Journal of Pathology Clinical Research最新文献

In alignment with the latest WHO classification system, which underscores the integration of molecular alterations in glioma diagnosis and grading, this study investigates the prognostic significance of MYCN amplification in IDH-mutant gliomas, a relationship that remains poorly characterized despite its established association with adverse outcomes in various malignancies. A cohort of 190 patients with IDH-mutant gliomas was analyzed for clinical and pathological characteristics. MYCN amplification status was determined using fluorescence in situ hybridization (FISH) with an MYCN-specific probe. Survival outcomes were assessed via Kaplan–Meier analysis, while independent prognostic factors were identified through multivariable Cox proportional hazards regression models. Tumor morphology was systematically evaluated in cases with MYCN amplification. MYCN amplification was identified in 28 of 190 cases (14.7%), demonstrating a significant correlation with advanced tumor grade and elevated Ki-67 proliferation indices (p < 0.05). Patients harboring MYCN amplification exhibited markedly reduced overall survival compared to non-amplified cases (112.13 ± 6.58 versus 91.14 ± 14.96 months, p = 0.001), with this association being particularly pronounced in lower-grade (WHO grades 2 and 3) IDH-mutant gliomas (122.12 ± 6.81 versus 47.76 ± 6.58 months, p < 0.001). To address limitations in current grading systems, we propose a refined classification approach that upgrades lower-grade IDH-mutant astrocytomas with MYCN amplification to high-grade status. This MYCN-based grading system demonstrated significant prognostic stratification (112.84 ± 10.40 versus 77.65 ± 11.15 months, p < 0.001). Morphological analysis revealed that 50% of MYCN-amplified cases (14/28) exhibited distinct epithelioid features, characterized by abundant eosinophilic cytoplasm and nuclear displacement. In conclusion, MYCN amplification emerges as a critical prognostic indicator in IDH-mutant gliomas, particularly in lower-grade tumors, and is frequently associated with unique epithelioid histological features. These findings highlight the necessity of incorporating MYCN amplification status into grading paradigms for IDH-mutant gliomas to enhance prognostic accuracy and inform clinical decision-making.

PD-L1 expression for the prediction of response to immune-checkpoint blockade remains the most broadly utilised clinically validated biomarker in a range of tumour types. In this study, we aimed to assess, in a prospectively collected matched cohort, the impact of sampling technique and both formalin and alcohol fixation on PD-L1 expression and heterogeneity in non-small cell lung carcinoma (NSCLC). Patients undergoing surgical resection for NSCLC were consented. Surgical specimens were received directly from theatre and sampled fresh to produce two sets of core biopsies, two fine-needle aspirates (FNAs) and two whole-block tissue sections from each specimen. A matched biopsy, FNA, and whole-block were placed into formalin or an alcohol-based fixative (Cytolyt™) prior to PD-L1 immunohistochemistry assessment. A total of 114 specimens from 57 patients were included. All whole-block cases (100%), 92% of core biopsies, and 88% of FNAs were adequate for PD-L1 expression analysis. Fixation had no significant impact on adequacy, but cytology specimens fixed in alcohol showed a significant reduction in PD-L1 expression, with 25% of cases placed into different clinically relevant categories of PD-L1 expression. PD-L1 expression by immunochemistry is an exemplar of the challenges of utilising a heterogeneously expressed protein-based predictive biomarker. Regardless of sampling technique, a good quality biopsy or FNA is likely to give a statistically representative PD-L1 expression, although expression ranges close to clinically relevant cut-offs of 1% and 50% remain a source of potential discordance.

Despite the use of targeted drugs for human epidermal growth factor receptor type 2 (HER2)-positive salivary duct carcinoma (SDC) treatment, the overall prognosis for SDC remains poor. In this study, we aimed to investigate whether the glycocalyx of SDC cells serves as a potential cell surface marker. To understand the complex structure of the glycocalyx of salivary gland tumors, we used a lectin with glycan-specific binding properties. Lectin staining was performed for five types of common salivary gland tumors. We determined the expression of the transmembrane glycoprotein mucin 1 with Tn antigen (GalNAc), Tn-MUC1, using 20 clinical SDC specimens. Vicia villosa lectin (VVL) was not stained in the vascular endothelium but specifically stained in the SDC tumor cells. GalNAc, to which VVL binds, formed Tn-MUC1 via glycosylation with N-acetylgalactosaminyltransferases (GALNTs). GALNT7 was highly expressed in SDC. Analysis of clinical SDC specimens revealed that Tn-MUC1 was also positive in the SDC tumor cells, suggesting its potential as a cell surface target for SDC.

