AGA Clinical Practice Update on Endoscopic Treatment of Barrett's Esophagus With Dysplasia and/or Early Cancer: Expert Review.

DESCRIPTION: The purpose of this best practice advice article is to describe the role of Barrett's endoscopic therapy (BET) in patients with Barrett's esophagus (BE) with dysplasia and/or early cancer and appropriate follow-up of these patients. METHODS: The best practice advice provided in this document is based on evidence and relevant publications reviewed by the committee. BEST PRACTICE ADVICE 1: In BE patients with confirmed low-grade dysplasia, a repeat examination with high-definition white-light endoscopy should be performed within 3-6 months to rule out the presence of a visible lesion, which should prompt endoscopic resection. BEST PRACTICE ADVICE 2: Both BET and continued surveillance are reasonable options for the management of BE patients with confirmed and persistent low-grade dysplasia. BEST PRACTICE ADVICE 3: BET is the preferred treatment for BE patients with high-grade dysplasia (HGD). BEST PRACTICE ADVICE 4: BET should be preferred over esophagectomy for BE patients with intramucosal esophageal adenocarcinoma (T1a). BEST PRACTICE ADVICE 5: BET is a reasonable alternative to esophagectomy in patients with submucosal esophageal adenocarcinoma (T1b) with low-risk features (<500-µm invasion in the submucosa [sm1], good to moderate differentiation, and no lymphatic invasion) especially in those who are poor surgical candidates. BEST PRACTICE ADVICE 6: In all patients undergoing BET, mucosal ablation should be applied to 1) all visible esophageal columnar mucosa; 2) 5-10 mm proximal to the squamocolumnar junction and 3) 5-10 mm distal to the gastroesophageal junction, as demarcated by the top of the gastric folds (ie, gastric cardia) using focal ablation in a circumferential fashion. BEST PRACTICE ADVICE 7: Mucosal ablation therapy should only be performed in the presence of flat BE without signs of inflammation and in the absence of visible abnormalities. BEST PRACTICE ADVICE 8: BET should be performed by experts in high-volume centers that perform a minimum of 10 new cases annually. BEST PRACTICE ADVICE 9: BET should be continued until there is an absence of columnar epithelium in the tubular esophagus on high-definition white-light endoscopy and preferably optical chromoendoscopy. In case of complete endoscopic eradication, the neosquamous mucosa and the gastric cardia are sampled by 4-quadrant biopsies. BEST PRACTICE ADVICE 10: If random biopsies obtained from the neosquamous epithelium demonstrate intestinal metaplasia/dysplasia or subsquamous intestinal metaplasia, a repeat endoscopy should be performed and visible islands or tongues should undergo targeted focal ablation. BEST PRACTICE ADVICE 11: Intestinal metaplasia of the gastric cardia (without residual columnar epithelium in the tubular esophagus) should not warrant additional ablation therapy. BEST PRACTICE ADVICE 12: When consenting patients for BET, the most common complication of therapy to be quoted is post-procedural stricture formation, occurring in about 6% of cases. Bleeding and perforation occur at rates <1%. BEST PRACTICE ADVICE 13: After complete eradication (endoscopic and histologic) of intestinal metaplasia has been achieved with BET, surveillance endoscopy with biopsies should be performed at the following intervals: for baseline diagnosis of HGD/esophageal adenocarcinoma: at 3, 6, and 12 months and annually thereafter; and baseline diagnosis of low-grade dysplasia: at 1 and 3 years. BEST PRACTICE ADVICE 14: Endoscopic surveillance post therapy should be performed with high-definition white-light endoscopy, including careful inspection of the neosquamous mucosal and retroflexed inspection of the gastric cardia. BEST PRACTICE ADVICE 15: The approach to recurrent disease is similar to that of the initial therapy; visible recurrent nodular lesions require endoscopic resection, whereas flat areas of columnar mucosa in the tubular esophagus can be treated with mucosal ablation. BEST PRACTICE ADVICE 16: Patients should be counseled on cancer risk in the absence of BET, as well as after BET, to allow for informed decision-making between the patient and the physician.

Allaying uncertainty in diagnosing buried Barrett's esophagus.

