Reappraisal of Grading in Intestinal-Type Sinonasal Adenocarcinoma: Tumor Budding as an Independent Prognostic Parameter

Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico-pathological single-institution study on consecutive ITAC patients between 1996 and 2020. Histopathological parameters including conventional subtypes and TB features (low, intermediate, high) were evaluated with the aid of pancytokeratin (AE1/AE3) immunohistochemical staining. Parameters were correlated to clinical data and outcome. A total of 31 ITAC patients were included. Overall, 19/31 patients (61.3%) presented with stage III/IV disease. Presence of lymph node or distant metastases was rare (1/31 patient, 3.2%). Treatment protocols consisted of tumor resection in 30/31 patients (96.8%) and primary radiochemotherapy in 1/31 patient (3.2%). Adjuvant radiation therapy was conducted in 20/30 surgically treated patients (66.7%). The 3- and 5-year overall survival (OS) was 83.9% and 78.3% and the 3- and 5-years disease-specific survival (DSS) 83.7% % and 78.5%, respectively. The presence of intermediate/high TB (defined as ≥ 5 buds) was associated with both, worse DSS (log rank p = 0.03) and OS (log rank p = 0.006). No patient with low TB revealed progressive disease or died of the disease. No association between TB and tumor stage or conventional tumor subtype was found. Tumor budding seems to be an independent prognostic factor of worse outcome in ITAC.

Association Between DCE-MRI Perfusion Histogram Parameters and EGFR and VEGF Expressions in Different Lauren Classifications of Advanced Gastric Cancer

Objective: To investigate the correlations between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion histogram parameters and vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions in advanced gastric cancer (AGC).Methods: This retrospective study included 80 pathologically confirmed patients with AGC who underwent DCE-MRI before surgery from February 2017 to May 2021. The DCE-MRI perfusion histogram parameters were calculated by Omni Kinetics software in four quantitative parameter maps. Immunohistochemical methods were used to detect VEGF and EGFR expressions and calculate the immunohistochemical score.Results: VEGF expression was relatively lower in patients with intestinal-type AGC than those with diffuse-type AGC (p < 0.05). For VEGF, Receiver operating characteristics (ROC) curve analysis revealed that Quantile 90 of Ktrans, Meanvalue of Kep and Quantile 50 of Ve provided the perfect combination of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for distinguishing high and low VEGF expression, For EGFR, Skewness of Ktrans, Energy of Kep and Entropy of Vp provided the perfect combination of sensitivity, specificity, PPV and NPV for distinguishing high and low EGFR expression. Ktrans (Quantile 90, Entropy) showed the strongest correlation with VEGF and EGFR in patients with intestinal-type AGC (r = 0.854 and r = 0.627, respectively); Ktrans (Mean value, Entropy) had the strongest correlation with VEGF and EGFR in patients with diffuse-type AGC (r = 0.635 and 0.656, respectively).Conclusion: DCE-MRI perfusion histogram parameters can serve as imaging biomarkers to reflect VEGF and EGFR expressions and estimate their difference in different Lauren classifications of AGC.

Higher Lymph Node Metastasis Rate and Poorer Prognosis of Intestinal-Type Gastric Cancer Compared to Diffuse-Type Gastric Cancer in Early-Onset Early-Stage Gastric Cancer: A Retrospective Study

Background: The incidence of early-onset gastric cancer (GC) that was diagnosed at <50 years is increasing, but there is a knowledge gap on early-onset early-stage GC (EEGC) that was defined as early-onset GC limited to the mucosa or submucosa. Therefore, we comprehensively analysed the clinical features based on Lauren type.Methods: Logistic and Cox analyses were used to investigate risk factors for lymph node metastasis (LNM) and prognosis, respectively. Propensity score matching (PSM) was used to adjust confounding factors. Protein mass spectrometry analysis was used to explore the molecular mechanism of LNM.Result: Our study included 581 patients with EEGC from the Surveillance, Epidemiology, and End Results (SEER) database and 226 patients with EEGC from our own centre. We identified intestinal type, T1b stage, and tumour size (>3 cm) as risk factors for LNM using SEER and our own data. We also found that the prognosis of patients with intestinal-type EEGC was poorer than patients with diffuse-type EEGC, and T1b stage and positive LNM were hazard factors for survival. After analysing the expression of proteins between positive and negative LNM in the intestinal or diffuse type, we found no similar proteins between these groups. The differentially expressed genes (DEGs) in the intestinal type functioned as epithelial cell signalling in Helicobacter pylori. The DEGs in the diffuse type functioned in the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation.Conclusion: For EEGC, our study was the first report to demonstrate that the intestinal type was a risk factor for LNM and survival compared to the diffuse type, and the oncogenic expression promoting the occurrence of LNM was different. These findings suggest that clinicians should pay more attention to intestinal-type EEGC than diffuse-type EEGC.

