Pathobiology最新文献

Introduction: The corded and hyalinized variant of endometrioid adenocarcinoma (CHEC) is a biphasic tumor composed of cords of epithelioid and/or spindle cells (CoES) within hyalinized or chondroid stroma, which is often misdiagnosed as carcinosarcoma. CHEC predominantly occurs in younger women, and it has a favorable clinical outcome. Thus, many patients wish to preserve their fertility and undergo conservative treatment. This study investigated a selective loss of progesterone receptor (PR) in the CoES component and reported clinical, histopathological, and immunohistochemical features of CHEC.

Methods: A total six patients with CHEC between 2004 and 2021 were searched. We performed immunohistochemistry for estrogen receptor (ER), PR, β-catenin, E-cadherin, cytokeratin, p53, and Ki-67.

Results: The patients were 21 to 40 years old. All of the tumors were FIGO grade 1 endometrioid adenocarcinoma (EAC) intermingled with CoES component. Notably, PR expression was completely lost in the CoES component in contrast to the EAC component, with a significantly different expression pattern of cytokeratin, ER, β-catenin, and E-cadherin from the areas of typical EAC. Four of the six patients initially received exogenous progestin treatment, and two of them ultimately had a hysterectomy after progestin treatment. All four patients treated with progestin had persistent tumors at the last follow-up curettage or hysterectomy.

Conclusion: Considering the usual high rate of complete remission with progestin treatment in patients with EAC, the high rate of persistent tumors in our case series suggests that CHEC may be intrinsically resistant to progestin treatment due to the lack of expression of PR in the CoES component.

Background: The subependymal giant cell astrocytoma (SEGA) predominantly occurs in patients with tuberous sclerosis. Here, we present an unusual aggressive transformation of SEGA-imitating fibrous meningioma in a child carrying a germline CHEK2 mutation Methods: This case study was conducted at a tertiary pediatric oncology center in accordance with current diagnostic and therapeutic standards. Tumor classification followed WHO CNS5 criteria and was complemented by genome-wide DNA methylation profiling. Comprehensive molecular workup included germline and somatic whole-exome sequencing, copy-number analysis, and RNA-sequencing; Results: An 8.5-year-old girl presented with an intraventricular tumor initially diagnosed as SEGA based on imaging and partial resection histology. Treatment with an mTOR inhibitor led to four years of stability before rapid progression and death due to postoperative brain edema. Re-examination of both specimens revealed transformation into an aggressive anaplastic meningioma, while the initial lesion was reclassified as fibrous meningioma. Whole-exome and microarray analyses excluded germline TSC1/TSC2 defects but identified a pathogenic germline CHEK2 variant (c.1466del, p.Asn489ThrfsTer23). Somatic alterations involving NF1, and TP53 were found in the primary tumor.

Conclusions: Constitutional CHEK2 mutations combined with somatic NF1 defect may have promoted the malignant progression of SEGA-imitating fibrous meningioma and its favorable initial response to mTOR inhibitors.

Background: Renal cell carcinoma (RCC) is a heterogeneous disease, with the last World Health Organization (WHO) classification introducing several novel entities, among which the molecularly defined RCCs. This growing complexity highlights the need for integration of morphology, immunohistochemistry (IHC) and molecular techniques, ensuring accurate classification and reducing the "RCC not otherwise specified (NOS) category".

Summary: Molecular assays such as next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) are increasingly necessary for diagnosing molecularly defined RCCs. IHC remains fundamental for diagnosing both "old" and newly defined RCCs, representing a surrogate for molecular alterations such as fumarate-hydratase (FH) and succinate-dehydrogenase (SDH) deficiency, anaplastic-lymphoma kinase (ALK) rearrangements, SMARCB1 loss, and TFE3 rearrangements. However, entities like ELOC-mutated RCC require molecular testing for diagnosis. Liquid biopsy offers a further diagnostic tool. Circulating microRNAs can support diagnosis, classification, and monitoring. Furthermore, circulating tumor DNA (ctDNA) methylation analyses and circulating tumor cells (CTCs) offer promising and minimally invasive tools for stratification, though their clinical use is still evolving.

Key messages: A precise diagnosis integrating histopathology, IHC, and molecular testing is critical for guiding management, identifying hereditary syndromes, and implementing personalized tumor biology-based therapies. With evolving molecular diagnostic and circulating biomarkers, careful clinical integration is needed to optimize outcomes and treatment.

Background: In cancers, key prognostic determinants such as clinical stage and mutational load are well recognized. However, mucinous adenocarcinomas (MACs) display distinct biological behavior, as a large proportion of their tumor volume consists of extracellular mucin, predominantly the MUC2 protein, rather than neoplastic cells. MUC2 provides a protective barrier for cancer cells against external factors, including chemotherapeutic agents and cytotoxic lymphocytes, while its anti-inflammatory and tumor-suppressive properties paradoxically support tumor persistence and immune evasion.