Subsquamous intestinal metaplasia (SSIM) in the setting of Barrett's esophagus (BE) is a technically challenging diagnosis. While the risk for progression of BE involving the surface mucosa is well documented, the potential risk for development of advanced neoplasia associated with SSIM has been controversial. This study aimed to determine the effects of specimen adequacy, presence of dysplasia, and interobserver agreement for SSIM interpretation. Adult patients (n = 28) who underwent endoscopic therapy for BE with high-grade dysplasia or intramucosal carcinoma (HGD/IMC) between October 2005 and June 2013 were included. Initial evaluation (n = 140 slides) by an experienced gastrointestinal pathologist was followed by an interobserver study by 8 pathologists. Forty-seven (34%) slides had insufficient subsquamous tissue to assess for SSIM. SSIM was found in 19% of all slides and 29% of slides with sufficient subsquamous tissue. At least one slide had SSIM in 54% to 64% of patients. Subsquamous low grade dysplasia (LGD) was found in 4 (15%) slides with SSIM and subsquamous HGD/IMC was found in 5 (19%) slides with SSIM. At the patient level, 8 (53%) had no dysplasia, 4 (27%) had LGD and 3 (20%) had HGD/IMC. Overall agreement for SSIM by slide was 92% to 94% (κ = 0.73 to κ = 0.82, moderate to strong agreement), and by patient was 82% to 94% (κ = 0.65 to κ = 0.87, moderate to strong agreement). This study confirms the need for assessing specimen adequacy and assessing the prevalence of SSIM and is the first to assess interobserver agreement for SSIM and dysplasia within SSIM.

Development of Evidence-Based Surveillance Intervals After Radiofrequency Ablation of Barrett's Esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) recurs in 25% or more of patients treated successfully with radiofrequency ablation (RFA), so surveillance endoscopy is recommended after complete eradication of intestinal metaplasia (CEIM). The frequency of surveillance is informed only by expert opinion. We aimed to model the incidence of neoplastic recurrence, validate the model in an independent cohort, and propose evidence-based surveillance intervals. METHODS: We collected data from the United States Radiofrequency Ablation Registry (US RFA, 2004-2013) and the United Kingdom National Halo Registry (UK NHR, 2007-2015) to build and validate models to predict the incidence of neoplasia recurrence after initially successful RFA. We developed 3 categories of risk and modeled intervals to yield 0.1% risk of recurrence with invasive adenocarcinoma. We fit Cox proportional hazards models assessing discrimination by C statistic and 95% confidence limits. RESULTS: The incidence of neoplastic recurrence was associated with most severe histologic grade before CEIM, age, endoscopic mucosal resection, sex, and baseline BE segment length. In multivariate analysis, a model based solely on most severe pre-CEIM histology predicted neoplastic recurrence with a C statistic of 0.892 (95% confidence limit, 0.863-0.921) in the US RFA registry. This model also performed well when we used data from the UK NHR. Our model divided patients into 3 risk groups based on baseline histologic grade: non-dysplastic BE; indefinite for dysplasia, low-grade dysplasia, and high-grade dysplasia; or intramucosal adenocarcinoma. For patients with low-grade dysplasia, we propose surveillance endoscopy at 1 and 3 years after CEIM; for patients with high-grade dysplasia or intramucosal adenocarcinoma, we propose surveillance endoscopy at 0.25, 0.5, and 1 year after CEIM, then annually. CONCLUSION: In analyses of data from the US RFA and UK NHR for BE, a much-attenuated schedule of surveillance endoscopy would provide protection from invasive adenocarcinoma. Adherence to the recommended surveillance intervals could decrease the number of endoscopies performed yet identify unresectable cancers at rates less than 1/1000 endoscopies.

Histologic Features of Hysterectomy Specimens From Female-Male Transgender Individuals.

