Long-term follow-up after endoscopic resection of gastric superficial neoplastic lesions in Portugal.

BACKGROUND AND STUDY AIMS: Although endoscopic resection for the treatment of gastric superficial neoplastic lesions is an established first-line treatment in Eastern countries, its role has yet to be considered in Western guidelines, mostly due to a lack of long-term studies. The aim of this study was to describe long-term outcomes for endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in the treatment of gastric neoplasias in Portugal. PATIENTS AND METHODS: This was a single-center, retrospective, cohort study between March 2003 and April 2013. A total of 162 consecutive patients with 195 gastric superficial neoplasias underwent EMR (n = 54) or ESD (n = 141) and were followed up for a median of 3.2 years. RESULTS: Resection was feasible in 97 %, with en bloc and R0 resection rates of 85 % (94 % ESD vs. 61 % EMR; P = 0.001) and 81 % (91 % ESD vs. 54 % EMR; P < 0.001), respectively. The recurrence rate was 7 %, and recurrence was associated with Rx/R1 resection irrespective of resection technique (OR 5.8; 95 % confidence interval 3.9 - 8.8). The long-term curative resection rate was 86 % after one procedure and 91 % after two procedures. Adverse events were observed in 13 % of cases: 8 % bleeding and 2 % of perforations (EMR = ESD). Surgery was performed in 7 %: 6 % after noncurative endoscopic resection and 1 % due to complications. Metachronous lesion detection rate was 1 % - 1.5 % per patient year. Cancer-specific survival rate was 100 % at follow-up. CONCLUSIONS: For the first time in a Western country, results are reported to be similar to those in Eastern countries. Endoscopic resection, particularly ESD, is a highly effective treatment for gastric superficial lesions, without compromising cancer survival. Endoscopic resection should also be considered as first-line treatment for gastric neoplasias in Western countries.

Helicobacter pylori induces increased expression of Toll-like receptors and decreased Toll-interacting protein in gastric mucosa that persists throughout gastric carcinogenesis.

BACKGROUND: Toll-like receptors (TLR) are essential for Helicobacter pylori (HP) recognition. Their role in the progression of gastric lesions leading to cancer is not established. AIM: To evaluate for the first time in humans the expression of TLR2, TLR4, and TLR5, as well as the expression of other related molecules in the entire sequence of gastric lesions. METHODS: Biopsy samples (n = 80, 48% HP+) from normal mucosa, HP gastritis, metaplasia, dysplasia or adenocarcinoma were obtained from 44 patients. mRNA quantification of TLR2, TLR4, TLR5, Toll-interacting protein (TOLLIP), PPAR-γ, NF-κB, TNF-α, COX-1, COX-2, and CDX-2 was performed by real-time RT-PCR. TLR2, TLR4, and TLR5 protein expression was quantified by immunohistochemistry. RESULTS: When compared to normal mucosa (1.0 arbitrary unit (AU)), HP gastritis presented higher expression of TLR2 (2.23 ± 0.36 AU), TLR4 (1.92 ± 0.40 AU) and TNF-α (2.14 ± 0.50 AU) and lower TOLLIP and PPARγ expression (0.72 ± 0.12 AU, p < .05 all genes). Metaplasia and dysplasia/carcinoma presented higher expression of TLR2 (1.66 ± 0.46 and 1.48 ± 0.20 AU, respectively, p < .05), lower expression of TOLLIP (0.66 ± 0.09 and 0.52 ± 0.04 AU, p < .05) and PPARγ (0.73 ± 0.12 and 0.63 ± 0.10 AU, p < .05). The significant trend for decrease in TOLLIP and PPARγ was associated with increasing levels of CDX-2 from normal mucosa to carcinoma (p < .05), translating that in diffuse and higher TLRs protein expression (p < .05). CONCLUSION: Gastric carcinogenesis is associated with decreasing levels of TLRs inhibitors and elevated TLRs levels throughout all the spectrum of lesions. Future studies should investigate if modulation of these receptors activity may influence gastric carcinogenesis and tumor progression.

A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families.