Although several prognostic models have been developed for clear cell renal cell carcinoma (ccRCC), these are still suboptimal and there is a need to identify additional prognostic biomarkers. Previously, we developed a prognostic model containing five DNA methylation markers (NEFH, NEURL, GATA5, GREM1, and LAD1) and clinicopathological characteristics based on the TNM 3rd edition and Fuhrman grading system. Here, we evaluated the effect of the recent ISUP/ 2022 WHO revisions on our previous prognostic model by incorporating the new ISUP/WHO standards, TNM 8th edition, and several novel prognostic factors (necrosis, lymphovascular invasion, sarcomatoid and rhabdoid features). Data from 308 ccRCC cases from the Netherlands Cohort Study were included for this study. Clinicopathological factors, novel prognostic factors, and the five methylation markers were analyzed for their individual and combined prognostic value using Kaplan–Meier analyses and Cox proportional hazard models. To compare models, the Akaike information criterion (AIC) and c-statistic were used. All evaluated factors were statistically significantly associated with cause-specific survival. The clinical model using the ISUP and TNM 8th edition performed similarly when compared to the Fuhrman/TNM 3rd edition model (AIC 592, c-statistic 0.63 and AIC 595, c-statistic 0.62, respectively). After addition of the five DNA methylation markers to the ISUP/TNM 8th model, this model was slightly improved (AIC 584, c-statistic 0.70). The addition of necrosis and lymphovascular invasion (LVI) did not further improve these results (AIC 586, c-statistic 0.71 and AIC 588, c-statistic 0.71, respectively). Despite the individual prognostic significance of necrosis, LVI, the presence of sarcomatoid and/or rhabdoid differentiation, ISUP, and TNM 8th edition, these factors did not influence the performance of our prognostic model. The model including the five DNA methylation markers, age at diagnosis, sex, TNM stage (8th edition), ISUP grading, and tumor size was the best performing model, thereby highlighting the potential importance of molecular markers.

In this study, we explored the genomic underpinnings of synchronous endometrial and ovarian/fallopian tube carcinoma (SEOC) and synchronous cervical and ovarian/fallopian tube carcinoma (SCOC), focusing on their clonal relationships to discern whether these malignancies represent dual primary tumors (DPTs) or have metastatic origins. We established a cohort comprising 54 SEOC patients and 7 SCOC patients. After selection, 17 patients (12 SEOC and 5 SCOC) underwent comprehensive analysis via whole-exome sequencing. The study encompassed a diverse array of histological subtypes, including high-grade serous carcinoma (HGSC) or uterine serous carcinoma (USC), endometrioid carcinoma exhibiting papillary/mucinous features, dedifferentiated carcinoma (DC), clear cell carcinoma (CCC), HPV-associated cervical squamous cell carcinoma, and HPV-independent cervical adenocarcinoma. Analysis revealed that 58.3% (7 of 12) of SEOC cases and all SCOC cases demonstrated shared mutations. This suggests a clonal relationship and supports a metastatic origin for these tumors. Notably, metastatic SEOC instances included co-occurrences of USC and HGSC in both the endometrium and the ovaries/fallopian tubes, endometrial and ovarian CCC, concurrent endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) with mucinous metaplasia, as well as cases of endometrial DC with ovarian CCC, and both EEC and ovarian DC. Among the SEOC cases classified as metastatic, patients with high-grade tumors and advanced ovarian stage succumbed to their disease, whereas the remainder survived without relapse. In the SCOC cohort, one patient died from the disease. The favorable survival outcomes across varied histotypes suggest that a stage upgrade may not be warranted. Given the favorable clinical outcomes observed, the term ‘trans-tubal spread’ may be more appropriate than ‘metastasis’ in this context to prevent potential overtreatment. Directionality analysis revealed a bidirectional pattern of trans-tubal spread between the uterus/cervix and ovary/fallopian tubes. The presence of dedifferentiated carcinoma confirms the manifestation of dedifferentiation during spread. These findings lend support to the trans-tubal implantation hypothesis and contribute novel insights into the molecular mechanisms underlying tumor dissemination in SEOC and SCOC.

