Abnormal TP53 Predicts Risk of Progression in Patients With Barrett's Esophagus Regardless of a Diagnosis of Dysplasia.

BACKGROUND AND AIMS: Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma. A major challenge is identifying the small group with BE who will progress to advanced disease from the many who will not. Assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation have precluded its use. The aim of this study was to develop a robust criteria for grading abnormal immunohistochemical (IHC) expression of p53 and to test its utility as a biomarker for progression in BE. METHODS: Criteria for abnormal IHC of p53 were developed in BE biopsies and validated with sequencing to assess TP53 mutations. The utility of p53 IHC as a biomarker for progression of BE was tested retrospectively in 561 patients with BE with or without known progression. The findings were prospectively validated in a clinical practice setting in 1487 patients with BE. RESULTS: Abnormal p53 IHC highly correlated with TP53 mutation status (90.6% agreement) and was strongly associated with neoplastic progression in the retrospective cohorts, regardless of histologic diagnosis (P < .001). In the retrospective cohort, abnormal p53 was associated with a hazard ratio of 5.03 (95% confidence interval, 3.88-6.5) and a hazard ratio of 5.27 (95% confidence interval, 3.93-7.07) for patients with exclusively nondysplastic disease before progression. In the prospective validation cohort, p53 IHC predicted progression among nondysplastic BE, indefinite for dysplasia, and low-grade dysplasia (P < .001). CONCLUSIONS: p53 IHC identifies patients with BE at higher risk of progression, including in patients without evidence of dysplasia. p53 IHC is inexpensive, easily integrated into routine practice, and should be considered in biopsies from all BE patients without high-grade dysplasia or cancer.

Detection of Mutations in Barrett's Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma.

BACKGROUND & AIMS: Barrett's esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress. METHODS: We performed a retrospective case-control study of 24 patients with BE that progressed to high-grade dysplasia (HGD, n = 14) or EAC (n = 10). The control group (n = 73, called non-progressors) comprised patients with BE and at least 5 years of total endoscopic biopsy surveillance without progression to HGD or EAC. From each patient, we selected a single tissue sample obtained more than 1 year before progression (cases) or more than 2 years before the end of follow-up (controls). Pathogenic mutations, gene copy numbers, and ploidy were compared between samples from progressors and non-progressors. RESULTS: TP53 mutations were detected in 46% of samples from progressors and 5% of non-progressors. In this case-control sample set, TP53 mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2-61.0) (P < .001). We did not observe significant differences in ploidy or copy-number profile between groups. We identified 147 pathogenic mutations in 57 distinct genes-the average number of pathogenic mutations was higher in samples from progressors (n = 2.5) than non-progressors (n = 1.2) (P < .001). TP53 and other somatic mutations were recurrently detected in samples with limited copy-number changes (aneuploidy). CONCLUSIONS: In genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number.

Sessile serrated adenomas strongly predispose to synchronous serrated polyps in non-syndromic patients.

AIMS: To determine the prevalence of various colonic polyps removed during a recent 8-month period; to determine the interobserver agreement in the diagnosis of serrated polyps; and to determine if harbouring a sessile serrated adenoma (SSA) predisposes to the presence of synchronous polyps with similar histology. METHODS AND RESULTS: All polyps resected during an 8-month period at a single tertiary medical centre were analysed. We also analysed all polyps in patients with an SSA or SSA with dysplasia since 2003. SSAs accounted for 4.3% of colonic polyps removed during an 8-month period. A review of 276 serrated polyps by two pathologists revealed good interobserver agreement (kappa = 0.66). Patients with one SSA were more likely to harbour additional serrated polyps. After removal of the index SSA, 18% of their remaining polyps were SSAs, SSAs with dysplasia, and traditional serrated adenomas, contrasting with the approximately 5% prevalence of these polyps in the control population. The hyperplastic polyps in the study population were also twice as likely to occur proximal to the splenic flexure. CONCLUSIONS: These data indicate that there is a strong colonic mucosal field defect in patients with sporadic SSAs that predispose them to develop additional serrated polyps.

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 Barrett's eradication endoscopic mucosal resection (CBE-EMR) is the endoscopic removal of all Barrett's 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 center's 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 Barrett's esophagus (BE) with HGD/IMC who had been entered into our center's 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 Barrett's epithelium on EMR specimens and/or treatment endoscopy biopsies. Overall, 1 of these 10 patients had Barrett's 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.