PURPOSE: Although Lynch syndrome is characterized by marked genetic heterogeneity, some specific mutations are observed at high frequency in well-defined populations or ethnic groups due to founder effects. METHODS: Genomic breakpoint identification, haplotype analysis, and mutation age determination were performed in 14 unrelated patients and 95 family members presenting the same MLH1 exonic rearrangement, among a series of 84 Lynch syndrome families with germline mutations in MLH1, MSH2, or MSH6. RESULTS: All 14 probands harbored an identical deletion, comprising exons 17-19 of the MLH1 gene and exons 26-29 of the LRRFIP2 gene, corresponding to the MLH1 mutation c.1896 + 280_oLRRFIP2:c.1750-678del. This mutation represents 17% of all deleterious mismatch repair mutations in our series. Haplotype analysis showed a conserved region of approximately 1 Mb, and the mutation age was estimated to be 283 ± 78 years. All 14 families are originated from the Porto district countryside. CONCLUSION: We have identified a novel MLH1 exonic rearrangement that is a common founder mutation in Lynch syndrome families, indicating that screening for this rearrangement as a first step may be cost-effective during genetic testing of Lynch syndrome suspects of Portuguese ancestry, especially those originating from the Porto district.

A European case series of endoscopic submucosal dissection for gastric superficial lesions.

BACKGROUND: EMR is an accepted method for resection of superficial lesions in the GI tract. However, because it leads, not unusually, to piecemeal resection, histopathologic interpretation problems and an increased risk of recurrence are noticeable. Endoscopic submucosal dissection (ESD) allows a higher rate of en bloc resection, with low recurrence. Nevertheless, this technique, namely in the upper-GI tract, has rarely been described in Western countries, probably because of the rarity of gastric cancer in most countries. OBJECTIVE: To describe the efficacy and safety of ESD for gastric superficial lesions in a European country. DESIGN: Consecutive case-series report. SETTING: A tertiary specialized center. PATIENTS: Nineteen patients with gastric superficial lesions (15-30 mm), with high-grade (n = 15) or low-grade (n = 4) noninvasive epithelial neoplasias, in the antrum (n = 12), incisura angularis (n = 2), body (n = 3), and cardia (n = 2). INTERVENTION: ESD with the patient under general anesthesia in the endoscopic room (40-300 minutes) by using an insulated-tip-knife. MAIN OUTCOME MEASUREMENTS: Complete (R0) and en bloc resection, and complications. RESULTS: ESD was achieved in all cases, with 89% R0 resection and 79% en bloc resection rates observed. Major bleeding was reported in 1 case (5%); there were no cases of perforation. With a median follow-up of 10 months, a single recurrence (5%) was observed. LIMITATIONS: A small series at a single center, with a short median follow-up time. CONCLUSION: We report the feasibility and effectiveness of gastric ESD in Europe. A further description of a Western series is expected, and guidelines for its dissemination are desirable to define the role of this technique in Western countries.

Pantoprazole: a proton pump inhibitor.

Pantoprazole is a proton pump inhibitor (PPI) that binds irreversibly and specifically to the proton pump, thereby reducing gastric acid secretion. Pantoprazole has a relatively long duration of action compared with other PPIs, and a lower propensity to become activated in slightly acidic body compartments. To date, no drug-drug interactions have been identified with pantoprazole in numerous interaction studies. Overall, in the short-term (8-10 weeks) initial treatment of gastro-oesophageal reflux disease (a condition that occurs when the reflux of gastric contents causes troublesome symptoms and/or complications) and long-term (6-24 months) maintenance therapy, oral pantoprazole 20 or 40 mg/day demonstrated similar efficacy to omeprazole, lansoprazole and esomeprazole and greater efficacy than histamine type 2 receptor antagonists. Pantoprazole is also effective in treating and preventing NSAID-related gastric and gastroduodenal injury. The optimal adult oral dose for gastric acid-related disorders is pantoprazole 40 mg once daily. Although data are limited, pantoprazole 20 or 40 mg/day was effective and well tolerated in the treatment of acid-related disorders in children and adolescents. Pantoprazole was also well tolerated in adults with acid-related disorders in short- and long-term studies. Thus, pantoprazole is a valuable agent for the management of acid-related disorders.

External validation of a classification for methylene blue magnification chromoendoscopy in premalignant gastric lesions.