Histologic changes in the female genital tract after prolonged androgen stimulation have been described in the past. However, these changes have not been systematically addressed in hysterectomy specimens from subjects undergoing surgical gender-reassignment, typically after treatment with exogenous androgens. The current study aims to provide practicing pathologists with a list of expected histologic features in hysterectomy specimens from female-male transgender individuals. Twenty-seven hysterectomy with bilateral salpingo-oophorectomy specimens were identified from our Laboratory Information System. Slides were retrieved and reviewed for features associated with androgen exposure. Clinical information for the 27 subjects (20-46 yr old, mean=29 yr) was obtained from the electronic medical records. Twenty-four subjects had received androgen 19 mo to 24 yr preoperatively. Focal decidua-like endometrial stromal change with glandular paucity was present in 16/27 (59%) uteri associated with predominantly inactive endometrial glands. Ectocervical or transformation zone transitional cell metaplasia was present in 17/27 (63%) subjects. Bilateral cystic follicles were present in all 23 subjects who underwent bilateral salpingo-oophorectomy and had preoperative androgen exposure. In these ovaries, follicular density appeared higher than that expected for age with counts ranging from 1.5 to 32.5 follicles/mm (average=10.7 follicles/mm). Predominantly inactive, sparse endometrial glands with focal decidua-like stromal change, cervical transitional cell metaplasia, bilateral cystic follicles and higher follicular density are observed in the majority of specimens from female-male transgender individuals. These histologic changes correlate with prolonged preoperative androgen administration. The significance of these findings relies on recognizing the spectrum of androgen-related histologic alterations and not confusing transitional cell metaplasia with cervical dysplasia.

Liquid Nitrogen Spray Cryotherapy in Treatment of Barrett's Esophagus, where do we stand? A Systematic Review and Meta-Analysis.

Radiofrequency ablation (RFA) is the preferred treatment option for Barrett's esophagus (BE) to achieve complete eradication (CE) of dysplasia (D), and intestinal metaplasia (IM). Cryotherapy, using liquid nitrogen (LNC), is a cold-induced tissue-injury technique option for the ablation of BE. We conducted a systematic review and meta-analysis to assess the overall efficacy and safety of LNC in the treatment of BE. We conducted a search of multiple electronic databases and conference proceedings from inception through June 2018. The primary outcome was to estimate the pooled rates of CE-IM, CE-D, and CE-HGD. The secondary outcome was to estimate the risk of adverse events and recurrence of disease after LNC. Nine studies reported 386 patients who were treated with LNC. The pooled rate of CE-IM was 56.5% (95% CI 48.5-64.2, I2 = 47), pooled rate of CE-D was 83.5% (95% CI 78.3-87.7, I2 = 22.8), and pooled rate of CE-HGD was 86.5% (95% CI 64.4-95.8, I2 = 88.1). Rate of adverse events was 4.7%, and the risk of BE recurrence was 12.7%. On subgroup analysis, the pooled rate of CE-IM with LNC in patients who failed RFA was 58.4% (95% CI 47.2-68.8, I2 = 32.5), and the pooled rate of CE-D in the same population was 81.9% (95% CI 72.5-88.6, I2 = 5.9). CE-D rates with LNC are comparable to RFA while CE-IM rates appear to be lower than the rates achievable with RFA. CE-IM rate in RFA failed patients is 58.4% and thus LNC is a rescue option to consider in this population.

Shorter time to achieve endoscopic eradication is not associated with improved long-term outcomes in Barrett's esophagus.

Quality indicators have been proposed for endoscopic eradication therapy of Barrett's esophagus (BE). One such measure suggests that complete eradication of intestinal metaplasia (CE-IM) should be achieved within 18 months of starting treatment. The aim of this study was to assess whether achievement of CE-IM within 18 months is associated with improved long-term clinical outcomes. This was a retrospective cohort study of BE patients who underwent endoscopic eradication. Time to CE-IM was recorded and categorized as ≤ or > 18 months. The main outcome measures were recurrence of IM and of dysplasia after CE-IM, defined as a single endoscopy without endoscopic evidence of BE or histologic evidence of intestinal metaplasia. Recurrence was analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards modeling. A total of 290 patients were included in the analyses. The baseline histology was high-grade dysplasia or intramucosal carcinoma in 74.2% of patients. CE-IM was achieved in 85.5% of patients, and 54.1% of the cohort achieved CE-IM within 18 months. Achieving CE-IM within 18 months was not associated with reduced risk of recurrence of IM or dysplasia in both unadjusted and adjusted analyses. In this cohort, older age and increased BE length were associated with IM recurrence, and increased hiatal hernia size was associated with dysplasia recurrence. Compared to longer times, achieving CE-IM within 18 months was not associated with a reduced risk of recurrence of IM or dysplasia. Alternative evidence-based quality metrics for endoscopic eradication therapy should be identified.

