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We used a mathematical approach to investigate the quantitative spatial profile of cancer cells and stroma in lung squamous cell carcinoma tissues and its clinical relevance. The study enrolled 132 patients with 3–5 cm peripheral lung squamous cell carcinoma, resected at the National Cancer Center Hospital East. We utilized machine learning to segment cancer cells and stroma on cytokeratin AE1/3 immunohistochemistry images. Subsequently, a spatial form of Shannon's entropy was employed to precisely quantify the spatial distribution of cancer cells and stroma. This quantification index was defined as the spatial tumor–stroma distribution index (STSDI). The patients were classified as STSDI‐low and ‐high groups for clinicopathological comparison. The STSDI showed no significant association with baseline clinicopathological features, including sex, age, pathological stage, and lymphovascular invasion. However, the STSDI‐low group had significantly shorter recurrence‐free survival (5‐years RFS: 49.5% vs. 76.2%, p < 0.001) and disease‐specific survival (5‐years DSS: 53.6% vs. 81.5%, p < 0.001) than the STSDI‐high group. In contrast, the application of Shannon's entropy without spatial consideration showed no correlation with patient outcomes. Moreover, low STSDI was an independent unfavorable predictor of tumor recurrence and disease‐specific death (RFS; HR = 2.668, p < 0.005; DSS; HR = 3.057, p < 0.005), alongside the pathological stage. Further analysis showed a correlation between low STSDI and destructive growth patterns of cancer cells within tumors, potentially explaining the aggressive nature of STSDI‐low tumors. In this study, we presented a novel approach for histological analysis of cancer tissues that revealed the prognostic significance of spatial tumor–stroma distribution in lung squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Researchers have attempted to identify the factors involved in lymph node recurrence in cT1‐2N0 tongue squamous cell carcinoma (SCC). However, studies combining histopathological and clinicopathological information in prediction models are limited. We aimed to develop a highly accurate lymph node recurrence prediction model for clinical stage T1‐2, N0 (cT1‐2N0) tongue SCC by integrating histopathological artificial intelligence (AI) with clinicopathological information. A dataset from 148 patients with cT1‐2N0 tongue SCC was divided into training and test sets. The prediction models were constructed using AI‐extracted information from whole slide images (WSIs), human‐assessed clinicopathological information, and both combined. Weakly supervised learning and machine learning algorithms were used for WSIs and clinicopathological information, respectively. The combination model utilised both algorithms. Highly predictive patches from the model were analysed for histopathological features. In the test set, the areas under the receiver operating characteristic (ROC) curve for the model using WSI, clinicopathological information, and both combined were 0.826, 0.835, and 0.991, respectively. The highest area under the ROC curve was achieved with the model combining WSI and clinicopathological factors. Histopathological feature analysis showed that highly predicted patches extracted from recurrence cases exhibited significantly more tumour cells, inflammatory cells, and muscle content compared with non‐recurrence cases. Moreover, patches with mixed inflammatory cells, tumour cells, and muscle were significantly more prevalent in recurrence versus non‐recurrence cases. The model integrating AI‐extracted histopathological and human‐assessed clinicopathological information demonstrated high accuracy in predicting lymph node recurrence in patients with cT1‐2N0 tongue SCC. [ABSTRACT FROM AUTHOR]

Background We quantified the pathological spatial intratumor heterogeneity of programmed death-ligand 1 (PD-L1) expression and investigated its relevance to patient outcomes in surgically resected non–small cell lung carcinoma (NSCLC). Methods This study enrolled 239 consecutive surgically resected NSCLC specimens of pathological stage IIA-IIIB. To characterize the spatial intratumor heterogeneity of PD-L1 expression in NSCLC tissues, we developed a mathematical model based on texture image analysis and determined the spatial heterogeneity index of PD-L1 for each tumor. The correlation between the spatial heterogeneity index of PD-L1 values and clinicopathological characteristics, including prognosis, was analyzed. Furthermore, an independent cohort of 70 cases was analyzed for model validation. Results Clinicopathological analysis showed correlations between high spatial heterogeneity index of PD-L1 values and histological subtype (squamous cell carcinoma; P  < .001) and vascular invasion (P  = .004). Survival analysis revealed that patients with high spatial heterogeneity index of PD-L1 values presented a significantly worse recurrence-free rate than those with low spatial heterogeneity index of PD-L1 values (5-year recurrence-free survival [RFS] = 26.3% vs 47.1%, P  < .005). The impact of spatial heterogeneity index of PD-L1 on cancer survival rates was verified through validation in an independent cohort. Additionally, high spatial heterogeneity index of PD-L1 values were associated with tumor recurrence in squamous cell carcinoma (5-year RFS = 29.2% vs 52.8%, P  < .05) and adenocarcinoma (5-year RFS = 19.6% vs 43.0%, P  < .01). Moreover, we demonstrated that a high spatial heterogeneity index of PD-L1 value was an independent risk factor for tumor recurrence. Conclusions We presented an image analysis model to quantify the spatial intratumor heterogeneity of protein expression in tumor tissues. This model demonstrated that the spatial intratumor heterogeneity of PD-L1 expression in surgically resected NSCLC predicts poor patient outcomes. [ABSTRACT FROM AUTHOR]

The article is a response to Drs Xuewei Wu and Bin Zhang's correspondence regarding the spatial heterogeneity of programmed cell death 1 ligand (PD-L1) expression in non-small cell lung cancer. The authors calculated a novel metric for intratumor heterogeneity called the spatial heterogeneity index of PD-L1 (SHIP) and used a patch size of 25 mm2 to capture intratumor heterogeneity. They also discussed the potential of integrating morphological analysis of hematoxylin and eosin-stained images with SHIP to gain deeper insights into intratumor heterogeneity. The authors acknowledged the limitations of their single-center study and performed propensity score matching to control for treatment variations. They found that SHIP-high cases had higher rates of tumor recurrences and disease-specific deaths compared to SHIP-low cases, underscoring the prognostic importance of SHIP. The authors appreciated the observations made by Drs Wu and Zhang and expressed their intention to consider them in future research. [Extracted from the article]

