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The rate and risk factors of recurrent or metachronous adenocarcinoma following endoscopic ablation therapy in patients with Barrett's esophagus (BE) have not been specifically reported.The aim of this study was to determine the incidence and predictors of adenocarcinoma after ablation therapy for BE high-grade dysplasia (HGD) or intramucosal carcinoma (IMC).This is a single center, retrospective review of prospectively collected data on consecutive cases of endoscopic ablation for BE. A total of 223 patients with BE (HGD or IMC) were treated by ablation between 1996 and 2011. Primary outcome measures were recurrence and new development of adenocarcinoma after ablation. Recurrence was defined as the presence of adenocarcinoma following the absence of adenocarcinoma in biopsy samples from two consecutive surveillance endoscopies. Logistic regression analysis was performed to assess predictors of adenocarcinoma after ablation.One hundred and eighty-three patients were included in the final analysis, and 40 patients were excluded: 22 for palliative ablation, eight lost to follow-up, five for residual carcinoma and five for postoperative state. Median follow-up was 39 months. Recurrence or new development of adenocarcinoma was found in 20 patients (11 %) and the median time to recurrence/development of adenocarcinoma was 11.5 months. Independent predictors of recurrent or metachronous adenocarcinoma were hiatal hernia size ≥ 4 cm (odds ratio 3.649, P = 0.0233) and histology (HGD/adenocarcinoma) after first ablation (odds ratio 4.141, P = 0.0065).Adenocarcinoma after endoscopic therapy for HGD or IMC in BE is associated with large hiatal hernia and histology status after initial ablation therapy.

To determine if multilayered epithelium (MLE) is a useful prognostic indicator for a benign natural history of Barrett's epithelium, we evaluated endoscopic biopsies from patients with Barrett's epithelium without and with dysplasia and/or adenocarcinoma and from non-Barrett's controls for the presence of MLE. MLE was found in 6% of non-Barrett's controls, 30% of Barrett's patients with no dysplasia, and 14% of Barrett's patients with dysplasia and/or adenocarcinoma. MLE was significantly associated with shorter lengths of Barrett's epithelium in both Barrett's groups. Three of 5 photodynamic therapy patients were noted to develop MLE after therapy. MLE may be found in patients with dysplasia and/or adenocarcinoma and after photodynamic therapy; its presence is not useful as a prognostic indicator for a more benign course of Barrett's. This study confirms that MLE is significantly associated with shorter lengths of Barrett's epithelium.

The efficacy of photodynamic therapy (PDT) is currently evaluated for the treatment of superficial neoplasms arising in Barrett's esophagus (BE). An accurate assessment of this technique requires the evaluation of biopsies before and after treatment. However, despite the importance of pathology, only a limited number of studies have systematically assessed the mucosal changes after PDT. To evaluate mucosal changes after PDT, and pathologic variables that may impact on the success of this therapy, we analyzed the pre- and post-PDT biopsies of a cohort of patients treated by this modality. Thirty-three patients (mean age, 71 years) with high-grade dysplasia (HGD) and/or intramucosal carcinoma (IMC) arising in BE and followed up after PDT using Porfimer sodium form the basis of this study. In all patients, a review of all pre- and post-PDT biopsies was performed. The variables recorded included the histologic grade and architecture of neoplasms, the distribution of neoplasms, and squamous re-epithelialization. IMC and HGD coexisted in the pre-PDT biopsies of 18 patients (54.5%). IMC and HGD showed a prominent tubular proliferation in 14 patients and displayed a papillary pattern (at least partially) in 19 patients. In post-PDT, patches of specialized columnar epithelium were buried under squamous epithelium in 17 patients (51.5%), and foci of dysplasia/carcinoma covered by squamous epithelium were found in 9 patients (27.3%). HGD and/or IMC were eradicated in 17 patients (eradicated group) and persisted in 16 patients (persistent group). In the persistent group, grade and architecture were unchanged after PDT in 62.5% and 87.5% of patients, respectively. The persistent group was characterized by: 1) a more frequent papillary architecture (P < 0.05), and 2) a diffuse distribution of the neoplasms on pre-PDT biopsies (P = 0.05). Singularly, the persistent neoplastic lesions were observed in the distal esophagus (P < 0.05). A systematic histopathologic evaluation allowed us to draw attention to the fact that distally located and papillary-type neoplasia seem resistant to PDT. The higher than expected incidence of buried residual neoplastic epithelium should also be emphasized since it represents a risk for undetected growth of malignancy.

