Amy Noffsinger

Complete Barrett's Eradication Endoscopic Mucosal Resection: An Effective Treatment Modality for High-Grade Dysplasia and Intramucosal Carcinoma—An American Single-Center Experience

OBJECTIVES:Complete Barretts eradication endoscopic mucosal resection (CBE-EMR) is the endoscopic removal of all Barretts epithelium with the curative intent of eliminating high-grade dysplasia (HGD)/intramucosal carcinoma (IMC) and reducing the risk of metachronous lesion development. We report our single tertiary referral centers long-term clinical experience using this modality in HGD/IMC management.METHODS:In this study, we retrospectively reviewed all patients who had CBE-EMR for Barretts esophagus (BE) with HGD/IMC who had been entered into our centers prospectively collected database. High-definition white-light and narrow-band imaging examinations were used according to the protocol. Staging endoscopic ultrasound was done before CBE-EMR to exclude invasive disease or suspicious lymphadenopathy. High-dose proton pump inhibition was instituted after initial treatment, and Seattle-type surveillance biopsies were performed on follow-up every 6 months once the CBE-EMR procedure was completed.RESULTS:A total of 49 patients (mean age 67 years, median 65, s.d. 11; 75% men) with histologically confirmed BE and HGD (33), IMC (16), underwent CBE-EMR from August 2003 to August 2008. The mean BE segment length was 3.2 cm (median 2, s.d. 2.2); 26 patients had short-segment BE, and 30 had visible lesions. A total of 106 EMR procedures were performed. On initial EMR, two patients had superficial submucosal carcinoma invasion (sm1) and two had IMC with lymphatic channel invasion. All four patients were referred for esophagectomy, but one opted for continued endoscopic management, without evidence of residual or recurrent carcinoma. A total of 14 patients await completion of EMR (9) or first follow-up endoscopy (5). CBE-EMR therapy was completed in 32 patients by an average of 2.1 sessions (median 2, s.d. 0.9). Surveillance biopsies showed normal squamous epithelium in 31 of 32 (96.9%) patients (mean remission time 22.9 months, median 17, s.d. 16.7, interquartile range 11–38). In all, 10 of 46 patients who continued in the endoscopic protocol had subsquamous Barretts epithelium on EMR specimens and/or treatment endoscopy biopsies. Overall, 1 of these 10 patients had Barretts underneath squamous mucosa on most recent surveillance biopsies. CBE-EMR upstaged pre-EMR pathology results in 7 of 49 (14%) of patients and downstaged pathology in 15 of 49 (31%) patients. In all, 18 of 49 (37%) patients developed symptomatic esophageal stenosis after a mean of 24.4 days (median 13.5, s.d. 27.8); all were successfully managed by endoscopic treatment. No perforations or uncontrollable bleeding occurred.CONCLUSIONS:To our knowledge, this is the largest American single-center experience demonstrating that CBE-EMR with close endoscopic surveillance is an effective treatment modality for BE with HGD/IMC. Although the rate of stenosis development is significant, it is easily treated by endoscopic dilation. Patients considering endoscopic ablation should be counseled appropriately. The role of CBE-EMR in patients with lymphatic invasion or superficial submucosal invasion remains to be defined.

Serrated Polyps and Colorectal Cancer: New Pathway to Malignancy

Until recently, two major forms of colorectal epithelial polyp were recognized: the adenoma and the hyperplastic polyp. Adenomas were perceived to represent the precursor to colorectal cancer, whereas hyperplastic polyps were viewed as innocuous lesions with no potential for progression to malignancy. We now recognize, however, that the lesions formerly classified as hyperplastic actually represent a heterogeneous group of polyps, some of which have a significant risk for neoplastic transformation. These serrated polyps include not only hyperplastic polyps but also traditional serrated adenomas and sessile serrated adenomas. These polyps demonstrate characteristic molecular alterations not commonly seen in colorectal adenomas, and they probably progress to colorectal cancer by means of a new pathway: the serrated neoplasia pathway. The morphologic features of serrated colorectal lesions, the molecular alterations that characterize them, and their role in colorectal cancer development are discussed herein.

