High-grade Neoplasia Research Articles

Expressions and significance of the second mitochondria-derived activator of caspase protein and Survivin in tissues of high-grade intraepithelial neoplasia and esophageal squamous cell carcinoma

Objective To detect the expressions of the second mitochondria-derived activator of caspase protein(Smac) and Survivin in tissues of high-grade intraepithelial neoplasia(HGIN)and esophageal squamous cell carcinoma (ESCC), and explore the influence of Smac and Survivin on occurrence and development of ESCC. Methods The retrospective case-control study was conducted. The clinicopathological data of 45 healthy controls with suspected esophagitis (control group), 41 patients with HGIN (HGIN group) and 57 patients with ESCC (ESCC group) who were admitted to the Qinghai University Affiliated Hospital between January 2012 and December 2014 were collected. Observation indicators included: (1) expressions of Smac and Survivin were detected by immunohistochemistry. (2) Expressions of mRNA of Smac and Survivin in tumor tissues and adjacent tissues were detected by real-time polymerase chain reaction (RT-PCR). (3) Correlation between relative expressions of Smac and Survivin in tumor tissues and adjacent tissues. (4) Relationship between expressions of Smac and Survivin in tumor tissues and clinicopathological factors. Measurement data with normal distribution were represented as ±s. The comparisons among groups was evaluated with the one-way ANOVA. The comparison between tumor tissues and adjacent tissues were analyzed by the paired t test, and comparison of rates was done using the chi-square test and Fisher exact probability. The correlation between expressions of Smac and Survivin was done using the Pearson correlation analysis. Results (1) Expressions of Smac and Survivin were detected by immunohistochemistry. The positive expression rate of Smac of esophageal tissues in the control group, HGIN group and ESCC group were respectively 82.2%(37/45), 43.9%(18/41) and 40.4%(23/57), with a statistically significant difference among the 3 groups (χ2=20.408, P 0.05). The positive expression rate of Smac of adjacent tissues in the ESCC group was 84.2%(48/57), with a statistically significant difference between tumor tissues and adjacent tissues (χ2=20.530, P 0.05). The positive expression rate of Survivin of adjacent tissues in the ESCC group was 15.8%(9/57), with a statistically significant difference between tumor tissues and adjacent tissues (χ2=32.386, P 0.05) and in adjacent tissues (r=-0.197, P>0.05). There was a correlation in the relative expression of Smac between tumor tissues and adjacent tissues (r=0.527, P 0.05). (4) The relationship between the expressions of Smac and Survivin in tumor tissues and clinicopathologic factors: the positive expression of Smac in tumor tissues was 51.6% in men, 9.1% in women, 64.7% in tumor diameter<3 cm, 28.0% in tumor diameter≥3 cm, 60.0% in stage Ⅰ-Ⅱ of TNM stage and 22.7% in stage Ⅲ-Ⅳ of TNM stage, respectively, showing statistically significant differences in the positive expression of Smac in tumor tissues of patients with different gender, tumor diameter and TNM stage (χ2=6.093, 5.567, 6.041, P<0.05). The positive expression of Survivin in tumor tissues was 54.5% in high- and moderate-differentiated tumors, 100.0% in low-differentiated tumors, 75.0% in stageⅠ-Ⅱ and 100.0% in stage Ⅲ-Ⅳ, respectively, showing statistically significant differences in the positive expression of Survivin in tumor tissues of patients with different tumor differentiation and TNM stage (P<0.05). Conclusions The expression of Smac in the progression of esophageal epithelial cells towards to high-grade intraepithelial neoplastia and proliferatoin is inhibited, while expression of Survivin is activated. Smac and Survivin participate in the occurrence of ESCC and maybe play an role in determining the biological features of carcinoma tissues. Key words: Esophageal Neoplasms; Second mitochondria-derived activator of caspase protein; Survivin protein; High-grade esophageal intraepithelial neoplasia

Significance of high-risk HPV detection in women with atypical glandular cells on Pap testing: Analysis of 1857 cases from an academic institution.