The origin of p40-negative and CDX2-positive primary squamous cell carcinoma of the stomach: case report.

BACKGROUND: Primary gastric squamous cell carcinoma (SCC) is a very rare disease. The origin of this tumor remains unclear, although there are some hypotheses. A 60-year-old man consulted a previous physician complaining of upper abdominal pain. Esophagogastroduodenoscopy revealed type 2 gastric cancer, and the patient was referred to our hospital. After close examination, the patient was diagnosed as cStage IIA gastric adenocarcinoma, and distal gastrectomy was performed. Histochemical studies showed typical findings of SCC, and the tumor was surrounded by intestinal metaplasia. Immunohistochemical examination was positive for cytokeratin (CK) 5/6 and caudal-type homeobox protein 2 (CDX2) and negative for p63/p40. CONCLUSION: The results of immunostaining for CK5/6 supported that this tumor was SCC, but the question why p63/p40 were negative and CDX2 was positive still remained. Concerning about the origin of p63/p40 and CDX2, it was suggested that the tumor cells were not derived from ectopic squamous epithelium but from intestinal metaplasia. And tumor cells looked like homogeneous and squamous metaplasia was not observed. These findings supported the idea that these tumor cells arose from stem cells in the intestinal metaplasia of the stomach.

Late Recurrence of Barrett's Esophagus After Complete Eradication of Intestinal Metaplasia is Rare: Final Report From Ablation in Intestinal Metaplasia Containing Dysplasia Trial.

BACKGROUND & AIMS: The goal of treatment for Barrett's esophagus (BE) with dysplasia is complete eradication of intestinal metaplasia (CEIM). The long-term durability of CEIM has not been well characterized, so the frequency and duration of surveillance are unclear. We report results from a 5-year follow-up analysis of patients with BE and dysplasia treated by radiofrequency ablation (RFA) in the randomized controlled Ablation of Intestinal Metaplasia Containing Dysplasia (AIM) trial. METHODS: Participants for the AIM Dysplasia trial (18-80 years old) were recruited from 19 sites in the United States and had endoscopic evidence of non-nodular dysplastic BE ≤8 cm in length. Subjects (n = 127) were randomly assigned (2:1 ratio) to receive either RFA (entire BE segment ablated circumferentially) or a sham endoscopic procedure; patients in the sham group were offered RFA treatment 1 year later, and all patients were followed for 5 years. We collected data on BE recurrence (defined as intestinal metaplasia in the tubular esophagus) and dysplastic BE recurrence among patients who achieved CEIM. We constructed Kaplan-Meier estimates and applied parametric survival analysis to examine proportions of patients without any recurrence and without dysplastic recurrence. RESULTS: Of 127 patients in the AIM Dysplasia trial, 119 received RFA and met inclusion criteria. Of those 119, 110 (92%) achieved CEIM. Over 401 person-years of follow-up (mean, 3.6 years per patient; range, 0.2-5.8 years), 35 of 110 (32%) patients had recurrence of BE or dysplasia, and 19 (17%) had dysplasia recurrence. The incidence rate of BE recurrence was 10.8 per 100 person-years overall (95% CI, 7.8-15.0); 8.3 per 100 person-years among patients with baseline low-grade dysplasia (95% CI, 4.9-14.0), and 13.5 per 100 person-years among patients with baseline high-grade dysplasia (95% CI 8.8-20.7). The incidence rate of dysplasia recurrence was 5.2 per 100 person-years overall (95% CI 3.3-8.2); 3.3 per 100 person-years among patients with baseline low-grade dysplasia (95% CI 1.5-7.2), and 7.3 per 100 person-years among patients with baseline high-grade dysplasia (95% CI 4.2-12.5). Neither BE nor dysplasia recurred at a constant rate. There was a greater probability of recurrence in the first year following CEIM than in the following 4 years combined. CONCLUSIONS: In this analysis of prospective cohort data from the AIM Dysplasia trial, we found BE to recur after CEIM by RFA in almost one third of patients with baseline dysplastic disease; most recurrences occurred during the first year after CEIM. However, patients who achieved CEIM and remained BE free at 1 year after RFA had a low risk of BE recurrence. Studies are needed to determine when surveillance can be decreased or discontinued; our study did not identify any BE or dysplasia recurrence after 4 years of surveillance.

