Non-invasive High-grade Neoplasia Research Articles

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

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

Transanal endoscopic surgery is effective and safe after endoscopic polypectomy of potentially malignant rectal polyps with questionable margins.

To determine the percentage of residual lesion observed in the pathology study of transanal endoscopic surgery (TEM) specimens after endoscopic polypectomy of malignant rectal polyps with questionable margins, and the need for further surgery. Secondary aims: to determine the morbidity and mortality associated with this procedure and to identify the percentage of recurrence after excision by TEM. Observational study with prospective data collection of all patients undergoing TEM after endoscopic polypectomy for malignant rectal polyps or non-invasive high-grade neoplasia, from January 2004 to December 2016. An en bloc full-thickness wall excision of the scar was performed. Variables recorded: histology of TEM specimen, 30-day morbidity and mortality according to the Clavien-Dindo classification, need for salvage surgery and recurrence. Fifty out of 690 patients undergoing TEM during the study period (36 adenocarcinomas, five non-invasive high-grade neoplasias and 9 neuroendocrine tumors) were included. Post-surgery histology showed residual lesion in 21 (42%) patients: 7 neuroendocrine tumors, 10 adenomas and 4 adenocarcinomas (two pT1, one pT2 and one pT3). The pT2 and pT3 patients (4%) underwent salvage surgery. No recurrence was observed, and mean follow-up was 29.1Â ± 21.6 months. The 30-day morbidity rate was 14%, but 4/7 with Clavien-Dindo grade I. After endoscopic polypectomy of malignant rectal polyps with questionable margins, the presence of residual lesion in the pathology study of transanal resection specimens is high. TEM with full-thickness resection of these lesions is an appropriate treatment, allowing disease control and achieving minimal morbidity.

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.

Reply to the letter by L. Czakó et al. regarding “Endoscopic submucosal dissection as a treatment for gastric noninvasive neoplasia: a multicenter study by Osaka University ESD Study Group”

We thank Dr. Laszlo Czako et al. for their letter and interest regarding our article [1]. Dr. Czako et al. made the following points concerning the strategy for treating gastric non-invasive neoplasia (NIN): (1) gastric NIN should be endoscopically resected; (2) concerning the modality of the treatment, endoscopic mucosal resection (EMR) may be recommended for the removal of small (\5 mm), elevated lesions, and endoscopic submucosal dissection (ESD) would be preferred for larger or depressed lesions. The concept of adenoma–carcinoma sequence has not been fully applied in the carcinogenesis of gastric cancer compared with colorectal cancer. Therefore, there are some controversies whether endoscopic resection is needed for low-grade gastric NIN, but endoscopic resection is acceptable for high-grade gastric NIN as well as early gastric cancer. Our study, which included patients with both lowand high-grade NIN, showed that 44% of the patients were diagnosed as having cancer after ESD. Moreover, another group reported that about 34% of gastric low-grade NINs (Vienna classification category 3) were diagnosed as high-grade NIN (category 4) or invasive cancer (category 5) [2]. These results are based on retrospective study and focused on the patients who underwent endoscopic resection; therefore, the incidence rate of gastric cancer might be overestimated. However, it would have been preferable if both highand low-grade gastric NIN had been the therapeutic target for endoscopic treatment. We cannot make a conclusion from this study whether all NINs need to be resected and which modality (conventional EMR or ESD) is optimal due to the limitations of our study. In order to validate endoscopic resection for low-grade gastric NIN, we are planning a multicenter prospective study to clarify the incidence rate of gastric cancer after endoscopic resection (both conventional EMR and ESD). We will then evaluate the efficacy of each endoscopic modality from the viewpoints of curability, safety, and economic aspects in the future.

