Pathobiology最新文献

Introduction: Testicular germ cell tumors (TGCTs) are the most common solid malignancies among young men. Despite good response to cisplatin-based chemotherapy, side effects negatively affect quality of life. Recent development of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors opens opportunity for targeted therapy, but ENPP1 expression in TGCTs has not been characterized. We aimed to assess ENPP1 immunoexpression in a cohort of primary and metastatic TGCTs, and in normal testicular parenchyma, looking into differential immunoexpression patterns among subtypes and clinicopathological correlations.

Methods: Overall, 90 TGCT individual tumor components from 63 patients diagnosed and treated at a comprehensive cancer center were assessed, using immunohistochemistry to ascertain biomarker expression (combined score of stained tumor cells percentage and intensity). In silico analysis of The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) datasets was performed for additional validation.

Results: Significant differences in ENPP1 expression across TGCT subtypes were disclosed. Seminomas and embryonal carcinomas (ECs) showed significantly higher ENPP1 expression compared to other subtypes, the highest levels being found in EC, which was confirmed with in silico analysis of TCGA and HPA. Expression in metastatic samples was overall lower compared to primary TGCTs. ENPP1 was not expressed in germ cells of healthy testicular parenchyma.

Conclusion: We demonstrate that ENPP1 is expressed in TGCTs, mostly EC (a frequently aggressive tumor subtype), followed by seminoma (the most common TGCT subtype), suggesting potential responsiveness to novel ENPP1 inhibitors. Absent expression in germ cells of healthy testicular parenchyma suggest cancer cells specificity and low probability of fertility-related toxicity.

Background: Lung cancer is the leading cause of cancer related death in the USA. A proven risk factor for the development and progression of lung cancer is human immunodeficiency virus (HIV).

Summary: HIV persists within the lung in alveolar macrophages and bronchial epithelial cells, reducing mucociliary function and decreasing epithelial integrity. This persistence yields chronic inflammation by way of matrix metalloproteinases, which causes pulmonary injury. Over time, this progresses to pulmonary disease and allows for the development of superimposed pulmonary infections and chronic inflammatory states. This injury is a risk factor for the development of dysplasia, and chronic pulmonary disease and infections further increase the risk for developing lung cancer. HIV persistence and chronic inflammation also lead to CD8+ T cell exhaustion and alterations to macrophages and dendritic cells that blunt the physiologic antitumor response. As such, HIV infection promotes initial dysplasia and allows for progression on preinvasive lesions to frank malignancy.

Key messages: The purpose of this review is to highlight HIV as an under-appreciated risk factor and summarize the biologic and immunologic role of HIV in lung cancer initiation and progression. Further research regarding risk reduction and surveillance in this population and the potential increased role of immunotherapy is warranted.

Introduction: Metastasis in the axillary lymph nodes (ALNs) occurs in 30-50% of breast cancers (BCs), where residing immune cells play a crucial role in disease progression. Specifically at diagnosis, the immune elements infiltrating the primary tumour are among the best established prognostic factors. However, their prognostic value in the metastatic ALNs (ALNs+) is poorly understood.

Methods: We aimed to retrospectively assess the immune populations of ALNs+ in luminal A (LA) and triple-negative BC (TNBC) patients using immunohistochemistry, to compare it with non-metastatic ALNs (ALNs-), and to determine their relationship with patient outcomes.

Results: We found differences in the immune concentrations of matched ALNs (ALNs- vs. ALNs+) from patients with positive nodal status in either LA or TNBC subtypes. In contrast, compared with LA, the levels of immune cells in ALNs- of the TNBC profile differ much more from ALNs+ than in the LA subtype, regardless of the nodal status. In addition, TNBC patients with higher levels of CD4 and CD8 lymphocytes in ALNs+ have worse cancer-specific survival (CSS) and higher levels of CD83 dendritic cells (DCs) are related to worse CSS and time to progression (TTP). Conversely, LA patients with higher levels of CD21 DC showed better TTP.

Conclusion: Our results showed that ALN immune profiles and their influence on disease evolution vary by molecular BC subtype and nodal status, suggesting that accurate ALN immune profiling at diagnosis could provide new insights into the immune BC landscape. These observations require validation in larger, prospective cohorts before they can be reliably used to inform clinical decision-making.

Introduction: Tumour budding (TB) is an emerging prognostic marker in solid cancers and has recently been endorsed by the IASLC as a component of grading in lung squamous cell carcinoma (LUSC). With the growing adoption of digital pathology, the reproducibility of TB assessment on whole-slide images (WSIs) warrants evaluation.

Methods: We assessed the utility of WSI for TB evaluation in a retrospective cohort of 204 resected LUSC cases. Peritumoral budding (PTB) and intratumoural budding (ITB) were independently scored by two pathologists, applying the International Tumour Budding Consensus Conference (ITBCC) criteria established for colorectal cancer and endorsed by the IASLC for use in LUSC. A total of 816 TB hotspot regions were analysed.

Results: Substantial intraobserver reliability was observed, with strong correlations between absolute bud counts in WSI and conventional light microscopy (CLM; R = 0.845, p < 0.001; R = 0.880, p < 0.001). Interobserver agreement was moderate for both PTB and ITB across platforms (Cohen's κ: CLM 0.582 [PTB], 0.570 [ITB]; WSI 0.593 [PTB], 0.423 [ITB]). Discordance mainly occurred in lower TB categories due to differences in hotspot selection and morphological mimics. When applying the recently proposed IASLC two-tier cutoff (0-9 buds vs. ≥10 buds), interobserver agreement for PTB improved modestly (κ = 0.49 for CLM; κ = 0.53 for WSI), with overall agreement exceeding 93%.

