High-grade Intraepithelial Neoplasia Research Articles

Clinical and histopathological parameters in transrectal ultrasound-guided biopsies associated with tumor upgrading after radical prostatectomy: A comparative analysis of risk groups.

Thanks to technological advances, prostate cancer (PCa) can be diagnosed at a younger age. It is known that most of these patients are in the low-intermediate risk group, and the histological grade of the tumor increases in half of those undergoing radical prostatectomy (Rp) compared to their diagnostic biopsies. This is especially important in terms of active surveillance (AS) and/or the timely evaluation of curative treatment options in patients diagnosed at an early age. Our aim was to investigate clinical and histopathological parameters that may be associated with an increase in the histological grade of the tumor in patients with acinar adenocarcinoma who were diagnosed by transrectal ultrasound-guided biopsy (TRUS-Bx) and underwent Rp. A total of 205 patients with classical acinar adenocarcinoma diagnosed by TRUS-Bx without metastasis and who underwent Rp were grouped according to the D'Amico risk classification. Age at diagnosis, serum prostate-specific antigen (PSA), PSA density, prostate volume, Prostate Imaging Reporting and Data System (PI-RADS) score, clinical stage, Gleason Grade Group (GGG), high-grade intraepithelial neoplasia in tumor-free cores (HGPIN) (single and ≥2 cores), perineural invasion (PNI), and lymphovascular invasion (LVI) was obtained. Additionally, GGG, pathological stage, lymph node metastasis, surgical margin positivity, and tumor volume obtained from Rp were evaluated. Comparisons were made between the case groups in which the tumor grade increased and remained the same, in terms of age, serum PSA, PSA density, HGPIN in tumor-free cores (single and ≥2 cores), PNI, and LVI in all biopsies (with or without tumors), as well as risk groups. In addition, the relationships of HGPIN in tumor-free cores (single and ≥2 cores), PNI, and LVI on TRUS-Bx with age, serum PSA and PSA density, tumor volume, surgical margin positivity, pathological stage, lymph node metastasis, and risk groups were examined separately. Of the patients, 72 (35.1%) were in the low-risk group, 95 (46.3%) in the intermediate-risk group, and 38 (18.5%) in the high-risk group. Most of the patients with an increased histological grade (n = 38, 48.1%) were in the low-risk group (p < 0.05) and had an advanced median age. HGPIN in single and ≥2 tumor-free cores and PNI were more common in these patients (p < 0.01, p < 0.001, and p < 0.05, respectively). According to the multivariable analysis, advanced age (odds ratio [OR]: 1.087, 95% confidence interval [CI]: 1.029-1.148, p < 0.05), high serum PSA (OR: 1.047, 95% CI: 1.006-1.090, p < 0.05), HGPIN in ≥2 tumor-free cores (OR: 6.346, 95% CI: 3.136-12.912, p < 0.001), and PNI (OR: 3.138, 95% CI: 1.179-8.356, p < 0.05) were independent risk factors for a tumor upgrade. Furthermore, being in the low-risk group was an independent risk factor when compared to the intermediate- and high-risk groups (OR: 0.187, 95% CI: 0.080-0.437, p < 0.001 and OR: 0.054, 95% CI: 0.013-0.230, p < 0.001, respectively). The HGPIN diagnosis was more common in the low- and intermediate-risk groups. Advanced age at diagnosis, high serum PSA and PSA density values were associated with PNI on TRUS-Bx. High serum PSA and PSA density values were associated with LVI on TRUS-Bx. Surgical margin positivity was higher in cases with PNI and LVI detected by TRUS-Bx. HGPIN in ≥2 tumor-free cores, PNI, and LVI on TRUS-Bx were associated with a higher rate of lymph node metastases. In patients diagnosed with acinar adenocarcinoma, the presence of HGPIN even in a single tumor-free core on TRUS-Bx was found to be significant in terms of showing an increase in the histological tumor grade in Rp. The diagnosis of HGPIN in ≥2 tumor-free cores on TRUS-Bx was determined as an independent risk factor for an increased Gleason score after Rp. Furthermore, an advanced age, a high serum PSA value, being in the low-risk group, and the presence of PNI were associated with a tumor upgrade. HGPIN in ≥2 tumor-free cores, PNI, and LVI were also associated with lymph node metastasis. Therefore, the diagnosis of HGPIN should be signed out on pathological reports.

