Argon plasma coagulation for Barrett's esophagus with low-grade dysplasia: a randomized trial with long-term follow-up on the impact of power setting and proton pump inhibitor dose.

BACKGROUND: This study evaluated the impact of power setting and proton pump inhibitor (PPI) dose on efficacy and safety of argon plasma coagulation (APC) of Barrett's esophagus (BE) with low-grade dysplasia (LGD). METHODS : 71 patients were randomized to APC with power set at 90 W or 60 W followed by 120 mg or 40 mg omeprazole. The primary outcome was the rate of complete (endoscopic and histologic) ablation of BE at 6 weeks. Secondary outcomes included safety and long-term efficacy. RESULTS : Complete ablation rate in the 90 W/120 mg, 90 W/40 mg, and 60 W/120 mg groups was 78 % (18/23; 95 % confidence interval [CI] 61-95), 60 % (15/25; 95 %CI 41-79), 74 % (17/23; 95 %CI 56-92), respectively, at 6 weeks and 70 % (16/23; 95 %CI 51-88), 52 % (13/25; 95 %CI 32-72), and 65 % (15/23; 95 %CI 46-85) at 2 years post-treatment (differences not significant). Additional APC was required in 28 patients (23 residual and 5 recurrent BE). At median follow-up of 108 months, 66/71 patients (93 %; 95 %CI 87-99) maintained complete ablation. No high-grade dysplasia or adenocarcinoma developed. Overall, adverse events (97 % mild) did not differ significantly between groups. Chest pain/discomfort was more frequent in patients receiving 90 W vs. 60 W power (P < 0.001). One patient had esophageal perforation and two developed stenosis. CONCLUSIONS: APC power setting and PPI dose did not impact efficacy and safety of BE ablation. Complete ablation of BE with LGD was durable in > 90 % of patients, without any evidence of neoplasia progression in the long term.

Immunohistochemical features and staging of early gastric cancer.

INTRODUCTION: The aim of this study was to analyze the particularities of early gastric cancer (EGC) and their importance for staging, prognosis, and therapy. MATERIAL AND METHODS: A total of 338 GCs diagnosed and surgically removed in three medical institutes from Eastern Europe were retrospectively examined, and the EGCs were further examined. Besides the demographic factors and tumor characteristics, immunostains were performed with E-cadherin, HER-2, p53, Ki67, MLH-1, MSH-2, COX-2, VEGF-A, CD31, and CD105. RESULTS: From the 338 GCs, 29 were EGCs, the average being similar in Poland and Hungary (12.37% and 13.33% respectively) but lower in Romania (5.61%). The rate of lymph node metastases was 20.69% (n = 6). Two of the cases presented liver metastases, both of them having a multifocal aspect. In 1 of these cases, limited to the mucosa, intramural carcinomatosis of the lymph vessels was seen in submucosa, muscularis propria, and subserosa. COX-2 positivity was observed in 14 (48.72%) cases. COX-2 was directly correlated with microvessel density determined with CD31 (p < 0.001) and CD105 (p = 0.03). Same correlation with CD31 and CD105 was seen for HER-2 (p = 0.03 and p = 0.0007). The only negative independent prognostic factors for overall survival were tumor localization at the proximal stomach and male gender, regardless of age. CONCLUSIONS: In EGCs, intramural carcinomatosis of the lymph vessels and multifocality should be separately described in every surgical pathology report, as indicators of aggressiveness. Microsatellite status, E-cadherin, HER-2, p53, and Ki67 do not have prognostic value in EGC, but the highly angiogenic pattern is a possible therapeutic target.

Adenocarcinoma risk in patients registered with Polish Barrett's Oesophagus Registry.

