycoproteins (NFKB1, F2, LTF, and DLD).

Background: Gastrointestinal schwannomas (GIS) are rare neurogenic tumors arising from Schwann cells in the gastrointestinal tract. Studies on GIS are limited to small case reports or focus on specific tumor sites, underscoring the diagnostic and therapeutic challenges they pose., Aim: To comprehensively examine the clinical features, pathological characteristics, treatment outcomes, associated comorbidities, and prognosis of GIS., Methods: The study population included patients diagnosed with GIS at the First Affiliated Hospital, Zhejiang University School of Medicine, between June 2007 and April 2024. Data were retrospectively collected and analyzed from medical records, including demographic characteristics, endoscopic and imaging findings, treatment modalities, pathological evaluations, and follow-up information., Results: In total, 229 patients with GIS were included, with a mean age of 56.00 years and a male-to-female ratio of 1:1.83. The mean tumor size was 2.75 cm, and most (76.9%) were located in the stomach. Additionally, 6.6% of the patients had other malignant tumors. Preoperative imaging and endoscopy frequently misdiagnosed GIS as gastrointestinal stromal tumors. However, accurate preoperative diagnosis was achieved using endoscopic ultrasound-guided fine-needle aspiration combined with immunohistochemical analysis, in which S100 and SOX-10 markers were mostly positive. Smaller tumors were typically managed with endoscopic resection, while larger lesions were treated with surgical resection. Follow-up results showed that most patients experienced favorable outcomes., Conclusion: Preoperative diagnosis of GIS via clinical characteristics, endoscopy, and imaging examinations remains challenging but crucial. Endoscopic therapy provides a minimally invasive and effective option for patients., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Patients with early-stage hepatocellular carcinoma (HCC) generally have good survival rates following surgical resection. However, a subset of these patients experience recurrence within five years post-surgery., Aim: To develop predictive models utilizing machine learning (ML) methods to detect early-stage patients at a high risk of mortality., Methods: Eight hundred and eight patients with HCC at Beijing Ditan Hospital were randomly allocated to training and validation cohorts in a 2:1 ratio. Prognostic models were generated using random survival forests and artificial neural networks (ANNs). These ML models were compared with other classic HCC scoring systems. A decision-tree model was established to validate the contribution of immune-inflammatory indicators to the long-term outlook of patients with early-stage HCC., Results: Immune-inflammatory markers, albumin-bilirubin scores, alpha-fetoprotein, tumor size, and International Normalized Ratio were closely associated with the 5-year survival rates. Among various predictive models, the ANN model generated using these indicators through ML algorithms exhibited superior performance, with a 5-year area under the curve (AUC) of 0.85 (95%CI: 0.82-0.88). In the validation cohort, the 5-year AUC was 0.82 (95%CI: 0.74-0.85). According to the ANN model, patients were classified into high-risk and low-risk groups, with an overall survival hazard ratio of 7.98 (95%CI: 5.85-10.93, P < 0.0001) between the two cohorts., Conclusion: A non-invasive, cost-effective ML-based model was developed to assist clinicians in identifying high-risk early-stage HCC patients with poor postoperative prognosis following surgical resection., Competing Interests: Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Screening tests, particularly liquid biopsy with circulating miRNAs, hold significant potential for non-invasive cancer detection before symptoms manifest., Methods: This study aimed to identify biomarkers with high sensitivity and specificity for multiple and specific cancer screening. 972 Serum miRNA profiles were compared across thirteen cancer types and healthy individuals using weighted miRNA co-expression network analysis. To prioritize miRNAs, module membership measure and miRNA trait significance were employed. Subsequently, for specific cancer screening, gastric cancer was focused on, using a similar strategy and a further step of preservation analysis. Machine learning techniques were then applied to evaluate two distinct miRNA panels: one for multi-cancer screening and another for gastric cancer classification., Results: The first panel (hsa-miR-8073, hsa-miR-614, hsa-miR-548ah-5p, hsa-miR-1258) achieved 96.1% accuracy, 96% specificity, and 98.6% sensitivity in multi-cancer screening. The second panel (hsa-miR-1228-5p, hsa-miR-1343-3p, hsa-miR-6765-5p, hsa-miR-6787-5p) showed promise in detecting gastric cancer with 87% accuracy, 90% specificity, and 89% sensitivity., Conclusions: Both panels exhibit potential for patient classification in diagnostic and prognostic applications, highlighting the significance of liquid biopsy in advancing cancer screening methodologies., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: One of the major challenges in the treatment of laryngeal squamous cell carcinoma (LSCC) with organ-preserving therapies is the emergence of treatment resistance. The JAK/STAT pathway has been increasingly implicated in this resistance, particularly through the overexpression or persistent activation of STAT3. Increased STAT3 expression is thought to be associated with resistance to radiotherapy and/or chemotherapy, and STAT3 inhibitors have been proposed as potential targeted treatments., Objectives: The primary objective of this study is to investigate the relationship between STAT3 expression and treatment resistance in patients with LSCC undergoing organ-preserving therapy and to evaluate the association between STAT3 expression and clinical/histopathologic prognostic parameters. A secondary objective is to evaluate STAT3 expression in diagnostic biopsies and laryngectomy specimens from treatment-resistant patients to investigate the potential predictability of treatment resistance from initial biopsy specimens., Methodology: The study included 123 patients diagnosed with LSCC between 2008 and 2022, all of whom received nonsurgical treatment. Patients were divided into two groups based on their response to treatment: treatment-sensitive patient group (TSPG) and treatment-resistant patient group (TRPG). Immunohistochemical staining for p-STAT3 was performed on a diagnostic biopsy for each TSPG patient and on both pre- and post-treatment biopsies for each TRPG patient. STAT3 expression levels were scored and their association with treatment resistance, clinical and pathological parameters was analysed., Results: No statistically significant difference in p-STAT3 expression was found between the two groups. TSPG patients were significantly older at diagnosis (p = 0.038), and tumor location differed between groups (p = 0.001). No significant differences in histopathologic or clinical prognostic parameters were observed between patients with high and low STAT3 expression. In addition, no significant difference in STAT3 staining was found between diagnostic biopsies and laryngectomy specimens in TRPG patients., Conclusion: STAT3 expression was not associated with treatment resistance in LSCC, and its expression level did not correlate with prognostic parameters or survival outcomes. Therefore, STAT3 does not appear to be a useful biomarker for predicting treatment resistance or prognosis in LSCC., Competing Interests: Declarations. Ethical Approval: Ethical approval for this study was obtained from the Clinical Research Ethics Committee of Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital on 12.09.2022 with decision number 146/35. Informed Consent: This study is a retrospective, single-center study, therefore the Clinical Research Ethics Committee of Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital approved this study and waived the informed consent. Consent for Publication: For this type of study consent for publication is not required. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The recent World Health Organization (WHO) classification of odontogenic tumours defines Sclerosing Odontogenic Carcinoma (SOC) as a rare primary intraosseous carcinoma (PIOC) of the jaws. With the exception of one case, there have been no cases of SOC with metastatic disease. We report a unique case of SOC with neck node metastases, further expanding the clinical, radiological and histological spectrum of this rare intriguing tumour., Methods: A 52-year-old female presented with a destructive radiolucent lesion of right mandible. Incisional biopsy was interpreted as desmoplastic ameloblastoma. The segmental mandibulectomy specimen was histologically consistent with SOC with positive anterior margin. Further resection with neck dissection revealed positive right levels IB and IIA nodes. Immunohistochemistry and Fluroscent In Situ Hybridization (FISH) were performed to confirm the diagnosis., Results: The tumour was positive for CK5, p63, p40 and negative for CK19, CK20, CK7, SOX-10, S100, ER, PR, BRAFV600E, and EWSR1 gene rearrangements. Ki67 was 15%., Conclusion: To avoid confusion with PIOC, a high grade squamous cell carcinoma of the jaws with poor prognosis, SOC may be best defined as a rare infiltrative and locally aggressive odontogenic carcinoma with metastatic potential but with a reasonably favourable outcome. SOC shares similar histologic features with many benign and malignant tumours. An appropriate panel of immunohistochemical markers, in conjunction with special stains and molecular studies can help refine the differential diagnosis. It appears that a Ki67 proliferation index of more than 10%, may pose a risk for nodal metastasis and may assist in planning the clinical management. To achieve lower rates of positive margins and tumour recurrence, a wider resection margin (more than a centimetre) is recommended., Competing Interests: Declarations. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This is a review paper. For this type of study formal consent is not required. Consent for Publication: For this type of study consent for publication is not required. Informed Consent: This is a review paper and informed consent was waived. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Approximately 10% of all lymphomatoid papulosis (LyP) cases affect pediatric patients. Pediatric LyP is clinically similar to adult LyP, frequently with cutaneous involvement, whereas the affectation of mucosal surface is rare. The LyP clinicopathological spectrum includes type A, B, C, D, E, and LyP with DUSP22/IRF4 rearrangement, with LyP type D representing < 5% of all LyP cases., Methods: We have previously reported 2 cases of exclusively intraoral LyP type C and E. To date, about 50 cases of LyP type D have been reported; of them, 8 cases, all but one with exclusive skin involvement, corresponded to pediatric patients. Rare LyP type C cases can lack CD30 expression, creating diagnostic difficulties with lymphoma., Results: Here, we report an extremely rare case of intraoral LyP type D with scarce/absent CD30 expression affecting a 12-year-old white Brazilian boy., Conclusions: To our best knowledge, this is the first pediatric case of LyP type D with exclusive intraoral involvement., Competing Interests: Declarations. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed Consent: Informed consent was obtained from all individual participants included in the study. Consent for Publication: Consent for publication was obtained for every individual person’s data included in the study. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lung cancer is one of the most common malignancy in the world, and early detection of lung cancer remains a challenge. The exhaled breath condensate (EBC) from lung and trachea can be collected totally noninvasively. In this study, our aim is to identify differential metabolites between non-small cell lung cancer (NSCLC) and control EBC samples and discriminate NSCLC group from control group by orthogonal projections to latent structures-discriminant analysis (OPLS-DA) models. The EBC differential metabolites between NSCLC patients ( n = 29) and controls ( n = 24) (20 healthy and 4 benign individuals) were identified using ultra-performance liquid chromatography-high resolution mass spectrometry based untargeted metabolomics method. The upregulated metabolites in EBC of NSCLC included amino acids and derivatives (phenylalanine, tryptophan, 1-carboxyethylisoleucine/1-carboxyethylleucine, and 2-octenoylglycine), dipeptides (leucyl-phenylalanine, leucyl-leucine, leucyl-histidine/isoleucyl-histidine, and prolyl-valine), and fatty acids (tridecenoic acid, hexadecadienoic acid, tetradecadienoic acid, 9,12,13-trihydroxyoctadec-10-enoic acid/9,10,13-trihydroxyoctadec-11-enoic acid (9,12,13-TriHOME/9,10,13-TriHOME), 3-hydroxysebacic acid/2-hydroxydecanedioic acid, 9-oxooctadeca-10,12-dienoic acid/9,10-Epoxy-12,15-octadecadienoate (9-oxoODE/9(10)-EpODE), and suberic acid). The downregulated metabolites in EBC of NSCLC were 3,4-methylenesebacic acid, 2-isopropylmalic acid/3-isopropylmalic acid/2,3-dimethyl-3-hydroxyglutaric acid, and trimethylamine-N-oxide. The OPLS-DA model based on 5 EBC metabolites achieved 86.2% sensitivity, 83.3% specificity and 84.9% accuracy, showing a potential to distinguish NSCLC patients from controls., (© 2025 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Autophagy is involved in several critical cellular processes regulating cell survival and death. Past research suggests that it may either act as a tumor suppressor or promote tumor progression. The purpose of this systematic review and meta-analysis was to evaluate the clinical and prognostic utility of a significant autophagy related protein-Beclin1, in oral squamous cell carcinoma (OSCC)., Methods: Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed. Relevant literature was retrieved from PubMed, ScienceDirect and Google Scholar database. After removal of duplicates quality of the studies was assessed using Newcastle-Ottawa Scale. Heterogeneity was assessed using I 2 index. Random effect model was used if I 2 was more than 50% else fixed effect model was selected. Meta-analysis was carried out using Review Manager (RevMan; Version 5.4)., Results: Five studies with 494 cases were included in this meta-analysis. Beclin1 expression in OSCC was not significantly associated (p > 0.05) with gender, age, tumor size, lymph node metastasis, histological differentiation and overall survival. Nevertheless, a trend for low Beclin1 expression favoring tumor progression was observed. Sensitivity analysis revealed significant nodal positivity related to low Beclin1 expression., Conclusion: This study provided an overview of Beclin1 expression in OSCC and highlighted additional evaluations while its use as a prognostic marker. It is suggested that future studies should assess both nuclear as well as cytoplasmic expression of Beclin1 and report intra- and inter-tumor variations in its expression relating to clinicopathological parameters., Competing Interests: Declarations. Conflict of Interest: The authors declare that they have no conflict of interest. Ethical Approval: For this type of study formal consent is not required. Consent to Participate: For this type of study informed consent is not required. Consent for Publication: For this type of study consent for publication is not required., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The screening of glycoprotein markers has become an integral part of the in vitro diagnosis of malignant tumors. Herein, an electrochemical method based on alkaline phosphatase (ALP)-mediated enzymatic silver deposition is reported for the highly sensitive detection of glycoprotein tumor markers, in which ALP enzymes are decorated to the glycan moieties of targets via the lectin-carbohydrate interactions. As glycoproteins are conjugated with multiple glycan chains, lectin-mediated labeling can result in the decoration of each target with multiple ALP enzymes. Moreover, the enzymatic hydrolysis of ascorbic acid 2-phosphate into ascorbic acid can result in the deposition of a high density of silver particles, which can then be sensitively assayed via the robust Ag/AgCl solid-state voltammetric process. As a result, the enzymatic silver deposition-based electrochemical method exhibits high sensitivity. Using the aptamer-based electrochemical detection of the breast cancer-associated glycoprotein CA15-3 as a proof of concept, a detection limit of 0.32 mU/mL has been demonstrated. Results show that the synergism of the aptamer-based capture and the glycoform-specific discrimination capability of the lectin-carbohydrate interactions can endow this method with high selectivity, and its practical use in the assay of CA15-3 levels in serum samples has been illustrated. With benefits from the high efficiency, mild reaction conditions, and user-friendly operation, the lectin-mediated labeling of ALP enzymes for enzymatic silver deposition is highly applicable to the electrochemical detection of low-abundance glycoprotein tumor markers.