Clip-and-snare method with a pre-looping technique versus conventional method in the treatment of precancerous lesion and early gastric cancer: a retrospective study

BackgroundLow grade intraepithelial neoplasia (LGIN) and high grade intraepithelial neoplasia (HGIN) are potential precancerous lesion of gastric neoplasms. Endoscopic submucosal dissection (ESD) is the first option for the treatment of precancerous lesion and early gastric cancer (EGC). Traction is an effective method to improve efficiency, and reduce complications during ESD. In this study, we shared a useful traction method using the clip-and-snare method with a pre-looping technique (CSM-PLT) for precancerous lesion and EGC.MethodsWe retrospectively analyzed patients received ESD combined with CSM-PLT or conventional ESD from June 2018 to December 2021 in Shenzhen People’s hospital. The primary outcome was resection speed.ResultsForty-two patients were enrolled in ESD combined with CSM-PLT group and sixty-five patients in conventional ESD group respectively. Baseline characteristics were comparable among two groups (P>0.05). There were no significant differences in terms of R0 resection rate, en bloc resection rate (97.6% vs. 98.5%, P = 1.000 and 97.6% vs. 96.9%, P = 1.000, respectively), operation costs (933.7 (644.1-1102.4) dollars vs. 814.7 (614.6-988.3) dollars, P = 0.107), and hospital stays (8.0 ± 3.1 days vs. 7.3 ± 3.2 days, P = 0.236). In addition, no significant difference was observed with respect to complications (P>0.05). However, the resection speed of ESD combined with CSM-PLT was faster than that of conventional ESD (11.3 (9.4–14.9) mm2/min vs. 8.0 (5.8–10.9) mm2/min, P < 0.001), particularly lesions located in anterior wall and lesser curvature. In addition, the association between ESD combined with CSM-PLT and resection speed was still supported after propensity matching scores (PMS).ConclusionsCSM-PLT can help to improve ESD efficiency without reducing the en bloc resection rate or increasing the incidence of complications.

Computer-aided colorectal cancer diagnosis: AI-driven image segmentation and classification

Colorectal cancer is an enormous health concern since it is among the most lethal types of malignancy. The manual examination has its limitations, including subjectivity and data overload. To overcome these challenges, computer-aided diagnostic systems focusing on image segmentation and abnormality classification have been developed. This study presents a two-stage approach for the automatic detection of five types of colorectal abnormalities in addition to a control group: polyp, low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, serrated adenoma, adenocarcinoma. In the first stage, UNet3+ was used for image segmentation to locate the anomalies, while in the second stage, the Cross-Attention Multi-Scale Vision Transformer deep learning model was used to predict the type of anomaly after highlighting the anomaly on the raw images. In anomaly segmentation, UNet3+ achieved values of 0.9872, 0.9422, 0.9832, and 0.9560 for Dice Coefficient, Jaccard Index, Sensitivity, Specificity respectively. In anomaly detection, the Cross-Attention Multi-Scale Vision Transformer model attained a classification performance of 0.9340, 0.9037, 0.9446, 0.8723, 0.9102, 0.9849 for accuracy, F1 score, precision, recall, Matthews correlation coefficient, and specificity, respectively. The proposed approach proves its capacity to alleviate the overwhelm of pathologists and enhance the accuracy of colorectal cancer diagnosis by achieving high performance in both the identification of anomalies and the segmentation of regions.

Effect of vinegar supplementation on patients with esophageal lesions lightly stained with Lugol’s iodine solution: Prospective single-centre trial

Effect of vinegar supplementation on patients with esophageal lesions lightly stained with Lugol’s iodine solution: Prospective single-centre trial

Percutaneous transhepatic cholangioscopy-assisted biliary polypectomy for local palliative treatment of intraductal papillary neoplasm of the bile duct.

Intraductal papillary neoplasm of the bile duct (IPNB) is a premalignant biliary-type epithelial neoplasm with intraductal papillary or villous growth. Currently reported local palliative therapeutic modalities, including endoscopic nasobiliary drainage, stenting and biliary curettage, endoscopic biliary polypectomy, percutaneous biliary drainage, laser ablation, argon plasma coagulation, photodynamic therapy, and radiofrequency ablation to relieve mechanical obstruction are limited with weaknesses and disadvantages. We have applied percutaneous transhepatic cholangioscopy (PTCS)-assisted biliary polypectomy (PTCS-BP) technique for the management of IPNB including mucin-hypersecreting cast-like and polypoid type tumors since 2010. To assess the technical feasibility, efficacy, and safety of PTCS-BP for local palliative treatment of IPNB. Patients with mucin-hypersecreting cast-like or polypoid type IPNB and receiving PTCS-BP between September 2010 and December 2019 were included. PTCS-BP was performed by using a half-moon type snare with a soft stainless-steel wire, and the tumor was snared and resected with electrocautery. The primary outcome was its feasibility, indicated by technical success. The secondary outcomes were efficacy, including therapeutic success, curative resection, and clinical success, and safety. Five patients (four with mucin-hypersecreting cast-like type and one with polypoid type IPNB) were included. Low- and high-grade intraepithelial neoplasia (HGIN) and recurrent IPNB with invasive carcinoma were observed in one, two, and two patients, respectively. Repeated cholangitis and/or obstructive jaundice were presented in all four patients with mucin-hypersecreting cast-like type IPNB. All five patients achieved technical success of PTCS-BP. Four patients (three with mucin-hypersecreting cast-like type and one with polypoid type IPNB) obtained therapeutic success; one with mucin-hypersecreting cast-like type tumors in the intrahepatic small bile duct and HGIN had residual tumors. All four patients with mucin-hypersecreting IPNB achieved clinical success. The patient with polypoid type IPNB achieved curative resection. There were no PTCS-BP-related serious adverse events. PTCS-BP appears to be feasible, efficacious, and safe for local palliative treatment of both mucin-hypersecreting cast-like and polypoid type IPNB.