BACKGROUND: Conventional endoscopy has low sensitivity, specificity, and interobserver agreement for the diagnosis of gastric atrophy, intestinal metaplasia, and dysplasia. Magnification chromoendoscopy (ME) may optimize the evaluation of premalignant gastric lesions. OBJECTIVE AND DESIGN: As part of a multicenter trial, we aimed at validating a previously proposed classification for gastric methylene blue ME at a different center. SETTING, PATIENTS, AND INTERVENTIONS: A sample of patients (n = 42) with previously diagnosed chronic atrophic gastritis with or without intestinal metaplasia underwent ME (Pentax EG-3430Z) with 1% methylene blue by 2 endoscopists. MAIN OUTCOME MEASUREMENTS: A simplified version of a previously published ME classification (group I, group II [further divided into subgroups IIE and IIF], and group III) was used for macroscopic lesions (n = 203) with Sydney-Houston and Vienna classifications being used for histologic analysis (n = 479 biopsy specimens). RESULTS AND LIMITATIONS: Excellent reproducibility (wK = 0.92 [95% CI, 0.88-0.96]) was observed for classification in groups and substantial reproducibility (wK = 0.78 [95% CI, 0.72-0.84]) was found for classification in subgroups. Global validity was 82% (range 78%-86%), showing no false negatives (sensitivity of 100% [1/1 biopsy]) and a very low rate of false positives (specificity 99% [297/299 biopsies]) for dysplasia detection. CONCLUSIONS: This classification for methylene blue ME was highly reproducible and valid for the diagnosis of premalignant gastric lesions when used in a center different from that involved in its conception. Despite requiring an unconventional endoscope and a longer procedure, these results could reinforce ME as a valuable technique in the surveillance of patients at risk for gastric cancer.

Web-based system for training and dissemination of a magnification chromoendoscopy classification.

AIM: To evaluate the use of web-based technologies to assess the learning curve and reassess reproducibility of a simplified version of a classification for gastric magnification chromoendoscopy (MC). METHODS: As part of a multicenter trial, a hybrid approach was taken using a CD-ROM, with 20 films of MC lasting 5 s each and an "autorun" file triggering a local HTML frameset referenced to a remote questionnaire through an Internet connection. Three endoscopists were asked to prospectively and independently classify 10 of these films randomly selected with at least 3 d apart. The answers were centrally stored and returned to participants together with adequate feedback with the right answer. RESULTS: For classification in 3 groups, both intra- [Cohen's kappa (kappa) = 0.79-1.00 to 0.89-1.00] and inter-observer agreement increased from 1st (moderate) to 6th observation (kappa = 0.94). Also, agreement with reference increased in the last observations (0.90, 1.00 and 1.00, for observers A, B and C, respectively). Validity of 100% was obtained by all observers at their 4th observation. When a 4th (sub)group was considered, inter-observer agreement was almost perfect (kappa = 0.92) at 6th observation. The relation with reference clearly improved into kappa (0.93-1.00) and sensitivity (75%-100%) at their 6th observations. CONCLUSION: This MC classification seems to be easily explainable and learnable as shown by excellent intra- and inter-observer agreement, and improved agreement with reference. A web system such as the one used in this study may be useful for endoscopic or other image based diagnostic procedures with respect to definition, education and dissemination.

-765G > C COX-2 polymorphism may be a susceptibility marker for gastric adenocarcinoma in patients with atrophy or intestinal metaplasia.

AIM: To investigate the relationship between the -765G > C COX-2 polymorphism and the development of different gastric lesions: atrophy or intestinal metaplasia and gastric adenocarcinoma. METHODS: A cross-sectional study was performed involving 320 Portuguese individuals (210 without evidence of neoplastic disease, 73 patients with gastric adenocarcinomas and 37 with atrophy or intestinal metaplasia) using a PCR-RFLP method. RESULTS: -765C allele was overrepresented in the patients with gastric adenocarcinoma (51%) when compared either with the control group (38%) or patients with atrophy or intestinal metaplasia (27%). Callele was found to be very common in our population (0.22), and a multivariate logistic regression analysis revealed nearly 3-fold increased risk for the progression to gastric adenocarcinoma in patients with atrophy or intestinal metaplasia carrying the -765C allele (OR = 2.67, 95% CI = 1.03-6.93; P = 0.04). CONCLUSION: -765C carrier status should be considered as another susceptibility marker for gastric adenocarcinoma development in patients with atrophy or intestinal metaplasia.

Gastric cancer in a Caucasian population: role of pepsinogen C genetic variants.