The role of high-risk human papillomavirus (hrHPV) testing in women with various types of atypical glandular cells (AGC) on Papanicolaou (Pap) test is undetermined. Herein, the authors retrospectively searched their pathology database for cases of AGC with concurrent hrHPV testing and histological follow-up results within 1 year between January 2008 and December 2013. Among 3709 AGC cases occurring during the study period, 2287 had concurrent Hybrid Capture 2 HPV testing results. The overall rate of hrHPV positivity (hrHPV+) was 27.7%. Of these 2287 cases, 1857 cases (81.2%) had histological follow-up results within 1 year, including 529 hrHPV + cases and 1328 hrHPV-negative (hrHPV-) cases. Among the hrHPV + cases, 16.8% had cervical intraepithelial neoplasia 2/3 (CIN2/3), 5.7% had cervical adenocarcinoma in situ (AIS)/adenocarcinoma (ADC), and 1.1% had an endometrial carcinoma. Among the hrHPV- cases, 0.6% had CIN2/3, 0.2% had AIS/ADC, and 3.8% had an endometrial carcinoma. The rate of high-grade cervical lesions (CIN2/3, AIS, or ADC) was significantly higher in women who were hrHPV + compared with hrHPV- women for all age groups. Endometrial carcinoma was most commonly present in women aged ≥50 years. To the authors' knowledge, the current study is the largest follow-up study published to date regarding women with AGC cytology and HPV testing. The study data indicate that hrHPV testing is useful for predicting the risk of high-grade cervical neoplasia in women with AGC, but has no significant value in evaluating the risk of endometrial carcinoma. The combination of cytology, hrHPV testing, and patient age can significantly aid in the appropriate management of these individuals. Cancer Cytopathol 2017;125:205-211. © 2016 American Cancer Society.

Can magnifying endoscopy with narrow-band imaging discriminate between carcinomas and low grade adenomas in gastric superficial elevated lesions?

Background and study aims: The aim of this study was to investigate the capability of magnifying endoscopy with narrow-band imaging (ME-NBI) to discriminate between early carcinomas (EC) and low grade adenomas (LGA) in gastric superficial elevated epithelial neoplasias. Patients and methods: We investigated 100 consecutive cases of gastric superficial elevated epithelial neoplasias that were removed using endoscopic submucosal dissection. The pathological diagnostic criteria were based on the revised Vienna classification; category 4 (mucosal high grade neoplasia) and category 5 (submucosal invasion by carcinoma) lesions were diagnosed as EC, whereas category 3 (mucosal low grade neoplasia) lesions were diagnosed as LGA. The associations between the postoperative pathological diagnoses and the ME-NBI findings were analyzed, and included the shape, specification, and area of irregularity in the microvascular architecture (MV) and the microsurface structure (MS). Results: Seventy-nine EC and 21 LGA cases diagnosed postoperatively were evaluated retrospectively. The lesion size (median; range (mm)) was significantly larger in the EC group (14; 2 – 95) compared to the LGA group (5; 2 – 16) (P < 0.001). Wavy forms in the MV shapes (P = 0.031), extension in the MV specifications (P = 0.035), and area with MV irregularity (P = 0.001) were found to be statistically significant predictive findings for EC. Villous forms in the MS shapes (P = 0.026), enlargement in the MS specifications (P = 0.044), and area with MS irregularity (P = 0.021) were also found to be statistically significant predictive findings for EC. The rates of preoperative sensitivity, specificity, and diagnostic accuracy of ME-NBI for discriminating EC were 86.1 %, 38.9 %, and 75 %, respectively. Conclusions: The present study suggests that ME-NBI is useful for the differential diagnosis of EC and LGA in gastric superficial elevated epithelial neoplasias.Study registration: UMIN000012925.

Prostatic intraepithelial neoplasia- the story evolves

Prostatic intraepithelial neoplasia is preneoplastic lesion described from early of this 20th century. PIN includes a spectrum of features ranging from low grade to high grade neoplasia. The studies are focused on their influence to predict the occurence of prostatic carcinoma. This review analyses the various development in the identification and differentiation of PIN and their clinical implication.

Cost-effectiveness analysis of anal cancer screening in women with cervical neoplasia in British Columbia, Canada.