Interobserver Variability in the Diagnosis of Ulcerative Colitis-Associated Dysplasia by Telepathology

Telepathology (TP) is the practice of remote diagnostic consultation of electronically transmitted, static, digitalized images. The diagnostic efficacy of TP-based consultation services has not been widely tested. Dysplasia that arises in association with chronic ulcerative colitis (CUC) is, at present, the most important marker of an increased risk of malignancy in patients with this disease. Unfortunately, dysplasia is difficult to diagnose histologically and, as a result, suffers from a significant degree of intra- and interobserver variability. Furthermore, it is often necessary to obtain expert consultation of potential CUC-associated dysplasia cases before treatment. Therefore, the aim of this study was to evaluate the utility and interobserver variability of diagnosing dysplasia in CUC with the use of TP. Static, electronically transmitted, digitalized images of 38 CUC cases with areas considered negative, indefinite, or positive for dysplasia (low or high grade) were evaluated independently by four gastrointestinal pathologists. All cases were then graded by each of the pathologists by light-microscopic examination of the hematoxylin and eosin–stained glass slides. The degree of interobserver variability was determined by κ statistics. Overall, there was a fair degree of agreement (κ = 0.4) among the four reviewing pathologists after analysis of the digitalized images. The poorest level of agreement was in the indefinite and low-grade dysplasia categories. Grouping together several diagnostic categories (for instance, indefinite and low-grade dysplasia, or low-grade dysplasia and high-grade dysplasia) had no effect on the overall level of agreement. The degree of variability in interpretation of glass slides was slightly better (κ = 0.43) but still remained fair. After reviewing all cases by glass slide analysis, the diagnosis was changed in 38% of the slides; in the majority of these, the grade of dysplasia was increased. Use of TP for consultation in CUC-associated dysplasia has a moderate level of interobserver agreement. Because of a variety of technical reasons, diagnoses rendered by evaluation of digitalized images tended to be of a lower grade than that observed after a review of the glass slides.

The molecular biology of esophageal and gastric cancer and their precursors: Oncogenes, tumor suppressor genes, and growth factors

The evolution of sequential histological changes from normal cells through invasive cancer affords the cancer biologist the opportunity to identify separate molecular steps involved in cancer progression. As one studies the development of human carcinoma, it becomes apparent that multiple genetic alterations affecting both cellular proto-oncogenes and tumor suppressor genes are involved during the development and progression of both esophageal and gastric cancers. The different histological forms of both esophageal and gastric carcinomas as well as their differing etiologies result in the possibility that a spectrum of genetic changes is involved in different tumor types. p53 abnormalities occur frequently in tumors arising in both organs, and in both sites p53 abnormalities can be observed in precancerous lesions as well as in overt cancer. Subsequent abnormalities affecting other genes (eg, epithelial growth factor receptors [EGFRs]) potentially enhance the growth potential of tumors. This review focuses on abnormalities of oncogenes, tumor suppressor genes, and growth factors commonly found in cancers of the esophagus and stomach.

Review Article: Aberrant Crypt Foci: A Review

laboratories at the VA Hospital. In 1990, she became the MacKenzie Professor and director of the Department of Pathology at the College of Medicine, University of Cincinnati. Dr. Fenoglio-Preiser has a longstanding interest in precursors to gastrointestinal malignancies Left) Cecilia M. Fenoglio-Preiser. Right) Amy Noffsinger. and has published over 300 articles, many relating to the pathological or molecular features of gastrointestinal malignancies. Dr. Noffsinger completed her pathology residency training at the University of Cincinnati College of Medicine and is currently an assistant professor of pathology and laboratory medicine in the same institution. She has received a number of awards, including a Clinical Oncology Career Development Award and a Cancer Research Fellowship from the American Cancer Society. She is a funded investigator in the area of molecular alterations. Our laboratory is involved in elucidating mechanisms of the development of gastrointestinal carcinomas as well as in defining molecular alterations that may predict therapeutic response and/or prognosis. We are interested in cancers

Genetic alterations in chronic ulcerative colitis-associated adenoma-like DALMs are similar to non-colitic sporadic adenomas.

Recent molecular studies have shown that there are differences in the prevalence and timing of certain molecular events between chronic ulcerative colitis (CUC)-associated dysplastic lesions and non-CUC-related sporadic adenomas. However, little is known regarding the molecular features of a specific subtype of CUC-related dysplasia-associated lesion or mass (DALM) that clinically, endoscopically, and pathologically resemble sporadic adenomas, and whether these lesions can be separated from non-CUC-related sporadic adenomas on the basis of their molecular genotype. Therefore, the purpose of this study was to evaluate loss of heterozygosity (LOH) of 3p, APC, and p16 in a specific group of CUC-associated “adenoma-like” DALMs and to compare the results of this tumor with those in a well-defined group of CUC-associated non-adenoma-like DALMs and non-CUC-associated sporadic adenomas. Polypectomy or resection specimens from 21 CUC patients with an adenoma-like DALM, 8 CUC patients with at least one non-adenoma-like DALM (12 lesions in total), and 23 non-CUC patients with a sporadic adenoma were evaluated for LOH of 3p, APC, and p16 by PCR analysis. The results were compared among the three different study groups and correlated with the clinical features of the patients and the pathology of their tumors. Chronic ulcerative colitis-associated adenoma-like DALMs showed LOH of 3p in five of 18 (28%) cases. This value was not significantly different from the 5% of non-CUC sporadic adenomas (p = 0.14) that were positive. However, 50% of CUC-associated non-adenoma-like DALMs were positive for LOH of 3p, and this value was significantly higher (p = 0.01) than the other groups. The frequency of LOH of APC did not differ significantly between the three patient groups (33%, 33%, and 43% in the three groups, respectively). Similar to the 3p results, CUC-associated adenoma-like DALMs and non-CUC-associated sporadic adenomas showed a similar low frequency of positivity for LOH of p16 (5% and 4%, respectively) in comparison to 56% of CUC-associated non-adenoma-like DALMs (p = 0.003). For all markers, no significant differences were detected in the CUC-associated adenoma-like DALM group between lesions that occurred within colitis compared with those that occurred in areas not involved by colitis. Chronic ulcerative colitis-associated non-adenoma-like DALMs have a different molecular genotype than CUC-related adenoma-like DALMs and non-CUC sporadic adenomas. Our data also suggests that the latter two groups of neoplasms may in fact represent a similar, if not identical, pathogenetic entity.