Microvascular architecture of early esophageal neoplasia

Progress in magnifying endoscopy has allowed endoscopic atypia to be evaluated on the basis of the presence or the absence of microvascular hyperplasia in a tumor. We focused our attention on intra-epithelial papillary capillary loops (IPCLs) and studied 20 cases of esophageal neoplasia (IPCL type III, 10 cases; IPCL type IV, 10 cases) and 99 vessels (IPCL type III, 24 vessels; IPCL type IV, 75 vessels). We evaluated the histopathological findings and measured vessel caliber, distance from the basement membrane, distance between blood vessels and thickness of the epithelium. According to the Vienna classification, the histological findings in the 10 patients with IPCL type III lesions were classified as category 1 (negative for neoplasia/dysplasia) in 8 patients and category 3 (non-invasive low grade neoplasia) in 2 patients. The histological findings in the 10 patients with IPCL type IV lesions were classified as category 1 in 1 patient, category 3 in 4 patients and category 4 (non-invasive high grade neoplasia) in 5 patients. The vessel caliber of IPCL type IV lesions (mean, 5.9 ± 2.7 µm) was significantly larger than that of IPCL type III lesions (mean, 4.8 ± 1.5 µm) (P=0.013). The distance from the basement membrane of IPCL type IV lesions (mean, 99.9 ± 34.4 µm) was significantly greater than that of IPCL type III lesions (mean, 58.0 ± 36.2 µm) (P=1.52562E-06). The distance between blood vessels and the thickness of the epithelium did not differ significantly between IPCL type III and IPCL type IV lesions. Our results revealed that changes in vessels of IPCL type IV lesions involve two factors: increased vessel caliber and prolongation of IPCLs toward the surface. These vascular changes appear to be associated with increased atypia of blood vessels.

Effectiveness of a colonoscopic screening programme in first-degree relatives of patients with colorectal cancer

The study aimed to assess the diagnostic yield of a colonoscopy screening programme in first-degree relatives of colorectal cancer (CRC) patients and to identify factors associated with advanced neoplasia. We conducted a cross-sectional study. Individual characteristics, family trees and colonoscopy findings of asymptomatic first-degree relatives of CRC patients were collected. The findings were classified into cancer (invasive carcinoma and/or non-invasive high-grade neoplasia), high-risk adenomas (≥ 10 mm and/or a villous component) and low-risk adenomas (tubular < 10 mm). The dependent variable was the presence of advanced neoplasia, defined as cancer and/or high-risk adenoma. Two hundred and sixty-three relatives (147 females), 50.0 ± 11.5 (range, 25-75) years of age, agreed to participate out of a total of 618 who were invited (acceptance rate 42.5%). Index cases were diagnosed at 63.8 ± 12.4 (range, 37-88) years of age. The closest familial relationship was parent/offspring in 168 (63.9%) participants and sibling in 95 (36.1%) participants; 14.8% had three or more relatives with CRC/cancer associated with Lynch syndrome, and two or more affected generations were identified in 24.0%. Advanced neoplasia was found in 56 (21.3%) participants. Of these, invasive cancer, non-invasive high-grade neoplasia and high-risk adenomas were detected in five (1.9%), six (2.3%) and 45 (17.1%) participants, respectively. Low-risk adenomas were detected in 20 (7.6%) participants. Male sex (odds ratio, 2.59; P = 0.003) and sibling relationship (odds ratio, 2.74; P = 0.001) were independently associated with advanced neoplasia. We detected advanced neoplasia in a considerable number of participants. Our data support colonoscopy screening in first-degree relatives of patients with CRC at an earlier age than in the medium-risk population. Male sex and sibling relationship were predictors of advanced neoplasia.

Abstract 3050: MicroRNA expression profiling of human Barrett's carcinogenesis

Abstract Barrett's Mucosa (BM) is a metaplastic replacement of the native esophageal (squamous) epithelium (ESq) by columnar-intestinalized mucosa. BM is the main risk factor for Barrett's adenocarcinoma (BAc). MicroRNAs (miRNAs) are a class of small non-coding RNAs that control gene expression by targeting mRNAs; miRNAs deregulation has been associated with Barrett's oncogenesis. To explore the hypothesis that a specific miRNAs signature is associated with BM (and its associated cancer risk) a miRNA microarray analysis (OSU-CCC version 4.0; Ohio State University) compared ESq versus all the spectrum of the phenotypic lesions of the Barrett's carcinogenesis. Specimens were collected at Department of Pathology of Padova University from 14 patients undergone esophagectomy for BAc or High-grade non-invasive neoplasia (HG-NiN). Tissues samples for the microarray study included: ESq= 14 samples; BM= 14; Low-grade non-invasive neoplasia (LG-NiN)= 7; HG-NiN= 5; BAc= 11. The miRNA-profiling study consistently disclosed increased expression of 6 miRNAs (hsa-miR-215, hsa-miR-560, hsa-miR-615-3p, hsa-miR-192, hsa-miR-326, hsa-miR-147), and decreased expression of 7 others (hsa-miR-100, hsa-miR-23a, hsa-miR-605, hsa-miR-99a, hsa-miR-205, hsa-let-7c, hsa-miR-203). Microarray results were further validated by qRT-PCR, using a different series of 10 consecutive BAc cases (Esq= 10 samples; BM= 6 samples; BAc= 10 samples). Interestingly, some of the miRNAs found deregulated in this series are already known as suitable markers of cancer progression in other models of epithelial oncogenesis (i.e.: hsa-let-7c, hsa-miR-192, hsa-miR-203, hsa-miR-205, hsa-miR-215). The results achieved by the miRNA profiling study were further validated by the immunohistochemical (IHC) analysis on a well-defined miRNA gene target (HMGA2 [hsa-let-7c]). The IHC expression of the protein product was consistent with the corresponding miRNA's deregulation. In fact, HMGA2 IHC expression was up-regulated in HG-NiN and BAc. The achieved results confirm that specific miRNAs are involved in BM carcinogenesis and that they may represent a novel diagnostic/prognostic tool in the characterization of BAc gene targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3050.