BackgroundPrecursors to anal squamous cell carcinoma may be detectable through screening; however, the literature suggests that population-level testing is not cost-effective. Given that high-grade cervical neoplasia (CIN) is associated with an increased risk of developing anal cancer, and in light of changing guidelines for the follow-up and management of cervical neoplasia, it is worthwhile to examine the costs and effectiveness of an anal cancer screening program delivered to women with previously-detected CIN.MethodsA model of anal cancer screening and treatment was constructed, to estimate the cost-effectiveness of a population of CIN II/III+ women who were screened using anal cytology vs. one that received no anal cancer screening. Costs were based on Canadian estimates, and survival was based on estimates taken from the scientific literature. Effectiveness was measured in terms of life years gained (LYG) and quality-adjusted life years (QALYs). The model was run for 50 cycles, with each cycle representing one year.ResultsIncremental cost (screened vs. unscreened) was $82.17 per woman in the model. Incremental effectiveness was 0.004 LYG, and was equivalent to zero in terms of QALY. An ICER of $20,561/LYG was calculated, while no meaningful incremental cost-effectiveness ratio (ICER) could be calculated for quality-adjusted survival.ConclusionOur analysis suggests that anal cancer screening is cost-effective in terms of overall survival in women with a previous diagnosis of CIN II or CIN III as part of regular follow-up, but may not contribute meaningfully-different quality-adjusted survival due to the adverse effects of screening-related interventions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-016-1442-2) contains supplementary material, which is available to authorized users.

Risk factors for missed diagnosis of high-grade gastric neoplasia

Objective To evaluate the potential risk factors for missed diagnosis of gastric high-grade neoplasia(HGN) lesion on the basis of endoscopic features. Methods A total of 43 lesions which were initially diagnosed as HGN without cancer by forceps biopsy and later underwent endoscopic submucosal dissection(ESD) were included from November 2011 to April 2015. According to histology of ESD specimens, they were divided into HGN group and the cancer group, and their endoscopic characteristics were compared. Results There was no significant difference in the age(t=6.124, P=0.101), gender distribution(χ2=0.189, P=0.663), lesion location(χ2=1.008, P=0.909), lesion morphology(χ2=0.537, P=0.765), mucosal nodular lesions surface(χ2=0.599, P=0.439)or biopsy times(u=1.833, P=0.591) between the HGN group and cancer group. Univariate analysis showed that there were significant differences in size(t=3.324, P=0.016), a red change of the mucosal surface(χ2=11.882, P<0.001)and mucosal ulceration(χ2=5.635, P=0.018)between the two groups. In the multivariate analysis, size larger than 20 mm(OR=2.041, 95%CI: 1.023-5.682, P<0.001) and mucosal ulceration(OR=3.764, 95%CI: 1.223-9.431, P<0.001) were independent risk factors for the missed diagnosis of cancer on the HGN by forceps biopsy. Conclusion For biopsy-proven HGN gastric mucosa lesions, whose sizes are larger than 20 mm or with superficial mucosal ulcer, we need to alert to the possible missed diagnosis of cancer. Due to the limited sample size and selection bias of retrospective study sample, further researches are still needed. Key words: Gastric cancer; High-grade neoplasia; Endoscopic forceps biopsy; Endoscopic submucosal dissection

PWE-042 Incidence and Risk Factors of Post Liver Transplant Colorectal Malignancy in PSC: Abstract PWE-042 Table 1

<h3>Introduction</h3> Patients with primary sclerosing cholangitis (PSC) and co-existing colonic inflammatory bowel disease (IBD) have an increased lifetime risk of developing colorectal cancer (CRC); a risk that persists after liver transplantation. Aim: Assess the incidence rate (I.R.) of colonic dysplasia and/or cancer in patients transplanted for PSC, and determine any factors specific to post-transplant care associated with an increased CRC risk. <h3>Methods</h3> The cohort included all patients transplanted from 1987 to 2015 for PSC with concomitant colitis. Time zero was set as the point of first liver transplant. The study end-point was the time to first dysplasia or any higher lesion. Patients were censored at time of colectomy (for a non-CRC indication), death or last date of CRC-free follow up. Statistical methods employed for determining potential risk factors included Cox-proportional hazards and Kaplan-Meier estimates. <h3>Results</h3> Overall, 306 patients were transplanted during this time period. 202 patients (66%) had underlying IBD and of this group 191 patients (95%) had co-existing colitis. The final study population was 163 patients who had colitis with an intact colon. The I.R. of developing colonic dysplasia or higher lesions was 18.9 cases per 1,000 patient years and of colonic high grade dysplasia (HGD) or neoplasia was 10.4 cases per 1,000 patient years. There has been an increase in incidence rates by year of transplant (Table 1). No risk factors for the development of colonic dysplasia or above post liver transplantation were statistically significant. These risk factors included the number of colitis flares (&gt;0, &gt;1, &gt;2), the use of cyclosporine (versus tacrolimus), the use of azathioprine (versus mycophenolate mofetil), thiopurine use, use of ursodeoxycholic acid, advancing age and male gender. <h3>Conclusion</h3> The incidence of colonic dysplasia in the PSC post-transplant population is rising. Further review of specific colitis findings need to be evaluated in order to aid in any potential risk factors for CRC development. <h3>Disclosure of Interest</h3> None Declared

Refinement of screening for familial pancreatic cancer

ObjectiveSurveillance programmes are recommended for individuals at risk (IAR) of familial pancreatic cancer (FPC) to detect early pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and...

