Smokeless tobacco keratosis in oral mucosa with epithelial dysplasia: A case report.

RATIONALE: Smokeless tobacco use is a risk factor for the development of various oral lesions, among which is smokeless tobacco keratosis (STK). This condition is caused by constant frictional irritation of smokeless tobacco products against the oral mucosa and appears as a White-to-gray plaque with wrinkling. PATIENT CONCERNS: A 50-year-old man who had been using smokeless tobacco for 24 years visited our clinic complaining of changes in the lower right sulcus of the oral cavity for 10 days. Clinical examination revealed a unilateral, nonhomogeneous White lesion in the area of the complaint. Histopathological examination showed hyperkeratosis, areas of keratin plugging, and mild dysplastic epithelial changes. DIAGNOSIS: The clinico-histopathological correlation suggested a diagnosis of STK with focal mild epithelial dysplasia. INTERVENTION AND OUTCOME: A comprehensive management plan included maintaining oral hygiene, education on the detrimental effects of smokeless tobacco, advice to cease smoking, and regular follow-up to monitor the potential for malignant transformation. The patient was referred to a tobacco cessation society for tailored advice and counseling. On follow-up visits, there was an improvement in the lesion after habitual cessation. LESSONS: The diagnosis of tobacco-related oral lesions is often delayed, which may result in malignant transformation. This illustrates the need to train healthcare professionals to identify tobacco-related conditions at an early stage and to educate patients regarding the harmful effects of tobacco use.

Fatty Acid Binding Protein 1 is an Independent Prognostic Biomarker for Gallbladder Cancer with Direct Hepatic Invasion.

Background: Direct liver invasion (DI) is a predominant pathway of gallbladder cancer (GBC) metastasis, but the molecular alterations associated with DI remain addressed. This study identified specific genes correlated with DI, which may offer a potential biomarker for the diagnosis and prognosis of advanced GBC. Methods: RNA samples from 3 patients with DI of GBC were used for RNA-seq analysis. Differentially expressed genes and metabolic pathways between primary tumor (T) and DI tissue was used to analyze aberrant gene expressions. Immunohistochemistry (IHC) of fatty acid binding protein 1 (FABP1) in 62 patients with DI was engaged to evaluate its association with clinicopathological characteristics and prognosis. IHC of CD3+ and CD8+ T cells was analyzed for their correlation with FABP1 expression, clinicopathological features and prognosis. Univariate and multivariate Cox hazards regression analyses were performed to identify independent prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: FABP1 mRNA levels were significantly upregulated in DI region compared to T tissue. IHC results showed identical results with elevated FABP1 (p < 0.0001). Expression of FABP1 in DI region was significantly associated with lymph node metastasis (P = 0.028), reduced DFS (P = 0.013) and OS (P = 0.022); in contrast, its expression in T region was not associated with clinicopathological characteristics and prognosis (P > 0.05). The density of CD8+ T cells in DI region with higher FABP1 expression was significantly lower than that with lower FABP1 expression (p = 0.0084). Multivariate analysis unveiled those hepatic metastatic nodules (HR = 3.35, 95%CI: 1.37-8.15, P = 0.008) and FABP1 expression in DI region (HR = 2.01, 95%CI: 1.05-3.88, P = 0.036) were high risk factors for OS, and FABP1(HR = 2.05, 95%CI: 1.04-4.06, P = 0.039) was also a high risk factor for DFS. Conclusions: Elevated expression of FABP1 in DI region serves as a potential prognostic biomarker for advanced GBC with DI.

Clinical implications of pediatric biliary intraepithelial neoplasia diagnosed from a choledochal cyst specimen.

BACKGROUND: Biliary intraepithelial neoplasia (BilIN), a noninvasive precursor of cholangiocarcinoma, can manifest malignant transformation. Since cholangiocarcinoma (CCA) may progress due to chronic inflammation in the bile ducts and gallbladder, choledochal cysts are considered a precursor to CCA. However, BilIN has rarely been reported in children, to date. METHODS: We reviewed medical records of patients (< 18 years of age, n = 329) who underwent choledochal cyst excision at Asan Medical Center from 2008 to 2022. BilIN was diagnosed in 15 patients. Subsequent analyses were performed of the demographics, surgical procedures, clinical course, and outcomes in these patients. Subgroup analysis and multivariate logistic regression test were performed to identify factors influencing BilIN occurrence. RESULTS: The mean age of the patients included in our study was 40.1 ± 47.6 months. In 15 patients, BilIN of various grades was diagnosed. Todani type I was prevalent in 80% of the patients. The median age at surgery was 17 months. During a mean follow-up of 63.3 ± 94.0 months, no adverse events such as stone formation in the remnant intrapancreatic common bile duct and intrahepatic duct or cholangiocarcinoma were observed, indicating a favorable outcome until now. CONCLUSIONS: The potential progression of choledochal cysts to BilIN in children was demonstrated. These results could underscore the importance of early and comprehensive excision of choledochal cysts, including resection margins for associated lesions and more thorough postoperative surveillance in patients with or at risk of BilIN.