Advanced pathology under squamous epithelium on initial EMR specimens in patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma: implications for surveillance and endotherapy management.

BACKGROUND: Prior studies report the presence of buried Barrett's epithelium under squamous mucosa after endoscopic ablative therapies for Barrett's esophagus (BE) with high-grade dysplasia (HGD) or intramucosal carcinoma (IMC). However, there still exists significant controversy about whether these glands represent a neoablative phenomenon or predate endoscopic therapy. OBJECTIVE: To determine the prevalence of buried BE underneath squamous epithelium on initial mucosectomy specimens for complete Barrett's eradication EMR (CBE-EMR) for BE with HGD or IMC. DESIGN: Retrospective double-blinded review. SETTING: A tertiary-care academic referral center. PATIENTS AND METHODS: Histopathology slides of all initial mucosectomy specimens for all patients who underwent CBE-EMR for BE with HGD or IMC at our center between August 2003 and February 2008 were reviewed retrospectively in a double-blinded fashion by 2 expert GI pathologists. None of the patients had undergone prior endoscopic ablative therapy for dysplastic BE. MAIN OUTCOME MEASUREMENTS: The prevalence of buried BE underneath squamous epithelium in initial mucosectomy specimens from CBE-EMR for BE with HGD or IMC. RESULTS: A total of 47 patients' initial mucosectomy slides were reviewed. The presence of Barrett's epithelium underneath the squamous resection margin (Z line) was identified in 13 of 47 patients (28%) at initial mucosectomy. The linear distance of the Barrett's epithelium from the resection's squamous margin ranged from 0.8 to 5.6 mm (mean 2.3 mm and median 1.9 mm). Histopathology revealed nondysplastic buried BE in 3 patients, HGD in 9 patients, and IMC in 1 patient. Thus, 10 of 13 patients (21% of 47 total) had buried glands with advanced pathology (HGD or IMC), whereas 3 of 13 (6% of 47 total) had specialized intestinal metaplasia without dysplasia. LIMITATIONS: A single-center, modest study population size. CONCLUSIONS: Our results revealed a significant prevalence of buried Barrett's epithelium with or without dysplasia under squamous mucosa (squamocolumnar junction) on initial mucosectomy specimens. Given the neoplastic potential of BE, the presence of these subsquamous BE glands may affect the extent and adequacy of mucosal resection margins. Based on these findings, surveillance biopsies and ablative therapy should extend to 1 cm proximal to the endoscopically determined squamocolumnar junction.

Is the risk of concomitant invasive esophageal cancer in high-grade dysplasia in Barrett's esophagus overestimated?

BACKGROUND & AIMS: Recent studies have claimed long neoplasia-free survival rates with endoscopic mucosal resection of high-grade dysplasia (HGD) in Barrett's esophagus (BE). However, reports have contended that approximately 40% of patients who have esophagectomy for HGD have occult invasive cancer. The aim of this study was to use explicit criteria to determine the true prevalence of invasive adenocarcinoma in reports of patients who had esophagectomy for HGD in BE. METHODS: Studies reporting rates of esophageal cancer in patients who underwent esophagectomy for HGD in BE were gathered using MEDLINE and PUBMED. We defined invasive esophageal adenocarcinoma (IEAC) as tumor with submucosal invasion or beyond. Intramucosal carcinoma (IMC) was not considered IEAC. RESULTS: Twenty-three articles were selected for analysis. Most investigators reported rates of invasive cancer in the esophagectomy specimen, and the pooled average was 39.9% among the 441 patients who underwent an esophagectomy for HGD. Reported rates varied from 0% to 73%. A total of 267 patients had American Joint Committee on Cancer stage 0 postoperatively, 132 patients had stage I, 23 patients had stage IIa, 10 patients had stage IIb, and 9 patients had stage III. Fourteen studies provided differentiation between intramucosal and submucosal invasion. Among 213 patients, only 12.7% had IEAC, whereas 87.3% had HGD or IMC. The IEAC rate of 11% among patients with visible lesions is greater than the rate of 3% among patients with no visible lesion. CONCLUSIONS: By using strict pathologic definitions of invasive disease, the present study indicates the true prevalence of IEAC in BE and HGD may have been overestimated significantly. Separating IMC from IEAC is clinically relevant because endoscopic techniques potentially may treat IMC.