A Review on HR-HPV: An Increasing Cause of Concern for Cervical Carcinoma

Human Papilloma virus, leads to widely prevalent viral infection with worldwide distribution of variable genotypes, it is the major cause of cancer in women and a leading cause of deaths due to cancer in India. Cervical cancer is the second most common cancer in women worldwide and the most common cancer cause of death in the developing countries. Notably, four out of every five cases of cervical cancer reported in India were attributed to infections from HPV types 16 and 18. India has a population of 483.5 million women aged 15 years and older who are at risk of developing cervical cancer. Infections with high-risk HPV types impair the function of cellular proteins and interfere with the expression of biological gene products. In high-grade intraepithelial neoplasias and cancers, HPV DNA is typically integrated into the host genome. WHO has recommended Screening of cervical cancer among young sexually-active females for early detection of HPV induced cervical carcinoma. Detection of HPV at earlier stages is essential in prevention of invasive cervical carcinoma. Based on clinical stage categories upon diagnosis, standard of care for cervical cancer management includes surgery, radiation, systemic therapy, or a combination of these therapeutic modalities.

Revealing molecular and cellular heterogeneity in hypopharyngeal carcinogenesis through single-cell RNA and TCR/BCR sequencing.

Hypopharyngeal squamous cell carcinoma (HSCC) is one of the malignant tumors with the worst prognosis in head and neck cancers. The transformation from normal tissue through low-grade and high-grade intraepithelial neoplasia to cancerous tissue in HSCC is typically viewed as a progressive pathological sequence typical of tumorigenesis. Nonetheless, the alterations in diverse cell clusters within the tissue microenvironment (TME) throughout tumorigenesis and their impact on the development of HSCC are yet to be fully understood. We employed single-cell RNA sequencing and TCR/BCR sequencing to sequence 60,854 cells from nine tissue samples representing different stages during the progression of HSCC. This allowed us to construct dynamic transcriptomic maps of cells in diverse TME across various disease stages, and experimentally validated the key molecules within it. We delineated the heterogeneity among tumor cells, immune cells (including T cells, B cells, and myeloid cells), and stromal cells (such as fibroblasts and endothelial cells) during the tumorigenesis of HSCC. We uncovered the alterations in function and state of distinct cell clusters at different stages of tumor development and identified specific clusters closely associated with the tumorigenesis of HSCC. Consequently, we discovered molecules like MAGEA3 and MMP3, pivotal for the diagnosis and treatment of HSCC. Our research sheds light on the dynamic alterations within the TME during the tumorigenesis of HSCC, which will help to understand its mechanism of canceration, identify early diagnostic markers, and discover new therapeutic targets.

VENet: Variational energy network for gland segmentation of pathological images and early gastric cancer diagnosis of whole slide images

Background and objective: Gland segmentation of pathological images is an essential but challenging step for adenocarcinoma diagnosis. Although deep learning methods have recently made tremendous progress in gland segmentation, they have not given satisfactory boundary and region segmentation results of adjacent glands. These glands usually have a large difference in glandular appearance, and the statistical distribution between the training and test sets in deep learning is inconsistent. These problems make networks not generalize well in the test dataset, bringing difficulties to gland segmentation and early cancer diagnosis.Methods: To address these problems, we propose a Variational Energy Network named VENet with a traditional variational energy Lv loss for gland segmentation of pathological images and early gastric cancer detection in whole slide images (WSIs). It effectively integrates the variational mathematical model and the data-adaptability of deep learning methods to balance boundary and region segmentation. Furthermore, it can effectively segment and classify glands in large-size WSIs with reliable nucleus width and nucleus-to-cytoplasm ratio features.Results: The VENet was evaluated on the 2015 MICCAI Gland Segmentation challenge (GlaS) dataset, the Colorectal Adenocarcinoma Glands (CRAG) dataset, and the self-collected Nanfang Hospital dataset. Compared with state-of-the-art methods, our method achieved excellent performance for GlaS Test A (object dice 0.9562, object F1 0.9271, object Hausdorff distance 73.13), GlaS Test B (object dice 94.95, object F1 95.60, object Hausdorff distance 59.63), and CRAG (object dice 95.08, object F1 92.94, object Hausdorff distance 28.01). For the Nanfang Hospital dataset, our method achieved a kappa of 0.78, an accuracy of 0.9, a sensitivity of 0.98, and a specificity of 0.80 on the classification task of test 69 WSIs.Conclusions: The experimental results show that the proposed model accurately predicts boundaries and outperforms state-of-the-art methods. It can be applied to the early diagnosis of gastric cancer by detecting regions of high-grade gastric intraepithelial neoplasia in WSI, which can assist pathologists in analyzing large WSI and making accurate diagnostic decisions.

