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Background & Aims Superficial (T1) esophageal adenocarcinoma (EAC) commonly is treated by endoscopic resection, yet little is known about factors that predict outcomes of this approach. We assessed clinical and histologic variables associated with the overall survival times of patients with T1 EAC who received therapy. Methods In a retrospective analysis, we collected data from patients who underwent endoscopic mucosal resection (EMR) for T1 EAC (194 patients with T1a and 75 patients with T1b) at the Mayo Clinic, from 1995 through 2011. EMR specimens were reviewed systematically for depth of invasion, presence of lymphovascular invasion, grade of differentiation, and status of resection margins. Kaplan–Meier curves and proportional hazards regression models were used in statistical analyses. Results Demographic characteristics were similar between patients with T1a and T1b EAC. Overall survival at 5 years after EMR was 74.4% for patients with T1a (95% confidence interval [CI], 67.6%−81.8%) and 53.2% for patients with T1b EAC (95% CI, 40.3%–70.1%). Of surviving patients with T1a EAC, 94.1% remained free of cancer (95% CI, 89.8%–98.5%), and 94.7% of surviving patients with T1b EAC remained free of cancer (95% CI, 85.2%−100%). A multivariable model associated older age (per 10-year increment), evidence of lymphovascular invasion, and deep margin involvement with reduced overall survival in patients with T1 EAC. Conclusions Systematic assessment of EMR specimens can help predict mortality and potentially guide treatment options for patients with T1 EAC.

To investigate the value of viscosity measured with ultrasonographic (US) elastography in liver fibrosis staging and to determine whether the use of a viscoelastic model to estimate liver elasticity can improve its accuracy in fibrosis staging.The study, which was performed from February 2010 to March 2011, was compliant with HIPAA and approved by the institutional review board. Written informed consent was obtained from each subject. Ten healthy volunteers (eight women and two men aged 27-55 years) and 35 patients with liver disease (17 women and 18 men aged 19-74 years) were studied by using US elasticity measurements of the liver (within 6 months of liver biopsy). US data were analyzed with the shear wave dispersion ultrasound vibrometry (SDUV) method, in which elasticity and viscosity are measured by evaluating dispersion of shear wave propagation speed, as well as with the time-to-peak (TTP) method, where tissue viscosity was neglected and only elasticity was estimated from the effective shear wave speed. The hepatic fibrosis stage was assessed histologically by using the METAVIR scoring system. The correlation of elasticity and viscosity was assessed with the Pearson correlation coefficient. The performances of SDUV and TTP were evaluated with receiver operating characteristic (ROC) curve analysis.The authors found significant correlations between elasticity and viscosity measured with SDUV (r = 0.80) and elasticity measured with SDUV and TTP (r = 0.94). The area under the ROC curve for differentiating between grade F0-F1 fibrosis and grade F2-F4 fibrosis was 0.98 for elasticity measured with SDUV, 0.86 for viscosity measured with SDUV, and 0.95 for elasticity measured with TTP.The results suggest that elasticity and viscosity measured between 95 Hz and 380 Hz by using SDUV are correlated and that elasticity measurements from SDUV and TTP showed substantially similar performance in liver fibrosis staging, although elasticity calculated from SDUV provided a better area under the ROC curve.