Malignant colorectal polyps

Nowadays, the number of cases in which malignant colorectal polyps are removed is increasing due to colorectal cancer screening programmes. Cancerous polyps are classified into non-invasive high grade neoplasia (NHGN), when the cancer has not reached the muscularis mucosa, and malignant polyps, classed as T1, when they have invaded the submucosa. NHGN is considered cured with polypectomy, while the prognosis for malignant polyps depends on various morphological and histological factors. The prognostic factors include, sessile or pedunculated morphology of the polyp, whether partial or en bloc resection is carried out, the degree of differentiation of the carcinoma, vascular or lymphatic involvement, and whether the polypectomy resection margin is tumor free. A malignant polyp at T1 is considered cured with polypectomy if it is a pedunculated polyp (Ip of the Paris classification), it has been completely resected, it is not poorly differentiated, the resection edge is not affected by the tumor and there is no vascular or lymphatic involvement. The sessile malignant polyp (Is of the Paris classification) at T1 is considered not cured with polypectomy. Only in some cases (e.g. older people with high surgical risk) local excision (polypectomy or endoscopic submucosal dissection or conventional endoscopic mucosal resection) is considered the definitive treatment.

Helicobacter pylori, inflammation, oxidative damage and gastric cancer: a morphological, biological and molecular pathway

Gastric carcinogenesis is a complex, multistep and multifactorial event, characterized by progressive cyto-histological dedifferentiation, in which the role of Helicobacter pylori infection has been established. Among the pathways relevant to gastric carcinogenesis and correlated with H. pylori infection, it has been demonstrated that the production of reactive oxygen species, with damage to the DNA, may be quite important. Oxidative damage, alone and/or in combination with exogenous and endogenous factors, induces several molecular changes. The assumption is that, in precancerous lesions, these molecular changes belong to the same biological spectrum as their invasive counterpart. The molecular profile of these preneoplastic lesions is heterogeneous, however, and there are still no molecular markers enabling the distinction between atypical hyperplastic lesions and low-grade noninvasive neoplasia (NiN) or between high-grade NiN and early invasive neoplasia. Indeed, within the spectrum of morphological changes characterizing this multistep evolution, dysplasia (NiN) is the lesion coming closest to the development of invasive adenocarcinoma. Several of the genetic and epigenetic alterations reported in gastric precancerous lesions affect DNA repair system genes, tumor suppressor genes, oncogenes, cell cycle regulators, growth factors, and adhesion molecules. Although we await reliable molecular markers, it is best to monitor patients harboring NiN closely with endoscopy and extensive bioptic sampling, and to eradicate any H. pylori to prevent the accumulation of oxidative DNA damage and its consequent progression. The growing body of evidence of the regression of precancerous changes and the high prevalence of superficial gastric carcinoma demonstrated in long-term follow-up studies on NiN make this approach mandatory.

Microsatellite instability and gastric non-invasive neoplasia in a high risk population in Cesena, Italy

Background/Aims: In the natural history of gastric cancer, non-invasive neoplasia (NiN) precedes invasive carcinoma. A histological classification of gastric NiN has recently been proposed by a World Health Organisation international...