Transcriptome sequencing reveals novel biomarkers and immune cell infiltration in esophageal tumorigenesis.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide, and its development comprises a multistep process from intraepithelial neoplasia (IN) to carcinoma (CA). However, the critical regulators and underlying molecular mechanisms remain largely unknown. To explore the genes and infiltrating immune cells in the microenvironment that are associated with the multistage progression of ESCC to facilitate diagnosis and early intervention. A mouse model mimicking the multistage development of ESCC was established by providing warter containing 4-nitroquinoline 1-oxide (4NQO) to C57BL/6 mice. Moreover, we established a control group without 4NQO treatment of mice. Then, transcriptome sequencing was performed for esophageal tissues from patients with different pathological statuses, including low-grade IN (LGIN), high-grade IN (HGIN), and CA, and controlled normal tissue (NOR) samples. Differentially expressed genes (DEGs) were identified in the LGIN, HGIN, and CA groups, and the biological functions of the DEGs were analyzed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The CIBERSORT algorithm was used to detect the pattern of immune cell infiltration. Immunohistochemistry (IHC) was also conducted to validate our results. Finally, the Luminex multiplex cytokine analysis was utilized to measure the serum cytokine levels in the mice. Compared with those in the NOR group, a total of 681541, and 840 DEGs were obtained in the LGIN, HGIN, and CA groups, respectively. Using the intersection of the three sets of DEGs, we identified 86 genes as key genes involved in the development of ESCC. Enrichment analysis revealed that these genes were enriched mainly in the keratinization, epidermal cell differentiation, and interleukin (IL)-17 signaling pathways. CIBERSORT analysis revealed that, compared with those in the NOR group, M0 and M1 macrophages in the 4NQO group showed stronger infiltration, which was validated by IHC. Serum cytokine analysis revealed that, compared with those in the NOR group, IL-1β and IL-6 were upregulated, while IL-10 was downregulated in the LGIN, HGIN, and CA groups. Moreover, the expression of the representative key genes, such as S100a8 and Krt6b, was verified in external human samples, and the results of immunohistochemical staining were consistent with the findings in mice. We identified a set of key genes represented by S100a8 and Krt6b and investigated their potential biological functions. In addition, we found that macrophage infiltration and abnormal alterations in the levels of inflammation-associated cytokines, such as IL-1β, IL-6, and IL-10, in the peripheral blood may be closely associated with the development of ESCC.

Characteristics of early gastric tumors with different differentiation and predictors of long-term outcomes after endoscopic submucosal dissection

BACKGROUND Gastric cancer is a common malignant tumor of the digestive tract, and endoscopic submucosal dissection (ESD) is the preferred treatment for early-stage gastric cancer. The analysis of the epidemiological characteristics of gastric mucosal tumors with different differentiation degrees and the influencing factors of long-term ESD efficacy may have certain significance for revealing the development of gastric cancer and ESD. AIM To analyze the features of gastric mucosal tumors at different differentiation levels, and to explore the prognostic factors of ESD. METHODS We retrospectively studied 301 lesions in 285 patients at The Second Affiliated Hospital of Xi'an Jiaotong University from 2014 to 2021, according to the latest Japanese guidelines (sixth edition), and divided them into low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and differentiated and undifferentiated early carcinoma. They are followed up by endoscopy, chest and abdominal computed tomography at 3, 6 and 12 months after ESD. We compared clinicopathologic characteristics, ESD efficacy, and complications with different degrees of differentiation, and analyzed the related factors associated with ESD. RESULTS HGIN and differentiated carcinoma patients were significantly older compared with LGIN patients (P &lt; 0.001) and accounted for more 0-IIc (P &lt; 0.001), atrophic gastritis was common (P &lt; 0.001), and irregular microvascular patterns (IMVPs) and demarcation lines (DLs) were more obvious (P &lt; 0.001). There was more infiltration in the undifferentiated carcinoma tissue (P &lt; 0.001), more abnormal folds and poorer mucosal peristalsis (P &lt; 0.001), and more obvious IMVPs, irregular microsurface patterns and DLs (P &lt; 0.05) than in the LGIN and HGIN tissues. The disease-free survival rates at 2, 5, and 8 years after ESD were 95.0%, 90.1%, and 86.9%, respectively. Undifferentiated lesions (HR 5.066), white moss (HR 7.187), incomplete resection (HR 3.658), and multiple primary cancers (HR 2.462) were significantly associated with poor prognosis. CONCLUSION Differentiations of gastric mucosal tumors have different epidemiological and endoscopic characteristics, which are closely related to the safety and efficacy of ESD.