Condyloma and Anal Dysplasia.

Anal intraepithelial neoplasia (AIN) are precancerous lesions and are sequela of human papilloma virus (HPV) infection. AIN is classified as low-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion. Screening with anal cytology and anoscopy should be considered for high-risk populations. Diagnosis is made through high resolution anaoscopy and biopsy. Options for treatment include ablation and several topical therapies; however, recurrence rates are high for all treatment options, and an ongoing surveillance is necessary to prevent progression to anal squamous cell carcinoma. HPV vaccination is recommended to prevent disease.

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 < 0.001) and accounted for more 0-IIc (P < 0.001), atrophic gastritis was common (P < 0.001), and irregular microvascular patterns (IMVPs) and demarcation lines (DLs) were more obvious (P < 0.001). There was more infiltration in the undifferentiated carcinoma tissue (P < 0.001), more abnormal folds and poorer mucosal peristalsis (P < 0.001), and more obvious IMVPs, irregular microsurface patterns and DLs (P < 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.

A paclitaxel-hyaluronan conjugate (ONCOFID-P-B™) in patients with BCG-unresponsive carcinoma in situ of the bladder: a dynamic assessment of the tumor microenvironment.

BACKGROUND: The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response. METHODS: The composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis. RESULTS: In baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68-1.00) for patient response prediction. CONCLUSIONS: The clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.

Pathologic significance of peribiliary capillary plexus in gallbladder neoplasm.

AIMS: Significance of peribiliary capillary plexus (PCP) in gallbladder neoplasms remains unclear. Aims are to characterize high-grade biliary intraepithelial neoplasm (BilIN), pyloric gland adenoma (PGA), and intracholecystic papillary neoplasm (ICPN), precursors of gallbladder carcinoma, and to differentiate invasive carcinoma from pseudo-invasive lesions in gallbladder walls, referring to PCP. MATERIALS AND METHODS: High-grade BilIN (38 cases), PGA (5 cases), and ICPN (25 cases) were examined using capillary immunostaining. Non-neoplastic gallbladders were used as controls. RESULTS: In non-neoplastic gallbladders, a single layer of regularly dotted capillaries (PCP) was located beneath lining epithelia and around non-neoplastic glands (NNGs), including Rokitansky-Aschoff sinus (RAS), presenting a two-layer of lining epithelia and PCP. Intra-luminal components of all cases of high-grade BilIN and PGA and one-third of ICPNs presented a two-layer pattern. In the remaining ICPNs, capillaries were irregular and sparse in intraluminal neoplastic components presenting irregular and complicated lesions. Neoplastic glands in gallbladder walls of high-grade BilIN and ICPN were classifiable into 2 types: glands that were underlain by densely dotted capillaries and those that were not, with the latter suggestive of invasive carcinoma, while the former suggestive of non-invasive neoplasms involving NNGs intraepithelially and/or showing an expanding growth into gallbladder wall (pseudo-invasion). CONCLUSION: A two-layer pattern of lining epithelia and underlining capillaries were preserved in all cases of high-grade BilIN and PGA and one-third of ICPN cases. Presence or absence of dotted capillaries around neoplastic glands may be able to be added as a new pathologic feature to differentiate invasive carcinomas from pseudo-invasion in gallbladder wall.

CT findings and clinical effects of high grade pancreatic intraepithelial neoplasia in patients with intraductal papillary mucinous neoplasms.