Barrett's Oesophagus (BO) is a complication of chronic gastro-oesophageal reflux disease (GORD) and is a major risk factor for oesophageal adenocarcinoma. Current guidelines are based on data showing a 0.5% annual malignancy progression rate. The Polish Barrett's Oesophagus Registry (POBOR) was established to characterize Polish patients with BO and estimate the risk of malignant progression. POBOR was established in 1999 after a dedicated training of endoscopists and histopathologists. Physicians registered patients using a dedicated registry form. After excluding patients known to have endoscopic treatment for BO, follow-up <1 year and adenocarcinoma found at index endoscopy we have linked patients personal identification numbers (PESEL) with the National Cancer Registry to identify those with a diagnosis of oesophageal or gastric cardia adenocarcinoma. In total, 843 patients were registered [609 men (72.2%), male to female ratio 2.6:1] with median age at diagnosis of 56 years (IQR:47-67). Long segment BE was found at index endoscopy in 294 patients (39.4%) whereas low grade dysplasia in 147 (17.4%). 112 patients (13.3%) fulfilled the exclusion criteria and the remaining 731 were followed for a median of 9.8 years (IQR: 9.3-10.0). After 6779 patient-years, 6 adenocarcinomas were diagnosed yielding an incidence rate of 0.89 per 1000 patients-years (95% confidence interval [CI 0.40-1.97]) which corresponds to annual malignancy progression rate of less than 0.1%. The malignancy rate in patients with low grade dysplasia was 3.70 per 1000 patient-years (95% CI 1.39-9.85). In Polish BO patients the risk of malignant progression was lower than previously reported. It was notably higher in patients with low grade dysplasia than in those with no dysplasia at index endoscopy, which may warrant strict surveillance in these patients.

Proposal of a Dukes-MAC-like staging system for gastric cancer.

The aim of this study was to present an epidemiological update regarding the classical prognostic parameters of gastric cancer (GC) in 3 countries from Eastern Europe and to suggest a modification of the pTNM staging system. In 333 consecutive cases which were diagnosed between 2003 and 2012 in 3 departments of pathology from Romania, Hungary, and Poland, the following parameters were analyzed: age and gender of patients, tumor localization, macroscopic and microscopic aspects including the degree of discohesivity, depth of tumor infiltration, and pTNM stage. From all of the studied parameters, the following proved to have independent prognostic value, indicating a lower survival rate: presence of distant metastases (p=0.001), lymph node positivity (p=0.0009), depth of tumor infiltration (p=0.04), age over 50 (p=0.02), proximally located tumors (p=0.03), and ulceroinfiltrative or diffusely infiltrative macroscopic aspect (p=0.0002). The pT2N1-3 staged cases showed a worse prognosis compared with the pT3N0 ones (p=0.02). Regardless of depth of invasion, the lymph node status remains the strongest indicator of the survival rate in GC. The pTN staging system should be adapted and a Dukes-MAC-like staging system should include the following groups: stage A1-T1N0, stage A2-T1N1-3, stage B1-T2N0, stage B2-T2N1-3, stage C1-T3N0, stage C2-T3N1-3, and stage D-T4N0-3. The grade of discohesivity/budding is not a prognostic factor in GC.

Maspin-related Orchestration of Aggressiveness of Gastric Cancer.