18F-FDG PET/CT of Intracholecystic Papillary Neoplasm in Cystic Neck and Duct.

We report 18F-FDG PET/CT appearances of intracholecystic papillary neoplasm (ICPN) in the gallbladder neck and duct of a 74-year-old woman with a history of hepatitis B cirrhosis. The lesion presented with a large and sessile soft mass in the neck and duct of gallbladder with obvious glucose metabolism on PET/CT images, which was confirmed pathologically as ICPN (gastric foveolar type) with high-grade intraepithelial neoplasia. ICPN localized in the gallbladder neck and duct is extremely rare, and is easily misdiagnosed as gallbladder carcinoma. Our report aids in the application of PET/CT in the differential diagnosis of ICPN and guiding early surgery.

Abstract LB109: Detection of high grade intraepithelial neoplasia in colorectal cancer using a new blood-based multiplex septin9 methylation assay

Abstract Colorectal cancer (CRC) is the third most common cancer worldwide, and regular screening is effective in reducing its mortality. Epi proColon was the first blood-based Septin9 gene methylation assay approved by the US FDA for CRC screening. However, the broader application of this assay has been hindered by its relatively lower sensitivity in detecting early-stage CRC and precancerous lesions. In this study, we developed a new multiplex Septin9 methylation assay, named ColonUSK, which simultaneously detects two CpG-rich subregions in the promoter of the Septin9 gene and an internal control in a single reaction. In comparison with the Sepin9 assay targeting only one CpG-rich subregion, this new assay demonstrated improved sensitivity, with a detection limit as low as 12pg of the positive DNA. To assess its value in CRC screening, we conducted an opportunistic screening study involving a total of 1366 subjects. Blind testing was performed to evaluate ColonUSK in comparison with clinical diagnosis using colonoscopy and pathological examination (the clinical gold standard). The clinical sensitivities of ColonUSK for detecting CRC and advanced adenoma were 77.34% (95% CI: 72.89%-81.26%) and 25.26% (95% CI: 17.16%-35.41%), respectively. The clinical specificity of the assay for non-CRC cases was 95.95% (95% CI: 94.36%-97.13%). Notably, ColonUSK was able to detect 54.29% of cases with high-grade intraepithelial neoplasia. The Kappa test value for this experiment was 0.76, indicating a high degree of consistency between ColonUSK and pathological diagnosis. Our results suggest that ColonUSK holds potential as a non-invasive screening tool for colorectal cancer. Citation Format: Youming Wu, Yongqin Tong Tong, Haitao Zhang, Yun Li, Ming Li, Lili Qiu, Wenlan Liu, Siqing Mei, Yu Mao, Yanhua Cao, Caiyan Su, Wentao Yu, Junli Wang, Taizhong Wang, Zhongyuan Zhu, Dehua Derek Yu. Detection of high grade intraepithelial neoplasia in colorectal cancer using a new blood-based multiplex septin9 methylation assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB109.

Mucosa color and size may indicate malignant transformation of chicken skin mucosa-positive colorectal neoplastic polyps.

Lipid metabolism reprogramming is suspected to exist in pre-cancerous lesions, including colorectal adenoma. Screening colonoscopy frequently reveals chicken skin mucosa (CSM; white or yellow-white speckled mucosa) surrounding colorectal polyps, caused by macrophages engulfing and accumulating the lipids decomposed by colon cells or adjacent tumors. CSM-positive colorectal polyps are associated with various diseases; however, their prognosis varies greatly. Cold snare polypectomy is commonly used to resect lesions up to 10 to 15 mm in diameter without signs of submucosal invasion but is controversial for CSM-positive colorectal polyps. Improved imaging is required to diagnose and treat CSM-positive colorectal polyps. To highlight the clinical significance of CSM surrounding colorectal polyps and clarify the associated treatment for endoscopists. This retrospective cohort study included 177 patients with CSM-positive colorectal polyps diagnosed using endoscopy. All patient-related information was extracted from the Goldisc soft-clinic DICOM system or electronic medical record system. Based on the pathological results, patients were classified as non-neoplastic polyps (five juvenile polyps), neoplastic polyps, non-invasive high-grade neoplasia (NHGN), or submucosal invasive carcinoma (SM stage cancer). We analyzed and compared the clinical features, suspected risk factors for malignant transformation of neoplastic polyps, and early infiltration of submucosal carcinoma. The diameters of NHGN and SM polyps were much smaller than those of neoplastic polyps. Most NHGN polyps had a deeper red mucosal color. On logistic regression analyses, diameter and deeper red mucosal color were independent risk factors for malignant transformation of neoplastic polyps. Type 1 CSM was more common in high-grade intraepithelial neoplasia and SM; type 2 CSM was more common in neoplastic polyps. Logistic regression analyses revealed no significant differences in the malignant transformation of neoplastic polyps or early submucosal invasion of CSM-positive colorectal cancer. Changes in the CSM mucosa surrounding neoplastic polyps and submucosal invasion of colorectal cancer disappeared within 12 months. No tumor recurrence was found during either partial or complete endoscopic resection of the CSM. CSM-positive colorectal polyps > 1 cm in diameter or with deeper red mucosa may be related to NHGN. Resection of CSM surrounding colorectal adenomas did not affect tumor recurrence.