Front-to-back & dabbing wiping behaviour post-toilet associated with anal neoplasia & HR-HPV carriage in women with previous HPV-mediated gynaecological neoplasia

BackgroundAnal cancer is a human papillomavirus (HPV)-mediated neoplasia of the anal squamous epithelium. Anal cancer is much more common among women, particularly those with a previous high-grade gynaecological neoplasia. MethodsCross-sectional study of women with a previous HPV-mediated gynaecological neoplasia in Tasmania, Australia. Women presenting for follow-up gynaecological care had anal swab samples taken for anal cytology by Hologic Liquid ThinPrep, followed by HPV genotyping. Women with abnormal anal cytology were invited for high-resolution anoscopy. Potential risk factors, including post-toilet wiping behaviours, were queried by questionnaire while clinical covariates were extracted from medical records. Covariates of anal outcomes evaluated by log-binomial and log-multinomial regression. ResultsFrom 163 women enrolled in the study, 65 (39.9%) had abnormal cytology, with 46 (28.2%) being high-grade. Of the 50 women with abnormal anal cytology having high-resolution anoscopy, 32 (64.0%) had abnormal histology with 13 (26.0%) being high-grade. Of the 123 women tested for HR-HPV DNA, 48 (39.0%) had HR-HPV detected, the most common genotypes being 16 and 51 (14/123, 11.4% for both).In addition to some known anal cancer risk factors, we found front-to-back wiping was associated with significantly increased (Prevalence ratio (PR) range: 1.99⿿3.60) prevalence of cytological and histological abnormality and HR-HPV carriage/co-carriage, while dabbing post-toilet was significantly associated with decreased prevalences (PR range: 0.50⿿0.62). ConclusionsPost-toilet wiping behaviours were significantly associated with the prevalence of anal cytological, histological and HR-HPV carriage outcomes. This suggests a biologically plausible mechanism for HR-HPV introduction and the higher frequencies of anal neoplasia in women.

Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital tract

Prenatal diethylstilbestrol (DES) exposure is associated with an excess risk of clear-cell adenocarcinoma of the vagina and cervix, and of high-grade squamous neoplasia. We explored whether neoplasia risk remains elevated among DES-exposed women as they age. In all, 4062 DES-exposed and 1837 unexposed daughters were followed for approximately 30 years (1982 through 2013) for pathology-confirmed diagnoses of cervical intraepithelial neoplasia grade ≥2 (CIN2+) of the lower genital tract (n= 178). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for birth year and individual study cohort. The cumulative incidence of CIN2+ in the DES-exposed group was 5.3% (95% CI, 4.1-6.5%) and in the unexposed group was 2.6% (95% CI, 1.5-3.7%). The HR for DES and CIN2+ was 1.98 (95% CI, 1.33-2.94), and was similar with further adjustment for frequency of cervical cancer screening (HR, 1.97; 95% CI, 1.33-2.93). The HR was 2.10 (95% CI, 1.41-3.13) with additional adjustment for other potential confounders. The HR for DES exposure was elevated through age 44 years (age <45 years HR, 2.47; 95% CI, 1.55-3.94), but not in women age ≥45 years (HR, 0.91; 95% CI, 0.39-2.10). In exposed women, HRs for DES were 1.74 (95% CI, 1.09-2.79) among those who had earlier evidence of vaginal epithelial changes (VEC), presumably reflecting glandular epithelium undergoing transformation to normal, adult-type squamous epithelium, and 1.24 (95% CI, 0.75-2.06) among those without VEC, compared with unexposed women. The HRs forDES and CIN2+ were higher among women with earlier intrauterine exposure (HR, 2.64; 95% CI, 1.64-4.25 for <8 weeks' gestation and HR, 1.41; 0.88-2.25 for ≥8 weeks' gestation), and lowest when exposure began >15th week (HR, 1.14; 95% CI, 0.59-2.20). CIN2+ incidence was higher among the DES exposed, particularly those with early gestational exposure and VEC. The HR for DES and CIN2+ remained positive and significant until the mid-40s, confirming that the recommendation of annual cytological screening among these women is appropriate. Whether those ≥45 years of age continue to require increased screening is unclear, and would require a careful weighing of possible risks and benefits.