BACKGROUND AND STUDY AIM: Although some hypotheses have been postulated on the genesis of gastric cancer (GC), the origin of this disease remains unclear. The aim of this study was to develop a hypothesis about gastric carcinogenesis based on our experience in the field of GC and on published reports on about 28 studies in the field of subcellular maspin expression in GC. In 180 cases of GC, the clinicopathologic features were correlated with the results obtained after paired immunohistochemical stains (tumor/normal mucosa) with 15 antibodies: E-cadherin, HER-2, VEGF, CD31, CD105, COX-2, maspin, bax, bcl-2, p53, Ki67, MLH-1, MSH-2, Mena protein, and vimentin. RESULTS: Cytoplasmic maspin was observed in foveolar cells with intestinal metaplasia, whereas mixed (combined nuclear-cytoplasmic) expressions were more characteristic of the intramucosal foci of signet-ring cells and dysplastic cells. The tumor cells that expressed cytoplasmic maspin were mostly intestinal type bax/COX-2/Mena/E-cadherin-positive differentiated adenocarcinomas with nodular growth and more superficial invasion. The nuclear shift of maspin was more frequent in HER-2/p53-positive intestinal type adenocarcinomas with diffuse architecture at the invasion front, as well as for node-positive poorly cohesive carcinomas. Loss of maspin expression induced a higher risk of distant metastases, without differences in the survival rate. CONCLUSIONS: In GC with associated metaplasia, cytoplasmic maspin is predominant; the nuclear shift induces local aggressiveness and risk of node metastases, whereas total loss can indicate a risk of distant metastases. In GC without associated metaplasia, nuclear expression of maspin is retained, indicating a more aggressive behavior.

Geographic particularities in incidence and etiopathogenesis of sporadic gastric cancer.

It is known that geographical differences in the prevalence and etiopathogenesis of gastric cancer exist across the world. Eastern Europe and East Asia are two of the largest endemic areas of gastric cancer in the world, yet there are few studies comparing its features in these two regions. Based on our experience and literature data, we performed a review that is mainly focused on the etiology and pathogenesis of sporadic gastric cancer and its geographic particularities. Geographic prevalence of specific Helicobacter pylori strains is also synthesized. The pathogenesis of gastric cancer in patients from countries of the authors, respectively Japan, Romania, Hungary and Poland, is particularly examined.

New Insights in Histogenetic Pathways of Gastric Cancer.

The aim of this paper was to describe 3 possible histogenetic pathways for poorly cohesive (diffuse) carcinomas and 2 for intestinal-type gastric carcinomas (GCs), which might influence the behavior of GC. In the present observational study, 102 patients with early (n = 50) and advanced GCs (n = 52) were evaluated, and the histogenetic background was analyzed. All of the cases were sporadic GCs. For particular aspects, Maspin, E-cadherin, and SLUG immunostains were performed. For our final conclusions, the results were correlated with literature data. In early stages, poorly cohesive carcinomas can display 3 histogenetic pathways, with particular molecular behaviors: "carcinoma with intraepithelial pagetoid onset" (with or without a switch from E-cadherin to SLUG positivity), "carcinoma with early lymphatic invasion" (carcinoma limited to mucosa but with carcinomatosis of the lymph vessels from subjacent layers), and "microglandular-type poorly cohesive carcinoma" (the onset is similar with adenocarcinoma but abrupt dedifferentiation can be seen in the submucosa, with persistence of a dual component in the deep layers). The intestinal type carcinoma can be developed on the background of superficially located dysplasia ("classic adenocarcinoma") or in the submucosal heterotopic mucosa ("adenocarcinoma arising from the mucosal infolding in the submucosa"). Based on personal observations correlated with literature data, 5 histopathogenetic pathways are proposed with specific denominations. Each of them can partially explain the aberrant behavior of early gastric cancer.

Hereditary diffuse gastric cancer--An overview.

The incidence of gastric cancer varies by up to ten fold throughout the world, and the geographic distribution of hereditary cases is not well explored. Familial clustering is seen in 10% of cases, and approximately 3% of all gastric cancers develop due to hereditary diffuse gastric cancer (HDGC). In this review, the characteristics of HDGC are presented according to molecular particularities, geographic distribution, and other parameters. Based on our experience and the data from the literature, we discuss the possibility of applying a mutation signature (spectrum) study and adductomic approaches to a comparative carcinogenesis of HDGC. We also provide a comprehensive, up-to-date review of genetic counseling and criteria for screening and surveillance of eligible families.

Suspicious macroscopic features of small malignant colorectal polyps.