AIM: To study the role of an insertion/deletion polymorphism in the pepsinogen C (PGC) gene, an effective marker for terminal differentiation of the stomach mucosa, in the susceptibility to the development of gastric lesions. METHODS: The study was performed with 99 samples of known gastric lesions and 127 samples without evidence of neoplastic disease. PCR was employed and the 6 polymorphic alleles were amplified: Allele 1 (510 bp), Allele 2 (480 bp), Allele 3/4 (450/460 bp), Allele 5 (400 bp) and Allele 6 (310 bp). RESULTS: Our results revealed that Allele 6 carriers seemed to have protection against the development of any gastric lesion (OR = 0.34; P<0.001), non-dysplastic lesions associated with gastric adenocarcinoma such as atrophy or intestinal metaplasia (OR = 0.28; P<0.001) or invasive GC (OR = 0.39; P = 0.004). CONCLUSION: Our study reveals that the Allele 6 carrier status has a protective role in the development of gastric lesions, probably due to its association with higher expression of PGC. Moreover, the frequency of Allele 6 carriers in the control group is far higher than that obtained in Asian populations, which might represent a genetic gap between Caucasian and Asian populations.

Validity of serum pepsinogen I/II ratio for the diagnosis of gastric epithelial dysplasia and intestinal metaplasia during the follow-up of patients at risk for intestinal-type gastric adenocarcinoma.

A cohort of individuals (n = 136) with lesions as severe as atrophic chronic gastritis (ACG) was cross-sectionally evaluated for the validity assessment of pepsinogen I (PGI) and pepsinogen II (PGII) serum levels for the diagnosis of intestinal metaplasia (IM) and gastric dysplasia. PGI/PGII ratio [median (range)] was 4 (0.5-7.5) in patients with ACG (n = 35); 4.6 (1.9-6.8) in type I IM (n = 18); 4.2 (1.4-5.9) in type II or type III IM limited to the antrum and incisura (n = 20); 2.4 (0.4-5.6) in extensive incomplete IM (n = 38); and 1.3 (0.4-6.4) in low-grade dysplasia (n = 23) (P = .002). Using histopathologic data as a reference test, the area under the receiver operating characteristic curves (CI 95%) was 0.73 (0.64-0.82) for extensive IM, 0.72 (0.58-0.85) for the diagnosis of dysplasia, and 0.81 (0.66-0.95) for the diagnosis of high-grade dysplasia. Using a PGI/PGII ratio of < or =3 as the cutoff for dysplasia diagnosis, the sensitivity was 70% (62-78%), the specificity was 65% (57-73%), and the negative predictive value estimates were over 90%. No differences in PG levels according to age or gender were observed. Helicobacter pylori did not significantly influence validity measurement estimates. PGI/PGII serum level ratio can be used even in the management of patients with a high a priori probability for a positive test. It may be useful for the exclusion of more advanced lesions (extensive IM and neoplastic lesions).

Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.

The pro-carcinogenic effects of prostaglandin E2 (PGE2) in colonic mucosa are not only regulated by the rates between Cyclooxygenase-2 (COX-2) biosynthesis and 15-Hydroxyprostaglandin Dehydrogenase (15-PGDH)-dependent degradation but also the steady-state levels of PGE2 in extracellular microenvironment, maintained by key specific prostaglandin transporters, the Multidrug Resistance Protein (MRP4) (efflux carrier) and Prostaglandin Transporter (PGT) (influx carrier). To understand the contribution of genetic variability in genes coding for COX-2/15-PGDH/MRP4/PGT proteins in CRC development, we conducted a hospital-based case-control study involving 246 CRC patients and 480 cancer-free controls. A total of 51 tagSNPs were characterized using the Sequenom platform through multiplexed amplification followed by mass-spectrometric product separation or allelic discrimination using real-time PCR. Seven tagSNPs were implicated in CRC development: the rs689466 in COX-2 gene, the rs1346271 and rs1426945 in 15-PGDH, the rs6439448 and rs7616492 in PGT and rs1751051 and rs1751031 in MRP4 coding genes. Upon a stratified analysis a measurable gene-environment interaction was noticed between rs689466 and smoking habits, with individuals ever-smokers carriers of rs689466 GG homozygous genotype having a nearly 6-fold increased susceptibility for CRC onset (95%CI: 1.49-22.42, P = 0.011). Furthermore, the multifactor dimensionality reduction (MDR) analysis identified an overall four-factor best gene-gene interactive model, including the rs1426945, rs6439448, rs1751051 and rs1751031 polymorphisms. This model had the highest cross-validation consistency (10/10, P<0.0001) and an accuracy of 0.6957 and was further associated with a 5-fold increased risk for CRC development (95%CI: 3.89-7.02, P<0.0001). In conclusion, specific low penetrance genes in the pro-carcinogenic PGE2 pathway appear to modulate the genetic susceptibility for CRC development. A clearer understanding on CRC etiology through the identification of biomarkers of colorectal carcinogenesis might allow a better definition of risk models that are more likely to benefit from targeted preventive strategies to reduce CRC burden.