PURPOSE: To investigate the common CT findings of high-grade (HG) PanIN and clinical effects in the remnant pancreas in patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. MATERIALS AND METHODS: Two hundred fifty-one patients with surgically confirmed IPMNs (118 malignant [invasive carcinoma/high-grade dysplasia] and 133 benign [low-grade dysplasia]) were retrospectively enrolled. The grade of PanIN (233 absent/low-grade and 18 high-grade) was recorded, and all patients underwent serial CT follow-up before and after surgery. Two radiologists analyzed CT findings of high-risk stigmata or worrisome features according to 2017 international consensus guidelines. They also analyzed tumor recurrence on serial follow-up CT after surgery. Statistical analyses were performed to identify significant predictors and clinical impact on postoperative outcomes of HG PanIN. RESULTS: PanIN grade showed a significant association with IPMN grade (p = 0.012). Enhancing mural nodules ≥5 mm, abrupt main pancreatic duct (MPD) changes with distal pancreatic atrophy, increased mural nodule size and MPD diameter were common findings in HG PanIN (P<0.05). In multivariate analysis, abrupt MPD change with distal pancreatic atrophy (odds ratio (OR) 6.59, 95% CI: 2.32-18.72, <0.001) and mural nodule size (OR, 1.05; 95% CI, 1.02-1.08, 0.004) were important predictors for HG PanIN. During postoperative follow-up, HG PanIN (OR, 4.98; 95% CI, 1.22-20.33, 0.025) was significantly associated with cancer recurrence in the remnant pancreas. CONCLUSION: CT can be useful for predicting HG PanIN using common features, such as abrupt MPD changes and mural nodules. In HG PanIN, extra caution is needed to monitor postoperative recurrence during follow-up.

[The timeline of the screening and treatment strategy of intraepithelial neoplasia of the uterine cervix adopted in Morocco]. / La chronologie d'évolution des modes de dépistage et de traitement des néoplasies intra épithéliales du col utérin adoptés au Maroc.

In Morocco, the purpose of the National Cancer Prevention and Control Plan (PNPCC) is to decrease the incidence, mortality, and morbidity attributable to cervical cancer (CC), including the general objective which is to improve women´s care by setting up an organized system for screening, early diagnosis and treatment of this disease, and as operational objectives an: 1) achievement of at least 30% of the annual coverage rate by cervical cancer (CC) screening; 2) achievement of at least 80% of the rate of participation in CC screening per screening cycle; 3) achievement of 100% of the treatment rate for precancerous lesions screened within the framework of the program. CC screening concerns all women aged 30 to 49 years old. Women who have already had CC and pregnant women from the 8th week of amenorrhea until the 6th week postpartum are excluded from the program. The screening test currently used is the naked eye inspection with acetic acid or visual inspection with acetic acid (VIA), which will be followed by a colposcopy exam and biopsy if a precancerous lesion is confirmed. The VIA is carried out at the level of urban and rural health centers, by a trained health professional. Knowing that the pap-smear test was widely used before. Thermo coagulation, also called: cold coagulation, is currently the main treatment for intraepithelial lesions (LIE) that are eligible for this treatment, and finally the national program has introduced anti-HPV vaccination within the national vaccination program (NPI).

Exosomal long non-coding RNA TRPM2-AS promotes angiogenesis in gallbladder cancer through interacting with PABPC1 to activate NOTCH1 signaling pathway.

BACKGROUND: Abnormal angiogenesis is crucial for gallbladder cancer (GBC) tumor growth and invasion, highlighting the importance of elucidating the mechanisms underlying this process. LncRNA (long non-coding RNA) is widely involved in the malignancy of GBC. However, conclusive evidence confirming the correlation between lncRNAs and angiogenesis in GBC is lacking. METHODS: LncRNA sequencing was performed to identify the differentially expressed lncRNAs. RT-qPCR, western blot, FISH, and immunofluorescence were used to measure TRPM2-AS and NOTCH1 signaling pathway expression in vitro. Mouse xenograft and lung metastasis models were used to evaluate the biological function of TRPM2-AS during angiogenesis in vivo. EDU, transwell, and tube formation assays were used to detect the angiogenic ability of HUVECs. RIP, RAP, RNA pull-down, dual-luciferase reporter system, and mass spectrometry were used to confirm the interaction between TRPM2-AS, IGF2BP2, NUMB, and PABPC1. RESULTS: TRPM2-AS was upregulated in GBC tissues and was closely related to angiogenesis and poor prognosis in patients with GBC. The high expression level and stability of TRPM2-AS benefited from m6A modification, which is recognized by IGF2BP2. In terms of exerting pro-angiogenic effects, TRPM2-AS loaded with exosomes transported from GBC cells to HUVECs enhanced PABPC1-mediated NUMB expression inhibition, ultimately promoting the activation of the NOTCH1 signaling pathway. PABPC1 inhibited NUMB mRNA expression through interacting with AGO2 and promoted miR-31-5p and miR-146a-5p-mediated the degradation of NUMB mRNA. The NOTCH signaling pathway inhibitor DAPT inhibited GBC tumor angiogenesis, and TRPM2-AS knockdown enhanced this effect. CONCLUSIONS: TRPM2-AS is a novel and promising biomarker for GBC angiogenesis that promotes angiogenesis by facilitating the activation of the NOTCH1 signaling pathway. Targeting TRPM2-AS opens further opportunities for future GBC treatments.