OBJECTIVE: The aim of this analysis was to retrospectively review video recordings of malignant polyps <10 mm in search for suspicious macroscopic features in white light endoscopy. METHODS: Database entries and recordings of screening colonoscopies from a single tertiary referral center between June 2009 and December 2012 were reviewed. Malignant polyps <10 mm were analyzed. The recordings were reviewed by two expert endoscopists in search for suspicious morphological features: irregular contours, central depression, contact bleeding, shape deformity, central depression, chicken skin sign, circumscribed area with abnormal vascular and/or surface pattern. Then, six experienced endoscopists watched the recordings in search of listed features. Next, video recordings of these malignant polyps were mixed with randomly drawn video recordings of 20 non-malignant polyps matched by size and reviewed by 14 blinded endoscopists to assess the sensitivity and specificity for the diagnosis of malignant polyps. RESULTS: Five of the 8651 (0.06%) subjects who underwent screening colonoscopy during the study period were diagnosed with a malignant polyp <10 mm. Only one of them was ad hoc identified by performing endoscopist as suspicious. On recordings review performed by the experts, each of the four remaining polyps presented at least one suspicious macroscopic feature. Presence of these features was confirmed by experienced endoscopists. The sensitivity and specificity for the diagnosis of malignant polyp were 73.21% and 85.35%, respectively, if at least two suspicious macroscopic features defined malignant polyp. CONCLUSIONS: On careful white light endoscopy examination small malignant colorectal polyps show suspicious macroscopic features, which were frequently unrecognized by examining endoscopists.

Predictive factors of proximal advanced neoplasia in the large bowel.

INTRODUCTION: The aim of the study was to evaluate the impact of sex, age, family history and distal findings on the risk of proximal advanced neoplasia (cancer or advanced adenoma) in the large bowel. MATERIAL AND METHODS: Records for 10 111 asymptomatic participants of the Colonoscopy Screening Program (CSP), recruited from the Warsaw region between 2000 and 2004, were analyzed. A multivariate logistic regression model was used to estimate the impact of sex, age, family history and most advanced distal lesions on the occurrence of proximal advanced neoplasia. To enhance comparability of the study two definitions of the proximal colon were applied - either the splenic flexure (1(st)) or the bend between the descending and sigmoid colon (2(nd) definition) represented the boundary. RESULTS: One hundred and thirty-three (1(st)) and 167 patients (2(nd) definition) were found to have at least one advanced neoplastic lesion in the proximal part, respectively. Eleven and 14 patients were found to have carcinoma, while in 130 and 163 patients at least one proximal advanced adenoma appeared. Men were at twice as high risk of having advanced neoplasia in the proximal colon than women (OR = 1.94, 95% CI: 1.31-2.87, p = 0.001 or OR = 1.69, 95% CI: 1.20-2.40, p = 0.003, respectively). The presence of distal advanced neoplastic lesions was associated with 3.5 times higher risk of proximal advanced neoplasia (OR = 3.58, 95% CI: 2.00-6.43, p < 0.0001 or OR = 3.41, 95% CI: 1.95-5.96, p < 0.0001), respectively. CONCLUSIONS: The results may confirm some limitation of flexible sigmoidoscopy in the screening settings in comparison with colonoscopy, at least in men and people with distal advanced neoplasia.

Cyclooxygenase-2 immunohistochemical expression in serrated polyps of the colon.