Prostate-specific membrane antigen expression in regeneration and repair.

Prostate-specific membrane antigen is a type II transmembrane glycoprotein, expressed in benign and neoplastic prostatic tissue as well as endothelial cells of neovasculature from a variety of tumors. The expression of prostate-specific membrane antigen in nonneoplastic neovasculature has not been well studied. Therefore, we studied nonneoplastic reparative and regenerative human tissues, as well as preneoplastic tissue, to determine the presence of prostate-specific membrane antigen-expressing neovasculature. Formalin-fixed paraffin-embedded tissue from keloids, granulation tissue from heart valves and pleura, proliferative and secretory endometrium, and Barrett's mucosa with and without dysplasia were stained for the expression of prostate-specific membrane antigen (3E6). Vessels of proliferative, mid-secretory, and late secretory endometrium were consistently strongly positive for prostate-specific membrane antigen expression in all ten cases of each type (100%). Vessels associated with granulation tissue from pleural peels and heart valves were positive in 10 of 12 cases (83%) and 7 of 10 cases (70%), respectively. Keloids had prostate-specific membrane antigen-expressing endothelial cells in 6 of 15 cases (40%). Prostate-specific membrane antigen was not expressed by vessels associated with Barrett's mucosa with low-grade dysplasia (12 foci), high-grade dysplasia (24 foci), or no dysplasia (18 foci). A variety of nonneoplastic neovasculature expresses prostate-specific membrane antigen, including vessels in proliferative endometrium, granulation tissue, and some scars. This is the first study showing that prostate-specific membrane antigen is expressed in neovasculature from physiologic regenerative and reparative conditions. The folate hydrolase activity of prostate-specific membrane antigen may facilitate vasculogenesis and angiogenesis by increasing local availability of folic acid. These findings will enhance our overall understanding of blood vessel development and will enable us to better understand the effects of anti-prostate-specific membrane antigen therapies, which are already being explored in clinical trials.

Preinvasive neoplasia in the stomach: diagnosis and treatment.

This article discusses the proper handling of biopsy samples from mucosal lesions taken from the stomach when there is a suspicion of a malignant process. In addition, the use of endoscopic mucosal resection for therapy and staging of gastric neoplasia is discussed.

A review of resistance patterns and phenotypic changes in gastrointestinal stromal tumors following imatinib mesylate therapy.

Gastrointestinal stromal tumors are neoplastic lesions that arise from the interstitial cells of Cajal and are associated with somatic mutations in the tyrosine kinase receptor, KIT. The only known curative therapy is complete surgical resection. Unfortunately, postsurgical recurrence rates exceed 50% and most tumors are resistant to standard chemotherapy and radiation. Imatinib mesylate, a novel tyrosine kinase inhibitor, holds promise as a potential adjuvant therapy to prevent recurrence and improve long-term survival. However, as resistance data emerge, it appears that a potential "escape pathway" may originate from secondary mutations in the KIT receptor. This paper reviews the historical clinical experience with imatinib mesylate and discusses resistance patterns following targeted therapy. We highlight this review with an interesting case report that illustrates unique phenotypic tumoral changes associated with imatinib mesylate resistance.

Clinical use of p53 in Barrett's esophagus.

Barrett's esophagus is an established precursor to esophageal adenocarcinoma. Whereas most patients with Barrett's esophagus do not progress to adenocarcinoma, patients with progression have a poor prognosis. Current management strategies use frequent endoscopic surveillance and multiple nontargeted biopsies. This approach, however, may miss dysplastic areas. Furthermore, given the relatively high prevalence of Barrett's esophagus but low incidence of progression, this invasive and expensive approach has not been shown to be cost-effective. Thus, there is intense interest in using biomarkers to identify patients at increased risk of progressing to adenocarcinoma. This has included examination of mutations in the tumor suppressor gene, p53. In this report, we discuss the biology of p53 and the incidence of p53 mutations in Barrett's esophagus and review relevant studies regarding the ability of p53 to predict neoplastic progression. Additionally, we report our results of the expression of p53 by immunohistochemistry in a group of 18 patients that have undergone endoscopic esophageal mucosal resection for dysplasia. Although the presence of a p53 mutation increases the risk of neoplastic progression, the absence of this mutation does not abrogate the risk. Continuing efforts, therefore, are needed to define and prospectively validate a panel of biomarkers to risk-stratify patients with Barrett's esophagus. Determination of p53 mutational status may ultimately be a component of such a panel.