Background: Gastric cancer (GC) poses significant challenges globally, ranking fifth in incidence and fourth in cancer-related mortality. SALL4, a stem cell transcription factor with multiple isoforms, includes SALL4-A as its full-length form. This study aims to evaluate the diagnostic potential of SALL4-A isoform expression in GC and its clinical significance., Method: Immunohistochemical (IHC) analysis was conducted on Tissue Micro Array (TMA) slides from 167 GC patients. Clinicopathological parameters were correlated with SALL4-A expression, and survival analysis was performed. Diagnostic performance was assessed using metrics such as sensitivity, specificity, and area under the curve (AUC)., Results: SALL4-A exhibited distinct cytoplasmic expression in GC, correlating with lower histological grade (p = 0.003) and TNM stage (p = 0.003), particularly in the intestinal subtype. Diagnostic evaluation showed an AUC of 0.803 for cytoplasmic expression, demonstrating high diagnostic potential. However, SALL4-A expression did not show significant prognostic value., Conclusion: Cytoplasmic SALL4-A expression in GC is associated with less aggressive tumor phenotypes and shows promise as a diagnostic marker. Further research is warranted to elucidate its mechanistic role and potential integration into clinical practice., Competing Interests: Declarations. Ethics approval and consent to participate: This study received ethical approval (Code: IR.IUMS.REC.1401.984) from the Research Ethics Committee of the Iran University of Medical Sciences. Consent for publication: The Authors grant the Publisher the sole and exclusive license of the full copyright in the Contribution, which licenses the Publisher hereby accepts. Consequently, the Publisher shall have the exclusive right throughout the world to publish and sell the Contribution in all languages. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Tumour vascular density assessed from CD-31 immunohistochemistry (IHC) images has previously been shown to have prognostic value in breast cancer. Current methods to measure vascular density, however, are time-consuming, suffer from high inter-observer variability and are limited in describing the complex tumour vasculature morphometry., Methods: We propose a method for automatically measuring a range of vascular parameters from CD-31 IHC images, which together provide a detailed description of the vasculature morphology. We first used a U-Net based convolutional neural network, trained and validated using 36 partially annotated whole slide images from 27 patients, to segment vessel structures and tumour regions from which the measurements are taken. The model also segments the vascular smooth muscle, benign epithelium, adipose tissue, stroma, lymphocyte clusters, nerves and CD-31 positive leukocytes, and we applied it to an additional 21 images from 15 patients. Using these segmentations, we investigated the relationship between the various tissue types and the vasculature and studied the relationship of various vascular parameters with clinical parameters. We also performed a 3D histology analysis on a separate tumour sample as a proof of principle, providing a more comprehensive visualization of vasculature morphology compared to the standard 2D cross-section of a tissue sample., Results: Using two-way cross-validation, we show that vessels were accurately segmented, with Dice scores of 0.875 and 0.856, and were accurately identified, with F1 scores of 0.777 and 0.748. All vascular parameters exhibit strong ( r > 0.7 ) and significant (p<0.001) correlations with measurements taken from the manual ground truth vessel segmentations. A significant relationship between the major/minor axis ratio, a measure of elongation, and the tumour grade was found., Conclusion: Our proposed method shows promise as a tool for studying the tumour vasculature and its relationship with surrounding cells and tissue types. Furthermore, the correlation with tumour grade highlights the clinical relevance of our approach. These findings suggest that our method could have substantial implications for improving prognostic assessments and personalizing therapeutic strategies in breast cancer treatment., Competing Interests: Declarations. Ethics approval and consent to participate: Patient data was acquired with informed consent and the approval of the local ethics board. All animal procedures were conducted in accordance with project (Bohndiek PE12C2B96) and personal licenses (Emma Brown - I544913B4), issued under the United Kingdom Animals (Scientific Procedures) Act, 1986 and approved locally under compliance forms CFSB1361, CFSB1567, CFSB1745 and CFSB1979. Consent for publication: This study used anonymized data, and no identifiable patient data were included in the study. Therefore, individual consent for publication was not required. Competing interests: T.W. is responsible for the development of the ScanXm software, and has a financial interest in Minogame Ltd. W.C., J.C.B., R.M., S.J.S., R.W., E.P., E.L.B., S.E.B., F.A.G., C.C., F.J.G. and F.M. have no Conflict of interest., (© 2025. The Author(s).)

Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer development. We conducted quantitative analysis of biomarkers for necroptosis [transient receptor potential cation channel subfamily M member 7 (TRPM7) and phosphorylated mixed lineage kinase domain-like protein], inflammation [cyclooxygenase-2 (COX-2)], apoptosis [BCL2-associated X (BAX) and terminal deoxynucleotidyl transferase dUTP nick end labeling], and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma-carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early colorectal cancer stages (Ptrend = 0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend = 0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio = 3.04; 95% confidence interval, 1.07-8.61; Ptrend = 0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps, whereas combined scores of phosphorylated mixed lineage kinase domain-like protein or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis. Prevention Relevance: Our findings suggest that COX-2 expression and combined scores of COX-2, TRPM7, and BAX hold promise for predicting the risk of metachronous polyps and could potentially serve as a tool for assessing the effectiveness of chemopreventive agents in preventing colorectal cancer during intervention trials., (©2024 American Association for Cancer Research.)

Introduction: A number of immunohistochemical stains have been examined for utility in establishing the site of origin for metastatic well-differentiated neuroendocrine tumors (NETs). In the gastrointestinal (GI) tract, distinguishing metastatic duodenal NETs from jejunoileal and other GI NETs is important for clinical work-up, prognosis, and therapy. A recent study indicated that prohormone convertase 2 (PCSK2 or PC2) had broad expression in small intestine and appendiceal NETs. Because the study did not include duodenal NETs, we examined PCSK2 expression in duodenal and other GI NETs., Methods: GI NETs (n = 69) and 13 corresponding lymph node metastases from stomach, duodenum, pancreas, ileum, appendix, and rectum were evaluated for the expression of PCSK2, along with ISL1, NKX2.2, CDX2, SATB2, and PAX8. Expression of each stain was evaluated using the H-score system, and differences in expression by site were evaluated by the chi square test., Results: PCSK2 was expressed at similar frequency in duodenal (50%), pancreatic (59%), and ileal NETs (40%). PCSK2 was infrequently expressed in stomach (0%), appendiceal (8%), and rectal (25%) NETs. However, incorporating PCSK2 into a panel including ISL1, NKX2.2, CDX2, and SATB2 allowed development of an algorithm which had 87% sensitivity and 93% specificity for classification of ileal NETs; and 68% sensitivity and 98% specificity for pancreaticoduodenal NETs., Conclusions: In contrast to previous findings, PCSK2 does not show specificity for any particular GI site. An algorithmic approach incorporating the expression of PCSK2 with that of ISL1, NKX2.2, CDX2, and SATB2 is useful in discriminating pancreatic, duodenal, ileal, appendiceal, and rectal NETs., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

TFE3 rearrangements characterize histogenetically, topographically, and biologically diverse neoplasms. Besides being a universal defining feature in alveolar soft part sarcoma (ASPS) and clear cell stromal tumor of the lung, TFE3 fusions have been reported in subsets of renal cell carcinoma, perivascular epithelioid cell tumor (PEComa), epithelioid hemangioendothelioma and ossifying fibromyxoid tumors. TFE3 -related neoplasms are rare in the head and neck and may pose diagnostic challenges. We herein describe 22 TFE3 fusion neoplasms affecting 11 males and 11 females aged 4 to 79 years (median, 25) and involving different head and neck sites: sinonasal cavities (n = 8), tongue (n = 4), oral cavity/oropharynx (n = 3), salivary glands (n = 2), orbit (n = 2), and soft tissue or unspecified sites (n = 3). Based on morphology and myomelanocytic immunophenotype, 10 tumors qualified as ASPS, 7 as PEComas (3 melanotic; all sinonasal), and 5 showed intermediate (indeterminate) histology overlapping with ASPS and PEComa. Immunohistochemistry for TFE3 was homogeneously strongly positive in all cases. Targeted RNA sequencing/FISH testing confirmed TFE3 fusions in 14 of 16 successfully tested cases (88%). ASPSCR1 was the most frequent fusion partner in ASPS (4 of 5 cases); one ASPS had a rare VCP::TFE3 fusion. The 6 successfully tested PEComas had known fusion partners as reported in renal cell carcinoma and PEComas ( NONO, PRCC, SFPQ , and PSPC1 ). The indeterminate tumors harbored ASPSCR1::TFE3 (n = 2) and U2AF2::TFE3 (n = 1) fusions, respectively. This large series devoted to TFE3-positive head and neck tumors illustrates the recently proposed morphologic overlap in the spectrum of TFE3 -associated mesenchymal neoplasms. While all PEComas were sinonasal, ASPS was never sinonasal and occurred in diverse head and neck sites with a predilection for the tongue. The indeterminate (PEComa-like) category is molecularly more akin to ASPS but shows different age, sex, and anatomic distribution compared with classic ASPS. We report VCP as a novel fusion partner in ASPS and PSPC1 as a novel TFE3 fusion partner in PEComa (detected in one PEComa). Future studies should shed light on the most appropriate terminological subtyping of these highly overlapping tumors., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Context.—: Salivary gland (SG) neoplasms (SGNs) display considerable immunophenotypic diversity. A significant proportion of SG carcinomas develop metastases, with increased diagnostic difficulty at metastatic sites. Transcriptional repressor GATA binding 1 (TRPS1), a novel immunohistochemical marker for breast cancer, has been found to stain certain SGNs., Objective.—: To investigate TRPS1 and SRY-related HMG-box 10 (SOX10) immunoexpression in various SGNs and non-SG carcinomas, head and neck paragangliomas, and head and neck mucosal melanomas., Design.—: TRPS1 immunoreactivity score (IRS) was determined as negative or low, intermediate, or high positive; SOX10 was reported as negative or positive., Results.—: One hundred forty-eight SGNs, 5 breast carcinomas, 105 nonbreast-non-SG carcinomas, including 33 head and neck squamous cell carcinomas (HNSCCs), 6 head and neck paragangliomas, and 6 head and neck mucosal melanomas, were assessed for TRPS1. All 23 benign SGNs showed TRPS1 positivity, with the majority having high-positive IRS (17 of 23 cases; 74%). Among 125 SG carcinomas, 115 of 125 (92%) were TRPS1 positive, with high-positive IRS in 94 of 125 (75%), intermediate-positive IRS in 15 of 125 (12%), and low-positive IRS in 6 of 125 (5%). Among nonbreast-non-SG carcinomas, HNSCC, lung, thyroid, kidney, and ovarian carcinomas showed frequent TRPS1 staining. Nearly half of HNSCCs had high (11 of 18; 33%) or intermediate (4 of 18; 12%) positive IRS. Mean IRS in SG carcinomas was significantly higher than that in nonbreast-non-SG carcinomas (P < .001). None of the TRPS1-positive nonbreast-non-SG carcinomas expressed SOX10., Conclusions.—: TRPS1 is positive in most benign and malignant SGNs. Its expression in several nonbreast-non-SG carcinomas indicates that it lacks specificity for breast and SG carcinomas, even if considering only high-positive IRS. Addition of SOX10 can increase the discriminatory utility of TRPS1., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2025 College of American Pathologists.)

Aims: The PEComa family of tumours is defined by spindle/epithelioid cells with myomelanocytic differentiation. A small subset harbours TFE3 fusion; however, YAP1::TEE3 has not been reported. Clear cell stromal tumour of the lung (CCST-L) is an emerging entity characterized by spindle to epithelioid cells with focal cytoplasmic clearing, inflammatory infiltrates, no myomelanocytic differentiation, and YAP1::TFE3 fusion. Herein, we report two cases of lung tumours with myomelanocytic differentiation that showed inflammatory spindle cell histology, focal epithelioid clear cells, as well as YAP1::TFE3 fusion., Methods and Results: The patients were both men, aged 61 and 68 years. The tumours in both cases presented as well-circumscribed solid masses involving the lung hilum. After lobectomy, no recurrence was observed at 7 and 32 months. Both tumours shared storiform to short fascicular growth of long spindle cells, with a minor component of epithelioid cells showing clear cytoplasm in the background of substantial intratumoral chronic inflammation and dilated blood vessels. One tumour showed focal melanin deposition. Both tumours were immunohistochemically positive for HMB45, Melan A, and h-caldesmon. Fluorescence in situ hybridization assays indicated the presence of YAP1::TFE3 fusions, which was confirmed by RNA sequencing in one case tested, and by immunohistochemical TFE3 expression and loss of YAP1 C-terminus staining., Conclusion: We present two cases of inflammatory spindle to epithelioid cell tumours of the lungs with myomelanocytic differentiation and YAP1::TFE3 fusion. This unique morphology and gene fusion suggest that these tumours may constitute a distinct subset of lung PEComa. Furthermore, morphological and molecular overlap with CCST-L gives rise to a hypothesis of a potential inherent relationship between PEComa and CCST-L., (© 2024 John Wiley & Sons Ltd.)

