Pathobiology最新文献

Introduction: Although urothelial papilloma (UP) is an indolent papillary neoplasm that can mimic the morphology of low-grade papillary urothelial carcinoma (PUC), there is no immunomarker to differentiate reliably these two entities. In addition, the molecular characteristics of UP are not fully understood.

Methods: We conducted an in-depth proteomic analysis of papillary urothelial lesions (n = 31), including UP and PUC along with normal urothelium. Protein markers distinguishing UP and PUC were selected with machine learning analysis, followed by internal and external validation using immunohistochemistry.

Results: In the proteomic analysis, UP and PUC showed overlapping proteomic profiles. We identified EHD4 and KRT18 as candidate diagnostic biomarkers of UP. Through immunohistochemical validation in two independent cohorts (n = 120), KRT18 was suggested as a novel UP diagnostic marker, able to differentiate UP from low-grade PUC. We also found that 3.5% of patients with UP developed urothelial carcinoma in subsequent resections, supporting the malignant potential of UP. KRT18 downregulation was significantly associated with UPs subsequently progressing to urothelial carcinoma, following their initial diagnosis.

Conclusion: This is the first study that successfully revealed UPs comprehensive proteomic landscape, while it also identified KRT18 as a potential diagnostic biomarker of UP.

Introduction: Targeted therapy with antibody-drug conjugates (ADCs) has achieved promising results in the treatment of different solid tumors. Sacituzumab-Govitecan (SG), a humanized anti-Trop2 monoclonal antibody linked with the cytotoxic topoisomerase I inhibitor SN-38, has been approved for the treatment of metastatic triple-negative breast cancer. The treatment approach with SG requires the expression of Trop2 within the tumor cells. Trop2 is overexpressed in many other cancer types, suggesting a broader therapeutic application beyond breast cancer to these ADCs. We explore expression of Trop2 vulvar squamous cell carcinomas (VSCCs) and how this relates to molecular classification.

Methods: Immunohistochemical Trop2 expression was evaluated on diagnostic biopsies of VSCC using an immunoreactive score. Staining results were compared to the molecular subtype of VSCC.

Results: Fifty-seven cases were included in the study. 63.2% of VSCC were p16-ve/p53abn (HPV-independent (p53abn)) molecular subtype, 29.8% p16+ve/p53wt (HPV-associated) and 1.4% p16-ve/p53wt (HPV-independent (p53wt)) tumors. All diagnostic biopsies (N = 57) showed at least a weak Trop2 expression. Moderate and strong expression was seen in 15/17 (88.2%) of the p16-ve/p53abn, 32/36 (88.8%) of the p16+ve/p53wt and 3/4 (75%) of the p16-ve/p53wt molecular subtype. Expression was significantly higher, as assessed by H score, in the HPV-associated VSCC, compared to HPV-independent.

Conclusion: VSCCs have high expression of Trop2 and represents a promising therapeutic target. Clinical trials exploring Trop2-directed ADCs such as SG are warranted in this rare cancer type, including in the prognostically poor HPV-independent VSCC with a TP53-mutation (p16-ve/p53abn molecular subtype). The targetable molecule, Trop2, can be easily assessed by immunohistochemistry on diagnostic biopsies from VSCC.

Introduction: Papillary renal neoplasm with reverse polarity (PRNRP) is an emerging entity characterized by distinctive histomorphological and molecular features. Often identified incidentally in imaging studies, its accurate diagnosis is essential considering its favorable prognosis. However, its cytological features need further characterization, since only one single publication with 2 cases diagnosed in fine-needle aspiration biopsies have been reported to date.

Case presentation: We report the case of a 70-year-old man recently diagnosed with primary lung adenocarcinoma. Fine-needle aspiration biopsy of a 15-mm nodule in the left kidney revealed cytological features consistent with a papillary neoplasm with eosinophilic features. Immunocytochemistry showed positivity for PAX-8, CK7, and GATA3 and negativity for TTF-1. Next-generation sequencing (NGS) identified a KRAS G12V mutation. Altogether, these findings enabled the diagnosis of PRNRP. The patient underwent conservative management of the renal tumor, which did not recur at 8 months since diagnosis.

Conclusion: PRNRP is a recently described tumor which can be managed conservatively. We describe the third case of PRNRP diagnosed on fine-needle aspiration biopsy, which enabled several diagnostic studies, including immunocytochemistry and NGS confirmation. With this case, we highlight the increasing role of fine-needle aspiration biopsy in the clinical management of a subset of patients with small renal masses.