Colorectal cancer anatomic distribution patterns remain the same after sessile serrated adenoma/polyp considered cancer precursor: a 9-year comparison study from community-based endoscopy centers.

BACKGROUND: The overall incidence of colorectal cancer (CRC) in the United States has steadily decreased. However, the incidence of right-sided CRC remains unchanged for the past two decades. The serrated neoplastic pathway (sessile serrated adenoma/polyp, SSA/P) has been considered an important pathway of colorectal carcinogenesis, especially in the right-sided CRC. The aim of this study was to compare CRC anatomic distribution patterns in a 9-year interval in the general population before and after SSA/P was recognized and treated as a CRC precursor. METHODS: The Miraca Life Sciences (MLS) pathology database was queried for all primary CRCs diagnosed between 8/3/2000 to 12/31/2005 (control group) and 1/1/2014 to 12/31/2014 (current group). Patients' demographics, clinical information, and pathology reports were collected and analyzed. RESULTS: A total of 5,602 patients with 5,685 CRCs were identified, of which 2,728 patients with 2,765 CRCs in current group and 2,874 patients with 2,920 CRCs in control group. Overall, there were no statistical differences in the current group in regards to the anatomical distribution patterns of CRCs in the proximal, right-sided, distal, and left-sided colon or genders compared with the control group (all P>0.05). Among the current group, there were 33 (1.2%) patients with 38 (1.4%) CRCs arising in SSA/Ps [serrated carcinomas (SCAs)], of which 33 (86.8%) were in the right-sided colon and 5 (13.2%) in the left-sided colon. Twenty-three (69.7%) SCA patients were female with significant advanced age than male (76.4 vs. 69.6, P=0.023). CONCLUSIONS: The overall current CRC anatomic distribution patterns after SSA/Ps managed as CRC precursor remain the same in the patients' population from the community-based endoscopy centers in the U.S. It is suggested that the current SSA/P management might need to be further modified.

Helicobacter infections with rare bacteria or minimal gastritis: Expecting the unexpected.

BACKGROUND: The routine use of special stains for detection of Helicobacter remains controversial. AIMS: To determine the frequency of histologically atypical Helicobacter infection. METHODS: All gastric biopsies received at a large pathology reference laboratory over a 6-month period were stained for Helicobacter, and the histologic and clinicopathologic parameters evaluated. RESULTS: Amongst 7663 Helicobacter-positive biopsies, 823 (10.7%) did not show typical chronic active gastritis with numerous Helicobacter organisms, and were therefore considered histologically atypical. Rare Helicobacter pylori organisms accounted for 58.0% of all atypical infections; the next most common atypical Helicobacter infection was that with minimal or no gastric inflammation (23.3% of atypical infections). Patients in these groups did not differ demographically from those with other forms of atypical or typical Helicobacter infection, although a small subgroup (6%) was more likely to have had a previously treated infection. CONCLUSIONS: In many of these atypical infections, Helicobacter would not have been suspected based on the histologic findings alone, and would have been missed without routine special stains. Performing a sensitive stain could prevent additional testing and allow prompt treatment of the affected patients, thus substantially reducing the risk for peptic ulcer and gastric cancer and preventing the transmission of the infection to family members.

Immunohistochemical screening of mismatch repair genes hMLH1, hMSH2, and hMSH6 in dysplastic lesions of the colon.

Immunohistochemical decrease in staining for mismatch repair proteins may be seen in either microsatellite instability or inactivation (methylation) of mismatch repair proteins. Both are features of the malignant phenotype in a range of colorectal neoplasms. Expression of mismatch repair proteins in dysplastic lesions in ulcerative colitis (UC) has not been studied extensively. The authors analyzed protein expression of hMLH1, hMSH2, and hMSH6 in 18 cases of dysplasia-associated lesion or mass (DALM) in patients with UC and 10 sporadic adenomas. Immunohistochemical studies revealed adequate staining in almost all of the cases. A significant decrease in protein expression was seen in 2 DALM and 2 sporadic adenomas. The authors conclude that immunohistochemical studies of mismatch repair proteins can be applied to dysplastic lesions in UC with adequate staining results. Decreased wild type expression of hMLH1, hMSH2, and hMSH6 is not a feature of DALM in the setting of UC.