AIM OF THE STUDY: Cyclooxygenase-2 (COX-2) expression has been observed in a substantial percentage of classical adenomas of the large bowel. The aim of the study was to assess and compare the expression of COX-2 in serrated polyps of the colon. MATERIAL AND METHODS: One hundred and nineteen serrated polyps were analyzed. There were 83 hyperplastic polyps (HP), 19 sessile serrated polyps (SSP) and 17 traditional serrated adenomas (TSA). COX-2 expression was assessed semi-quantitatively (0-2) and each lesion was fully characterized in terms of anatomical location, size, histology, age and sex of the patient. The general estimating equation (GEE) model with logit link was used in the statistical analysis. RESULTS: Epithelial expression of COX-2 was found in 85/119 serrated polyps (71.43%): 57/83 (68.67%) HP, 16/19 (84.21%) SSP, and 12/17 (70.59%) TSA. In HP and SSP it was predominantly of weak (49/83 HP, 12/19 SSP), whereas in TSA it was mainly of medium/strong intensity (8/17). The TSA category was associated with more frequent COX-2 expression (OR = 7.00, 95% CI: 1.49-32.88, p = 0.014) than HP, but such relation was not found for SSP vs. HP (p > 0.1). No associations between COX-2 expression and clinical parameters were found. CONCLUSIONS: Immunohistochemical COX-2 expression cannot serve as a diagnostic adjunct to differentiate HP and SSP.

Serrated polyps of the colon: how reproducible is their classification?

For several years, the lack of consensus on definition, nomenclature, natural history, and biology of serrated polyps (SPs) of the colon has created considerable confusion among pathologists. According to the latest WHO classification, the family of SPs comprises hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The term SSA/P with dysplasia has replaced the category of mixed hyperplastic/adenomatous polyps (MPs). The present study aimed to evaluate the reproducibility of the diagnosis of SPs based on currently available diagnostic criteria and interactive consensus development. In an initial round, H&E slides of 70 cases of SPs were circulated among participating pathologists across Europe. This round was followed by a consensus discussion on diagnostic criteria. A second round was performed on the same 70 cases using the revised criteria and definitions according to the recent WHO classification. Data were evaluated for inter-observer agreement using Kappa statistics. In the initial round, for the total of 70 cases, a fair overall kappa value of 0.318 was reached, while in the second round overall kappa value improved to moderate (kappa = 0.557; p < 0.001). Overall kappa values for each diagnostic category also significantly improved in the final round, reaching 0.977 for HP, 0.912 for SSA/P, and 0.845 for TSA (p < 0.001). The diagnostic reproducibility of SPs improves when strictly defined, standardized diagnostic criteria adopted by consensus are applied.

Proximal shift of advanced adenomas in the large bowel--does it really exist?

INTRODUCTION: During the last decades, the proximal shift in the distribution of colorectal carcinomas (CRCs) has been described. It is uncertain whether the shift is the result of actual changes in CRC incidence or reflects population aging. Most CRCs develop as a result of malignant progression of benign epithelial neoplasms--advanced adenomas (AA). OBJECTIVES: The aim of the study was to investigate whether the proximal shift of AA occurs over time. PATIENTS AND METHODS: Two databases were used. The first one (RETRO) included consecutive patients of the Department of Gastroenterology treated between the years 1981 and 1994. The secondone (Colonoscopy Screening Program--CSP) included asymptomatic participants of the colonoscopy screening program recruited between 2000 and 2004 from the Warsaw region. Only patients with AA who underwent total colonoscopy were included in the analysis. AA was defined as adenoma of 10 mm or more in diameter, with high-grade neoplasia, and villous or tubulovillous morphology, or any combination of the above features. The analysis was conducted using 2 different definitions of the proximal segment in the large intestine--either splenic flexure or the bend between the descending and sigmoid colon. To compare the distribution of AA, a multiple logistic regression model was used. RESULTS: 41 of 200 patients (20.5%) in RETRO and 122 of 430 patients (28.4%) in CSP group, respectively, were found to have AA located proximally to the splenic flexure. No proximal shift of AA was found after age and sex adjustment (P>0.1). CONCLUSIONS: The risk of having proximal AA was similar in both groups. The results suggest the lack of proximal shift in the distribution of advanced colorectal adenomas.

Serrated polyps of the colorectum: histological classification and clinical significance.