Summary: Excessive mucin secretion and its viscoelastic properties facilitate rapid local expansion and dissemination into adjacent tissues. These effects are particularly significant in organs that open into body cavities, such as the colon and appendix, whereas they are less pronounced in confined organs such as the breast. In ductal organs, overexpression of MUC2 may promote early invasion through pressure-induced disruption of ductal structures.

Key messages: Consequently, in MACs, tumor location and organ architecture, alongside clinical stage and mutational profile, are critical determinants of biological behavior. Accurate differential diagnosis and therapeutic approaches should address both organ-specific pathways and MUC2-related mechanisms, including its structural, anti-inflammatory, and tumor-suppressive functions. MUC2-targeted therapies may thus represent a promising adjunct to conventional, organ-based treatment strategies.

Introduction: High inter- and intraobserver variability is acknowledged in Negative for Intraepithelial Lesion or Malignancy (NILM), Atypical Squamous Cells of Undetermined Significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) diagnostic categories in cervical cytology. As digital cytology (DC) has emerged, whole-slide images (WSI) have been compared to conventional light microscopy (LM) to evaluate its feasibility in routine practice.

Methods: Six cytopathologists evaluated 20 liquid-based cervical samples diagnosed as ASC-US, LSIL or NILM with known hrHPV status, both by conventional LM and WSI, equalling 240 evaluations. Interobserver agreement was measured using Fleiss's Kappa, Kendall´s coefficient and interclass correlation (ICC).

Results: Most of the samples (93.75%) were assigned to the same original range of categories: NILM 5 (25%), ASC-US 10 (50%) and LSIL 5 (25%). WSI versus LM interobserver agreement varied with Fleiss's Kappa (0.324 versus 0.319), Kendall's W (0.670 versus 0.572) and ICC (0.585 versus 0.414). Interobserver agreement for the ASC-US category was higher in Kendall's W (0.435 for WSI versus 0.329 for LM) and in ICC (0.394 versus 0.118). Fleiss's kappa showed lower interobserver agreement for ASC-US in WSI than LM (0.000 versus 0.039).

Conclusion: This study illustrated that despite overall better agreement in WSI, ASC-US results were less favourable in WSI than LM, according to Fleiss's kappa test, but not other tests.

Introduction: We recently proposed SARIFA (Stroma AReactive Invasion Front Areas), defined as direct tumour-adipocyte interaction, as an H&E-based histopathologic biomarker in gastrointestinal cancers, particularly gastric (GC) and colorectal cancer (CRC). Despite SARIFA's well-validated prognostic value, its mechanistic underpinnings remain unclear. We hypothesized that extracellular matrix remodelling, specifically the plasmin/plasminogen activator system, may contribute to SARIFA formation.

Methods: To test this, we compared the prognostic value of H&E-based SARIFA-status with ELISA-based protein levels of the serine proteases urokinase-type plasminogen activator (uPA, encoded by PLAU) and plasminogen activator inhibitor-1 (PAI-1, encoded by SERPINE1) in CRC. We further examined associations between SARIFA-status and the plasmin/plasminogen activator system as well as downstream metalloproteinases using both protein (ELISA, immunohistochemistry) and bulk gene expression data (TCGA-COAD/READ and TCGA-STAD), as well as spatial gene expression profiling in CRC (n=8) and GC (n=12).

Results: Our findings show that high expression of the plasmin/plasminogen activator system and downstream metalloproteinases correlates with SARIFA-positivity. Digital spatial profiling revealed PLAU upregulation in tumour cells and PLAUR (encoding uPAR) upregulation in adjacent stromal cells at SARIFAs, suggesting a potential receptor-ligand interaction. Notably, SARIFA-positive tumours showed significantly higher numbers of tumour buds.

Conclusion: These results provide new insights into the biological basis of SARIFAs and suggest therapeutic vulnerabilities related to the plasmin/plasminogen activator system.

Introduction: REV7 functions in various biological processes, including the DNA damage response. REV7 expression has been linked to the prognosis and chemoresistance in several human cancers. This study investigated the significance of REV7 in gallbladder adenocarcinoma (GBAC).

Methods: REV7 expression was examined immunohistochemically in 77 resected GBAC specimens, and its association with clinicopathological features was analyzed. REV7-depleted GBAC cell lines were established, and the biological effects of REV7 depletion were evaluated.

Results: High REV7 expression in GBAC tissues correlated with increased cell proliferation, as assessed by Ki-67 labeling indices (p < 0.001), and was associated with a trend toward shorter overall survival (p = 0.070) and significantly shorter post-progression survival (p = 0.035). REV7-knockout and REV7-knockdown cell lines derived from NOZ and G415 GBAC cells (NOZ-KO and G415-KD, respectively) showed reduced proliferation and increased sensitivity to cisplatin, however, REV7 depletion did not affect cell migration and invasion. Reintroduction of REV7 into NOZ-KO cells restores chemoresistance. Furthermore, RNA sequencing analysis comparing wild-type NOZ and NOZ-KOs revealed that REV7 inactivation downregulates genes involved in the DNA damage response.