Gene signature distinguishes patients with chronic ulcerative colitis harboring remote neoplastic lesions.

BACKGROUND: Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer. The standard method of surveillance for neoplasia in UC by colonoscopy is invasive and can miss flat lesions. We sought to identify a gene expression signature in nondysplastic mucosa without active inflammation that could serve as a marker for remote neoplastic lesions. METHODS: Gene expression was analyzed by complementary DNA microarray in 5 normal controls, 4 UC patients without dysplasia, and 11 UC patients harboring remote neoplasia. Common gene ontology pathways of significantly differentially expressed genes were identified. Expression of genes which were progressively and significantly upregulated from controls to UC without neoplasia, to UC with remote neoplasia were evaluated by real-time polymerase chain reaction. Several gene products were also examined by immunohistochemistry. RESULTS: Four hundred and sixty-eight genes were significantly upregulated, and 541 genes were significantly downregulated in UC patients with neoplasia compared with UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly upregulated from controls to nondysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increased expression of S100A9 and REG1α in UC-associated cancer and in nondysplastic tissue from UC patients harboring remote neoplasia compared with UC patients without neoplasia and controls. CONCLUSIONS: Gene expression changes occurring as a field effect in the distal colon of patients with chronic UC identify patients harboring remote neoplastic lesions. These markers may lead to a more accurate and less invasive method of detection of neoplasia in patients with inflammatory bowel disease.

Hereditary diffuse gastric cancer: multidisciplinary case report with review of the literature.

Hereditary diffuse gastric cancer (HDGC) is a rare, inherited cancer syndrome with at least one fourth of HDGC patients having an autosomal dominantly inherited mutation of CDH1 (E-Cadherin). Penetrance is relatively high (70-80% lifetime risk for gastric cancer). It is important for pathologists to recognize the syndrome's phenotype in early gastric lesions: patchy intramucosal signet ring cells often associated with pagetoid spread. Due to the insidious nature of this lesion, surveillance is limited and currently prophylactic gastrectomy is an option chosen by many HDGC patients. We present a case report from a multidisciplinary team of authors with a review of the literature that includes the updated guidelines for CDH1 genetic testing.

Serrated adenoma: a distinct form of non-polypoid colorectal neoplasia?

Until recently, 2 major forms of colorectal polyp were recognized: the adenoma and the hyperplastic polyp. Adenomas were known to represent a precursor to colorectal cancer, whereas hyperplastic polyps were viewed as nonneoplastic, having no potential for progression to malignancy. We now recognize, however, that the lesions diagnosed as hyperplastic polyps in the past represent a heterogeneous group of polyps, some of which truly are hyperplastic, and others that truly have a significant risk for transformation to colorectal cancer. These polyps have a characteristic serrated architecture, and include not only hyperplastic polyps but also the recently recognized serrated adenomas. Serrated adenomas occur in 2 forms: the traditional serrated adenoma, which is usually a polypoid lesion endoscopically, and the sessile serrated adenoma, a flat or slightly raised, usually right-sided lesion. Serrated adenomas of both types show characteristic molecular alterations not commonly seen in traditional colorectal adenomas, and probably progress to colorectal cancer by means of a different pathway, the so-called 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.

Drug-induced Injury of the Gastrointestinal Tract.

The effects of drugs on the gastrointestinal tract are diverse and depend on numerous factors. Diagnosis is centered on histologic findings, with mostly nonspecific patterns of injury that must be interpreted in the correct clinical context. Nonsteroidal antiinflammatory drugs are a common cause of drug-induced gastrointestinal injury, with effects primarily in the gastric mucosa but also throughout the gastrointestinal tract. Another common class of drugs causing a variety of pathologic findings in the gut is chemotherapeutic agents. This article discusses the differential diagnosis of the various patterns of injury, including ischemic damage, and the histologic findings specific for certain drugs.