Outcome after surveillance of low‐grade and indefinite dysplasia in patients with ulcerative colitis

Background: The management of low‐grade (LGD) and indefinite dysplasia (IND) in patients with ulcerative colitis (UC) remains controversial, as outcomes after a diagnosis of LGD or IND in previous studies vary widely. Methods: All patients evaluated were from a single institution referral center who had a history of UC and a diagnosis of either LGD or IND between 1994 and 2008 as confirmed by 2 expert gastrointestinal (GI) pathologists. Data were collected by chart review of electronic and paper medical records. All patients who did not undergo a colectomy within 90 days of their dysplasia diagnosis were included in the final analysis. Hazard ratios for risk factors as well as incidence rates and Kaplan–Meier estimates were used to calculate the progression to high‐grade dysplasia (HGD) or colorectal cancer (CRC). Results: Thirty‐five patients were included in the analysis, of whom 2 patients with IND and 2 patients with LGD developed HGD or CRC over a mean duration of 49.8 months. In total, the incident rate for advanced neoplasia for all patients was 2.7 cases of HGD or CRC per 100 person‐years at risk. For flat and polypoid LGD the incident rate of advanced neoplasia was 4.3 and 1.5 cases per 100 person‐years at risk, respectively. Patients with primary sclerosing cholangitis (PSC) had an incident rate of 10.5 cases per 100 years of patient follow‐up. Conclusions: We report a low rate of progression to HGD or CRC in patients who underwent surveillance for LGD or IND; polypoid dysplasia showed less risk of progression than flat dysplasia. (Inflamm Bowel Dis 2010)

Alterations in exon 4 of the p53 gene in gastric carcinoma

BACKGROUND & AIMS Our long-term goal was to evaluate the role of p53 in the prognosis of gastric cancer. We previously showed a discrepancy between p53 expression and the presence of mutations when only exons 5-9 were examined. We then evaluated exon 4. METHODS DNA was sequenced from 217 gastric cancers to detect exon 4 alterations. Codon 72 was examined by restriction enzyme digestion. RESULTS Mutations were present in 3.2% of tumors. In addition, 2 polymorphic sites were found at codons 36 and 72. Polymorphisms at codon 36 were only found in 2 patients. In contrast, the codon 72 polymorphism was very frequent. The genotype frequency was arg/arg (54%), arg/pro (33%), and pro/pro (14%). The genotype of the polymorphic site varied with race (P = 0.001): 64% of whites had the arg/arg genotype, compared with 24% of blacks. The difference in genotype by site, sex, or histological tumor type was not statistically significant (P = 0.067). CONCLUSIONS There are several exon 4 alterations in gastric cancers. These include the rare mutations and the very rare codon 36 polymorphism. The most common change is the codon 72 polymorphism, the genotype of which differs significantly with race. The more common arg/arg genotype in whites may explain why whites are more prone to develop cardiac cancer, whereas the more common proline allele in blacks may explain why they are more prone to develop antral cancers. Further studies are required to determine whether the codon 72 polymorphism affects patient predisposition to gastric cancer.

Detection of human papillomavirus in esophageal squamous cell carcinoma

Human papillomavirus (HPV) DNA has been identified in esophageal carcinomas. However, the incidence of HPV varies significantly in different geographic locations. In the current study, neoplasms from two separate geographic regions were analyzed for the presence of HPV DNA.

The pattern of cell proliferation in neoplastic and nonneoplastic lesions of ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by repeated episodes of inflammation and epithelial regeneration. Patients with long‐standing UC have an increased risk for the development of dysplasia and subsequent colon carcinoma. Because dysplasia likely results from deregulated cell proliferation, the authors examined Ki‐67 immunoreactivity in tissues from UC patients to examine patterns of proliferation in neoplastic and nonneoplastic lesions.