Dirty necrosis (DN) is a form of tumor necrosis (TN) with prominent neutrophil infiltration and cell detritus in the necrotic foci. This study aimed to characterize the clinicopathological features of DN in metastatic lung cancers of the colon and rectum (MLCRs). A total of 227 patients who underwent pulmonary metastasectomy and complete resection for MLCR were included in this study. TN was evaluated using digitally scanned resection specimens. These slides were immunostained for biomarkers of NETosis (citrullinated histone H3 [citH3] and myeloperoxidase [MPO]), and the area positive for citH3 and MPO was further quantified. TN was observed in 216 cases (95.2%), and 54 (25.0%) of these cases had DN. The presence of TN was not associated with a worse prognosis; however, patients with DN had a significantly shorter overall survival than those without DN (p < 0.01). Furthermore, the presence of DN was a poor prognostic factor in both the univariate and multivariate analyses. Immunohistochemical analysis revealed that the percentage of citH3‐positive and MPO‐positive areas in the DN‐positive cases was significantly higher than that in the DN‐negative cases (p < 0.01 and p < 0.01, respectively). In surgically resected MLCR, DN is the characteristic TN subtype associated with poor prognosis and neutrophil extracellular traps (NETs). [ABSTRACT FROM AUTHOR]

Aim: Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable prognostic indicator. This study aimed to analyze the pathological and biological features of DN. Materials and Methods: A total of 81 RCC tumors, including 33 cases of DN and 48 cases of tumor necrosis without DN features (ghost necrosis [GN]), were enrolled in this study. We compared the number of neutrophils; the activation of cell death pathways, including ferroptosis, NETosis, and apoptosis; the rate of epithelial‐mesenchymal transition (EMT); and proliferation status using immunohistochemistry. We further assessed the effect of the necrosis type on systemic inflammation. Results: DN tumors had a significantly higher number of neutrophils in both areas around the necrotic foci and far from the necrotic foci. Ferroptosis status did not differ between DN and GN; however, DN tumors had significantly larger areas exhibiting cell detritus with neutrophil extracellular traps (NETs) detected by citrullinated histone H3 (citH3) than GN tumors. DN tumors also had more apoptotic cells within areas around the necrotic foci. There was no significant difference between the EMT and proliferation status between DN and GN groups. Systemic inflammation markers including C‐reactive protein (CRP), CRP‐to‐albumin ratio (CRP/Alb), platelet‐to‐lymphocyte ratio (PLR), and hemoglobin were significantly higher in patients with DN. In addition, some of these inflammation markers (CRP/Alb and PLR) significantly decreased after surgery. Conclusions: DN in RCC is characterized by NETs production and systemic inflammation. [ABSTRACT FROM AUTHOR]

Aims Methods and Results Conclusion 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.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.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. [ABSTRACT FROM AUTHOR]

Pulmonary pleomorphic carcinoma (PC) is a rare non-small-cell lung carcinoma (NSCLC) with a poor prognosis, characterized by tumor necrosis (TN). NETosis is a form of neutrophil-specific cell death, which is morphologically characterized by prominent neutrophil infiltration and cell detritus in the necrotic foci. Seventy-six patients with pulmonary PC who underwent complete resection were enrolled. Tumor necrosis was evaluated using digitally scanned resected specimens. The regions of NETosis were quantified using citrullinated histone H3 (citH3)- and myeloperoxidase-positive regions. We examined the association between the NETosis area and the prognostic outcomes and assessed the correlation between the NETosis area and systemic inflammation. Tumor necrosis was observed in 70 patients (92%). In all the cases, the TN region was accompanied by a citH3-positive region. The patients with high NETosis area (n = 54) had significantly shorter overall survival than those with low NETosis area (n = 16) (p = 0.013). Furthermore, a high NETosis area was an independent poor prognostic factor in the multivariate analyses. Systemic inflammatory markers, including C-reactive protein (CRP), CRP-to-albumin ratio, and neutrophil-to-lymphocyte ratio, were significantly higher in patients with high NETosis area than in those with low NETosis area. Furthermore, the levels of these inflammatory markers were significantly decreased postsurgery. This study shows that in surgically resected pulmonary PC, patients with high NETosis areas have higher systemic inflammation and worse prognosis., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors (ICIs) has shown efficacy against many types of cancers, including non-small cell lung cancer (NSCLC). We investigated the feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a vascular endothelial growth factor (VEGF) receptor-2 antagonist for patients with PD-L1-positive NSCLC and its influence on the tumor microenvironment (TME)., Patients and Methods: Patients with pathologically proven NSCLC with PD-L1-positive, clinical stage IB-IIIA were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every three weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response (MPR) rate by a blinded independent pathology review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on TME., Results: The 24 eligible patients were enrolled between July 2019 and April 2022. The MPR rate was 50.0% (90% confidence interval, 31.9-68.1%). Six patients showed pathological complete response. Grade 3 adverse events (AEs) occurred in 9 patients (37.5%), including 3 immune-related AEs (acute tubulointerstitial nephritis in 2 cases and polymyalgia rheumatica in one). There were no grade 4 or 5 AEs. The transcriptome and multiplexed immunohistochemistry results suggested that tumors with greater CD8+ T-cell infiltration and higher expression of effector molecules at the baseline could show better sensitivity to treatment., Conclusions: This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible and anti-VEGF agents may enhance the effects of ICIs.