Conclusion: These findings support the feasibility and reproducibility of TB assessment using WSI and highlight its potential for standardizing LUSC TB evaluation in digital pathology workflows. WSI also demonstrated practical advantages, including easier field selection and annotation.

Introduction: We experienced a case of esophageal squamous cell carcinoma (ESCC) exhibiting mucus-negative cytoplasmic vacuoles. The carcinoma cells with vacuoles were positive for p63, a marker of squamous cell carcinoma (SCC). Since the first description by Cramer and Heggeness in 1989, 24 cases of SCC with mucus-negative vacuoles have been reported to date. However, little is known about the clinical course of SCC with vacuoles (SCCVs) and the nature of the cytoplasmic vacuoles themselves, due to its rarity and the lack of suitable models.

Methods: We established a novel organoid line - designated ECO_Vac - from residual cancer tissue of a patient with esophageal SCCV (ESCCV) after neoadjuvant chemotherapy, evaluated its applicability as a model of ESCCV, and characterized its cytoplasmic vacuoles by electron microscopic and organelle-specific fluorescent probe uptake assays.

Results: ECO_Vac was successfully established and was found to be applicable to in vitro drug assays and experiments involving in vivo tumor formation. We also found that the vacuoles in ESCCV were enlarged autolysosomes.

Conclusion: We established a novel organoid line, ECO_Vac, as a useful model for investigating the molecular pathogenesis of ESCCV. By using ECO_Vac, we demonstrated that the cytoplasmic vacuoles in ESCCV were unphysiologically enlarged autolysosomes.

Introduction: Oncocytic cell tumours (OCTs), previously referred to as Hürthle cell tumours of the thyroid, are a subset of thyroid and endocrine neoplasms that pose diagnostic and therapeutic challenges owing to their unpredictable clinical behaviour. The transcriptomic and proteomic landscapes of OCTs remain poorly characterized compared with those of mitochondrion-rich neoplasms (MRNs: thyroid tumours with ≥75% oncocytic cells that share similar morphology but harbour nuclear driver mutations consistent with their respective histotypes rather than mitochondrial alterations).

Methods: We performed RNA and protein sequencing on 12 OCT samples and 6 MRNs. This study was prompted by the understanding that oncocytic morphology alone does not necessarily predict tumour behaviour.

Results: RNA sequencing analysis identified 47 downregulated and 38 upregulated differentially expressed genes (DEGs) in OCTs relative to MRNs, with significant enrichment in pathways related to heme metabolism. Protein sequencing further revealed 20 under-expressed and 64 over-expressed differentially expressed proteins (DEPs) in OCTs. Notably, all oncocytic carcinomas formed a distinct cluster separate from the MRNs, indicating a unique proteomic profile.

Conclusion: Most of the DEPs were involved in three key cellular pathways: epigenetic regulation, the tumour microenvironment, and protein biogenesis, suggesting that these processes may underlie the distinctive morphology and behaviour of OCTs. These findings highlight the need for continued research into these molecular mechanisms to improve the diagnostic accuracy and develop targeted therapies for patients with OCTs.

Introduction: Grainyhead-like 2 (GRHL2) regulates epithelial-to-mesenchymal transition (EMT) in cancer. This study analyzed the expression and prognostic role of GRHL2 in high-grade serous carcinoma (HGSC).

Methods: GRHL2 protein expression by immunohistochemistry was analyzed in 411 HGSC (198 effusions, 213 surgical specimens). Expression score was generated by combination of staining extent and intensity and was assessed for association with clinicopathologic parameters and survival.

Results: GRHL2 expression was significantly higher in effusions compared to surgical specimens in both analysis of all specimens (p < 0.001) and patient-matched tumors (n = 39 patients; p < 0.001). Expression was additionally higher in post-chemotherapy compared to chemo-naive effusions (p < 0.001). Higher GRHL2 score in effusions was associated with a trend for shorter overall survival (OS; p = 0.088). Higher GRHL2 score in surgical specimens was significantly related to nonoptimal (>0 cm) debulking (p = 0.004), non-complete chemoresponse at diagnosis (p = 0.003), primary chemoresistance (p = 0.045), and shorter OS (p = 0.038) and progression-free survival (PFS; p = 0.024). Both OS and PFS findings remained significant in Cox multivariate analysis (OS: p = 0.048; PFS: p = 0.04).

Conclusion: GRHL2 is overexpressed in HGSC effusions compared to solid lesions, possibly reflecting altered EMT status. However, high expression in solid lesions is associated with chemoresistance and poor survival, possibly due to mediation of tumor cell migration and invasion.

Introduction: Cervical cancer, primarily driven by oncogenic HPV16/18, often relapses despite standard treatments. HPV circulating tumor DNA (ctDNA), which reflects tumor-derived genetic material in the bloodstream, has emerged as a promising noninvasive biomarker for monitoring disease progression.

Methods: A prospective study was conducted on 20 patients with HPV16/18-associated cervical cancer. Posttreatment blood samples were collected, and HPV ctDNA levels were measured using droplet digital PCR. The correlation between HPV ctDNA levels and disease progression was examined.

Results: HPV ctDNA was detected in 21% (18/85) of samples, with 6% (5/85) showing positivity. Patients without disease progression (n = 15) were HPV ctDNA negative, indicating a false positivity rate of zero. HPV ctDNA concentrations appeared higher in samples collected before or during disease progression, suggesting a potential association with disease status. Patients with positive HPV ctDNA tended to have shorter progression-free survival compared to those with negative ctDNA.

Conclusions: This study suggests that HPV ctDNA may aid in monitoring disease progression in patients with HPV16/18-associated cervical cancer, highlighting the need for further validation.