Endotherapy in case of relapse of neoplastic Barrett's esophagus after successful initial endoscopic resection.

BACKGROUND: Endotherapy in cases of neoplastic Barrett esophagus (BE) relapse after successful initial endoscopic management is commonly accepted, but few studies analyze this topic and also take into account the metachronous lesions. AIMS: To evaluate the efficiency of endotherapy in the case of neoplastic BE relapse after successful complete endoscopic eradication of neoplastic BE and metaplastic BE. METHODS: Retrospective review of medical records was collected in a computerized and prospective manner between 2000 and 2015, in a single tertiary care center. Recurrence was defined by histological presence of high-grade dysplasia or superficial adenocarcinoma at least 6 months after the end of successful initial endotherapy. RESULTS: Eighteen patients were assessed (1F/17 M). Delay between initial treatment and relapse was 16.6 months (range 6-33). Endotherapy for relapse obtained a sustained and complete remission for 8/18 (44%) patients, with an average endoscopic follow-up of 28 months. The complication rate of endotherapy was 6%. Surgical management was required in 33% (2 pT2N0M0, 2 pTisN0M0, 1 pTm2N0M0 and 1 pTm3N0M0) and salvage radiochemotherapy in 17% (3/18). One patient treated by 6 sessions of ER was considered as a failure given the multiple sessions of endotherapy. Multivariate analysis showed that length of BE (>5 cm), late stenosis adverse events and the quality of vertical margin during initial ER are predictive factors for disease-free survival (p value < 0.01, Hazard Ratio up to 0.076). CONCLUSION: Endotherapy could be a treatment for management of neoplastic BE relapse, but should be carefully used, with strict follow-up.

[The molecular genetic alterations in mucosa of intestines as markers of oncologic progression and estimate of effectiveness of anti-reflux operations in patients with Barrett's esophagus].

The development of disease of Barrett's esophagus is based on processes of metaplasia of epithelium of esophagus when as a result of reflux of gastric juice and bile acids the normal planocellular epithelium of esophagus is replaced by cylindrical epithelium of intestinal type. Thereupon, Barrett's esophagus is progressing up to dysplasia and adenocarcinoma of esophagus. The progression from precancerous states up to tumor is related to development of genome disorders in cells associated with malignant transformation. The genetic and epigenetic alterations conditioning tumor growth can be used as markers of prognosis of clinical course of disease. To receive possible markers of progression of Barrett's esophagus the study was organized concerning methylation of such genes-suppressors of tumor growth as MGMT, CDH1, p16/CDKN2A, DAPK, RAR-ß and RUNX3 in patients with Barrett's esophagus and adenocarcinoma of esophagus. The effectiveness of applied anti-reflux surgical treatment was evaluated too. The abnormal methylation of studied genetic panel in patients with Barrett's esophagus prior to surgical treatment was observed reliably more frequently in altered epithelium as compared with unaltered epithelium (p<0.0001), under dysplasia as compared with metaplasia (p<0.0358) and in the presence of long (>3 cm) segments of altered epithelium as compared with short (<3 cm) segments (p=0.0068). In normal epithelium, prior to operation, abnormal methylation of panel of genes was detected in 7/60 (12%) of patients. Against the background of surgical treatment number of long and short segments of altered epithelium of esophagus reliably decreased (p<0.05). At that, in short segments after operation rate of methylation increased significantly (p=0.0068). Though after operation number of patients with Barrett's esophagus and dysplasia and metaplasia decreased, the rate of abnormal methylation in the other patients increased. It is demonstrated that anti-reflux operation ameliorates condition of mucous membrane of esophagus under Barrett's esophagus. However, in cases without regression significant increasing of rate of abnormal methylation of studied panel of genes is occurred. This is a proof that abnormal methylation of system of genes is related to worse response to application of anti-reflux surgical treatment.

Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

AIMS: Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC). METHODS AND RESULTS: We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment-naïve high-grade columnar dysplasia (HGD) or EAC, and 23 non-EAC oesophagectomy cases. A gastrointestinal pathologist assessed haematoxylin and eosin-stained ESMG images by using a scoring system that assigns individual ESMG acini to five histological types (mucous, serous, oncocytic, dilated, or ductal metaplastic). In our model, ductal metaplastic acini were more common in patients with HGD/EAC (12.7%) than in controls (3.5%) (P = 0.006). We also identified greater proportions of acini with dilation (21.9%, P < 0.001) and, to a lesser extent, ductal metaplasia (4.3%, P = 0.001) in non-EAC oesophagectomy cases than in controls. Ductal metaplasia tended to occur in areas of mucosal ulceration or tumour. CONCLUSIONS: We found a clear association between ductal metaplastic ESMG acini and HGD/EAC. Non-EAC cases had dilated acini and some ductal dilation. Because ESMGs and ducts harbour putative progenitor cells, these associations could have significance for understanding the pathogenesis of EAC.

Osseous Metaplasia and Subsequent Spontaneous Pregnancy Chance: A Case Report and Review of the Literature.

BACKGROUNDS: What is not clear as yet is not only the etiology, but also the management of osseous metaplasia. We describe an infertile patient with osseous metaplasia and subsequent pregnancy after treatment and review the literature from infertility perspective. METHOD: We presented a 30-year-old woman with 8 years of secondary infertility who conceived spontaneously after removal of osseous tissue by operative hysteroscopy (HS) following one failed in vitro fertilization cycle. The current literature regarding the osseous metaplasia and fertility potential after removal of osseous tissue was also systematically reviewed in which 21 reports (n = 64 women) were eligible. RESULTS: The available data suggest that restoration of endometrial cavity with HS or curettage provides a spontaneous pregnancy rate of 54.2% within 12 months. CONCLUSION: According to the available data, irrespective from the duration of subfertility, spontaneous pregnancy should be expected for at least 1 year following the 'complete' restoration of endometrial cavity. In that context, further infertility treatments such as assisted reproduction cycles should be postponed, unless there is another reason for infertility.

Colorectal dysplasia in inflammatory bowel disease: a clinicopathologic perspective.

Surveillance for neoplasia in colitis is the most challenging diagnostic colonoscopic procedure. The detection and treatment of colorectal dysplasia in inflammatory bowel disease remain problematic to the point that unsuspected colorectal cancers (CRCs) are still identified. Excellent bowel preparation and use of high-resolution colonoscopes with chromoendoscopy facilitate the detection and characterization of subtle neoplasia. This approach is superior to taking random biopsy specimens and should be the standard of care for surveillance but requires adequate training. Suspicious lesions should be assessed carefully and described using objective terminology. The terms dysplasia-associated lesions/masses and flat dysplasia are best avoided because they may be open to misinterpretation. Most suspicious lesions detected during surveillance can be removed endoscopically, precluding the need for surgery. Nevertheless, endotherapy in colitis can be difficult as a result of underlying inflammation and scarring. Lesions that are not endoscopically resectable need to be removed surgically, although the possibility that some lesions might be amenable to local resection (including lymphadenectomy) rather than subtotal colectomy may need to be re-evaluated. Despite surveillance programs, patients still present clinically with CRC. This may occur because lesions are missed (possibly because of the failure to use optimal techniques), lesions are not adequately removed, patients fail to return for colonoscopy, or CRCs arise rapidly in mucosa that is minimally dysplastic and the CRCs are not recognized as being potentially invasive even on biopsy. Future advances in, for example, stool DNA assays, use of confocal endomicroscopy, or use of endoscopic ultrasound, may help in the identification of high-risk patients and the assessment of dysplastic lesions.

Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus.