Cell Cycle Regulation and DNA Damage Response Networks in Diffuse- and Intestinal-Type Gastric Cancer

Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of the network analysis with Ingenuity Pathway Analysis (IPA) showed that the activation states of several canonical pathways related to cell cycle regulation were altered. The G1/S checkpoint regulation pathway was activated in diffuse-type GC compared to intestinal-type GC, while canonical pathways of the cell cycle control of chromosomal replication, and the cyclin and cell cycle regulation, were activated in intestinal-type GC compared to diffuse-type GC. A canonical pathway on the role of BRCA1 in the DNA damage response was activated in intestinal-type GC compared to diffuse-type GC, where gene expression of BRCA1, which is related to G1/S phase transition, was upregulated in intestinal-type GC compared to diffuse-type GC. Several microRNAs (miRNAs), such as mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451 and mir-605, were identified to have direct relationships in the G1/S cell cycle checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in epithelial-mesenchymal transition (EMT) conditions. The alterations in the activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC highlighted the significance of cell cycle regulation in EMT.

Computed tomographic pneumogastrography in determining the types of gastric cancer according to the Lauren classification

Objective. To assess the capabilities of computed tomographic pneumogastrography in determining the types of gastric cancer according to the Lauren classification at the stage of clinical staging.Materials and methods. This study is a single-center retrospective study with 202 patients with gastric cancer included who was treated at the National Medical Research Center of Oncology named after N. N. Petrov from 2015 to 2018. All patients underwent subtotal gastric resection or gastrectomy and computed tomographic pneumogastrography at the stage of clinical staging. For patients undergoing neoadjuvant chemotherapy, CT was performed twice: before chemotherapy and after, immediately before surgery. We studied quantitative and qualitative imaging biomarkers, measured densitometric indices of stomach tumor density in the arterial, portal and delayed phases of scanning at five different points. For patients receiving NACT, all density indices were recorded twice — both before the start of therapeutic treatment, and after, immediately before the surgery.Results. The distribution of gastric cancer types according to Lauren»s classification was as follows: in 59 (29,2 %) intestinal type, 69 (34,2 %) — diffuse, 16 (7,9 %) — mixed, 58 (28,7 %) — indeterminate type. Based on visual characteristics, taking into account the characteristics of tumor growth, 3 main CT-PGG of the gastric cancer type were identified: 1 — tuberous (n = 68, 34,0 %), 2 — intramural (n = 57,3 %) and 3 — mixed (n = 77,4 %). CT-PGG tumor type is associated with Lauren type (χ2 = 185,19, p <0,001). With a tuberous CT-PGG type, it is possible to assume that the tumor is of an intestinal or indeterminate Lauren type; sensitivity 0,58 (95% CI: 0,49-0,67), specificity 0,1 (95% CI: 0,96-0,1). With an intramural CT-PGG type, the diffuse type of tumor according to Lauren is most likely; sensitivity 0,75 (95% CI: 0,64-0,85), specificity 0,96 (95% CI: 0,91-0,99). With a mixed CT-PGG type, the definition of the type according to Lauren is difficult. In the definition of mixed tumor type according to Lauren, the sensitivity and specificity of mixed CT-PGG tumor type are 0,94 (95% CI: 0,70% -0,1) and 0,67 (95% CI: 0,59-0,73) respectively.Conclusion. The shape of the stomach tumor, determined by CT-PGG, has a high diagnostic efficiency in determining the types of gastric cancer according to Lauren. The tuberous CT-PGG type is typical for tumors of the intestinal type according to Lauren, and the intramural CT-PGG type is typical for tumors of the diffuse type according to Lauren. Tumors of indeterminate Lauren type have any CT-PGG type and contrast pattern. For tumors of a mixed type according to Lauren, a mixed type according to CT-PGG is characteristic, but differential diagnosis with tumors of a tuberous and diffuse type according to Lauren of an atypical form for them is impossible. Tumors of the intestinal and diffuse Lauren type of the CT-PGG type, which is not typical for them, have an atypical contrast pattern.