Evaluating the efficacy and safety of a novel endoscopic fluorescence imaging modality using oral 5-aminolevulinic acid for colorectal tumors.

Background and study aims: Five-aminolevulinic acid (5-ALA) is being increasingly used for photodynamic diagnosis and therapy of various types of tumors including brain, urologic, and other neoplasias. The use of 5-ALA to treat Barrett’s carcinomas has been documented, but its clinical effectiveness for diagnosis of gastrointestinal tumors, particularly early cancers, remains unknown. Patients and methods: The aim of our feasibility study was to evaluate the visibility of colorectal tumors using endoscopic fluorescence imaging (EFI) after oral administration of 5-ALA. The lesions identified by direct visualization and by the spectrums produced using EFI modality with 5-ALA were compared to the clinicopathologic features of resected specimens. Results: Twenty-three patients with a total of 27 known colorectal lesions were enrolled in the study. The median tumor size was 30 mm (range 10 – 75). Eleven of the lesions were flat or depressed lesions and 16 were sessile. Red fluorescence was observed in 22 out of 27 lesions. Red fluorescence was negative in 4 out of 11 flat or depressed lesions. In comparison with histopathologic findings, the rates of red fluorescence visibility were 62.5 % in low-grade intraepithelial neoplasia, 77.8 % in high-grade neoplasia, and 100 % in submucosal carcinoma. Red fluorescence visibility increased with the degree of dysplasia. There were no significant adverse events identified in this study. Conclusions: This feasibility study using EFI with 5-ALA demonstrated high visibility of superficial colorectal neoplasia. EFI with 5-ALA appears to be a novel, safe technique for improving real-time colorectal tumor imaging.

Use of Pathology Data to Improve High-Value Treatment of Cervical Neoplasia

We investigated the influence of pathology data to improve patient outcomes in the treatment of high-grade cervical neoplasia in a joint pathology and gynecology collaboration. Two of us (B.S.D. and M.D.) reviewed all cytology, colposcopy and surgical pathology results, patient history, and pregnancy outcomes from all patients with loop electrosurgical excision procedure specimens for a 33-month period (January 2011-September 2013). We used this to determine compliance to 2006 consensus guidelines for the performance of loop electrosurgical excision procedure and shared this information in 2 interprofessional and interdisciplinary educational interventions with Obstetrics/Gynecology and Pathology faculty at the end of September 2013. We simultaneously emphasized the new 2013 guidelines. During the postintervention period, we continued to provide follow-up using the parameters previously collected. Our postintervention data include 90 cases from a 27-month period (October 2013-December 2015).Our preintervention data include 331 cases in 33 months (average 10.0 per month) with 76% adherence to guidelines. Postintervention, there were 90 cases in 27 months (average 3.4 per month) and 96% adherence to the 2013 (more conservative) guidelines (P < .0001, χ2 test). Preintervention, the rate of high-grade squamous intraepithelial lesion in loop electrosurgical excision procedures was 44%, whereas postintervention, there was a 60% high-grade squamous intraepithelial lesion rate on loop electrosurgical excision procedure (P < .0087 by 2-tailed Fisher exact test). The duration between diagnosis of low-grade squamous intraepithelial lesion and loop electrosurgical excision procedure also increased significantly from a median 25.5 months preintervention to 54 months postintervention (P < .0073; Wilcoxon Kruskal-Wallis test). Postintervention, there was a marked decrease of loop electrosurgical excision procedure cases as well as better patient outcomes. We infer improved patient safety, and higher value can be achieved by providing performance-based pathologic data.

Synthetic evaluation of precancerous lesions and early esophageal cancers after endoscopic submucosal dissection