BACKGROUND & AIMS: The existence of slowly cycling, adult stem cells has been challenged by the identification of actively cycling cells. We investigated the existence of uncommitted, slowly cycling cells by tracking 5-iodo-2'-deoxyuridine (IdU) label-retaining cells (LRCs) in normal esophagus, Barrett's esophagus (BE), esophageal dysplasia, adenocarcinoma, and healthy stomach tissues from patients. METHODS: Four patients (3 undergoing esophagectomy, 1 undergoing esophageal endoscopic mucosal resection for dysplasia and an esophagectomy for esophageal adenocarcinoma) received intravenous infusion of IdU (200 mg/m(2) body surface area; maximum dose, 400 mg) over a 30-minute period; the IdU had a circulation half-life of 8 hours. Tissues were collected at 7, 11, 29, and 67 days after infusion, from regions of healthy esophagus, BE, dysplasia, adenocarcinoma, and healthy stomach; they were analyzed by in situ hybridization, flow cytometry, and immunohistochemical analyses. RESULTS: No LRCs were found in dysplasias or adenocarcinomas, but there were significant numbers of LRCs in the base of glands from BE tissue, in the papillae of the basal layer of the esophageal squamous epithelium, and in the neck/isthmus region of healthy stomach. These cells cycled slowly because IdU was retained for at least 67 days and co-labeling with Ki-67 was infrequent. In glands from BE tissues, most cells did not express defensin-5, Muc-2, or chromogranin A, indicating that they were not lineage committed. Some cells labeled for endocrine markers and IdU at 67 days; these cells represented a small population (<0.1%) of epithelial cells at this time point. The epithelial turnover time of the healthy esophageal mucosa was approximately 11 days (twice that of the intestine). CONCLUSIONS: LRCs of human esophagus and stomach have many features of stem cells (long lived, slow cycling, uncommitted, and multipotent), and can be found in a recognized stem cell niche. Further analyses of these cells, in healthy and metaplastic epithelia, is required.

Hormone receptor status does not affect prognosis in metaplastic breast cancer: a population-based analysis with comparison to infiltrating ductal and lobular carcinomas.

BACKGROUND: Metaplastic breast cancer is a rare histologic variant among breast cancers. We sought to investigate the impact of hormone receptor status in metaplastic breast cancer and compare outcomes with common histologic variants of breast cancer. METHODS: The study was performed utilizing the Surveillance, Epidemiology, and End Results database. A query was made for patients with metaplastic breast cancer from 2000 to 2010. A separate query identified all patients with infiltrating ductal (IDC) or lobular (ILC) carcinoma during the same period. Effect of hormone receptor status was evaluated using Cox regression analysis. Significance was assessed for p < 0.05. RESULTS: A total of 2,338 patients with metaplastic breast cancer were available for study. Most tumors were hormone receptor negative (79.0 %) and greater than or equal to grade 3 (82.9 %). For comparison, 382,667 and 44,813 patients with IDC and ILC, respectively, were obtained. Overall 5-year survival for metaplastic breast cancer was 62.2 % compared with 81.2 % for IDC (p < 0.001) and 80.2 % for ILC (p < 0.001). For metaplastic cases, no difference in 5-year survival was found between hormone-positive and hormone-negative tumors (65.7 vs. 63.5 %; p = 0.70). Multivariate analysis demonstrated metaplastic histology as an independent risk factor for cancer-related mortality both among hormone-positive (hazard ratio [HR] 2.4; 95 % confidence interval [CI] 1.8-3.0; p < 0.001) and hormone-negative (HR 1.7; 95 % CI 1.5-1.9; p < 0.001) breast cancers. CONCLUSION: Metaplastic breast cancer is an aggressive histologic variant that portends a poor prognosis compared with common breast cancer subtypes. Contrary to other breast cancers, hormone receptor positivity does not improve prognosis in metaplastic breast cancer.

Systematic review comparing radiofrequency ablation and complete endoscopic resection in treating dysplastic Barrett's esophagus: a critical assessment of histologic outcomes and adverse events.