The new Vienna classification of epithelial neoplasia of the gastrointestinal tract: advantages and disadvantages

A number of seminars have shown considerable differences between Japanese and Western pathologists in the diagnostic differentiation of reactive changes, dysplasia and well-differentiated adenocarcinoma in gastroenterological biopsy material. Lesions that most Western pathologists identify as "dysplasia" are often considered adenocarcinomas in Japan. A comparison of the biopsy-based diagnoses with those established in resected mucosa, however, reveals appreciable diagnostic inexperience on the part of Western pathologists, with significant discrepancies between their diagnoses based on biopsies and those based on resected material. Against this background, a new classification of epithelial neoplasia of the gastrointestinal tract was drafted on the occasion of the World Congress of Gastroenterology in Vienna in 1998. By collapsing the diagnoses "high-grade adenoma/dysplasia, noninvasive carcinoma (carcinoma in situ), and suspected invasive carcinoma" into a single category ("noninvasive high-grade neoplasia", category 4), this scheme should largely eliminate the diagnostic discrepancies between Western and Japanese pathologists. As with every classification, the Vienna classification has its advantages and disadvantages; these are discussed here. The most important advantage of the Vienna classification is that the various categories are associated with different recommendations for further diagnostic and therapeutic measures. This applies in particular to category 4, with the recommendation for only local treatment initially (endoscopic mucosal resection or surgical excision). Since the introduction of the Vienna classification, the new World Health Organization classification of neoplasia of the gastrointestinal tract has recently been published, in which the term dysplasia has been replaced by "intraepithelial neoplasia". This means that the Vienna classification needs to be modified accordingly.

Intraglandular necrotic debris in gastric biopsy and surgical specimens.

To clarify whether intraglandular necrotic debris (IND) is a diagnostic clue to noninvasive high-grade neoplasia or invasive neoplasia of the stomach, we reviewed 135 gastric biopsy specimens and 55 surgical materials. Intraglandular necrotic debris is defined as an eosinophilic material with necrotic epithelial fragments within the lumen of a dilated atypical gland. Using the Vienna classification, the incidence of IND in category 4 (noninvasive high-grade neoplasia) and category 5 (invasive neoplasia) was significantly higher than that of category 1 (negative for neoplasia/dysplasia), category 2 (indefinite for neoplasia/dysplasia), and category 3 (noninvasive low-grade neoplasia). The incidence of IND was much higher in category 5 than in category 4 in biopsy specimens. In addition, cases with IND in category 4 in biopsy specimens turned out to be either carcinoma in situ or invasive carcinoma in the surgical specimens. According to the histologic classification of surgically removed invasive carcinoma, moderately differentiated adenocarcinoma showed the highest incidence of IND. Intraglandular necrotic debris was not found in either signet-ring cell carcinoma or mucinous adenocarcinoma. Our results indicate that IND in biopsy specimens is a diagnostic clue to noninvasive high-grade neoplasia or invasive carcinoma, and the origin of IND may be associated with necrotic atypical epithelium.

The Vienna classification of gastrointestinal epithelial neoplasia

BACKGROUNDUse of the conventional Western and Japanese classification systems of gastrointestinal epithelial neoplasia results in large differences among pathologists in the diagnosis of oesophageal, gastric, and colorectal neoplastic lesions.AIMTo develop...

Nuclear translocation of glutathione transferase omega is a progression marker in Barrett's esophagus

Barrett's esophagus (BE) represents a major risk factor for esophageal adenocarcinoma (AC). For this reason, patients with BE are subjected to a systematic endoscopic surveillance to detect initial evolution towards non-invasive neoplasia (NiN) and cancer, that eventually occurs only in a small fraction of BE patients. This study was aimed to investigate the possible role of glutathione-S-transferase-omega 1 (GSTO1), a recently discovered member of the glutathione-S-transferase family, as a progression marker in the Barrett's disease in order to improve the diagnosis of NiN in BE and to understand the mechanisms of the progression from BE to AC. We investigated the expression and subcellular localization of GSTO1 in biopsies from patients with BE and in human cancer cell lines subjected to heath shock treatment. A selective nuclear localisation of GSTO1 was found in 16/16 biopsies with low- or high-grade NiN, while it appeared in only 4/22 BE biopsies without signs of NiN (P<0.0001). Among biopsies of BE without NiN, diffuse (nuclear and cytoplasmic) staining was found in 5/22 cases, while selective cytoplasmic localisation was found in 13/22. The 6 cases with indefinite grade of NiN were equally divided between nuclear, cytoplasmic and diffuse staining (2 each, respectively). Experiments in vitro showed that in human HeLa cancer cells, GSTO1 translocates into the nucleus as a consequence of heath shock. These findings suggested that the nuclear translocation of glutathione-S-transferase-omega 1 could be involved in the stress response of human cells playing a role in the cancer progression of Barrett's esophagus. Its immunohistochemical detection could represent a useful tool in the grading of Barrett's disease.