Clinicopathological and molecular characteristics of esophageal carcinoma with ductal differentiation: analysis of 17 cases

Objective: To investigate the clinicopathological features and molecular genetic characteristics of esophageal carcinoma with ductal differentiation, and to summarize the experiences in its diagnosis and treatment. Methods: A total of 17 cases of esophageal carcinoma with ductal differentiation diagnosed in Ningbo Clinical Pathological Diagnosis Center, Ningbo, China from June 2011 to December 2022 were collected. The clinical information and pathological diagnosis was reviewed. The tumor histological features and immunohistochemical results were analyzed. The next-generation sequencing was performed to detect and analyze the gene mutations in tumor samples. Results: The 17 patients included in this study were 54-77 years old, with a median age of 66 years. There were 16 males and 1 female. Among them, 9 cases were mainly carcinoma with ductal differentiation. The squamous epithelium on the tumor's surface was accompanied by high-grade intraepithelial neoplasia. The tumor and atypical squamous epithelium were transitional, and the focus was accompanied by various proportions of squamous cell carcinoma component (less than 10%). The other 8 cases were mostly squamous cell carcinoma, basaloid squamous cell carcinoma or sarcomatoid carcinoma with various degrees of tumor specific differentiation and focal area of carcinoma with ductal differentiation (less than 10%). The tumor cells in the area with ductal differentiation were mainly arranged in small tubes, while the tubes showed a double-layer structure, including the inner cells and outer cells of the lumen. Immunohistochemical results showed that the outer cells of the tumorous tubules expressed p63, p40, CK5/6 and CK34βE12, while the inner cells expressed CK7. Compared with esophageal squamous cell carcinoma reported in the literature, the frequency of gene mutations such as MYC (P=0.002), TP63 (P=0.002), CDKN1C (P=0.002) and NFE2L2 (P=0.045) was significantly lower in this group of cases. At the signaling pathway level, the mutation frequency of NOTCH signaling pathway (P=0.041) was significantly higher, while the mutation frequencies of NRF2 pathway (P=0.013) and PI3K pathway (P=0.009) were significantly lower than that of esophageal squamous cell carcinoma. Conclusion: Esophageal carcinoma with ductal differentiation is a type of esophageal carcinoma with unique morphology, and its molecular changes are also significantly different from those of conventional esophageal squamous cell carcinoma.

Retrospective cohort study investigating association between precancerous gastric lesions and colorectal neoplasm risk.

Colorectal cancer (CRC) is considered the most prevalent synchronous malignancy in patients with gastric cancer. This large retrospective study aims to clarify correlations between gastric histopathology stages and risks of specific colorectal neoplasms, to optimize screening and reduce preventable CRC. Clinical data of 36,708 patients undergoing gastroscopy and colonoscopy from 2005-2022 were retrospectively analyzed. Correlations between gastric and colorectal histopathology were assessed by multivariate analysis. Outcomes of interest included non-adenomatous polyps (NAP), conventional adenomas (CAs), serrated polyps (SPs), and CRC. Statistical analysis used R version 4.0.4. Older age (≥50 years) and Helicobacter pylori infection (HPI) were associated with increased risks of conventional adenomas (CAs), serrated polyps (SPs), non-adenomatous polyps (NAP), and colorectal cancer (CRC). Moderate to severe intestinal metaplasia specifically increased risks of NAP and CAs by 1.17-fold (95% CI 1.05-1.3) and 1.19-fold (95% CI 1.09-1.31), respectively. For CRC risk, low-grade intraepithelial neoplasia increased risk by 1.41-fold (95% CI 1.08-1.84), while high-grade intraepithelial neoplasia (OR 3.76, 95% CI 2.25-6.29) and gastric cancer (OR 4.81, 95% CI 3.25-7.09) showed strong associations. More advanced gastric pathology was correlated with progressively higher risks of CRC. Precancerous gastric conditions are associated with increased colorectal neoplasm risk. Our findings can inform screening guidelines to target high-risk subgroups, advancing colorectal cancer prevention and reducing disease burden.

Establishment and Evaluation of a Risk Prediction Model for Pathological Escalation of Gastric Low-Grade Intraepithelial Neoplasia.