Conclusion: REV7 may contribute to tumor progression and chemoresistance in GBAC and may serve as a prognostic biomarker and molecular target for GBAC management.

Introduction: Around 25% of patients with a biopsy diagnosis of pure ductal carcinoma in situ (DCIS) will be upstaged to invasive breast carcinoma (IBC) after surgery. Because of this upstaging risk, patients with high grade DCIS frequently undergo a sentinel lymph node procedure (SLNP), which can cause surgery-induced morbidity. Presentation with a palpable mass increases the upstaging risk, but histopathological predictors are currently unclear. This PROSPERO-registered systematic review aims to identify which biopsy-based histopathological markers can predict the presence of IBC in the subsequent resection. These results might help to reserve SLNPs for selected high-risk patients, aiming to personalize treatment.

Methods: PubMed, Embase, and Scopus were searched for content using predefined search queries. Three reviewers independently screened the literature in Rayyan by applying predefined criteria and retained 36 reports. Studies including DCIS with micro-invasion were excluded.

Results: This systematic review comprised 18,475 patients. The median cohort size was 267 patients (range: 67-3,780). Most studies were retrospective (33/36). The median upstaging risk was 26% (range: 8-52%). The reports studied twenty-three histopathological and immunohistochemical features. Only seven features were investigated in multiple studies, all yielding contradictory results. For instance, thirty-three studies investigated nuclear grade, but only 18 reports demonstrated a significant association with upstaging, independent from cohort size.

Conclusion: No robust histopathological features can be recommended at present to reliably predict the upstaging risk to IBC after a biopsy diagnosis of pure DCIS. We discuss several hypotheses, aiming to explain these contradictory data. Ideally, large-scale multicentre prospective studies should be organized to answer this unmet clinical need.

Introduction: This study aimed to observe the expression of far upstream element-binding protein 1 (FUBP1) in gastrointestinal stromal tumors (GISTs) and explore its impact on the biological behavior of GIST cells.

Methods: Fifty patients with GIST who underwent surgical resection were selected, and cancer tissues and adjacent normal tissues were gathered. The expression level of FUBP1 and its correlation with clinicopathological data and prognosis in patients with GISTs were assessed. GIST-T1 cell lines in the logarithmic growth phase were transfected with lentiviruses overexpressing FUBP1, small hairpin RNA targeting FUBP1, and their respective negative controls. FUBP1 expression levels in each group, cell biological behavior were tested, and the effect of FUBP1 on tumor growth in vivo were tested.

Results: Compared to adjacent normal tissues, FUBP1 expression level was elevated in GIST cancer tissues and was concerned with tumor size, NIH risk category, and tumor metastasis in patients. Knockdown of FUBP1 inhibited cell malignant behaviors and promoted cell apoptosis, while overexpression of FUBP1 had the opposite effects. FUBP1 facilitated the growth of GIST cells in vivo.

Conclusion: FUBP1 is upregulated in GISTs and facilitates the invasion, migration, and proliferation of GIST cells. This provides a new perspective for understanding the pathogenesis of GIST and lays a foundation for developing potential therapeutic strategies targeting FUBP1.

Introduction: Extrahepatic cholangiocarcinoma (eCCA) is an aggressive malignancy with a poor prognosis. Immune checkpoint inhibitors (ICIs) targeting PD-L1 enhance antitumor immunity, but reliable predictive biomarkers remain unclear. This study investigated tumor-infiltrating immune cells, including T cells and macrophages, as potential biomarkers for ICI efficacy in eCCA.

Methods: A retrospective analysis was conducted on 15 eCCA patients who received durvalumab for recurrent or unresectable disease after surgery. Immunohistochemical staining assessed PD-L1, HLA-class I/II, CD8, and CD103 expression in resected tumor specimens. ICI response was evaluated using RECIST 1.1 criteria and classified as partial response (PR), stable disease (SD), or progressive disease (PD). Correlations between immune cell infiltration and clinical outcomes were analyzed.

Results: Five patients achieved PR, five SD, and five PD. CD8+ and CD103+ T-cell infiltration within tumor nests was significantly higher in PR and SD groups than in PD (p = 0.032, p = 0.0147). High HLA-class I expression correlated with response, while PD-L1 and HLA-class II showed no significant association. Patients with increased CD8+CD103+ T cells demonstrated better disease control.

Conclusion: Intratumoral CD8+ and CD103+ T cells may serve as predictive biomarkers for ICI efficacy in eCCA, highlighting tissue-resident immune cells as therapeutic targets.