The biology of tumor spread to bone is poorly understood, not least in classic Hodgkin lymphoma (cHL). We used gene expression profiling and immunohistochemistry to characterize the nodal tumor microenvironment of cHL cases with and without skeletal involvement at diagnosis. Gene expression profiling of 66 pretreatment lymphoma samples revealed that lymph nodes from patients with skeletal cHL (s-cHL) exhibited a higher abundance of cells expressing macrophage markers, particularly M2-like markers, than nodal-only cHL (n-cHL). These markers included CD163, MRC1 (CD206), MARCO, and SIGLEC1. Additionally, there was a notable downregulation of genes encoding B-cell-associated markers such as MS4A1 (CD20), CD19, PAX5, and CD79A/B. We further evaluated the protein expression of macrophage markers (CD68, CD163, and CD206) and the B-cell marker CD20 in 193 pretreatment lymphoma samples using immunohistochemistry. Our analysis revealed significantly higher expression levels of all three macrophage markers in s-cHL samples compared to n-cHL samples (p < 0.001). Conversely, the expression level of CD20 was significantly lower in s-cHL compared with n-cHL (p < 0.001). All three macrophage markers correlated positively with Ann Arbor stage, indicating their potential involvement in the dissemination of cHL in general. Our findings suggest a potential role for tumor-associated macrophages in the dissemination of cHL to bone.

It has not been determined which descriptor spread through air spaces (STAS) should be incorporated into the context of the ninth Tumor, Node and Metastasis (TNM) staging system: the T or the uncertain resection [R(un)] category. A multicenter retrospective cohort of 807 patients with pathological stage I lung adenocarcinoma was included in this study to assess the feasibility of incorporating STAS into the T descriptor or the R(un) category by analyzing recurrence-free survival (RFS) and overall survival (OS). Decision curve analysis (DCA) was performed to evaluate the standardized net benefit of the proposed T (nT) and that of the proposed residual tumor classification (nR) versus the current staging systems. Log-rank tests indicated that patients with pT1/STAS-positive lung adenocarcinoma had similar RFS and OS to patients with pT2a disease irrespective of R status. Regarding STAS as an indicator for upgrading R0 to R(un), comparable survival was observed between pT1-2a/STAS-positive patients undergoing R0 segmentectomy and pT1-2a patients undergoing R(un) segmentectomy. We further assessed the effects of the combination of STAS with either T or R category on survival in a validation cohort. Subgroup analyses stratified by surgical procedures further identified the consistency of the nT category in discriminating RFS and OS. However, the separation of nR0 and nR(un) disease in pT2a tumors treated by lobectomy or segmentectomy was not sufficiently distinguished. DCA further corroborated a greater predictive capability of nT versus the current T category. In conclusion, STAS might be preferentially considered as an indicator for upgrading pT1 disease into pT2a in the future TNM staging system.