Cyclooxygenase-2 expression is upregulated in Barrett’s esophagus and esophageal adenocarcinoma. Photodynamic therapy using porfimer sodium can result in ablation of dysplasia and intramucosal carcinoma, eradication of Barrett’s esophagus, and restitution of squamous epithelium. The aim of this study was to determine the effect of photodynamic therapy on cyclooxygenase-2 expression in esophageal epithelium. Paired pre- and post-photodynamic therapy biopsy samples from the same anatomical levels of 20 individuals who had undergone photodynamic therapy for Barrett’s esophagus with high-grade dysplasia and/or intramucosal carcinoma were immunostained using a cyclooxygenase-2 monoclonal antibody. Cyclooxygenase-2 expression was graded in squamous epithelium, Barrett’s esophagus, and neoplasia (if present) as follows: grade 0 (no staining), grade 1 (staining in 1–10% of cells), grade 2 (staining in 11–90% of cells), and grade 3 (staining in >90% of cells). Pre-photodynamic therapy median cyclooxygenase-2 expression was grade 2 (range 1–3) in neoplastic foci and grade 1 (range 1–3) in nondysplastic Barrett’s esophagus (P = 0.0009 for pairwise comparison). With the exception of a few cells staining in the basal epithelial layers, median cyclooxygenase-2 expression was graded as 0 (similar to controls) in both pre-photodynamic therapy squamous epithelium and post-photodynamic therapy neosquamous epithelium. This was significantly lower when compared to either neoplastic foci (P < 0.0001) or nondysplastic Barrett’s esophagus (P < 0.0001) pre-photodynamic therapy. Notably, in four patients with post-photodynamic therapy recurrent neoplasia, cyclooxygenase-2 expression returned to elevated levels. Cyclooxygenase-2 expression is elevated in Barrett’s esophagus with high-grade dysplasia or intramucosal carcinoma prior to photodynamic therapy. Following successful photodynamic therapy, cyclooxygenase-2 expression in neosquamous epithelium returns to a low baseline level similar to that observed in native esophageal squamous epithelium. Post-photodynamic therapy neoplastic recurrence is associated with elevated cyclooxygenase-2 expression. Prospective studies should determine whether cyclooxygenase inhibitors have a role as adjuvant therapy to prevent recurrence of Barrett’s esophagus following endoscopic therapy.

Spectrally encoded confocal microscopy and optical frequency domain imaging are two non-contact optical imaging technologies that provide images of tissue cellular and architectural morphology, which are both used for histopathological diagnosis. Although spectrally encoded confocal microscopy has better transverse resolution than optical frequency domain imaging, optical frequency domain imaging can penetrate deeper into tissues, which potentially enables the visualization of different morphologic features. We have developed a co-registered spectrally encoded confocal microscopy and optical frequency domain imaging system and have obtained preliminary images from human oesophageal biopsy samples to compare the capabilities of these imaging techniques for diagnosing oesophageal pathology.

Background Spectrally encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technique that has the potential to be used for acquiring comprehensive images of the entire distal esophagus endoscopically with subcellular resolution. Objective The goal of this study was to demonstrate large-area SECM in upper GI tissues and to determine whether the images contain microstructural information that is useful for pathologic diagnosis. Design A feasibility study. Setting Gastrointestinal Unit, Massachusetts General Hospital. Patients Fifty biopsy samples from 36 patients undergoing routine EGD were imaged by SECM, in their entirety, immediately after their removal. Results The microstructure seen in the SECM images was similar to that seen by histopathology. Gastric cardia mucosa was clearly differentiated from squamous mucosa. Gastric fundic/body type mucosa showed more tightly packed glands than gastric cardia mucosa. Fundic gland polyps showed cystically dilated glands lined with cuboidal epithelium. The presence of intraepithelial eosinophils was detected with the cells demonstrating a characteristic bilobed nucleus. Specialized intestinal metaplasia was identified by columnar epithelium and the presence of goblet cells. Barrett's esophagus (BE) with dysplasia was differentiated from specialized intestinal metaplasia by the loss of nuclear polarity and disorganized glandular architecture. Limitations Ex vivo, descriptive study. Conclusions Large-area SECM images of gastroesophageal biopsy samples enabled the visualization of both subcellular and architectural features of various upper GI mucosal types and were similar to the corresponding histopathologic slides. These results suggest that the development of an endoscopic SECM probe is merited.