Categorizing breast neoplasia as ductal or lobular is a daily exercise that relies on a combination of histologic and immunohistochemical tools. The historically robust link between loss of the E-cadherin molecule and lobular neoplasia has rendered staining for E-cadherin by immunohistochemistry a staple of this diagnostic process. Unfortunately, discordances between E-cadherin expression and histomorphology, and variations in E-cadherin staining patterns and intensities abound in clinical practice, but are often neglected in favour of a binary interpretation of the E-cadherin result. In this article, we highlight the complexities of E-cadherin expression through a review of the E-cadherin protein and its associated gene (CDH1), the mechanisms leading to aberrant/absent E-cadherin expression, and the implications of these factors on the reliability of the E-cadherin immunohistochemical stain in the classification of ductal versus lobular mammary neoplasia., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

A 23-year-old female patient presented with radicular back pain, perineal numbness, and urinary retention. The patient was diagnosed with cauda equina syndrome and magnetic resonance imaging (MRI) of the spine revealed an enhancing osseous lumbar lesion causing severe central stenosis. A core needle biopsy of the lumbar spine showed microscopic features compatible with a small round blue cell tumor. CD99 and FLI1 were positive in the tumor cells. Next-generation sequencing demonstrated a EWSR1::FLI1 fusion. Given these findings, the spine lesion was diagnosed as Ewing sarcoma. The patient underwent surgical decompression of L2. On further workup, an MRI revealed an ill-defined enhancing mass of the right distal femur. This area was biopsied, demonstrating a fibro-osseous lesion with osteoblast proliferation containing nuclear atypia, low mitotic activity, and SATB2 positivity, diagnosed as low-grade central osteosarcoma (LGCOS). The patient underwent resection, which showed a classic LGCOS by histomorphology. Although fluorescence in-situ hybridization study for MDM2 gene amplification was negative, the overall findings are most consistent with LGCOS. These neoplasms are considered to be synchronous due to the presentation of each entity within 6 months. Considering the aggregate yearly incidence of Ewing sarcoma (approximately 1 case per 750 000 per year) and LGCOS (approximately 1 case per 10 million per year), the aggregate yearly probability of developing both of these genetically unrelated tumors in a single individual is 1 per 7.5 trillion per year, and it is likely such an event has never happened in the past., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In the fifth edition of the World Health Organization's (WHO) classification of tumors of the central nervous system (CNS), molecular analysis is required for not only determining each tumor type but assessing its prognosis based on malignancy (CNS WHO grade). A notable example is the loss of tumor suppressor gene cyclin-dependent kinase inhibitor 2A (CDKN2A), and CDKN2A homozygous deletion (HD) is a novel CNS WHO grade 4 marker in isocitrate dehydrogenase gene (IDH)-mutant astrocytoma. However, incorporating molecular workup into the "routine diagnostics" of each brain tumor type remains a major challenge, especially in resource-limited settings, including low- and middle-income countries. We herein validated the usefulness of p16 and methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) as potential surrogates for the assessment of CDKN2A status in 20 IDH-mutant astrocytoma cases. Of note, loss or retention of p16 and MTAP could accurately predict CDKN2A HD (p16: 87.5%, MTAP: 88.9%) or non-HD (p16: 100%, MTAP: 100%) with a single marker alone. Importantly, we revealed contributing factors to gray-zone IHC results (p16: 5-20%, MTAP: mosaic), including (1) hemizygous deletion of CDKN2A, (2) degenerative findings, and (3) intratumoral CDKN2A HD heterogeneity, the detailed histologic and molecular assessment of which would be a key to achieving integrated assessment of malignancy in IDH-mutant astrocytoma. We characterized the pitfalls of each method and provided for the first time a practical flowchart of astrocytoma grading, contributing to a normalization of WHO2021-based molecular diagnostics in resource-limited settings., (© 2024 Japanese Society of Neuropathology.)

MicroRNAs (miRNAs) are noncoding RNA transcripts with myriad physiologically important regulatory roles in the human body. These miRNAs have also recently emerged as promising biomarkers for the diagnosis of particular cancers. Conventional miRNA detection strategies, however, are characterized by many limitations. As electrochemical biosensors offer advantages including low costs, high levels of sensitivity, and amenability to miniaturization, they hold great promise as an alternative approach to miRNA detection. Nanomaterials are commonly used in the context of electrochemical sensor production, and this review provides an overview of the use of various carbon nanomaterials, metallic nanomaterials, metal-organic frameworks, magnetic nanomaterials, and conductive polymer nanocomposites to modify electrochemical biosensors in order to facilitate the detection of miRNA-21. A range of materials and detection methods for particular cancer types are discussed herein highlighting the superior sensitivity and specificity of these analytical strategies., which allow for the stable and reproducible detection of miRNAs in clinical samples. Ultimately, this review demonstrates the promising clinical prospects of these modified electrochemical biosensors as tools for early cancer diagnosis and the prognostic evaluation of affected patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Melanoma is a relatively rare malignancy with a highly aggressive biological behavior. Metastases to other sites, like lymph nodes and liver are common, but primary hepatic melanoma is a rarity with poor survival ranging from months to few years. Diagnosis of primary hepatic melanoma via clinical features and imaging technology is difficult because of its ambiguous features. Here, we present a 26-year-old North Indian woman admitted in the department of gastrointestinal surgery at our tertiary care hospital with the complaint of pain in the abdomen for a month associated with the loss of appetite and subsequent weight loss. The liver function tests were within normal limits and viral markers were negative. The triple-phase computed tomography scan of abdomen showed significant hepatomegaly and two well-defined lesions in both lobes of the liver. Histopathological evaluation was performed on the core liver biopsies submitted from the liver lesions. A malignant tumor with abundant black intracytoplasmic pigment was identified. Immunohistochemistry proved the tumor to be melanoma. The detailed clinical history, laboratory, and radiological investigations were acquired and analyzed to rule out a metastatic lesion of the same. A final diagnosis of primary hepatic melanoma was thus rendered. Primary hepatic melanoma is extremely uncommon and has been rarely reported. Preoperative diagnosis is challenging due to low index of suspicion and nonspecific clinical features. In this case report, we discuss the clinicopathological features of primary hepatic melanoma and review the literature so as to increase the awareness and improve our understanding of the disease.

Clonal isotype switch (CIS) in multiple myeloma (MM) refers to the emergence of new immunoglobulin bands distinct from those present at diagnosis. CIS often appears after high-dose chemotherapy and autologous stem cell transplantation (ASCT), reflecting post-transplant immune recovery. However, its prognostic significance remains unclear. In this study, CIS was observed (CIS-positive) in 31.7 % (26/82) of patients undergoing ASCT. Patients receiving bortezomib-containing induction therapy showed a higher prevalence of CIS compared to those treated with vincristine-doxorubicin-dexamethasone chemotherapy (37.9 % vs. 16.7 %, p = 0.061). Median overall survival (OS) was not estimable (NE) in the CIS-positive group, while it was 47 months in the CIS-negative group (hazard ratio [HR]: 0.27, 95 % CI: 0.11-0.67; p = 0.005). Median progression-free survival (PFS) was also NE in the CIS-positive group versus 26 months in the CIS-negative group (HR: 0.25, 95 % CI: 0.11-0.58; p = 0.001). These findings suggest that CIS is an independent biomarker associated with favorable outcomes in MM patients undergoing ASCT., Competing Interests: Declaration of Competing Interest I declare on behalf of my co-authors and myself that we do not have any conflict of interests pertaining to this study. This study has not been published or submitted for publication elsewhere. My co-authors are aware of the submission of our manuscript to Leukemia Research., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Aims: To test the efficacy of artificial intelligence (AI)-assisted Ki-67 digital image analysis in invasive breast carcinoma (IBC) with quantitative assessment of AI model performance., Methods and Results: This study used 494 cases of Ki-67 slide images of IBC core needle biopsies. The methods were divided into two steps: (i) construction of a deep-learning model (DL); and (ii) DL implementation for Ki-67 analysis. First, a DL tissue classifier model (DL-TC) and a DL nuclear detection model (DL-ND) were constructed using HALO AI DenseNet V2 algorithm with 31,924 annotations in 300 Ki-67 digital slide images. Whether the class predicted by DL-TC in the test set was correct compared with the annotation of ground truth at the pixel level was evaluated. Second, DL-TC- and DL-ND-assisted digital image analysis (DL-DIA) was performed in the other 194 luminal-type cases and correlations with manual counting and clinical outcome were investigated to confirm the accuracy and prognostic potential of DL-DIA. The performance of DL-TC was excellent and invasive carcinoma nests were well segmented from other elements (average precision: 0.851; recall: 0.878; F1-score: 0.858). Ki-67 index data and the number of nuclei from DL-DIA were positively correlated with data from manual counting (ρ = 0.961, and 0.928, respectively). High Ki-67 index (cutoff 20%) cases showed significantly worse recurrence-free survival and breast cancer-specific survival (P = 0.024, and 0.032, respectively)., Conclusion: The performances of DL-TC and DL-ND were excellent. DL-DIA demonstrated a high degree of concordance with manual counting of Ki-67 and the results of this approach have prognostic potential., (© 2024 John Wiley & Sons Ltd.)