Assessing the Potential of HPV16 E6 Seroprevalence as a Biomarker for Anal Dysplasia and Cancer Screening-A Systematic Review and Meta-Analysis.

Elevated rates of human papillomavirus (HPV)-related anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer (AC) in populations like men who have sex with men (MSM) living with HIV underscore the need for effective screening. While high-resolution anoscopy-guided biopsy is the gold standard, limited provider availability poses a challenge. This has spurred interest in identifying biomarkers for improved AC prevention. Antibodies against HPV16 oncoprotein E6, known as markers for cervical and oropharyngeal cancers, are the focus of the current study. The systematic review and meta-analysis included six studies meeting inclusion criteria, assessing HPV16 E6 seroprevalence in individuals with anal HSIL or AC. A two-step meta-analysis estimated pooled odds ratios and 95% confidence intervals (CI) for HPV16 E6 seroprevalence and HSIL or AC. Pooled prevalence, sensitivity, specificity, and diagnostic odds ratios were also calculated. This meta-analysis revealed a 3.6-fold increased risk of HSIL for HPV16 E6 seropositive individuals, escalating to a 26.1-fold risk increase for AC. Pooled specificity and sensitivity indicated a high specificity (0.99; 95%CI: 0.99, 0.99) but lower sensitivity (0.19; 95%CI: 0.10, 0.34) for HPV16 E6 serostatus as an AC biomarker. In conclusion, while HPV16 E6 seroprevalence demonstrates specificity as a potential biomarker for HPV-related AC, its utility as a standalone screening tool may be limited. Instead, it could serve effectively as a confirmation test, particularly in high-risk populations, alongside other diagnostic methods. Further research is imperative to explore HPV16 E6 seroconversion dynamics and alternative screening algorithms.

Exposure to di-2-ethylhexyl phthalate and breast neoplasm incidence: A cohort study.

BACKGROUND: Phthalates are ubiquitous environmental endocrine disruptors. As the predominant phthalate, di-2-ethylhexyl phthalate (DEHP) has been considered possibly carcinogenic to humans but large-scale longitudinal evidence is needed to further clarify its carcinogenicity. OBJECTIVES: To examine the association between DEHP exposure and incidence of breast malignant neoplasm, carcinoma in situ and benign neoplasm. METHODS: A total of 273,295 women from UK Biobank cohort were followed up for a median of 13.5 years. Disease information was collected from National Health Service Cancer Registry and National Death Index. Baseline and yearly-average level of DEHP exposure were estimated for each individual by linking chemical monitoring record of European Environment Agency with home address of the participants by Kriging interpolation model. Cox proportional hazard model was employed to estimate the association between DEHP exposure and breast neoplasms. RESULTS: The median (IQR) of baseline and yearly-average DEHP concentration were 8000.25 (interquartile range: 6657.85-11,948.83) and 8000.25 (interquartile range: 1819.93-11,359.55) µg/L. The highest quartile of baseline DEHP was associated with 1.11 fold risk of carcinoma in situ (95 % CI, 1.00, 1.23, p < 0.001) and 1.27 fold risk of benign neoplasm (95 % CI, 1.05, 1.54, p < 0.001). As for yearly-average exposure, each quartile of DEHP was positively associated with higher risk of malignant neoplasm (HR, 1.05; 95 % CI, 1.03, 1.07, p < 0.001), carcinoma in situ (HR, 1.08; 95 % CI, 1.04, 1.11, p < 0.001) and benign neoplasm (HR, 1.13; 95 % CI, 1.07, 1.20, p < 0.001). Stratification analysis showed no significant modification effects on the DEHP-neoplasm relationship by menopausal status or ethnicity but a suggestive higher risk in younger women and those who underwent oral contraceptive pill therapy. In sensitivity analysis, the associations remained when excluding the cases diagnosed within 2 years post baseline. CONCLUSIONS: Real-world level of DEHP exposure was associated with higher risk of breast neoplasms. Because of the health risks associated with DEHP, its release to the environment should be managed.

Multiple high-risk HPV infections probably associated with a higher risk of low-grade cytological abnormalities but not with high-grade intraepithelial lesions of the cervix.