Background & Aims: The most common significant adverse event after photodynamic therapy (PDT) with porfimer sodium is esophageal stricture formation. This study assessed whether pretreatment variables, including prior endoscopic therapy for Barrett's esophagus, are associated with post-PDT stricturing. Methods: Data from all patients who had undergone PDT with porfimer sodium for Barrett's esophagus with high-grade dysplasia, intramucosal carcinoma, or T1 cancer at our institution since 1997 were reviewed. Results: One hundred sixteen patients underwent 160 courses of PDT. The incidence of stricture formation after index PDT was 16% (19/116). For all PDT courses, the overall incidence of stricture was 23% (37/160). Stricture rate was significantly higher after a second PDT course compared with index PDT (43% vs 16%, P = .0007). There was no association between post-PDT stricture development and age, gender, body mass index, or prior endoscopic mucosal resection. Patients who developed a stricture had a longer length of Barrett's esophagus before treatment than those who did not develop a stricture (7.7 vs 5.7 cm for index PDT only, P = .025; 7.4 vs 5.7 cm for all PDT courses, P = .007). Length of Barrett's esophagus, multiple PDT courses, and presence of intramucosal carcinoma on pretreatment pathology were independent predictors of post-PDT stricture in a stepwise logistic regression analysis controlling for treatment variables, including treatment length. Conclusions: An increased risk of stricture development was seen after multiple courses of PDT. An association between post-PDT stricture and length of Barrett's esophagus but not treatment length was also found. Endoscopic mucosal resection did not appear to influence the likelihood of stricture development after porfimer sodium–based PDT.

Background Photodynamic therapy (PDT) has been used extensively for endoscopic ablation of Barrett's esophagus with high-grade dysplasia (HGD) or intramucosal carcinoma. Objective To identify patient variables that influence the likelihood of response to PDT. Design A retrospective cohort study. Setting Tertiary-referral center. Patients A total of 116 patients with Barrett's esophagus and with HGD, intramucosal carcinoma, or T1 cancer. Interventions PDT with porfimer sodium. Main Outcome Measurements (1) Ablation of HGD and/or intramucosal carcinoma and (2) eradication of all Barrett's epithelium. Results Of the patients, 51% underwent treatment for HGD and 49% of patients had intramucosal carcinoma or T1 cancer. At 12-month follow-up, ablation of HGD and/or cancer was observed in 70% of patients, and ablation of all Barrett's epithelium was observed in 39%. In multivariate analysis, the pretreatment length of Barrett's esophagus was inversely correlated with successful ablation of all Barrett's epithelium. Patients with Barrett's esophagus length more than 3 cm were less likely to experience complete ablation compared with patients with Barrett's esophagus length 3 cm or less (odds ratio [OR] 0.15 [95% CI, 0.04-0.50]). Patients with intramucosal carcinoma were not significantly less likely to experience elimination of HGD and/or cancer (OR 0.77 [95% CI, 0.30-2.00]) or ablation of all Barrett's epithelium (OR 0.82 [95% CI, 0.32-2.07]) compared with patients with HGD alone. Limitations Retrospective study, limited sample size without a control group for comparison. Conclusions PDT of Barrett's esophagus with HGD, intramucosal carcinoma, or T1 cancer can result in ablation of dysplasia and/or eradication of all Barrett's epithelium. Factors associated with the likelihood of response include length of Barrett's esophagus. The presence of intramucosal carcinoma or T1 cancer was not associated with higher likelihood of treatment failure.

The restoration of squamous epithelium after photodynamic therapy (PDT) for Barrett esophagus (BE) and its related neoplasms has been noted. It may result in the development of buried neoplasms and/or BE underneath restored squamous epithelium which maintain their potential for malignant transformation. The purpose of this study was to evaluate the prevalence, endoscopic, and histologic characteristics and also response to further treatment of buried neoplastic epithelium developing after PDT. Fifty-two BE patients with high-grade dysplasia (n=19), intramucosal adenocarcinoma (n=28), and invasive adenocarcinoma (n=5) were treated with porfimer PDT. Buried neoplasms completely covered by squamous epithelium were seen in 1 patient before and in 13 patients after PDT. Their prevalence was 0.6% and 7.4% of pre and post-PDT biopsy levels positive for neoplasia (P=0.001). Buried neoplasms, representing the highest grade of residual neoplasm, were noted in a series of 11 post-PDT endoscopies (7.1% of 155 post-PDT endoscopies with neoplastic diagnoses) of 8 patients. Their occurrence after PDT was neither associated with the length of BE, the diffuseness of neoplasms nor the presence of buried lesions before treatment. There was no prevalent location for these lesions in relation to the original segment of BE, although the majority of both surface and buried neoplasms were found in the prior neoplastic sites. Patients with buried neoplasms responded to further treatment similarly to those with only surface neoplasms (8 of 13 vs. 17 of 24) (P=0.33). In conclusion, buried neoplasms are not uncommon after PDT. Thorough endoscopic surveillance with extensive biopsies, especially of the sites previously positive for neoplasia is important to avoid overlooking buried neoplasms that may progress.