In addition to "classic" and eosinophilic subtype, chromophobe renal cell carcinoma (RCC) is well-known to demonstrate various morphological patterns including adenomatoid, microcystic, pigmented, multicystic, papillary, neuroendocrine-like, and small cell-like, all of which are important to appreciate for accurate diagnosis. Herein, we expand on a unique chromophobe RCC morphology not previously described consisting of tumor cells with extensive stromal retraction, mimicking upper urothelial tract micropapillary carcinoma (MPC). Twelve MPC-like chromophobe RCC nephrectomies were reviewed with clinicopathological features recorded; molecular testing was performed on 7 of 12 tumors. Patients were mostly men (n=10) with a mean age of 65 years. Mean tumor size was 6.4 cm with pathological stage distribution as follows: 4 (33%) T1a, 2 (17%) T1b, 1 (8%) T2b, and 3 (25%) T3a. The extent of MPC-like chromophobe RCC foci ranged from 10% to 40% (mean=26%; there was no correlation between the extent of MPC-like chromophobe RCC foci and tumor stage). Other chromophobe RCC morphological patterns were not identified. When performed, all (100%) tumors depicted prototypic chromophobe RCC staining pattern of KIT positivity/KRT7 positivity. Molecular showed 6 of 7 (86%) with multiple chromosomal losses. Clinically significant mutations were identified in NF1, TP53, FLCN (likely somatic), CHEK2, and ZFHX3 genes. Follow up available in 9 patients showed no evidence of disease (mean=23 months). Although the etiology behind the extensive stromal retraction in our tumors is unknown, this may likely be artifactual in nature. Nonetheless, it is important to include MPC-like chromophobe RCC in the spectrum of "variant" morphologies to avoid diagnostic pitfalls from micropapillary carcinoma., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with a benign clinical course. In contrast, leiomyosarcoma (LMS) is a high-grade, malignant neoplasm characterized by high recurrence rates and poor survival. While LM-BN and LMS show distinct morphologies, they share similar immunoprofiles and molecular alterations, with both considered 'genomically unstable'. Rare cases of LM-BN associated with LMS have been reported; however, the histogenesis and molecular relationship between these two tumors remains unclear. In this study, we assessed 11 cases of LMS arising in conjunction with LM-BN confirmed by histology and immunohistochemistry (IHC), further analyzed by clinical, histologic, and molecular characteristics of these distinct components. LM-BN and LMS had similar p16 and p53 IHC patterns, but LMS had a higher Ki-67 index and lower estrogen and progesterone eceptor expression. Digital image analysis based on cytologic features revealed spatial relationships between LMS and LM-BN. Genomic copy number alterations (CNAs) demonstrated the same clonal origin of LMS arising from existing LM-BN through conserved CNAs. LMS harbored highly complex CNAs and more frequent losses of the TP53, RB1, and PTEN genomic regions than LM-BN (p = 0.0031), with CDKN2A/B deletion identified in LMS only. Mutational profiling revealed many shared oncogenic alterations in both LM-BN and LMS; however, additional mutations were present within LMS, indicative of tumor progression through progressive genomic instability. Analysis of spatial transcriptomes defined uniquely expressed gene signatures that matched the geographic distribution of LM-BN, LMS, and other cell types. Our findings indicate for the first time that a subset of LMS arises from an existing LM-BN, and highly complex genomic alterations could be potential high risks associated with disease progression in LM-BN. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Cervical cancer (CC) is the fourth most common cancer among women worldwide, following breast, colorectal, and lung cancers. Each year, it accounts for approximately 600,000 new cases and 340,000 deaths. Early-stage cervical cancer is treatable with surgery and chemoradiotherapy (CCRT). However, treatment for metastatic cervical cancer is limited, with bevacizumab combined with chemotherapy being one of the few options, though survival rates remain low. Currently, the diagnosis of cervical cancer primarily relies on Pap smears and colposcopy. Although these methods are essential for detection, they are costly, labor-intensive, and require significant resources. Therefore, there is an urgent need to identify effective biomarkers that can detect cervical cancer at an early stage, improving both the accuracy of diagnosis and the efficacy of treatment. Although numerous cervical cancer biomarkers have been identified for the cervical cancer thanks to advances in technology. In recent times, electrochemical methods have proven to be particularly effective in cervical cancer detection. In this paper, we reviewed the important cervical cancer biomarkers and their detection through electrochemical biosensors, which offer advantages such as higher sensitivity, affordability, and ease of analysis. Furthermore, we discussed the limitations and future prospects of electrochemical biosensors in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Squamous cell carcinoma of the vulva (vSCC) is currently categorized either as human papillomavirus (HPV) associated or independent. Immunohistochemical stains, p16 INK4a (p16) and p53 are helpful biomarkers to support the designation of vSCC into 1 of the 3 tumor pathways: (1) HPV-associated, (2) HPV-independent, TP53 mutant, or (3) HPV-independent, TP53 wild type. Recently, a framework of p53 expression patterns in vSCC was proposed. In this international and multi-institutional study, we evaluated the interrater agreement for p53 and p16 and tumor pathway classification in a cohort of 50 invasive vSCC across a variety of practice settings (private practice, academic medicine) and levels of expertise (trainees, gynecologic pathologists, dermatopathologists, private practice pathologists). Our study shows that the overall interrater agreement for the interpretation of p16 in vSCC is strong to near perfect, while the agreement for p53 and tumor pathway assignment is overall moderate. Interrater agreement for p53 and tumor pathway is higher (strong) in the academic practice setting. Pathologists without gynecologic subspecialty expertise benefited the most from a brief educational module, which fostered a better understanding and improved comfort level with the p16/p53 stain interpretation and tumor pathway designation in the diagnosis of vSCC. Some interpretative challenges remain, particularly in regard to select p53 patterns and high-risk HPV-in situ hybridization utilization, warranting additional research., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Early diagnosis and screening of tumor markers are essential for effective cancer treatment and improve the treatment efficiency and prognosis of tumor recurrence and metastasis. In this study, a split-ring resonator (SRR) circuit based on an interdigital electrode structure was developed and applied to microwave biosensors along with machine learning to detect extremely low concentrations of Carcinoembryonic Antigen (CEA). CEA was detected using a microwave sensor operating at a resonance frequency of 4.33 GHz. When the microwave sensor is exposed to CEA analytes, it generates a new frequency in the range of 1-2 GHz. The position and intensity of the newly generated frequency can be used to characterize and predict the concentration of the CEA solution. The proposed sensor exhibits excellent resonance linearity for various concentrations of CEA (R 2  = 0.999), as well as a very low detection limit (39 pg/mL) and high sensitivity (27.5 MHz/(ng/mL)). A machine learning approach was implemented to predict the CEA concentration in blood samples. The results showed close concurrence with the CEA concentration detected by the sensor. Western Blot (WB) was used to compare the CEA contents of four different cell types, and a biosensor was used for validation; the results of the two experiments showed good agreement. This is the first demonstration of the validation of biosensor reliability at the cellular level. The proposed concept exhibits outstanding detection performance with convenient and rapid tumor marker detection. Hence, it has important implications as an auxiliary diagnosis method for cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we describe a patient of primary cutaneous acral CD8-positive lymphoproliferative disorder located in a nonacral region. A 65-year-old male presented with an ill-defined lesion of rubbery consistency and a maximum diameter of 2.5 cm localized in the right thigh. Histologically, it was composed of a diffuse dermal infiltration of medium-sized atypical lymphocytes that expressed CD3, CD8, and TIA-1. In addition, a characteristic paranuclear positivity with CD68 was observed. During the follow-up, the patient had a recurrence of the disease in the abdomen with a lesion showing similar morphology and phenotype. To our knowledge, < 20 patients of primary cutaneous acral CD8-positive lymphoproliferative disorder with a nonacral presentation have been described in English literature. Although rare, its identification is essential to differentiate it from other T-cell lymphoma that express CD8 and cytotoxic markers, and whose clinical courses are very aggressive., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In the setting of hepatocellular carcinoma (HCC) surveillance, a range of observations can be identified. Often, imaging findings and biochemical results are consistent with the diagnosis of HCC. However, challenges in HCC surveillance can arise in different clinical contexts, particularly when imaging results and tumor biomarkers are discordant. In this article, the authors describe 5 clinical scenarios based on our experiences in which additional evaluation was necessary to determine whether HCC was present or not., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Neuroblastoma (NBL), is the most common, non-CNS solid tumor of childhood. This disease presents with unique biological and clinical challenges necessitating accurate diagnosis, prognosis assessment, treatment, and vigilant monitoring. Liquid biopsy is an upcoming, innovative, and non-invasive diagnostic modality. It has the potential to detect tumors and perform therapeutic monitoring through the analysis of circulating biomarkers in blood, urine, saliva, and other bodily fluids., Methodology: This scoping review offers an in-depth exploration, of the current landscape of liquid biopsy-based biomarkers in NBL. The review looks at the clinical implications, prevalent challenges, and future outlook of their clinical applications in NBL. The scoping review adhered to the guidelines of the PRISMA extension for scoping reviews, known as PRISMA-ScR, as the skeletal framework. The review involved comprehensive searches for liquid biopsy-based biomarkers in NBL across multiple databases, including PUBMED, EMBASE, SCOPUS, and WEB of Science, without restrictions., Results: The scoping review process uncovered a significant body of literature (n = 201) that underwent meticulous scrutiny, ultimately leading to the final selection of studies (n = 15). The liquid biopsy biomarkers included circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and other entities in bodily fluids. Their evaluation focused on associations with clinical outcomes such as overall survival, event-free survival, and risk stratification in NBL., Conclusion: Our findings highlight the potential of liquid biopsy biomarkers to revolutionize NBL diagnosis and therapeutic monitoring. This rapidly evolving frontier in pediatric oncology suggests significant advancements in precision medicine for the management of NBL., Competing Interests: Conflict of interest All authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chondroblastoma is currently described as a benign bone tumor, histopathologically characterized by its classical features including chondroblasts, pink cartilage, and a variable number of osteoclast-like giant cells with foci of dystrophic calcification. Although recurrent and metastasizing chondroblastomas are reported, a malignant chondroblastoma is exceedingly rare and somewhat a contentious entity. A 35-year-old male presented with a lump in his ankle of 15 years' duration. Imaging disclosed a lytic destructive lesion involving the lower ends of the tibia and fibula with a soft tissue component, indicative of atypical/"worrisome" features. Microscopic examination of the biopsy revealed distinct foci of chondroblastoma, transitioning to areas of high-grade sarcoma, including pleomorphic cells, increased mitoses, and prominent stromal hyalinization. Immunohistochemically, the entire tumor was positive for H3K36M, while DOG1 highlighted the areas of chondroblastoma. SATB2 highlighted the areas of high-grade sarcoma, sparing the areas of chondroblastoma. Additionally, the areas of a high-grade sarcoma showed multifocal desmin immunostaining. A diagnosis of a malignant transformation in a chondroblastoma was offered. The patient defaulted to further treatment and unfortunately died 8 months, post-diagnosis. The conceptual evolution of a malignant chondroblastoma with H3K36M immunostaining in the few reported tumors is described herewith., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare aggressive lymphoma. Recently, genetic classification using Next Generation Sequencing (NGS) demonstrated that PSDLBCL largely consists of the MCD genotype, which has a poor prognosis mainly driven by MYD88 L265P and CD79B gene abnormalities. This study investigated the prevalence and clinicopathological significance of MYD88 L265P and CD79B Y196 mutations using droplet digital PCR in 55 patients with PSDLBCL, as well as the translocation of BCL2 / BCL6 / c-Myc with FISH. We found mutations in MYD88 L265P (29/55, 52.7%) and CD79B Y196 (20/55, 36.4%). The MCD-like subtype, defined by the mutation of MYD88 and/or CD79B , was found in 32 out of 55 cases (58.2%). This subtype largely consists of non-GCB type (31/32, 96.9%; P <0.01) and double-expressor cases (20/32, 62.5%; P =0.01) compared with the MYD88 / CD79B co-wild type, with BCL6 translocation in a small subset (2/32, 6.3%) and no translocations of BCL2 (0/32) or c-Myc (0/32). The MCD-like subtype tended to relapse in specific sites such as the central nervous system, testis, and/or skin compared with the co-wild type ( P =0.03), showing poorer outcomes in overall survival ( P =0.02) and progression-free survival ( P =0.01). In conclusion, our study highlights a high prevalence of MYD88 and CD79B mutations in PSDLBCL, identifying an aggressive MCD-like subtype with a distinct relapse pattern. This molecular subclassification can be helpful for both prognostic prediction and therapeutic strategy in patients with PSDLBCL., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Urothelial carcinoma and prostatic adenocarcinoma can have overlapping histologic features and in some instances pose challenges to pathologists. GATA binding protein 3 (GATA3) immunohistochemistry (IHC) is a well-established tool to aid in this specific diagnostic dilemma as it has been shown to be a sensitive marker for urothelial carcinoma and a putatively specific marker in excluding prostatic adenocarcinoma. However, in encountering an index tumor of prostatic adenosquamous carcinoma positive for GATA3, herein we sought to investigate this potential diagnostic pitfall in a larger series of tumors. In this study, we retrospectively reviewed prostatic adenosquamous carcinomas diagnosed in 17 patients across the authors' institutions and personal consult collections in the past 10 years. GATA3 IHC was either reviewed or performed on tumors not previously tested. We also recorded other immunostains that were performed at initial diagnosis. Positivity for GATA3 was found in 9 of 17 (53%) tumors, all within squamous regions (2 tumors also showed concomitant moderate GATA3 positivity within glandular elements). The GATA3 positive tumors were all positive for p63 in the 7 tumors where p63 was also performed. Of all tumors tested, NKX3.1 was positive in 100% (13/13) of the glandular elements (3 tumors also showed NKX3.1 concomitant positivity within squamous regions). In summary, when encountering a carcinoma with mixed glandular/squamous features in which prostatic origin is being considered, awareness of GATA3 immunoreactivity in a subset of prostatic adenosquamous carcinoma is critical to avoid diagnostic pitfalls., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The occurrence of fumarate hydratase-deficient leiomyoma of the abdominal wall is exceptionally rare., Case Presentation: A 50-year-old female patient with a past medical history of fumarate hydratase-deficient uterine leiomyoma presented with a left lower quadrant abdominal mass that has been present for the past 2 years. An ultrasound revealed a 3.5 cm oval hypoechoic mass. A subsequent CT scan showed a 3.5 cm hyperdense mass within the left internal oblique musculature. No family history is noted. A biopsy of the mass exhibited bundles of spindle cell neoplasm exhibiting bizarre ovoid nuclei and eosinophilic cytoplasm. No evidence of mitotic figures or tumor necrosis was noted. Immunohistochemical staining showed positive staining for desmin and smooth muscle actin (SMA), but negative staining for MART-1, S100, and CD34. Lesional cells showed expression of 2-succinocysteine and loss of fumarate hydratase expression. A diagnosis of fumarate hydratase-deficient leiomyoma was rendered., Conclusion: This report reinforces the importance of considering genetic testing for fumarate hydratase mutations in the evaluation of extra-uterine leiomyomatous lesions. Comprehensive follow-up and clinical screening in individuals with new lesions and a known history of fumarate hydratase-deficient neoplasms is mandatory. Recent recommendations support the integration of morphology-based evaluation along with immunohistochemical staining and genetic testing as a part of the standard evaluation for all uterine leiomyomas., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