Background There are currently 2 existing confocal laser endomicroscopy (CLE) platforms: probe-based CLE (pCLE) and endoscope-based CLE (eCLE) systems, each with its own criteria for identifying dysplasia in Barrett's esophagus (BE). The diagnostic performance of these 2 systems has not been directly compared. Design Preclinical, feasibility study. Objectives We compared the interrater agreement and diagnostic performance of the pCLE and eCLE systems. In addition, we evaluated a new BE endomicroscopy criteria based on fluorescent glucose intensity uptake. Patients Thirteen patients with Barrett's esophagus and high-grade dysplasia or early cancer undergoing 16 EMR. Intervention CLE imaging was performed using two different probes with 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose, a fluorescent glucose analog with preferential uptake in dysplastic mucosa to supply contrast. Four quadrants were imaged per specimen with a total of 64 imaged mucosal sites presented to three gastroenterologists. Main Outcome Measurements Interobserver agreement and accuracy for dysplasia was assessed of images classified according to Miami criteria, stacked eCLE images classified using the Mainz criteria and a novel fluorescence intensity criteria. Results The interrater agreements were 0.17, 0.68, and 0.87 for the Miami, Mainz, and the fluorescence intensity criteria, respectively. Overall accuracy in detecting dysplasia was 37% (95% CI, 30.3-43.9), 44.3% (95% CI, 37.3-50.9), and 78.6% (95% CI, 72.2-83.3) for the Miami, Mainz, and the fluorescence intensity criteria, respectively. Limitations This imaging technique and proposed fluorescence intensity criteria using 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose in EMR tissue will require in vivo validation and cannot be directly used with the current eCLE and pCLE clinical applications. Conclusions In this preclinical feasibility study, the use of an eCLE system with a topical fluorescent contrast in ex vivo EMR tissue demonstrated higher interrater agreement and accuracy.

Sclerosing cholangitis can be primary (PSC) or secondary. One unusual cause of secondary sclerosing cholangitis is the newly recognized entity of IgG4-associated cholangitis. The prevalence and significance of IgG4 plasma cells in patients, who are clinically and radiologically classified as PSC, however, are unknown. Clinical information and histology of liver explants of 98 consecutive liver transplants performed for PSC were reviewed. IgG4 immunohistochemical stain was performed on sections from hilar areas that contained large bile ducts and corresponding cholecystectomy specimens (available in 74 cases). Serum IgG4 levels were measured in stored serum from 81 cases. Tissue IgG4 positivity (>or=10 IgG4+ plasma cells/high power field) was correlated with clinical features (age, sex, presence of inflammatory bowel disease and cholangiocarcinoma, pancreatogram, PSC duration, PSC recurrence after transplant, and number of acute rejection episodes) and histologic findings (periductal lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis) in the liver explants. Twenty-three (23%) liver explants showed periductal infiltration with IgG4+ plasma cells. Eighteen cases (22%) had elevated serum IgG4 levels, including 8 without tissue IgG4 positivity. All cases showed dense periductal fibrosis; none had storiform fibrosis or obliterative phlebitis. IgG4 positivity in the liver strongly correlated with moderate-to-marked periductal lymphoplasmacytic inflammation (P=0.002). Clinically, IgG4 positivity in tissue, but not in serum, was correlated with shorter PSC duration before transplant and higher risk of recurrence after transplant. Nearly one quarter of explanted livers that carry a clinical diagnosis of PSC contain increased IgG4+ periductal plasma cell infiltrates and positive serum IgG4 levels. However, none of the explants show histologic features diagnostic of IgG4-associated cholangitis. PSC with tissue IgG4 positivity has a more aggressive clinical course manifested by shorter time to transplant and a higher likelihood of recurrence than IgG4 negative PSC.

Esophageal food impaction (FI) is a distressing condition requiring urgent endoscopic intervention, with a reported recurrence rate between 10% and 20%. Knowledge of factors predisposing to recurrent FI may enable preventive measures to minimize the risk of recurrence.To identify risk factors associated with recurrent FI.Retrospective case-control study.Tertiary referral center.A prospectively maintained database and medical records of all patients undergoing emergent endoscopy for FI from 1989 to 2000 were reviewed. Cases were defined as those presenting with more than 1 episode of FI, whereas controls were defined as those without recurrence within 5 years of the index episode. Several demographic, clinical, endoscopic, and follow-up variables were extracted. Statistical analysis included chi2 tests and t tests for univariate analysis, and stepwise logistic regression for multivariate analysis.NA.Predictors of recurrent FI.A total of 52 cases and 124 controls were identified (recurrence rate 30%). Presence of a diaphragmatic hernia [odds ratio (OR) 2.65; confidence interval (CI) 1.19-5.89], disimpaction by piecemeal extraction (OR 2.32; CI 1.09-4.97), and acquisition of esophageal biopsies (OR 3.69; CI 1.42-9.66) increased odds for recurrent FI. Physician follow-up after FI decreased the odds for recurrent FI (OR 0.38; CI 0.18-0.80).Retrospective study.The presence of a diaphragmatic hernia, complexity of endoscopic disimpaction technique, and lack of follow-up increased risk for recurrent FI. Collection of esophageal biopsies as a risk factor suggests a visibly more severe esophageal disorder as a potential cause for recurrent FI.