To evaluate the safety and prognosis for patients with early esophageal cancer and precancerous lesions after endoscopic submucosal dissection (ESD). A total of 89 patients were admitted to the Department of internal medicine in the First People's Hospital of Anqing from August 2008 to August 2011. All patients were treated with ESD at the early stage of esophageal cancer and precancerous lesions. The patients' laboratory data and relevant medical history were collected. The postoperative complications and long-term effects of ESD were analyzed. Eighty-nine patients were followed up with 100% response rate. Among 89 cases, 16 were early esophageal cancer, 38 were high-grade esophageal neoplasia and 35 were low-grade esophageal neoplasia. The one-time whole piece resection rate, complete resection rate and curative resection rate was 93.3% (84/89), 92.1% (82/89) and 92.1% (82/89), respectively. Two cases suffered intraoperative perforation with a rate of 2.2% and these 2 patients performed the intraoperative endoscopic repair; one case suffered the postoperative delayed bleeding with a rate of 1.1% and the patient underwent the conservative treatment; three cases suffered the esophageal stenosis with a rate of 3.4%. All patients were followed-up for 10-58 (36.3±21.2) months. In this period, one case recurred after ESD for 3 years with a rate of 1.1%; two cases were dead. The three-year survival rate was 97.8%. The early esophageal cancer and precancerous lesions can be treated with ESD. The method is safe and the prognosis is good.

Pathological changes of gallbladder mucosa induced by pancreaticobiliary reflux

Objective To investigate pathologic changes of gallbladder mucosa induced by continuous pancreaticobiliary reflux(PBR) in the preliminary stage and occult PBR stage. Methods Female Syrian golden hamsters were assigned into four groups: PBR model group (established by surgery), the blank control group, PBR with BOP group (to induce gallbladder cancer) and the simple BOP group. In addition, 87 patients with normal pancreaticobiliary junction (NPBJ) who underwent cholecystectomy or percutaneous transhepatic cholecystoscopy for gallbladder stones were assigned into two groups based on the value of bile amylase (BA): PBR group and the control group. Pathological changes of gallbladder mucosa between groups were analyzed and compared. Results In PBR model group, the incidences of gallbladder epithelial hyperplasia, pyloric gland metaplasia, intestinal metaplasia and low-grade neoplasia were 6/6, 3/6, 4/6 and 2/6, respectively. The incidence of gallbladder epithelial hyperplasia in PBR model group (6/6) was significantly higher than that of the blank control group (0/5). Incidence of gallbladder cancer (3/6) and high-grade neoplasia(1/6) was higher in PBR with BOP group than in the simple BOP group(0/5). In the clinical study, 70.6%(24/34) patients in PBR group presented high BA value (>1 000 U/L). Significantly higher occurrence of low-grade neoplasia can be observed in this group (73.5%, 25/34) compared with the control group (24.5%, 13/53, P<0.05). Conclusion Gallbladder mucosal hyperplasia and the tendency of high incidence of metaplasia can be detected in the preliminary stage of continuous PBR. High probability of gallbladder carcinoma or high-grade neoplasia can be induced with BOP in PBR model hamsters. Occult PBR can lead to low-grade cell dysplasia and therefore may be the factor of gallbladder malignancy. Key words: Gallbladder neoplasms; Pancreaticobiliary reflux(PBR); Gallbladder mucosa; Pathologic changes

Expression of adipophilin in gastric epithelial neoplasia is associated with intestinal differentiation and discriminates between adenoma and adenocarcinoma.

Adipophilin, a lipid droplet-associated protein that regulates lipid droplet structure and formation, is expressed in a wide variety of tumors. The aims of this study were to evaluate the frequency and distribution pattern of adipophilin expression in gastric epithelial neoplasia and to correlate these variables with clinicopathological features and the mucin phenotype. We retrospectively examined 159 cases of gastric epithelial neoplasia, which were classified according to the Vienna classification system as 52 noninvasive low-grade adenoma (category 3), 65 noninvasive high-grade neoplasia (category 4), and 42 invasive neoplasia (category 5). Immunohistochemistry for adipophilin was performed, and phenotypic marker expression was determined by immunohistostaining with MUC2, MUC5AC, CD10, MUC6, and villin. Adipophilin was expressed in 41 of the 52 (79%) category 3 cases, in 42 of the 65 (65%) category 4 cases, and in 23 of the 42 (55%) category 5 cases. Expression of adipophilin was only present in lesions with complete or incomplete intestinal phenotypes. Adipophilin was expressed more frequently in the surface epithelium in category 3, whereas there was a stepwise increase in cryptal staining of adipophilin from category 3 to category 5. In conclusion, adipophilin expression is closely related to the intestinal differentiation of the tumor. The pattern of immunostaining for adipophilin might be a useful new marker for discriminating adenomas from adenocarcinomas.