DEK :: AFF2 fusion nonkeratinizing squamous cell carcinoma (NKSCC) is an emerging entity in the sinonasal tract, temporal bone, and skull base. However, the clinical behavior of these tumors has not been well studied. Here, we report the largest cohort of DEK :: AFF2 carcinomas to determine if morphology, mitotic rate, and/or Ki-67 IHC are associated with patient outcomes, including a comparison with high-risk human papillomavirus (HPV)-associated and independent patients. We solicited cases of molecularly or AFF2 immunohistochemistry (IHC) proven DEK :: AFF2 SCC from surgical pathologists to collect patient demographic, clinical, and outcome data. Using representative H&E slides, we characterized the morphology and counted mitoses. Ki-67 immunohistochemistry was performed. We also compared the DEK :: AFF2 survival rates to those in a cohort of AFF2 IHC-negative HPV-associated and HPV-independent SCC. DEK :: AFF2 carcinomas most commonly arose in the nasal cavity (13/30, 43%), and the average number of recurrences was 1.8 (range: 0 to 10). At the last follow-up, most patients were disease free (19/30, 63%) or were alive with disease (9/30, 30%). There was an average mitotic rate of 2 per 2 mm 2 (range: 0 to 9) and Ki-67 proliferation rate of 26% (range: 3% to 60%). Local recurrence was common, but morphology, mitotic activity, and Ki-67 index were not associated with recurrence or survival. On Kaplan-Meier survival analysis, DEK :: AFF2 patients had lower disease-free survival but otherwise had similar outcomes to conventional SCC patients. Our multi-institutional study shows that local recurrence is common in DEK :: AFF2 fusion nonkeratinizing SCC patients, but patients have survival rates similar to conventional SCC. Despite showing a range of different features and proliferation rates, traditional grading by morphology, mitotic rate, and/or Ki-67 activity does not seem to be predictive of outcome., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Context.—: Insulinoma-associated protein-1 (INSM1) is a recently developed immunohistochemical marker claimed to be highly specific and sensitive for the diagnosis of neuroendocrine malignancies. Recent studies, however, have demonstrated that this marker can also be expressed in non-neuroendocrine neoplasms including squamous cell carcinoma of the thymus., Objective.—: To examine INSM1 expression in lymphoepithelial thymic carcinomas., Design.—: Thirty-four cases of lymphoepithelial carcinoma of the thymus were examined by immunohistochemistry or in situ hybridization for INSM1, synaptophysin, chromogranin, CD5, CD117, Epstein-Barr virus-encoded small ribonucleic acid (EBER), and Ki-67. Basic clinical information was abstracted from the medical record., Results.—: The patients were 14 women and 20 men, aged 20 to 85 years. The tumors arose in the anterior mediastinum without any previous history or evidence of malignancy at other sites. Immunohistochemical staining showed moderate to strong positivity of the tumor cells for INSM1 in 65% of cases (22 of 34), focal weak positivity in 20% (7 of 34), and negative staining in 5 cases. Chromogranin staining was focally and weakly positive in 1 case, and synaptophysin showed only focal weak positivity in scattered tumor cells in 12 cases. No significant correlation could be identified between the pattern and intensity of staining for INSM1 and staining for CD5, CD117, and Ki-67., Conclusions.—: INSM1 positivity in lymphoepithelial carcinoma of the thymus may represent a pitfall for diagnosis, particularly in small biopsy samples. Awareness of this finding may be of importance to avoid misdiagnosis of neuroendocrine malignancy., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2025 College of American Pathologists.)