Purpose Cigarette smoking and alcohol use have markedly decreased in the past 40 years. However, there has been an increasing trend in the incidence of tongue cancer, particularly in young patients without traditional risk factors. This study sought to examine the prevalence and significance of human papillomavirus (HPV) infection and its clinical significance in patients with oral tongue cancer. Patients and Methods Fresh-frozen tissues from 51 patients with oral tongue cancer, treated with primary surgery from January 2004 to December 2006, were included in the study. The presence of HPV infection in tumor specimens was analyzed by polymerase chain reaction with HPV L1 consensus primers (GP 5+/GP 6+) and HPV-16-specific E6 primer pairs. Demographic and clinical data were collected to analyze patient outcomes. Results The overall frequency of HPV in oral tongue cancer in our study was 1.96% (1/51). Young patients below the age of 45 years accounted for 15.7% (8/51) of the total number of patients. Eighty-seven percent of the younger age group, including a single patient with an HPV-16-positive tumor, were alive and free from disease during the follow-up period. The overall survival of the study group was 81.4%. Conclusions Our data suggest that the incidence of HPV in oral tongue cancer is low and is unlikely to play a significant role in the etiology, pathogenesis, and clinical outcomes of oral tongue cancer. In addition, HPV is unlikely to constitute a significant factor in the rising trend of oral tongue cancer in the young population.

Although EMR has been used for elimination of neoplasia in BE, the significance of positive carcinoma margins and depth of invasion on endoscopic resection pathology has not been assessed using a valid standard. The aim of this study was to assess the accuracy of tumor staging by EMR using esophagectomy as the standard.Medical records of patients, who underwent endoscopic resection for esophageal carcinoma or high-grade dysplasia in BE followed by esophagectomy, were reviewed. Data were abstracted from a prospectively maintained EMR database. Endosonography and endoscopic resection were performed by a single experienced endoscopist. Two experienced GI pathologists interpreted all histological results. Standard statistical tests were used to compare continuous and categorical variables.Twenty-five patients were included in the study. Three patients had mucosal carcinoma and 16 had submucosal carcinoma following endoscopic resection. Surgical pathology staging was consistent with preoperative EMR staging in all patients. No patient with negative mucosal resection margins had residual tumor at the resection site at esophagectomy. In patients with submucosal carcinoma, 8 had residual carcinoma at the EMR site at surgery and 5 patients had metastatic lymphadenopathy.Tumor staging using EMR pathology is accurate when compared with surgical pathology following esophagectomy. Negative margins on EMR pathology correlate with absence of residual disease at the EMR site at esophagectomy. Submucosal carcinoma on EMR specimens was associated with a high prevalence of residual disease at surgery (50%) and metastatic lymphadenopathy (31%).