BACKGROUND: For women diagnosed with HR-HPV DNA positivity in community hospitals, the necessity of investigating the potential presence of multiple HR-HPV infections upon referral to tertiary medical institutions remains unclear. METHODS: In our cohort, women tested positive for HR-HPV DNA during examinations in community hospitals, were subsequently referred to tertiary medical facilities, reevaluated HR-HPV genotype and categorized based on cytological and histopathological results. The risk of cytologic/histopathology abnormalities and ≧ high grade squamous intraepithelial lesion(HSIL) or Cervical Intraepithelial Neoplasia (CIN) 2 associated with individual genotypes and related multiple HPV infections are calculated. RESULTS: A total of 1677 women aged between 21 and 77 were finally included in the present study. The cytology group included 1202 women and the histopathological group included 475 women with at least one HR-HPV infection of any genotype. We only observed a higher risk of low grade cytological abnormalities in women with multiple infections than those in corresponding single infections (for all population with an OR of 1.85[1.39-2.46]; p < 0.05). However, this phenomenon was not observed in histopathology abnormalities (CIN1). The risk of developing of ≥ HSIL/CIN2 in women who were infected with multiple HR-HPV also showed a similar profile to those with a single HR-HPV genotype. CONCLUSION: Multiple HR-HPV infections is only associated with a higher associated risk of low grade cytological abnormalities. There is no evidence of clinical benefit to identify the possible presence of multiple HR-HPV infection frequently in a short period of time for women with HR-HPV-DNA positive.

Male ductal carcinoma in situ: diagnosis and management of a rare disease in men.

Ductal carcinoma in situ is very rare in male patients, accounting for approximately 5%-7% of all male breast cancers. We present a case of a man in his early 70s who presented with bloody nipple discharge and gynaecomastia and was subsequently diagnosed with ductal carcinoma in situ (DCIS). We discuss his management with surgical resection and the consideration of adjuvant treatment. We also review the existing literature on the presentation, diagnosis and management of DCIS in men.

Incidence and Risk Factors for Recurrence and Progression of HPV-Independent Vulvar Intraepithelial Neoplasia.

OBJECTIVES: Human papillomavirus (HPV)-independent vulvar intraepithelial neoplasia (VIN) is a rare yet aggressive precursor lesion of vulvar cancer. Our objectives were to estimate its long-term incidence, the risk of recurrent disease and progression to vulvar cancer, and risk factors thereof. MATERIALS AND METHODS: Patients with HPV-independent VIN between 1991 and 2019 in a selected region were identified from the Dutch Nationwide Pathology Databank (Palga). Data were collected from the pathology reports. Crude and European age-standardized incidence rates were calculated for 10-year periods. Kaplan-Meier analyses were performed to determine the cumulative recurrence and cancer incidence, followed by Cox regression analyses to identify associated risk factors. RESULTS: A total of 114 patients were diagnosed with solitary HPV-independent VIN without prior or concurrent vulvar cancer. The European age-standardized incidence rate increased from 0.09 to 0.69 per 100,000 women-years between 1991-2010 and 2011-2019. A cumulative recurrence and cancer incidence of 29% and 46% were found after 8 and 13 years of follow-up, respectively. Nonradical surgery was identified as the only independent risk factor for recurrent HPV-independent VIN. Risk factors associated with progression to cancer were increasing age and a mutant p53 immunohistochemical staining pattern. CONCLUSIONS: The incidence of detected HPV-independent VIN has substantially increased the last decade and the subsequent recurrence and vulvar cancer risks are high. Although HPV-independent VIN may present as a wide morphologic spectrum, surgical treatment should aim for negative resection margins followed by close surveillance, especially for p53 mutant lesions.

Upgrade Rates of Variant Lobular Carcinoma In Situ Compared to Classic Lobular Carcinoma In Situ Diagnosed in Core Needle Biopsies: A 10-Year Single Institution Retrospective Study.