Functional polymorphisms of Toll-like receptors 2 and 4 alter the risk for colorectal carcinoma in Europeans.

BACKGROUND: Colon carcinogenesis is associated with increased expression levels of Toll-like receptor 2 and Toll-like receptor 4. AIM: To determine in a Caucasian population the role of Toll-like receptor 2 and Toll-like receptor 4 polymorphisms in colorectal cancer development. METHODS: Hospital based multicentre case control study involving 193 colorectal cancer patients and 278 healthy individuals. DNA samples were extracted from blood cells and genotyping of TLR2+597T>C, TLR2-4760T>C, TLR4-3745A>G, TLR2Arg753Gln, TLR4Asp299Gly was performed. Functionality of risk polymorphisms was evaluated through production of TNF-α in cell culture and Toll-like receptors levels quantified by real-time RT-PCR. RESULTS: TLR2+597CC homozygous had 5-fold decreased risk (odds ratio (OR)=0.21, 95% CI: 0.09-0.50, p<0.001) and TLR4 299Gly homozygous 3-fold increased risk of colorectal cancer (OR=3.30, 95% CI: 1.18-9.28, p=0.015). In stratified analysis, TLR2+597CC genotype protective effect was even higher in overweight individuals (OR=0.17, 95% CI: 0.06-0.53, p<0.001) and in never smokers (OR=0.11, 95% CI: 0.02-0.51, p=0.001). Also, the increased risk effect for TLR4 299Gly homozygous genotype was higher in overweight individuals (OR=8.67, 95% CI: 1.11-87.85, p=0.011). TLR2+597T>C polymorphism conferred 41% less (p=0.03) and TLR4Asp299Gly 65% more TNF-α production (p=0.02) with no differences in Toll-like receptors levels. CONCLUSION: Functional Toll-like receptor 2 and Toll-like receptor 4 polymorphisms significantly alter the risk to have colorectal cancer. Obesity and smoking may influence the risk for colorectal cancer in individuals presenting these genetic profiles.

Decreased Toll-interacting protein and peroxisome proliferator-activated receptor γ are associated with increased expression of Toll-like receptors in colon carcinogenesis.

BACKGROUND: Animal data suggest that Toll-like receptors (TLR) may play an important role in colon carcinogenesis. Studies in humans to support that hypothesis are scarce. AIM: To evaluate the expression of TLR2, TLR4 and TLR5, and the expression of several other related molecules, in different human colonic lesions. METHODS: Colon biopsy samples from normal mucosa, normal mucosa adjacent to lesion, adenoma or sporadic carcinoma were obtained from 35 consecutive patients undergoing colonoscopy. Quantification of TLR2, TLR4, TLR5, Toll-interacting protein (TOLLIP), peroxisome proliferator-activated receptor γ (PPAR-γ), nuclear factor κB, tumour necrosis factor (TNF) α, cyclooxygenase (COX) 1 and 2 mRNA was performed by real-time reverse transcription PCR. TLR2, TLR4 and TLR5 protein expression was quantified by immunohistochemistry. RESULTS: When compared with normal mucosa (1.0 arbitrary unit (AU)), adjacent normal mucosa presented higher expression of COX-2 (1.86±0.3 AU, p=0.01) and TNFα (1.44±0.18 AU, p=0.04) and lower TOLLIP expression (0.75±0.05 AU, p=0.004). Adenomas and carcinomas presented higher expression of COX-2 (1.63±0.27 and 1.38±0.14 AU, p=0.03 and p=0.05, respectively) and lower expression of TOLLIP (0.44±0.04 AU, p<0.001), with diffuse and higher TLR protein expression (p<0.001). Carcinomas also expressed higher TLR2 (2.31±0.32 AU, p=0.006) and lower PPAR-γ (0.56±0.12 AU, p=0.003). There was a trend towards decreased TOLLIP (p<0.001) and PPAR-γ (p=0.05) from normal mucosa to adenoma/carcinoma. CONCLUSIONS: Persistently positive TLR expression and lower expression of TLR inhibitors was associated with higher TLR protein levels throughout the spectrum of lesions of colon carcinogenesis. Increasing activation of these receptors by bacteria may play a crucial role in colon carcinogenesis and tumour progression.