Purpose To assess immunohistologic features of angiogenesis of T1N0M0 oral squamous cell carcinoma (OSCC), and to identify predictors of regional recurrence. The identification of prognostic markers of early lymph node involvement in OSCC could allow for the use of more targeted biologic therapies for patients with early-stage tumors. Patients and Methods The study included patients treated for T1N0M0 OSCC at the Mayo Clinic from 1986 to 2001. All patients had initial surgical resection without neck dissection, and all had adequate follow-up with histologic specimens for review. Patients with lip, pharyngeal, or salivary gland tumors were excluded. Patient specimens were regraded and assessed for the histologic markers p53 and CD34 (penetrating and circumscribing patterns). The Kaplan-Meier method was used to estimate patient survival and survival free of regional recurrence. Results The study included 175 patients. The overall 5-year survival was 75%, and 5-year survival free of regional recurrence was 80.3%. Twenty-eight patients had regional recurrence. High-grade tumors ( P = .03) and the penetrating pattern of CD34 ( P = .02) were significantly associated with early regional metastasis from early-stage OSCC. The presence of p53 was not independently associated as a marker for regional metastasis. Conclusion Early-stage T1 OSCC with high-grade lesions and a penetrating pattern of CD34 was associated with a statistically significant risk of cervical lymph node metastasis, compared with a circumscribing pattern of CD34.

The majority of the facial skeleton myxomas are diagnosed between the second and third decades of life, with the average age of diagnosis between 25 to 30 years. Some authors suggest that there is a slight female predilection (male to female ratio 1:1.5); whereas others report an equal gender predilection between males and females. 6-8 Approximately two thirds of myx omas are located in the mandible, and one third are located in the maxilla. There is a wide variety in clinical and radiologic appearance; however, the most common presentation is as an asymptomatic jaw expansion and as a multilocular radiolucency. We present an unusual case of pediatric myxoma of the maxilla and discuss the presentation, histopathology, and treatment management.

Background & Aims: The aim of this study was to assess the validity of frozen section analysis of endoscopic mucosal resection (EMR) specimens from Barrett's esophagus as compared with permanent sections for the detection of neoplasia. Frozen sections help to give immediate feedback for surgical procedures. It has not been determined whether EMR can be adequately interpreted by using frozen sections to aid endoscopists in completely resecting neoplastic lesions. Methods: EMR specimens from Barrett's esophagus with high-grade dysplasia (HGD) and/or carcinoma were tested by frozen section. Pathologists evaluated EMR specimens for the depth of invasion as well as the appearance of clear margins of resection. The κ statistic was calculated to assess the degree of agreement between the frozen section and permanent section diagnoses. Results: Twenty-three consecutive patients underwent 30 EMRs with frozen section diagnosis. Frozen section revealed a carcinoma in 7 specimens (23%) and dysplasia in 20 (66%). Permanent sections found carcinoma in 8 specimens (26%), dysplasia in 19 specimens (63%), and normal or nondysplastic Barrett's esophagus in the remainder. The κ statistic for the depth of invasion of EMR specimens was 0.93 (near perfect agreement). The κ statistic for the margins of the EMR specimens was 0.80 (excellent agreement). Conclusions: This study indicated that frozen section analysis of esophageal EMR specimens is valid as compared with permanent section. This technique might allow rapid evaluation about the degree and depth of involvement of cancers. This allows physicians to make decisions regarding further therapy if margins are involved or decrease the use of EMR for histologically benign–appearing lesions.

Fluorescence in situ hybridization (FISH) and immunohistochemical analysis for assessment of HER-2 status in breast carcinomas are discordant in a significant proportion of cases with equivocal (2+) immunostaining. To evaluate the role of intratumoral heterogeneity and degree of amplification, we performed additional HER-2 immunostains and FISH on tumor-bearing blocks from 20 invasive breast carcinomas with immunohistochemical scores of 2+ with gene amplification and in 18 cases without amplification. Of the amplified cases, 11 (55%) had a 3+ immunohistochemical score on at least 1 additional slide, 8 (40%) remained 2+, and 1 (5%) had a slide scored 1+. All cases rescored 3+ showed high-level amplification in original and repeated FISH; cases remaining 2+ had a heterogeneous FISH profile (low-level amplification or a mosaic mixture of high-level amplified and nonamplified cells) in original and repeated FISH. Of nonamplified cases, 13 (72%) had a 1+ score on at least 1 additional slide, 4 (22%) remained 2+, and 1 (6%) had 1 slide scored 3+. In the nonamplified cases, 17 (94%) showed no amplification in repeated FISH. Significant intratumoral heterogeneity and minimal (low-level) HER-2 amplification account for many breast cancers with 2+ HER-2 protein expression.