The primary aim of this study was to determine the upgrade rates of variant lobular carcinoma in situ (V-LCIS, ie, combined florid [F-LCIS] and pleomorphic [P-LCIS]) compared with classic LCIS (C-LCIS) when diagnosed on core needle biopsy (CNB). The secondary goal was to determine the rate of progression/development of invasive carcinoma on long-term follow-up after primary excision. After institutional review board approval, our institutional pathology database was searched for patients with "pure" LCIS diagnosed on CNB who underwent subsequent excision. Radiologic findings were reviewed, radiologic-pathologic (rad-path) correlation was performed, and follow-up patient outcome data were obtained. One hundred twenty cases of LCIS were identified on CNB (C-LCIS = 97, F-LCIS = 18, and P-LCIS = 5). Overall upgrade rates after excision for C-LCIS, F-LCIS, and P-LCIS were 14% (14/97), 44% (8/18), and 40% (2/5), respectively. Of the total cases, 79 (66%) were deemed rad-path concordant. Of these, the upgrade rate after excision for C-LCIS, F-LCIS, and P-LCIS was 7.5% (5 of 66), 40% (4 of 10), and 0% (0 of 3), respectively. The overall upgrade rate for V-LCIS was higher than for C-LCIS (P = .004), even for the cases deemed rad-path concordant (P value: .036). Most upgraded cases (23 of 24) showed pT1a disease or lower. With an average follow-up of 83 months, invasive carcinoma in the ipsilateral breast was identified in 8/120 (7%) cases. Six patients had died: 2 of (contralateral) breast cancer and 4 of other causes. Because of a high upgrade rate, V-LCIS diagnosed on CNB should always be excised. The upgrade rate for C-LCIS (even when rad-path concordant) is higher than reported in many other studies. Rad-path concordance read, surgical consultation, and individualized decision making are recommended for C-LCIS cases. The risk of developing invasive carcinoma after LCIS diagnosis is small (7% with ∼7-year follow-up), but active surveillance is required to diagnose early-stage disease.

A Comparison of Spatial and Phenotypic Immune Profiles of Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and compare the immune microenvironments (IMEs) of PDAC and its precursor lesions. We demonstrate that the IME of IPMN was abundantly infiltrated with CD8+ T cells and PD-L1-positive antigen-presenting cells (APCs), whereas the IME of PanIN contained fewer CD8+ T cells and fewer PD-L1-positive APCs but elevated numbers of immunosuppressive regulatory T cells (Tregs). Thus, immunosuppression in IPMN and PanIN seems to be mediated by different mechanisms. While immunosuppression in IPMN is facilitated by PD-L1 expression on APCs, Tregs seem to play a key role in PanIN. Our findings suggest potential immunotherapeutic interventions for high-risk precursor lesions, namely, targeting PD-1/PD-L1 in IPMN and CTLA-4-positive Tregs in PanIN to restore immunosurveillance and prevent progression to cancer. Tregs accumulate with malignant transformation, as observed in PDAC, and to a lesser extent in IPMN-associated PDAC (IAPA). High numbers of Tregs in the microenvironment of PDAC went along with a markedly decreased interaction between CD8+ T cells and cancerous epithelial cells (ECs), highlighting the importance of Tregs as key players in immunosuppression in PDAC. We found evidence that a defect in antigen presentation, further aggravated by PD-L1 expression on APC, may contribute to immunosuppression in IAPA, suggesting a role for PD-L1/PD-1 immune checkpoint inhibitors in the treatment of IAPA.

Role of the fatty pancreatic infiltration in pancreatic oncogenesis.

Although pancreatic precancerous lesions are known to be related to obesity and fatty pancreatic infiltration, the mechanisms remain unclear. We assessed the role of fatty infiltration in the process of pancreatic oncogenesis and obesity. A combined transcriptomic, lipidomic and pathological approach was used to explore neoplastic transformations. Intralobular (ILF) and extralobular (ELF) lipidomic profiles were analyzed to search for lipids associated with pancreatic intraepithelial neoplasia (PanINs) and obesity; the effect of ILF and ELF on acinar tissue and the histopathological aspects of pancreatic parenchyma changes in obese (OB) and non-obese patients. This study showed that the lipid composition of ILF was different from that of ELF. ILF was related to obesity and ELF-specific lipids were correlated to PanINs. Acinar cells were shown to have different phenotypes depending on the presence and proximity to ILF in OB patients. Several lipid metabolic pathways, oxidative stress and inflammatory pathways were upregulated in acinar tissue during ILF infiltration in OB patients. Early acinar transformations, called acinar nodules (AN) were linked to obesity but not ELF or ILF suggesting that they are the first reversible precancerous pancreatic lesions to occur in OB patients. On the other hand, the number of PanINs was higher in OB patients and was positively correlated to ILF and ELF scores as well as to fibrosis. Our study suggests that two types of fat infiltration must be distinguished, ELF and ILF. ILF plays a major role in acinar modifications and the development of precancerous lesions associated with obesity, while ELF may play a role in the progression of PDAC.