The study aims to explore the risk factors for pathological escalation after endoscopic surgery for gastric low-grade intraepithelial neoplasia (LGIN) and to establish and evaluate a risk prediction model for LGIN. A total of 120 patients diagnosed with gastric LGIN by biopsy and endoscopic submucosal dissection (ESD) between November 2020 and June 2022 were retrospectively analyzed. Gender, age, Helicobacter pylori (HP) infection, lesion size, lesion location, morphology, gastric mucosal congestion, nodules status, surface ulceration and erosion, and ME-observation of all patients were collected and divided into upgraded and non-upgraded groups according to the biopsy and ESD postoperative pathological diagnosis results. Independent risk factors for pathological escalation after ESD surgical treatment were screened by logistic regression analysis, and a risk prediction model was established. Among the 120 patients with gastric LGIN, 49 patients developed postoperative pathological upgrading; the rate of pathological upgrading was 40.83%. Among them, 42 patients were upgraded to high-grade intraepithelial neoplasia (HGIN), 1 case was upgraded to advanced gastric cancer, and 6 cases were upgraded to early gastric carcinoma (EGC). Univariate analysis showed that age, lesion size, gastric mucosal congestion, surface ulcers, and erosion were significantly different between the groups (p < 0.05). Multivariate Logistic regression analysis revealed that age ≥60 years, focal length ≥2 cm, gastric mucosal congestion, and surface ulceration and erosion were independent risk factors for postoperative pathological escalation in patients with gastric LGIN. Final joint probability forecasting model for P = 1/[1 + e(26.515-0.161 x β1-0.357 x β2+0.039 x β3-0.269 x β4)]. Age, lesion size ≥2 cm, gastric mucosal congestion, and lesion surface ulceration and erosion are risk factors for postoperative pathological upgrading in patients with gastric LGIN. The risk prediction model established in this study based on risk factors has predictive value and can provide a scientific reference for the clinical treatment of patients with gastric LGIN.

Human papillomavirus genotyping in high-grade vaginal intraepithelial neoplasia: Amulticentric Italian study.

This study aimed to analyze the human papillomavirus (HPV) genotype distribution in a large cohort of high-grade vaginal intraepithelial neoplasia (VaIN) (vaginal HSIL, VaIN2/3) patients from two Italian referral centers. We included all patients with histologically confirmed VaIN2/3 from the Department of Surgical Sciences, Sant'Anna Hospital, University of Torino, Torino, Italy, and Ospedale Maggiore della Carità, Novara, Italy, between 2003 and 2022. After the histological evaluation of formalin-fixed paraffin-embedded samples, we performed HPV genotyping with VisionArray HPV Chip 1.0. We detected HPV DNA in 94.4% of VaIN2/3 (168/178), with HPV 16 as the most prevalent genotype, accounting for 51.8% of all infections, 41.2% of VaIN2and 77.6% of VaIN3 cases. Other frequent genotypes were HPV 58 (8.3%, 10.9% of VaIN2and 2.0% of VaIN3), HPV 73 (5.4%, 5.0% of VaIN2and 6.1% of VaIN3), and HPV 31 (5.4%, 6.7% of VaIN2and 2.0% of VaIN3). 73.2% of VaIN2/3 had a single HPV genotype infection and 26.8% a multiple infection (20.8% a double infection, 4.8% a triple infection, and 1.2% a quadruple infection). Single infection was more frequently present in VaIN3 than VaIN2 (81.6% vs. 69.8%). 69.1% of single infections and 73.3% of multiple infections had one or more genotypes covered by nine-valent HPV vaccine. HPV vaccination is expected to have a large impact on reducing the incidence of vaginal intraepithelial neoplasia.

Updated German guideline on diagnosis and treatment of squamous cell carcinoma and adenocarcinoma of the esophagus.

Diagnosis and therapy of esophageal carcinoma is challenging and requires a multidisciplinary approach. The purpose of the updated German guideline "Diagnosis and Treatment of Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus-version 3.1" is to provide practical and evidence-based advice for the management of patients with esophageal cancer. Recommendations were developed by a multidisciplinary expert panel based on an extensive and systematic evaluation of the published medical literature and the application of well-established methodologies (e.g. Oxford evidence grading scheme, grading of recommendations). Accurate diagnostic evaluation of the primary tumor as well as lymph node and distant metastases is required in order to guide patients to a stage-appropriate therapy after the initial diagnosis of esophageal cancer. In high-grade intraepithelial neoplasia or mucosal carcinoma endoscopic resection shall be performed. Whether endoscopic resection is the definitive therapeutic measure depends on the histopathological evaluation of the resection specimen. Esophagectomy should be performed minimally invasive or in combination with open procedures (hybrid technique). Because the prognosis in locally advanced esophageal carcinoma is poorwith surgery alone, multimodality therapy is recommended. In locally advancedadenocarcinomas of the esophagus or esophagogastric junction, perioperative chemotherapy or preoperative radiochemotherapy should be administered. In locally advanced squamous cell carcinomas of the esophagus, preoperative radiochemotherapy followed by complete resection or definitive radiochemotherapy without surgery should be performed. In the case of residual tumor in the resection specimen after neoadjuvant radiochemotherapy and R0 resection of squamous cell carcinoma or adenocarcinoma, adjuvant immunotherapy with nivolumab should be given. Systemic palliative treatment options (chemotherapy, chemotherapy plus immunotherapy, immunotherapy alone) in unresectable or metastastic esophageal cancer depend on histology and are stratified according to PD-L1 and/or Her2 expression.