We report a case of an inflammatory pseudotumor (IPT) of the spleen occurring in an 81-year-old woman with a history of a monoclonal gammopathy of undetermined significance. Eighteen-month follow-up after splenectomy demonstrated no tumor recurrence or progression of underlying plasma cell disease. Histologic examination of the tumor demonstrated a polymorphic population of inflammatory and epithelioid and spindle cells. Immunophenotyping showed large numbers of T cells, B cells, and polyclonal plasma cells. The epithelioid and spindle cells were positive for vimentin and CD68 but lacked expression of follicular dendritic cell markers and actin. Epstein-Barr virus (EBV) genome was identified in the epithelioid and spindle cell population by in situ hybridization using probes specific for EBV-encoded RNAs (EBER1 and EBER2). Southern blot analysis of digested DNA extracted from the tumor using an EBV-specific probe (XhoI) demonstrated the presence of a single high-intensity band, indicative of EBV monoclonality. While there have been 2 previous reports of hepatic IPTs containing a monoclonal population of EBV-infected tumor cells, this is the first report of such an association occurring in the spleen. The presence of clonal EBV DNA suggests some splenic IPTs may be true neoplasms.

Double Trouble: Two Cases of Squamous Carcinoma Arising From Barrett's Dysplasia After Endoscopic Mucosal Resection

Background: Screening for Barrett's esophagus and esophageal adenocarcinoma is not currently advocated due to lack of data supporting its efficacy and concerns regarding expense. The cost of a screening program is primarily related to sedation and physician expertise. Performance of unsedated procedures by physician extenders (PEs) in the primary care setting could lead to an increased uptake of screening and decreased costs. Objective: Determine feasibility andmeasure learning curve while training PEs to independently perform transnasal endoscopy (TNE) screening for Barrett's esophagus. Methods: Two PEs underwent a one week structured didactic training program, which reviewed basic esophageal anatomy and pathology. This was followed by observation of nasopharyngoscopy procedures in ENT clinic to familiarize trainees with nasopharyngeal anatomy. To learn TNE, patients were then recruited with research consent among veterans undergoing sedated EGD in the Louis Stokes Veteran Affairs Medical Center in Cleveland, OH. Supervised TNE training procedures were assessed by two attendings who measured learning of individual technical and cognitive components of TNE and overall performance on a 9 point structured scale. Scores of 7 or more defined procedural competence. TNEs performed by two PEs were analyzed by method of cumulative summation (CUSUM) to construct individual learning curves. Results: Only 1 of 55 procedures could not be completed in the training phase. PE 1 and 2 could both identify anatomic landmarks including GE junction, diaphragm and gastric folds after 16 consecutive procedures and needed to complete 19 and 22 procedures, respectively to satisfactorily learn the technique of nasal intubation. Esophageal intubation was satisfactorily learned by PE 1 after 22 procedures whereas PE 2 is approaching but has not yet achieved a satisfactory score after 25 procedures. Figure 1 illustrates gradual improvement in overall performance based on number of completed procedures. Conclusion: A program to train PEs in the performance of TNE has been developed. PEs require a moderate number of supervised procedures to train in TNE. Esophageal intubation is the most challenging aspect of TNE.