Bronchial papillomas are benign tumors, which can be divided into different subtypes based on the cellular features. So far, no bronchial papilloma with basaloid cell features has been reported. We report a bronchial basaloid papillary tumor in a 67-year-old woman. Tumor recurrence and malignant transformation were observed after a long-term follow-up. The clinical, histological, immunohistochemical, and genetic features were reappraised. The primary tumor was characterized by papillary growth pattern and basaloid neoplastic cells, only a small amount of neoplastic cells showed mature characteristics. The tumor originated from respiratory epithelium and had a low proliferation index by Ki-67. Keratin (KRT) 5/6 and KRT7 showed patchy or partial positivity. Myoepithelial markers were negative. P63 was diffusely positive, but it was negative in the small amount of tumor cells with mature characteristics. The common genetic alterations ( EGFR , KRAS , BRAF V600E, HER2 , and ALK ) of lung cancers were not detected. However, tumor recurrence was observed in the mediastinum and esophagus 12 years after surgery. The recurrent tumor had a morphology overlapping with that of the primary tumor; however, it displayed significantly malignant characteristics. The recurrent tumor was not related to high-risk HPV. A high variant allele frequency was observed in tumor suppressor gene BRCA1 , TP53 , oncogene GNA11 , and KIT , which were all missense mutations. Considering the bland features of the primary tumor and the fact of tumor recurrence and undisputed malignant transformation, the basaloid papillary tumor was considered a tumor with uncertain malignant potential., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rhabdomyosarcoma is a highly malignant tumor with striated muscle differentiation, which is histologically classified as alveolar, embryonal, pleomorphic, and spindle cell/sclerosing histological subtype. Rhabdomyosarcoma with TFCP2 rearrangement, which usually occurs in the bone, is a newly identified rare spindle and epithelioid rhabdomyosarcoma with characteristic clinicopathological features and molecular alterations. We report a 39-year-old female patient who underwent local excision of the mandibular lesion. Microscopically, the intraosseous tumor was composed of spindle-shaped, epithelioid, and rhabdomyoblastic cells with atypical nuclei and atypical mitotic figures. In addition, TFCP2 rearrangement was revealed by the fluorescence in situ hybridization. The tumor was thus correctly diagnosed as rhabdomyosarcoma with TFCP2 rearrangement. The patient was scheduled to undergo radiotherapy, and triple-agent chemotherapy after surgery, and no tumor recurrence or metastasis was detected during the 3-month postoperative follow up. Since this tumor is relatively rare and newly recognized, it can be easily misdiagnosed or missed and might be a conundrum of pathological diagnosis. Familiarity with its clinicopathological features and molecular alterations is essential for its correct diagnosis. Therefore, we summarized the clinicopathological, immunohistochemical, and molecular alterations of 43 cases of this rare rhabdomyosarcoma variant in the English-language literature. In addition, the differential diagnosis of this lesion is crucial either., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Molecular diagnosis plays a significant role in detection of biomolecules linked to early stage cancer since it offers greater sensitivity and reliability for identification of biomarker level changes as the disease progresses. The application of vibrational spectroscopy in biomarker detection is defined by the fingerprint spectrum of a molecule originating from single-molecule vibrations. This characteristic makes surface enhanced Raman spectroscopy (SERS) a promising tool for identification of biomarkers. The performance of the SERS technique largely depends on the material being used as the SERS substrate. Graphene, with its large surface area and abundance of aromatic regions, is considered advantageous as SERS substrate. Combining graphene with metal nanomaterials considerably increases SERS signal intensity, thereby enhancing detection sensitivity. Therefore, this review emphasizes the significance of selecting graphene-metal nanohybrids as suitable SERS substrates for signal amplification. The detail understanding of the mechanism of graphene-metal hybrid in SERS based detection of early stage cancer is also presented. Furthermore, several examples demonstrated the application of graphene-metal hybrid nanomaterials in detecting biomarkers and cancer cell differentiation using SERS imaging., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Transanal excision of rectal cancer can be considered the definitive surgical treatment if the depth spread is T1 or lower, and the lesion is completely included within the resection margin. This study aims to analyze the immune microenvironment in healthy rectal mucosa as a possible predictor of tumor infiltration depth, lateral tumor spread, and recurrence of rectal cancer after transanal local excision., Methods: This study is a subanalysis of data from the IMMUNOREACT 1 and 2 trials (NCT04915326 and NCT04917263, respectively) including all the patients who underwent transanal excision of rectal cancer. This multicentric study collected healthy mucosa surrounding the neoplasms of patients with rectal cancer. A panel of immune markers was investigated at immunohistochemistry: CD3, CD4, CD8, CD8β, Tbet, FoxP3, PD-L1, MSH6, and PMS2 and CD80. Flow cytometry determined the proportion of epithelial cells expressing CD80, CD86, CD40, HLA ABC or HLA DR and the proportion of activated CD8+ T cells, CD4+ Th1 cells, and Treg., Results: Receiver operating characteristic curve analysis for predicting deep tumor spread showed an area under the curve of 0.70 (95% confidence interval: 0.60-0.80) for CD25+FoxP3+ cell rate and 0.74 (95% confidence interval: 0.53-0.92) for CK+CD86+ cell rate. Receiver operating characteristic curve analysis for predicting lateral tumor spread showed an area under the curve of 0.82 (95% confidence interval: 0.61-0.99) for CD8+CD38+ MFI, 0.96 (95% confidence interval: 0.85-0.99) for CD8β infiltration, and 0.97 (95% confidence interval: 0.87-0.99) for CK+HLAabc+ cell rate. Receiver operating characteristic curve analysis for predicting recurrence showed an area under the curve of 0.93 (95% confidence interval: 0.76-0.99) for CD8+CD38+ MFI and 0.94 (95% confidence interval: 0.78-0.99) for CD8+CD28+ MFI. Low CD8+CD38+ MFI and low CD8+CD28+ MFI were associated with shorter disease-free survival (P = .025 and P = .021, respectively)., Conclusion: Our study showed that the association between the high proportion of epithelial cells acting as presenting cells and deep or lateral tumor spread may be explained by the presence of a greater tumor load at the site. Moreover, it showed that weak activation of CD8+ T cells within the rectal mucosa is associated with lateral tumor spread and eventually a higher recurrence rate. The mucosal level of CD8β infiltration detected at immunohistochemistry might be tested as a marker of lateral tumor spread and potentially translated into clinical practice., Competing Interests: Conflict of Interest/Disclosure The authors have no relevant financial disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Primary carcinoma of the ovary (OCs) are responsible for a significant number of deaths related to cancer, and have the highest rate of death related to cancers of the female reproductive organs. Programmed cell death 1 (PD1) protein, acts as an immune checkpoint, and has an important role in the down-regulation of the immune system by preventing the activation of T-cells, which will weaken the autoimmunity and increases self-tolerance. This study aimed at the evaluation of the immunohistochemical (IHC) expression of PD-L1 in various primary surface ovarian epithelial tumours and to test its correlation with different clinicopathological parameters together with the expression of a panel of P53, ER and PR., Methods: A set of 102 cases of primary ovarian surface epithelial neoplasms (benign, borderline and malignant) were collected to construct Tissue Microarray (TMA) using 3 tissue cores from each case. IHC for PD-L1, p53, PR and ER was performed. The expression of PD-L1 was evaluated in relation to some clinicopathological parameters and to the expression patterns of other markers., Results: Expression of PD-L1 was detected in about 51% (n = 36) of malignant tumours. The malignant group significantly showed PD-L1 positivity compared to borderline and benign groups. The malignant tumours significantly showed PD-L1 and total p53 positivity in comparison to borderline group. Also, malignant tumours significantly showed higher combined positivity of PD-L1 and either PR or ER compared to borderline and benign lesions. No significant correlation was appreciated between PD-L1 expression and with any of the studied clinicopathological parameters., Conclusions: This study showed a significant PD-L1 expression in malignant primary surface epithelial tumours. Construction of a panel of IHC markers, including PD-L1, could have a potential value to define patients those would benefit from the addition of immunotherapy to the treatment plan., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: This study was approved by the Ethics Committee of the Mansoura University [Institutional Review Board (IRB) Ref. MDP.19.10.31 dated October 2019] and in agreement with Declaration of Helsinki of 1964 and its later amendments. There were no required written consents with a waiver from the Institutional Review Board., (© 2024. The Author(s).)