Endoscopic mucosal resection (EMR), which is advocated for the treatment of early (superficial) gastroesophageal neoplasms, has also been alluded to represent a superior diagnostic and staging modality. We compared the diagnostic concordance of preceding biopsies with EMR specimens in 31 gastric and 10 esophageal EMRs consisting of 6 low-grade and 12 high-grade dysplasias, 21 intramucosal adenocarcinomas, and 2 submucosal invasive adenocarcinomas. Discrepancies were considered as either major or minor if the histologic grades differed by 2 or more, or by only 1, respectively. Discrepant and concordant cases were compared with regard to the size of lesion (maximum dimension and surface area), number of biopsy fragments, and extent of biopsy sampling (ratio between lesion size and number of biopsy fragments). These same variables were used to evaluate the differences seen between gastric and esophageal cases. Of the 41 cases, 16 (39%) had discrepant diagnoses, including 14 gastric and 2 esophageal neoplasms. A major discrepancy was seen in 2% of the cases (n = 1, gastric) and a minor discrepancy, in 15 cases. All but 2 of the discrepant cases were found to have a higher grade on EMR. The average number of biopsy fragments was 4.4 in both concordant and discrepant groups. The maximal dimension, surface area, and biopsy sampling ratios of the lesion were significantly greater in the discrepant cases than in the concordant cases. The esophageal cases trended toward having smaller size and a significantly extensive biopsy sampling. We conclude that EMR is superior to biopsy for diagnosing superficial gastroesophageal tumors. Discrepancies between the specimens occur in larger lesions (>10 mm) with less extensive biopsy sampling. EMR can substantially modify the diagnostic grade of a lesion and therefore facilitate optimal therapeutic decisions by avoiding undertreatment and overtreatment based on inaccurate grading and staging.

Endoscopic mucosal resection (EMR), a relatively new endoluminal therapeutic technique with low morbidity and no mortality reported to date, is advocated for the treatment of Barrett's esophagus (BE)-related superficial neoplasms. However, recent studies revise its success downward, particularly regarding the ability to achieve complete excision. To evaluate what remains an evolving technique, we analyzed our experience with a series of 27 esophageal EMRs (20 lesions in 18 patients). Our goal was to evaluate the diagnostic, staging, and therapeutic advantages of EMR separately by correlating the initial biopsies and pre-EMR endoscopic ultrasound (EUS) staging with the final histologic diagnoses and stage. Persistence/recurrence of neoplastic tissue was also correlated with the margin status of the resections. The mean size of the neoplasms, which included low-grade dysplasias (n=2), high-grade dysplasias (n=8), intramucosal carcinomas (n=14), and submucosal invasive carcinomas (n=3), was 11 mm. EUS correctly reported an intramucosal or submucosal lesion in 70% of the cases while it overstaged 18% and understaged 12% of the cases. The biopsy diagnosis corresponded to the EMR diagnosis in 63% of the cases. The biopsy underestimated the grade of the lesion in 21% of the cases. EMR revealed a lower histologic grade compared with the biopsy in 16% of the cases. The resection was microscopically complete in only 4% of the cases. No residual/recurrent disease was observed in 10 lesions (9 patients) at 4 to 63 months (mean, 23 months) post-EMR. However, 9 lesions (8 patients) persisted/recurred 28 days to 25 months (mean, 6 months) after treatment; 56% of the cases with positive lateral margin(s) and negative deep margin persisted/recurred. However, 86% of the EMRs with positive deep margin showed residual tumor/recurrence on follow-up biopsies. In conclusion, we observed that EMR offers improved diagnosis and staging as compared with biopsy and EUS. This is a significant advantage since it can modify patients' management. However, frequent incompleteness of resection and high persistence/recurrence are significant pitfalls that dictate continued endoscopic surveillance.