Serrated polyps of the colorectum are heterogeneous lesions, a subset of which is now regarded as the precursor of colorectal cancer with DNA microsatellite instability. The serrated pathway encompassing hyperplastic aberrant crypt foci, hyperplastic polyps, sessile serrated polyps (adenomas), mixed polyps, and traditional serrated adenomas, with a meticulous review of their up-to-date histological classifications, is presented. Some remarks concerning genetics of serrated polyps and the mechanism leading to carcinoma development are also included.

Large intra- and inter-individual variability of genes expression levels limits potential predictive value of molecular diagnosis of dysplasia in Barrett's esophagus.

Barrett's esophagus represents a well-defined precursor lesion of esophageal adenocarcinoma, although only a subset of patients with these lesions advances to invasive cancer. Currently, reliable markers predicting neoplastic progression in Barrett's esophagus are lacking. The only clinically useful risk factor is the presence of dysplasia in Barrett's epithelium, but its use as a prognostic marker of disease progression has several significant limitations. Thus, identification of biomarkers of potential prognostic value in dysplasia development in Barrett's esophagus is highly important. The aim of the study was to determine if expression levels of selected genes support histologic diagnosis of dysplastic changes in Barrett's esophagus. Upon rigorous sampling and independent histopathologic examination of endoscopic specimens by two experienced gastrointestinal pathologists, 56 patients with Barrett's esophagus (16 negative for dysplasia, 15 with indefinite, 21 with low-grade, and 4 with high-grade dysplasia) were selected for molecular analysis. The relative mRNA levels of ten selected genes were estimated by quantitative real-time polymerase chain reaction (PCR) analysis. Although expression of nine genes showed trends toward down- or upregulation during progression from Barrett's esophagus without dysplasia to Barrett's esophagus with high-grade dysplasia, only a decrease in S100A2 mRNA levels was statistically significant (P<0.05). However, there was considerable variation among individuals and significant overlapping of ranges. Furthermore, detailed, comparative analysis of serial samples from Barrett's mucosa and normal squamous epithelium shows large intra-individual variability of gene expression levels. In conclusion, expression of this set of ten genes cannot be used as a molecular marker aiding histological examination of dysplasia in Barrett's esophagus. Significant inter- and intra-patient variations of gene expression levels makes use of the selected genes impractical.

Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia.

BACKGROUND: Recommendations for colorectal-cancer screening are based solely on age and family history of cancer, not sex. METHODS: We performed a cross-sectional analysis of the data from a large colonoscopy-based screening program that included 50,148 participants who were 40 to 66 years of age. People 40 to 49 years of age were eligible only if they had a family history of cancer of any type. Of the 43,042 participants 50 to 66 years of age, 13.3% reported a family history of colorectal cancer, as did 66.3% of the 7106 participants who were 40 to 49 years of age. We defined advanced neoplasia as cancer or adenoma that was at least 10 mm in diameter, had high-grade dysplasia, or had villous or tubulovillous histologic characteristics, or any combination thereof. We used multivariate logistic regression to identify associations between participants' characteristics and advanced neoplasia in a primary (or derivation) data set, and we confirmed the associations in a secondary (or validation) data set. RESULTS: Advanced neoplasia was detected in 2553 (5.9%) participants 50 to 66 years of age and in 243 (3.4%) participants 40 to 49 years of age. The rate of complications during colonoscopy was 0.1%, and no participants died. In the validation set, a logistic-regression model showed that male sex was independently associated with advanced neoplasia (adjusted odds ratio, 1.73; 95% confidence interval, 1.52 to 1.98; P<0.001). In each age group (40 to 49 years, 50 to 54 years, 55 to 59 years, and 60 to 66 years), the number of persons who would have to undergo colorectal-cancer screening in order to detect one advanced neoplasia was significantly lower in men than in women (23 vs. 36, 17 vs. 28, 12 vs. 22, and 10 vs. 18, respectively). CONCLUSIONS: We detected advanced neoplasia at a significantly higher rate in men than in women, which may warrant refinement of the screening recommendations for colorectal cancer.