Rapidly progressive high-grade cervical intraepithelial neoplasia in a Hodgkin lymphoma patient: A Case Report

The progressive behavior of human papillomavirus (HPV) associated neoplasia in immunossuppressed patients has been clearly demonstrated. Hodgkin’s disease and its treatment render a patient highly susceptible to persistent HPV and its consequences, thus requiring a more aggressive treatment and a closer follow-up protocol. We present the case of a 41-years old patient diagnosed with nodular sclerosing Hodgkin lymphoma receiving radiochemotherapy regimen. After having completed the oncologic therapy the patient was addressed to our clinic presenting abnormal uterine bleeding; a HPV 16-positive high-grade cervical intraepithelial neoplasia diagnosis was established. We obtained persistent disease after conservative treatment which finally leads us to performing a total hysterectomy. We observed a rapidly progressive course of high-grade HPV-induced neoplasia in a case of Hodgkin’s disease patient which may represent an accelerated version of untreated neoplasia in the immunocompetent. Screening and prompt treatment are of utmost importance in this group at risk.

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV+ tumors when combined with an E6/E7 peptide vaccine

Antibody modulation of T-cell coinhibitory (e.g., CTLA-4) or costimulatory (e.g., 4-1BB) receptors promotes clinical responses to a variety of cancers. Therapeutic cancer vaccination, in contrast, has produced limited clinical benefit and no curative therapies. The E6 and E7 oncoproteins of human papilloma virus (HPV) drive the majority of genital cancers, and many oropharyngeal tumors. We discovered 15-19 amino acid peptides from HPV-16 E6/E7 for which induction of T-cell immunity correlates with disease-free survival in patients treated for high-grade cervical neoplasia. We report here that intranasal vaccination with these peptides and the adjuvant alpha-galactosylceramide elicits systemic and mucosal T-cell responses leading to reduced HPV(+) TC-1 tumor growth and prolonged survival in mice. We hypothesized that the inability of these T cells to fully reject established tumors resulted from suppression in the tumor microenvironment which could be ameliorated through checkpoint modulation. Combining this E6/E7 peptide vaccine with checkpoint blockade produced only modest benefit; however, coadministration with a 4-1BB agonist antibody promoted durable regression of established genital TC-1 tumors. Relative to other therapies tested, this combination of vaccine and α4-1BB promoted the highest CD8(+) versus regulatory FoxP3(+) T-cell ratios, elicited 2- to 5-fold higher infiltration by E7-specific CTL, and evoked higher densities of highly cytotoxic TcEO (T cytotoxic Eomesodermin) CD8 (>70-fold) and ThEO (T helper Eomesodermin) CD4 (>17-fold) T cells. These findings have immediate clinical relevance both in terms of the direct clinical utility of the vaccine studied and in illustrating the potential of 4-1BB antibody to convert therapeutic E6/E7 vaccines already in clinical trials into curative therapies.

Low Discrepancy Between Tissue Biopsy Plus Magnifying Endoscopy With Narrow-Band Imaging and Endoscopic Resection in the Diagnosis of Gastric Epithelial Neoplasia (STROBE).

Tissue biopsy is often not very accurate for the diagnosis of gastric epithelial neoplasia (GEN), and the results differ notably from endoscopic resection (ER) in terms of the pathological diagnosis. The aims of this study were to evaluate the diagnostic performances of biopsy, magnifying endoscopy with narrow-band imaging (ME-NBI), and biopsy plus ME-NBI for GEN.This study retrospectively analyzed 101 cases diagnosed as GEN using ER samples. The discrepancies between biopsy and ER, as well as between biopsy plus ME-NBI and ER in the diagnosis of GEN were evaluated. Factors that contributed to such discrepancies were analyzed. The sensitivity and specificity of biopsy and ME-NBI for the diagnosis of high-grade neoplasia (HGN) were determined.The discrepancy in the pathological diagnosis between biopsy and ER was 39.6% for GEN and 54.2% for HGN. The discrepancy between biopsy combined with ME-NBI and ER was 15.9% for GEN and 10.2% for HGN. Factors that undermined the diagnostic accuracy of biopsy included the lesion size (≤10 mm, odds ratio [OR] 1; 10–20 mm, OR 0.2, 95% confidence interval [CI] 0.1–0.7; >20 mm, OR 0.5, 95% CI 0.1–2.1, P = 0.03) and the number of biopsy fragments (OR 0.6, 95% CI 0.5–0.8, P = 0.001). The sensitivity and specificity for HGN were 45.8% (33.7%–58.3%) and 100% (87.5%–100%) for biopsy, and 88.1% (77.5%–94.1%) and 92.9% (81.0%–97.5%) for ME-NBI, respectively.In conclusion, biopsy-based diagnoses for GEN should be interpreted with caution. Biopsy combined with ME-NBI can contribute to the diagnosis of GEN, which improves diagnostic consistency with pathological result of ER specimens.