Introduction: Upregulated microtubule-associated serine/threonine kinase like (MASTL), a cell cycle kinase required for a progression through mitosis, expression has been associated to poor prognosis. This study aimed to investigate the clinical relevance of MASTL expression in oral squamous cell carcinoma (OSCC) and a possible mechanistic link with epithelial-mesenchymal transition (EMT).

Methods: Immunohistochemical analysis of MASTL, E-cadherin, vimentin, and Smad7 was performed in paraffin-embedded tissue specimens from 148 OSCC patients.

Results: Nuclear MASTL expression was detected in 115 (77.7%) OSCC specimens. High MASTL expression was significantly associated with the male gender, smoking habit, T stage, early clinical stage, and absence of vascular invasion. MASTL expression was inversely correlated with Smad7, whereas no association was observed with E-cadherin and vimentin. Patients harboring tumors with low MASTL expression exhibited a poorer overall survival. Smad7 expression was significantly related to reduced disease-specific and overall survival. High levels of MASTL expression were associated with better prognosis in T3 patients, N0 cases, and patients treated by surgery combined with radiotherapy and chemotherapy.

Conclusion: The present study uncovers MASTL as a good prognostic factor in OSCC and a potential link with EMT via Smad7.

Introduction: Artificial intelligence image recognition has applications in clinical practice. The purpose of this study was to develop an automated image classification model for lung cancer cytology using a deep learning convolutional neural network (DCNN).

Methods: Liquid-based cytology samples from 8 normal parenchymal (N), 22 adenocarcinoma (ADC), and 15 squamous cell carcinoma (SQCC) surgical specimens were prepared, and 45 Papanicolaou-stained slides were scanned using whole-slide imaging. The final dataset of 9,141 patches consisted of 2,737 N, 4,756 ADC, and 1,648 SQCC samples. Densenet-121 was used as the DCNN to classify N versus malignant (ADC+SQCC) and ADC versus SQCC images. AdamW optimizer and 5-fold cross-validation were used in the training.

Results: For malignancy prediction, the sensitivity, specificity, and accuracy were 0.97, 0.85, and 0.94, respectively, in the patch-level classification, and 0.92, 0.88, and 0.91, respectively, in the case-level classification. For SQCC prediction, the sensitivity, specificity, and accuracy were 0.86, 0.91, and 0.90, respectively, in the patch-level classification and 0.73, 0.82, and 0.78, respectively, in the case-level classification.

Conclusion: The DCNN model performed excellently in predicting malignancy and histological types of lung cancer. This model may be useful for predicting cytopathological diagnosis in clinical situations by reinforcing training.

Introduction: Transdifferentiation of multiple myeloma (MM) into histiocytic sarcoma (HS) is exceptionally rare. We report a unique case, confirming this phenomenon through cytogenetics and molecular analyses. Case Presentation: A 46-year-old woman with high-risk light chain MM developed extramedullary disease despite multiple lines of therapy. Biopsies revealed atypical histiocytic proliferation consistent with HS. Shared immunoglobulin gene rearrangements, cytogenetic alterations, and gene mutations, including a rare BRAF L485F, confirmed clonal relatedness between the two neoplasms. IGH::MAF translocation specific to MM and IGVH somatic hypermutation in HS suggests divergent evolution from a putative germinal center B-cell (GCB) precursor. Conclusions: This case highlights lineage plasticity of MM to undergo HS transdifferentiation, potentially mediated through a mutated common GCB precursor antecedent to the plasma cell stage, and the subsequent development of HS and MM through acquisition of additional genetic events. Recognition of this exceptional phenomenon and understanding its underlying mechanism have implications for diagnosis, classification, and personalized treatment.

Introduction: A recent multiregional whole-exome sequencing of 48 tumour samples from 9 gastric adenocarcinomas discovered PCLO mutations in 23 (47.9%) tumour samples. Based on that unexpected high prevalence of PCLO mutations, we hypothesized a tumour biological significance of PCLO in gastric cancer (GC).

Methods: Tumour samples (whole tissue sections) obtained from 466 patients resected for therapy-naive GC were stained with an anti-PCLO antibody. The histoscore for tumour cells and the presence of immunostaining of stromal cells and tumour vessels was documented for each case. An algorithm for PCLO immunopositivity was formed and correlated with clinicopathological patient characteristics.