Background Photodynamic therapy of pancreatic cancer by using percutaneously placed light catheters has been reported. The feasibility and safety of EUS-guided photodynamic therapy of the pancreas was studied in a porcine model. Methods After injection of porfimer sodium, a 19-gauge needle was inserted into the pancreas, the liver, the spleen, and the kidney under EUS guidance. A small diameter quartz optical fiber was passed through the EUS needle and used to illuminate the tissue with laser light. The tissue response to photodynamic therapy was examined. Results Localized tissue necrosis was achieved in all organs, without significant complication. There was no significant difference in inflammation induced by photodynamic therapy within the various organs. Conclusions EUS-guided photodynamic therapy is a safe and simple technique that can induce small areas of focal tissue ablation within the liver, the pancreas, the kidney, and the spleen, and potentially could be used to treat a variety of benign and malignant conditions.

A high speed, power-efficient, catheter-based optical coherence tomography system has been used to image the esophagus and stomach in over 90 patients and can differentiate normal tissue from Barrett’s esophagus and esophageal adenocarcinoma.

Frequent Persistence of Dysplasia by Systematic Pathological Evaluation After Photodynamic Therapy for Barrett’s Esophagus With High-Grade Dysplasia or Early Adenocarcinoma Masaya Ohana, Mari Mino-Kenudson, Shinichi Ban, William Puricelli, Norman Nishoka Background: Photodynamic therapy (PDT) is extensively evaluated for the treatment of superficial neoplasia arising in Barrett’s Esophagus (BE). Several reports have demonstrated marked reduction of neoplastic tissue post PDT, but only few have included a systematic pathologic assessment. Methods: 49 BE patients (M:41;F:8) with high-grade dysplasia (HGD, n Z 21), intramucosal carcinoma (IMC, n Z 25) and invasive carcinoma (InvCa, n Z 3) were treated with PDT. Photosensitizing agents were porfimer sodium (2 mg/kg)(n Z 45) or 5aminolevulinic acid (30 mg/kg)(n Z 4). Biopsies were taken with jumbo forceps from 4-quadrant every 2 cm over the length of the BE. During follow-up, the protocol surveyed the length of the original BE, including areas of squamous reepithelialization. Acid suppression with proton pump inhibitors was maintained in all patients. Results: Mean length of BE was 6.63 cm (range, 1-13). Mean follow-up was 27.7 months (range, 6-85). PDTwas successful after one session in 15 patients (30.6%; HGD 9, IMC 6) with no recurrence during follow-up (mean 19.9 months, range 7-32). Thirty four patients were treated with additional PDTalone (n Z 1), in combination with mucosal fulguration (nZ 19) or fulguration alone (n Z 13). One patient refused additional treatment. In toto, neoplasias were eradicated in 39 patients (79.6%)(HGD 17, IMC 21, InvCa 1) with a mean disease free interval of 12.8 months (0-32). The neoplastic lesions were downgraded in 2 patients (HGD to LGD, InvCa to IMC), unchanged in 7 (14.3%; HGD 3, IMC 3, InvCa 1), or progressed in one (IMC to InvCA). Thirteen of 24 patients (54.2%) with neoplasias spanning over less than 3 cm were successfully treated by one course of PDT. Conversely, it was successful in only 2 of 25 patients (8%) with neoplasia spanning over 3 cm. Residual neoplasias were more common in the distal (n Z 9) or middle (n Z 8) than in the proximal (none) segment of BE. Patches of BE covered by squamous epithelium were found in 30 patients (61.2%), and foci of buried neoplasia were found in 18 (36.7%) patients after PDT, while they were observed in only 17(34.7%) and 5(10.2%) before PDT, respectively. Conclusion: Post PDT detailed pathologic evaluation reveals a high frequency of persistent neoplasia. Diffuseness and distal location of the lesions are associated with treatment failure. Residual neoplasia is often covered by unremarkable squamous epithelium. These characteristics underline the importance of close follow-up.

Background: In 1997, we described muhilayered epithelium (MLE), a hybrid epithelium with morphologic and cytokeratin features of squamous and columnar epithelium (Gastroenterology 1997;112:760-65), that is significantly associated with Barrett's epithelium (p