Primary anal cancers are rare and typically driven by high-risk human papillomavirus (HPV) infection. Though squamous cell carcinoma is most common, a spectrum of HPV-related nonsquamous anogenital neoplasms with similarities to cervical stratified mucin-producing carcinoma has been reported. In this study, we mined our institutional archives to characterize the clinicopathologic features of this emerging entity. Six cases were identified from the files at 2 institutions, including 4 cases of invasive stratified mucin-producing carcinoma and 2 stratified mucin-producing intraepithelial lesions (SMILE). Four patients were women, and the mean age was 70 years. Patients presented with rectal/anal mass or polyp, rectal bleeding or pain, weight loss, or at the time of screening colonoscopy. Tumors displayed histologic features as described in the gynecologic tract. Cases of invasive stratified mucinous carcinoma showed infiltrative tumor nests with variable intracytoplasmic mucin, peripheral palisading, prominent apoptosis, and neutrophilic infiltrate. One invasive stratified mucinous carcinoma associated with high grade glandular dysplasia, whereas 1 SMILE was next to conventional low-grade squamous intraepithelial lesion. All lesions stained with p16 showed block-like p16 expression. HPV in situ hybridization was performed in 5 cases, 4 of which were positive; one was interpreted as equivocal. Follow-up information, available in 4 patients, revealed 1 local recurrence followed by death due to unrelated causes in a patient with invasive stratified mucin-producing carcinoma. We report the first series of HPV-associated primary anal stratified mucin-producing neoplasms analogous to those seen in the gynecologic tract, further broadening the spectrum of HPV-related anal neoplasia., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Histiocytic and dendritic cell neoplasms, especially histiocytic sarcoma, can show morphologic and phenotypic overlap with immature monocytic neoplasms. IRF8 immunohistochemical staining has been demonstrated to be useful in identifying monoblasts, but it has not been extensively studied in histiocytic and dendritic cell neoplasms. IRF8 immunohistochemistry was performed on cases of histiocytic sarcoma (HS, n=6), Langerhans cell histiocytosis (LCH, n=25), Rosai Dorfman disease (RDD, n=17), follicular dendritic cell sarcoma (FDCS, n=3), and Erdheim Chester disease (ECD, n=5), along with a control group that included a subset of myeloid neoplasms with monocytic differentiation. Of 89 total cases, IRF8 was positive in 3/6 cases of HS, 3/5 cases of ECD, 12/17 cases of RDD, 7/25 cases of LCH, and 0/3 cases of FDCS. Control cases were stained similarly to previous reports, with IRF8 expression roughly correlating to monoblast count and normal staining in other control groups. We demonstrate that IRF8 is expressed in a significant subset of tested neoplasms of histiocytic and dendritic cell lineage. While we confirmed that IRF8 is useful to identify monoblasts, these results highlight that IRF8 cannot be reliably used to distinguish histiocytic sarcomas from myeloid neoplasms of monocytic lineages, and caution is advised interpreting IRF8 staining in that setting., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Breast cancer with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+ or 2+ with negative in-situ hybridisation (ISH) (HER2-low) can now be targeted by HER2 antibody drug conjugates. We set out to compare HER2 status between matched primary invasive breast carcinoma (IBC) and distant metastases (DM) with clinical-pathological correlation, with specific interest in HER2-low., Methods: Biomarker studies and clinical-pathological features of primary IBC with matched DM diagnosed between 2021 and 2022 were retrospectively analysed. HER2 status was assessed per 2023 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for IHC (4B5) and ISH (IQFISH pharmDX). Bilateral breast primaries were excluded. HER2 IHC 0 to 1+ were reassessed., Results: One hundred and forty-seven cases of primary IBC with matched DM were identified. Biomarkers were performed on core biopsy (n = 74) and resection (n = 73). One hundred and twenty-six (86%) were initially classified as 'HER2-negative'; of these, 67 (46%) were reclassified as HER2-low. Patients with HER2-positive primaries were younger (P = 0.01) and had an increased incidence of micropapillary carcinoma (P = 0.02). HER2-low primaries also had an increased incidence of micropapillary carcinoma (P = 0.02) and oestrogen receptor (ER) positivity (P = 0.02) compared to HER2 0. One hundred and sixty-nine matched DM cases excluding bone metastasis were identified (range = one to seven metastases per IBC). The most common sites of metastases were liver (50 of 169, 30%), lung (36 of 169; 21%), distant lymph node (26 of 169, 15%); 138 DM cases (82%) were previously classified as 'HER2-negative', and 62 (37%) were reclassified as HER2-low. Like HER2-low primaries, HER2-low metastases were frequently ER-positive (52 of 62; 84%) (P = 0.02). Brain metastases were more frequently HER2-positive (five of 32; 16%) (P = 0.04). Comparing HER2 status in matched primaries and DM, HER2 status was discordant in 62 cases (37%). Most changes occurred from HER2-low to HER2 0 (33 of 169, 20%), HER2 0 to HER2-low (17 of 169, 10%) and HER2-low to positive (10 of 169, 6%). All HER2-low to HER2 0 changes were HER2 1+ to 0. In 30 patients with multiple DM sites (47 cases), HER2 status among different DM samples was discordant in 16 patients (53%), mainly from HER2-low to HER2 0 (16 of 47, 34%)., Conclusion: A significant proportion of previous 'HER2-negative' primaries and DM cases were reclassified as HER2-low. Discordant HER2 status between IBC primary and metastasis and between different DM sites demonstrated tumour heterogeneity and highlights the need for HER2 retesting in distant metastasis., (© 2024 John Wiley & Sons Ltd.)

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare aggressive type of renal cell carcinoma. The significant morphologic overlap with other types of renal neoplasia and the limited availability of FH and 2-succinylcholine immunostains for diagnostic use outside large referral centers have created numerous diagnostic pitfalls. As FH-deficient RCC can be associated with hereditary leiomyomatosis and renal cell cancer syndrome, the importance of an accurate diagnosis goes beyond the prognosis and treatment of an individual patient. We present 2 patients with FH-deficient RCC showing a peculiar pattern of GATA3 immunoexpression restricted to tumor nucleoli. If confirmed in further larger studies, this could provide an additional diagnostic clue for considering the FH-deficient RCC diagnosis, and given the frequent papillary morphology and possible hilar location can lead to the misdiagnosis as high-grade urothelial carcinoma, and is an important diagnostic pitfall to be aware of., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: MYC overexpression is a known phenomenon in breast cancer. This study investigates the correlation of MYC gene copy number amplification and MYC protein overexpression with coexisting genetic abnormalities and associated clinicopathologic features in breast cancer patients., Methods: The study analyzed data from 81 patients with localized or metastatic breast cancers using targeted next-generation sequencing and MYC immunohistochemical studies, along with pathological and clinical data., Results: Applying the criteria of MYC /chromosome 8 ratio ≥5, MYC copy number amplified tumors (n = 11, 14%) were associated with invasive ductal carcinoma (91% vs 68%, P  = .048), poorly differentiated (grade 3, 64% vs 30%, P  = .032), mitotically active (Nottingham mitotic score 3, 71% vs 20%, P  = .004), estrogen receptor (ER)-negative (45% vs 12%, P  = .008), and triple-negative (56% vs 12%, P  = .013) compared to MYC non-amplified tumors. Among MYC -amplified breast cancer patients, those with triple-negative status showed significantly shorter disease-free survival time than non-triple negative MYC -amplified patients (median survival month: 25.5 vs 127.6, P  = .049). MYC amplification is significantly associated with TP53 mutation ( P  = .007). The majority (10 of 11; 91%) of MYC -amplified tumors showed positive c-MYC immunostaining., Conclusion: Breast cancers with MYC copy number amplication display distinct clinicopathologic characteristics indicative of more aggressive behavior., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.