Results: 175 GCs were classified as PCLO positive within tumour cells, and 291 as negative. Stromal cells were positive for PCLO in 106 cases and tumour vessels in 84. PCLO-positive GCs more often showed an intestinal phenotype, a lower T category and were more commonly associated with Helicobacter pylori infection. A separate analysis of PCLO expression in intestinal and diffuse type GCs, respectively, showed no significant correlations. Patients with PCLO negative/low tumour cells showed a shortened overall (14.0 ± 1.4 vs. 16.0 ± 1.8 months) and tumour-specific survival (15.0 ± 1.6 months vs. 17.9 ± 3.6). Comparison of PCLOs genotype with its phenotype in 48 tumour samples obtained from nine cases showed no direct correlations with missense mutations.

Conclusion: Our data provide evidence that PCLO is differentially expressed in GC and might delay tumour progression.

Introduction: Undifferentiated small round-cell sarcomas with BCL6 corepressor (BCOR) alterations, such as an internal tandem duplication (ITD) within exon 15, are typically described as a pediatric group of Ewing-like small round-cell sarcomas.

Case presentation: In contrast to this notion, we report the case of a 71-year-old woman with a nasosinusal sarcoma featuring a BCOR ITD. To the best of our knowledge, this presence had not been previously documented in a sarcoma of the nasal and sinus cavities in an elderly patient. The identified duplication shares a similar minimal critical region as described in clear-cell sarcomas of the kidney in children. This alteration, located within the PCGF1 binding domain, is believed to disrupt the activity of PRC1.1.

Conclusion: This case underscores the need for in-depth research into the molecular biology of these rare tumors and explores potential alternative treatment options. The patient achieved remission after two cycles of doxorubicin and cyclophosphamide chemotherapy, highlighting the promise of potential therapeutic options for BCOR ITD sarcomas.

Introduction: ATF4, a stress-responsive transcription factor that upregulates adaptive genes, is a potential prognostic marker and modulator of glutamine metabolism in breast cancer. However, its exact role remains to be elucidated.

Methods: ATF4 expression was evaluated at genomic and transcriptomic levels using METABRIC (n = 1,980), GeneMiner (n = 4,712), and KM-Plotter datasets. Proteomic expression was assessed via immunohistochemistry (n = 2,225) in the Nottingham Primary Breast Cancer Series. ATF4 genomic copy number (CN) variation and mRNA/protein in association with clinicopathological parameters, amino acid transporters (AATs), and patient outcome were investigated.

Results: Genomic, transcriptomic, and proteomic overexpression of ATF4 was associated with more aggressive ER-negative tumours. ATF4 mRNA and protein expression were significantly associated with increased expression of glutamine related AATs including SLC1A5 (p < 0.01) and SLC7A11 (p < 0.02). High ATF4 and SLC1A5 protein expression was significantly associated with shorter breast cancer-specific survival (p < 0.01), especially in ER+ tumours (p < 0.01), while high ATF4 and SLC7A11 protein expression was associated with shorter survival (p < 0.01).

Conclusion: These findings suggest a complex interplay between ATF4 and AATs in breast cancer biology and underscore the potential role for ATF4 as a prognostic marker in ER+ breast cancer, offering a unique opportunity for risk stratification and personalized treatment strategies.

Introduction: Many mouse models for autoimmune diseases also have lesions in non-target organs, which may make it difficult to determine whether the target organ lesion is primary or secondary. Hyposalivation has conventionally been studied using genetically modified mouse models for Sjogren's syndrome as well as spontaneous autoimmune mice with systemic lesions, none of which has salivary gland-specific injury.

Methods: In this study, we established a salivary gland-specific injury mouse model using the toxin receptor-mediated cell knockout (TRECK) system by gene modification with the transgene composed of the 5' untranslated region of human salivary mucin gene MUC7 (highly expressed specifically in human salivary gland) inserted at the upstream of hHB-EGF (diphtheria toxin receptor) in the TRECK vector.

Results: In this transgenic mouse model, we confirmed salivary gland-specific expression of hHB-EGF gene, and hyposalivation after treatment with diphtheria toxin. Histological assessment of the salivary gland from these mice showed granular convoluted tubule epithelial cells destruction at the same position as a positivity in TUNEL assay.

Conclusion: This transgenic mouse model may become a useful tool for elucidating the mechanisms involved in hyposalivation and for developing pharmaceuticals and tissue regenerative medical products for this condition.