Germline BRCA1/2 pathogenic variant carriers have an increased risk for high-grade serous carcinoma (HGSC) and are therefore advised to have risk-reducing salpingo-oophorectomy around the age of 40. However, a risk of 0.9% to develop peritoneal HGSC remains in these women, which increases to 27.5% when serous tubal intraepithelial carcinoma (STIC) is detected. The pathophysiological mechanism that leads to the development of peritoneal HGSC after salpingectomy or salpingo-oophorectomy is still largely unknown. In this systematic review, we aim to provide insights into the pathogenic pathways of peritoneal HGSC after salpingectomy or salpingo-oophorectomy. Therefore, we performed a systematic search for studies investigating pathophysiological mechanisms related to peritoneal HGSC in PubMed and EMBASE. A total of 49 articles were included in this study. Most evidence was found on mechanisms following a tubal origin, such as clonality between STIC and peritoneal HGSC as well as molecular similarities between fallopian tube (FT) epithelium and peritoneal HGSC. Additionally, FT epithelium was shown to adhere to the ovary and could therefore stay present after isolated salpingectomy. There might be a role for the endometrium, as it was observed that serous endometrial intraepithelial carcinoma (SEIC) has a clonal relationship with extra-uterine HGSC. The role of the ovary seems limited, although some mouse models show a role for follicular fluid in the dissemination of malignant cells on the peritoneum. In conclusion, different mechanisms might be responsible for peritoneal HGSC development after bilateral salpingectomy or salpingo-oophorectomy. Most available evidence supports the dissemination of precursor cells originating in the FT. Also, a possible role for the endometrium was found. An ovarian origin seems less likely; however, execution of oophorectomy does not seem obsolete in clinical practice as follicular fluid might promote dissemination and residual tubal tissue can be present on the ovary after salpingectomy.

Squamous cell carcinoma of the oral tongue (SCCOT) represents an aggressive malignancy characterized by high metastatic potential and significant heterogeneity in its tumor microenvironment. The tumor-stroma ratio (TSR) has emerged as a prognostic biomarker, with higher stromal content frequently correlating with worse survival outcomes. Traditional approaches using the standard 50% TSR cutoff may not be optimal for SCCOT, and visual TSR estimation introduces variability during TSR region annotation. This study aimed to develop and validate a dedicated TSR estimation model for SCCOT by incorporating representative TSR regions from the invasive tumor front of whole slide images and to determine the optimal TSR threshold for prognostic stratification. Using hematoxylin and eosin-stained images from The Cancer Genome Atlas as a discovery cohort and whole slide images from Norrland's University Hospital Umea, Sweden (NUS) as a validation cohort, we developed a computational model to estimate TSR. The model demonstrated a high correlation with pathologist-based TSR estimation in both discovery (R = 0.848, p < 0.01) and validation (R = 0.783, p < 0.01) cohorts. The optimal 55% cutoff identified by the model improved prognostic accuracy over the traditional 50% threshold, with patients having high stroma within the tumor invasive front showing worse overall (log-rank p = 0.006) and disease-specific (log-rank p = 0.016) survival. Our computational TSR model for SCCOT demonstrates that automated TSR estimation enhances prognostic accuracy at an optimal cutoff of 55%, contributing to more precise risk stratification and potentially enabling personalized treatment strategies in SCCOT management.

Hyaluronan (HA), a large extracellular matrix glycosaminoglycan, is associated with malignant features in several human cancers. The accumulation of HA in renal cell carcinomas (RCC) correlates with unfavorable outcomes, higher tumor grade, and more advanced disease stages. However, the mechanisms responsible for HA buildup in these neoplasms remain unclear, and studies on the expression of hyaluronan-metabolizing and -degrading enzymes are either lacking or conflicting. This study aims to address this knowledge gap. Formalin-fixed paraffin-embedded (FFPE) RCC samples of various histological subtypes from 315 patients were immunohistochemically stained for CD44 (the main receptor of HA), hyaluronan-synthesizing enzymes HAS1–3, and degrading enzymes HYAL1–2. Protein expression levels were correlated with clinicopathological variables and their prognostic significance was evaluated. Additionally, the mRNA expression levels of these proteins were examined using RNA extracted from the same samples and publicly available data from the cancer genome atlas (TCGA). CD44 protein expression was associated with increased tumoral HA content, poor prognosis, higher tumor grade, advanced stage, and sarcomatoid/rhabdoid changes. HYAL1 and HYAL2 protein levels were reduced in HA-positive tumors, and low HYAL2 expression predicted worse prognosis. Elevated HAS2 protein expression was associated with poor differentiation, while low HAS1 protein levels were associated with reduced survival. mRNA levels of CD44 and HYAL2 correlated with their respective protein expression levels, and CD44 mRNA expression was also associated with HA content. In RCC, HA accumulation appears to be primarily driven by decreased degradation. HAS1 and HYAL2 were identified as novel prognostic biomarkers. These findings provide new insights into HA metabolism in RCC and open potential avenues for better understanding and management of these tumors.