Frozen Section Diagnosis for Endoscopic Mucosal Resection of Barrett’s Esophagus Ganapathy Prasad, Kenneth K. Wang, Navtej S. Buttar, Jason Lewis, Michel WongKeeSong, Lynn Borkenhagen, Lori Lutzke, Sarah Papenfuss Endoscopic mucosal resection (EMR) is a useful technique in the staging and treatment of Barrett’s esophagus (BE). However, the procedure would be improved if margins and diagnosis could be established in a single session. Aim: To assess the use of frozen section analysis of EMR specimens compared to permanent sections in BE. Methods: Prospective study of patients who underwent EMR for a diagnosis of high-grade dysplasia (HGD) and/or carcinoma (Ca). The presence or absence of dysplasia and/or Ca in the body and margins of the EMR specimens was assessed by frozen section. Margins were coded as being involved by or free of Ca and/or dysplasia. The k statistic was calculated to assess the degree of agreement between the frozen section and permanent section diagnoses. Results: 23 consecutive patients referred to the Barrett’s Esophagus Unit at the Mayo Clinic were included in the study. 21 patients were male (91%) and the mean age 70.47 years. 7 patients underwent 2 EMRs and hence a total of 30 specimens were analyzed.15 patients (65%) had a diagnosis of HGD, 7 (30%) had a diagnosis of Ca and 1 had a history of esophageal Ca and HGD. One patient had a diagnosis of squamous cell Ca. 18 patients (78%) had nodules, 1 had mucosal irregularity and 4 (17%) had no visible lesions. Frozen section revealed a carcinoma in the body of 7 EMR specimens (23%), dysplasia in 20 specimens (66%) and normal or non dysplastic BE in 3 specimens (1%). Final histopathology by permanent sections revealed Ca in 8 (26%), dysplasia in 19 (63%) and normal or non-dysplastic BE in the remainder. The k statistic for the degree of agreement between the frozen section and permanent sections in the body of the EMR specimens (for all diagnoses) was 0.93 indicating near perfect agreement. The k statistic for the margins of the EMR specimens was 0.77 indicating substantial agreement. The k statistic for the degree of agreement for diagnosis cancer in the body of EMR specimens was 0.91, indicating near perfect agreement. Discussion: This study demonstrates the feasibility and accuracy of frozen section analysis of esophageal EMR specimens when compared to permanent sections. The correlation for assessing the margins was lower than that for the body of the EMR specimens which could be explained by the increased thickness of the frozen sections. The ability to obtain a rapid and accurate diagnosis and margins of EMR specimens will enhance complete removal of cancers. S1199 Endoscopically Placed Titanium Plicator for GERD: Feasibility Phase Results Jack I. Ramage, Christopher J. Gostout, Brian Fennerty, Joseph A. Murray, Charles Termin, Robert Sixto Background: Endoscopic treatment of GERD has emerged as an alternative to pharmacotherapy & surgery. The Syntheon Anti-Reflux Device (ARD) is a titanium compression implant that creates a full-thickness plication in the gastric cardia along the anteriorly and contiguous to the lesser curve. Implantation is performed with a standard upper endoscope, no overtube and is removable in the first 48 hours post placement. Aim: Determine safety of ARD in treatment of GERD. Methods: Eight subjects with symptomatic chronic GERD, abnormal esophageal pH studies, normal esophageal motility & responsiveness to daily use of PPI therapy were recruited. Exclusion criteria included hiatal herniaO 2cm, BMIO35, LA grade ‘‘C’’ or ‘‘D’’ esophagitis, Barrett’s or non-responsiveness to medication. Baseline and follow-up testing (off anti-secretory medications) at 1, 3 & 6 months included medication history, 48 hr pH study, esophageal manometry, EGD, GSRS, GERDHRQL, SF-36. No re-treatments were performed. Results: 6 males & 2 females (mean age 45, mean BMI 27) underwent full thickness plication with the titanium implant. Six months later, 6 of 8 (75%) were off PPI therapy. Mean GERD-HRQL improved 68% (26.1 vs 8.4) while mean GSRS:GERD score improved 40% (5 vs 2). 48-hr pH showed a trend to improvement & there was no significant difference in manometry. Mean ARD procedure time was 21 minutes (range 10-65). All implants were in place at follow-up endoscopy. Adverse events resolved spontaneously and included sore throat (nZ3), epigastric/referred chest pain (nZ4) & gas/bloat syndrome (nZ1). Conclusions: The ARD device for full-thickness plication of the gastric cardia proved to be safe & time efficient. Although numbers are limited in this feasibility phase, medication use & symptoms were significantly decreased. An expanded multicenter pivotal phase study is ongoing.