Abstract B093: Alcoholic chronic inflammation driven CREB mediates acinar-to-ductal reprogramming and promote neoplastic progression

Abstract Introduction: Alcoholic chronic pancreatitis (ACP) is a progressive fibroinflammatory disease of the pancreas often characterized by extensive acinar cell injury leading to acinar-to-ductal metaplasia (ADM). However, the impact of ADM associated with ACP on the acceleration of oncogenic mutant Kras (Kras*)-driven tumorigenesis remains poorly understood. In this study, we aimed to unravel the underlying mechanism by which ACP-induced dysfunction and with Kras*, leads to the development of irreversible ADM and premalignant lesions that establish a tumor-permissive microenvironment for the emergence of high-grade pancreatic intraepithelial neoplasia (PanINs). Methods: ACP mice model was developed in acinar cell-specific Ptf1aCreERTM/+, Ptf1aCreERTM/+; LSL-KrasG12D/+ (KC), and genetic ablation of cyclic AMP response element-binding protein 1 (CREB) in KC (KCC−/−) mice crossed with or without R26R-EYFP reporter mice, and these mice were fed with alcohol-enriched or regular diet along with repetitive caerulein administration. Lineage tracing studies and acinar explants were employed to investigate the fate of adult acinar cells. ACP-induced mice were subsequently euthanized either 3 days or 21 days after ACP induction, the pancreas was collected for immunohistochemical analysis and examined for ADM, PanINs, fibrosis, and inflammation. To gain insights into the molecular mechanisms; kinase array analysis, acinar cell explant culture, Western blot and qPCR-based studies were conducted. Additionally, single-cell RNA sequencing (scRNA-seq) was employed to investigate cell-specific transcriptomic changes focusing on distinct cellular compartments. Results: Lineage tracing studies showed that ACP-induced ADM stems from direct transdifferentiating adult acinar cells to a ductal phenotype in Kras* mice. ACP induction with Kras* cooperatively provided a sustained Kras - dependent oncogenic program in inflammation-induced metaplastic progenitor cells. The upregulation of CREB accompanied this process of malignant transformation. CREB activation persists even after ACP withdrawal in KC mice compared to Ptf1aCreERTM/+ mice without mutant Kras. Acinar-specific CREB ablation attenuated advanced PanIN lesion development, impeding tumor progression in Kras* mice. Additionally, it reduced inflammation-induced tissue injury and facilitated acinar cell recovery. ScRNA-seq analysis revealed gene enrichment favoring acinar cell homeostasis and downregulation of ductal gene signatures in KCC−/− mice, further emphasizing CREB's pivotal role in modulating these cellular processes. Conclusion: Our findings demonstrate that Kras* sustains an irreversible ADM and PanIN through continuous activation of CREB. Additionally, we have identified that CREB mediates an oncogenic transcriptional program that drives tumor progression in the context of inflammation-induced disease. Importantly, our study reveals that ACP synergistically cooperates with Kras*-driven activated CREB, promoting the progression of ADM toward high-grade PanINs. Citation Format: Siddharth Mehra, Supriya Srinivasan, Anna Bianchi, Austin Dosch, Samara Singh, Vanessa Garrido, Iago De Castro Silva, Varunkumar Krishnamoorthy, Sudhakar Jinka, Jashodeep Datta, Nipun B. Merchant, Nagaraj Nagathihalli. Alcoholic chronic inflammation driven CREB mediates acinar-to-ductal reprogramming and promote neoplastic progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B093.

The Native Flip-Flop-Intrahepatic Papillary Neoplasm of Bile Duct

Intrahepatic papillary neoplasm of bile duct configures as a papillary neoplasm with a distinct fibro-vascular stalk layered by variant epithelium pervading intrahepatic bile ducts with cystic dilatation. Neoplasm configures as a premalignant lesion associated with low grade, intermediate grade or high grade intraepithelial neoplasia. Tumour progression is concordant with preliminary inactivation of TP53 and p16, antecedent activating mutations within KRAS and delayed loss of SMAD4/ DPC4 gene. Cogent clinical symptoms arising due to biliary obstruction as hyper-bilirubinaemia or abdominal pain may emerge. Cytological smears are hyper-cellular and comprised of broad, double layered sheets and aggregates of columnar epithelial cells enmeshed within a fine stroma commingled with complex, three dimensional, branching papillary configurations. Morphologically, complex tubulovillous structures or micropapillary articulations appear to distend bile ducts or enlarged, multi-locular cysts are layered by pancreaticobiliary, intestinal, gastric or oncocytic epithelium.