Increased hepatic expression of TLR2 and TLR4 in the hepatic inflammation-fibrosis-carcinoma sequence.

We evaluated expression of TLR2, TLR4 and proinflammatory genes [NF-κB, TNF-α, cyclooxygenase-2 (COX-2)] in liver samples of patients in different stages of liver disease. Fifteen patients with unexplained transaminases elevation (reference group), 22 with viral chronic hepatitis (hepatitis group), 14 with virus-induced severe fibrosis/cirrhosis (cirrhosis group) and 10 with hepatocarcinoma (hepatocarcinoma group) were consecutively included in the study. Quantification of TLR2, TLR4, NF-κB, TNF-α and COX-2 mRNA was done by real-time RT-PCR and TLR2 and TLR4 protein expression was evaluated by immunohistochemistry. Compared with reference, TLR2 and TLR4 mRNA was increased in hepatitis (TLR2: 2.66 ± 0.69; TLR4: 3.11 ± 0.79; P < 0.05) and cirrhosis (TLR2: 2.14 ± 0.5; TLR4: 1.74 ± 0.27; P < 0.05) and decreased in hepatocarcinoma (TLR2: 0.48 ± 0.15; TLR4: 0.54 ± 0.10; P < 0.05). This associated with increased TNF-α and COX-2 mRNA in hepatitis (TNF-α: 3.24 ± 0.79; COX-2: 2.47 ± 0.36; P < 0.05) and cirrhosis (TNF-α: 1.73 ± 0.28; COX-2: 1.8 ± 0.35, P < 0.05), whereas NF-κB mRNA was increased in hepatitis (2.42 ± 0.31; P < 0.05) and unchanged in cirrhosis (1.34 ± 0.17; P = 0.3). Hepatocarcinoma presented increased COX-2 mRNA (1.63 ± 0.15; P < 0.05) and maintained (at decreased levels) mRNA of NF-κB (0.52 ± 0.12) and TNF-α (0.52 ± 0.12; P < 0.05, all genes). Immunohistochemistry confirmed increased expression of TLR2 and TLR4 in hepatitis and cirrhosis and maintained expression in hepatocarcinoma. Upregulation of TLR2, TLR4 and their proinflammatory mediators is associated with virus-induced hepatic IFC sequence.

Increased expression of toll-like receptors (TLR) 2, 4 and 5 in gastric dysplasia.

TLRs are important innate immunity receptors. Even though TLR2, 4 and 5 appear to be important for Helicobacter pylori (HP) recognition, their role in the evolution of gastritis to more advanced lesions is still unknown. To compare the expression of TLR2, 4 and 5 in normal gastric mucosa, HP+ gastritis, intestinal metaplasia, dysplasia and adenocarcinoma. Immunohistochemistry for TLR2, 4 and 5 was performed with anti-TLR2-TLR4-TLR5 antibodies in 117 histological samples of normal gastric mucosa (n = 22), HP+ gastritis (n = 20), intestinal metaplasia (n = 33), dysplasia (mucosectomy specimens, n = 20) and intestinal type adenocarcinoma (surgery specimens,n = 22); quantification of expression was performed independently by two pathologists taking into account the percentage of positive epithelial cells and the degree of expression (zero to three score). A statistically significant trend for progressive increase of TLRs expression from normal mucosa to gastric dysplasia was found (mean expression: normal mucosa 0.1; gastritis 1.0; metaplasia 2.2; dysplasia 2.8, p < 0.01). All dysplasia samples presented more than 90% positive epithelial cells with strong expression (2.8;95%CI2.7-3). There was less TLRs expression in carcinomas (TLR2:1.0; TLR4:2.0 and TLR5:1.2, p < 0.05) when compared with dysplasia, with TLR4 being more expressed than TLR2 and 5 in these lesions (p = 0.03). A score of all markers' expression of eight leads to a low (4%) false positive rate in patients with precancerous conditions. Progression of gastric lesions associated with gastric carcinogenesis is associated with increased TLRs expression. Gastric dysplasia presents a high level of TLRs expression, suggesting that these receptors may play a role in adenocarcinoma development.