BACKGROUND: With recent advances in endoscopy, endoscopic techniques have surpassed esophagectomy in the treatment of dysplastic Barrett's esophagus (BE). OBJECTIVE: To compare the efficacy and safety of complete EMR and radiofrequency ablation (RFA) in the treatment of dysplastic BE. DESIGN: Systematic review of literature. PATIENTS: Diagnosis of BE with high-grade dysplasia or intramucosal cancer. INTERVENTION: Complete EMR or RFA. MAIN OUTCOME MEASUREMENTS: Complete eradication of dysplasia and intestinal metaplasia at the end of treatment and after >12 months' follow-up. Adverse event rates associated with treatment. RESULTS: A total of 22 studies met the inclusion criteria. Only 1 trial directly compared the 2 techniques; most studies were observational case series. Dysplasia was effectively eradicated at the end of treatment in 95% of patients after complete EMR and 92% after RFA. After a median follow-up of 23 months for complete EMR and 21 months for RFA, eradication of dysplasia was maintained in 95% of patients treated with complete EMR and 94% treated with RFA. Short-term adverse events were seen in 12% of patients treated with complete EMR but in only 2.5% of those treated with RFA. Esophageal strictures were adverse events in 38% of patients treated with complete EMR, compared with 4% of those treated with RFA. Progression to cancer appeared to be rare after treatment, although follow-up was short. LIMITATIONS: Small studies, heterogeneous in design, with variable outcome measures. Also follow-up durations were short, limiting evaluation of long-term durability of both treatments. CONCLUSION: RFA and complete EMR are equally effective in the short-term treatment of dysplastic BE, but adverse event rates are higher with complete EMR.

Verrucous carcinoma of the endometrium: a rare and challenging diagnosis.

Verrucous carcinoma of the endometrium is an exceedingly rare disease with only a few cases reported in the literature. We describe the case of a 68-year-old postmenopausal patient who presented with vaginal discharge. PAP smears were repeatedly reported negative and an endometrial curettage 2 years prior to the diagnosis only showed fragments of benign squamous epithelium. Because of continuous symptoms a hysterectomy was performed and revealed extensive squamous metaplasia of the endometrium with focal transition to verrucous carcinoma. This case demonstrates that benign appearing squamous epithelium in curettage specimens, especially when abundant, is not necessarily ordinary portio epithelium. In this setting, the clinical presentation becomes paramount for considering a well differentiated squamous carcinoma of the endometrium and avoiding diagnostic delay.

Radiofrequency ablation for Barrett's-associated intramucosal carcinoma: a multi-center follow-up study.

BACKGROUND: Radiofrequency ablation (RFA), with or without endoscopic mucosal resection (EMR), has been validated as a safe, effective and durable treatment option for dysplastic Barrett's esophagus. Its durability in eradicating Barrett's-associated intramucosal carcinoma (IMC), however, is unclear. We set out to assess the long-term safety and efficacy of RFA for IMC. METHODS: Retrospective review of two tertiary care facility records for patients undergoing RFA, with or without EMR, for biopsy-proven IMC. Our primary outcome of interest was to quantify the rate of durable complete eradication for intestinal metaplasia and for IMC and associated dysplasia. A multi-variate regression analysis was performed to identify features which correlate with durable eradication of IMC/dysplasia. Our secondary outcome of interest was treatment-related complications. RESULTS: 36 patients (26 male; mean age 64 ± 12 years), with a mean Barrett's length of 3.5 ± 2.5 cm, underwent RFA for biopsy-proven IMC. EMR was performed in 31 (86%) prior to or during RFA. Complete eradication of IMC/dysplasia was achieved in 32/36 (89%) and patients required a mean of 1 ± 1 EMR and 2 ± 1 RFA sessions to achieve eradication. During a mean follow-up period of 24 ± 19 months, durable complete eradication of IMC/dysplasia was achieved in 29/36 (81%) patients. On multi-variate regression analysis, undergoing an EMR prior to RFA was associated with an increased likelihood of maintaining durable eradication of IMC/dysplasia (p = 0.03). Treatment-related complications included: bleeding (3%) and stricture formation (19%). CONCLUSION: RFA is an effective and durable treatment option for Barrett's-associated IMC. Greater than 80% of patients will achieve and maintain complete eradication of IMC at a mean of 2 years follow-up.