Stratification of HPV-induced cervical pathology using the virally encoded molecular marker E4 in combination with p16 or MCM

High-risk human papillomavirus (HPV) types cause cervical lesions of varying severity, ranging from transient productive infections to high-grade neoplasia. Disease stratification requires the examination of lesional pathology, and possibly also the detection of biomarkers. P16INK4a and MCM are established surrogates of high-risk HPV E6/E7 activity, and can be extensively expressed in high-grade lesions. Here we have combined these two cellular biomarkers with detection of the abundant HPV-encoded E4 protein in order to identify both productive and transforming lesions. This approach has allowed us to distinguish true papillomavirus infections from similar pathologies, and has allowed us to divide the heterogeneous CIN2 category into those that are CIN1-like and express E4, and those that more closely resemble nonproductive CIN3. To achieve this, 530 lesional areas were evaluated according to standard pathology criteria and by using a multiple staining approach that allows us to superimpose biomarker patterns either singly or in combination onto an annotated hematoxylin and eosin (H&E) image. Conventional grading of neoplasia was established by review panel, and compared directly with the composite molecular pathology visualized on the same tissue section. The detection of E4 coincided with the onset of vacuolation, becoming abundant in koilocytes as the MCM marker declined and cells lost their defined nuclear margins as visualized by standard H&E staining. Of the dual marker approaches, p16INK4a and E4 appeared most promising, with E4 generally identifying areas of low-grade disease even when p16INK4a was present. Extensive p16INK4a expression usually coincided with an absence of E4 expression or its focal retention in sporadic cells within the lesion. Our results suggest that a straightforward molecular evaluation of HPV life-cycle deregulation in cervical neoplasia may help improve disease stratification, and that this can be achieved using complementary molecular biomarker pairs such as MCM/E4 or, more promisingly, p16INK4a/E4 as an adjunct to conventional pathology.

OC-027 Buried barrett’s dysplasia: rfa is not the only culprit: Abstract OC-027 Table 1

<h3>Introduction</h3> Buried Barrett’s’ or Subsquamous Intestinal Metaplasia (SSIM) refers to glands which are ‘buried’ underneath the squamous epithelium. Buried Barrett’s can pose significant diagnostic and surveillance challenges. Buried Barrett’s has mainly been reported in the post ablation context (APC, RFA, PDT). We aim to evaluate its prevalence in patients who are ablation naïve, and understand the reasons behind it. <h3>Method</h3> This is a prospective cohort study. We investigated our Barrett’s database for patients who were referred for endoscopic treatment (EMR) of Barrett’s neoplasia between June 2006 to June 2014. We assessed histology reports before and after endoscopic therapy (EMR), specifically looking for evidence of buried Barrett’s. Biopsy: Biopsies were first obtained from any suspicious looking area. Following this, biopsies were then obtained from the neosquamous area. Finally, random biopsies were obtained. These were sent in separate cassettes. Histopathology was reported by two independent GI pathologists and was prospectively recorded on a central pathology database. Buried Barrett’s was defined as any metaplastic or glandular tissue beneath the squamous epithelium. Pathology specimens were reported by 2 independent, accredited GI pathologists. <h3>Results</h3> Our study shows that in the pre-EMR cohort, there was an overall prevalence of 12.2% of buried Barrett’s and a 9.1% prevalence of buried Barrett’s with high grade neoplasia (HGD or IMC). Our results in the post EMR cohort shows an overall prevalence of 16.8% of buried Barrett’s with 6.1% prevalence of buried high grade neoplasia (HGD or IMC). This has significant implications for post EMR endoscopic assessment and surveillance. <h3>Conclusion</h3> Buried Barrett’s and Barrett’s cancer are seen in endotherapy naïve patients. This is likely to be related to intensive biopsies. EMR, despite being a non ablation technique, still results in buried Barrett’s and Barrett’s cancer. The overall prevalence of buried Barrett’s is higher than previously reported. We need to be aware of this while assessing Barrett’s patients. Buried Barrett’s glands after ablation (APC/RFA/PDT) are well reported. This is the first study to report on the prevalence of Barrett’s in endotherapy naïve patients and in the post EMR cohort. <h3>Disclosure of interest</h3> None Declared.