Management Of High-grade Dysplasia Research Articles

This Month in Gastroenterology

The management of high-grade dysplasia (HGD) in Barrett’s esophagus is an issue of ongoing controversy. With the increasing age of the population in Western countries, the increasing prevalence of gastroesophageal reflux disease, and the declining rates of Helicobacter pylori infection, the occurrence of HGD is likely to increase. Esophagectomy can be considered the most accepted standard of care for patients with HGD in Barrett’s esophagus. However, this type of surgery is associated with considerable morbidity and mortality, and not every patient is a suitable surgical candidate.

Quality of life in patients with various Barrett's esophagus associated health states

BackgroundThe management of Barrett's esophagus (BE), particularly high grade dysplasia (HGD), is an area of much debate and controversy. Surgical esophagectomy, intensive endoscopic surveillance and mucosal ablative techniques, especially photodynamic therapy (PDT), have been proposed as possible management strategies. The purpose of this study was to determine the health related quality of life associated with Barrett's esophagus and many of the pivotal health states associated with Barrett's HGD management.Methods20 patients with Barrett's esophagus were enrolled in a pilot survey study at a large urban hospital. The utility of Barrett's esophagus without dysplasia (current health state) as well as various health states associated with HGD management (hypothetical states as the subject did not have HGD) were measured using a validated health utility instrument (Paper Standard Gamble). These specific health states were chosen for the study because they are considered pivotal in Barrett's HGD decision making. Information regarding Barrett's HGD was presented to the subject in a standardized format that was designed to be easily comprehendible.ResultsThe average utility scores (0–1 with 0 = death and 1 = perfect health) for the various Barrett's esophagus associated states were: BE without dysplasia-0.95; Post-esophagectomy for HGD with dysphagia-0.92; Post-PDT for HGD with recurrence uncertainty-0.93; Post-PDT for HGD with recurrence uncertainty and dysphagia-0.91; Intensive endoscopic surveillance for HGD-0.90.ConclusionWe present the scores for utilities associated with Barrett's esophagus as well as various states associated with the management of HGD. The results of our study may be useful in advising patients and providers regarding expected outcomes of the various HGD management strategies as well as providing utility scores for future cost-effectiveness analyses.

High-Grade Dysplasia in Adenoma-Like Mass Lesions Is Not an Indication for Colectomy in Patients with Ulcerative Colitis

Purpose: The management of polypoid dysplasia in ulcerative colitis (UC) is evolving. There are at least 3 reports of polypectomy as a safe alternative to colectomy in pts with adenoma-like mass lesions (ALMs) (Rubin, et al Gastro 1999;117:1295 [n = 30]; Odze, et al Clinical Gastro Hep. 2004;2:534 [n = 24]; Kundu et al. Gastro 2005; S128(4): A579 [n = 30]). The management of high grade dysplasia (HGD) in ALMs is not well characterized. Aim of this study was to ascertain the course of pts with HGD in ALMs in the absence of any synchronous flat dysplasia. We hypothesize that colectomy is not mandated in pts after complete excision of ALMs with HGD. Methods: Pathology/clinical databases were systematically searched for dysplastic lesions in inflammatory bowel disease from 1997–2004. Pts were identified with UC who had ALM lesions, and a subset with high-grade dysplastic polyps were defined as our study cohort. Pt demographics, disease characteristics, surveillance protocol, histopathology of biopsies and colectomy specimens were evaluated. Results: 113 pts were identified with dysplastic lesions .102 (90%) of these had UC, 5(4%) had Crohn's disease and 6(6%) had indeterminate colitis. 30 of the 102 (29%) pts with UC had ALMs in the absence of synchronous flat dysplasia; of which 9(30%) had HGD in these polyps. The mean age of cohort was 61 yrs (28–75 yrs); 6/9(66%) were male. The mean duration of disease was 16.3 yrs (6–26 yrs). 7/9 (77%) pts had pancolitis .9 pts had 10 ALMs with HGD. 9/10 (90%) of these polyps were within the area of colitis. The polyps were found in: 1(10%) in cecum, 3(30%) in ascending colon, 1(10%) in descending colon, 3(30%) in sigmoid colon, and 2(20%) in rectum. Most polyps (8/10) were adenomatous and 2/10 were villous. The mean polyp size was 5.4 mm (2–12mm). 32 surveillance colonoscopies were performed (mean 3.6 colonoscopies/pt). The pts were followed for a mean of 64.5 mos (40–87 mos). 3/9 pts (33%) had colectomy. No pts in this cohort were detected to have carcinoma in surveillance biopsies and/or in their resection specimens. Conclusions: Our data suggests that the presence of high grade dysplasia in ALMs does not mandate colectomy. Continued close observation is suggested in this pt cohort after complete excision of polyps. Further prospective evaluation of this pt population is merited.

Endoscopic Mucosal Resection (EMR) for High Grade Dysplasia (HGD) and Early Esophageal Cancer

Purpose: Endoscopic mucosal resection (EMR) is considered a major advance in minimally invasive surgery in the gastrointestinal tract. EMR is particularly appealing in the management of high-grade dysplasia in Barrett's esophagus which has been a difficult area in clinical decision-making. This utility of endoscopic therapy is based on the notion that there is no lymph node metastasis in high-grade dysplasia and very low rate of metastasis in invasive cancer confined to the mucosa. Endoscopic ablative therapies like photodynamic therapy have been successful for high-grade dysplasia in Barrett's esophagus. However, important limitation of such therapy is the lack of pathology specimen confirming that disease is confined to the mucosa and uncertainty of complete ablation especially where the disease might be deeper than superficial mucosa. Methods: Patients: During the period of January 2002 to May 2005, 52 patients had 183 EMR for the treatment of esophageal lesions. There were 39 males and 13 females, mean age was 70 (34–86). The indications were endoscopic resection of HGD (n = 24), early cancer (n = 27), endoscopic resection of a lesion which pathology biopsy was not conclusive (n = 1). Methods: EMR was performed using submucosal injection of either normal saline or dextrose 50% along with methylene blue. EMR kit (Olympus) was used to excise the specimen. Mean size of resected specimen was 1.2 cm (0.5–2.0). Different specimen bottles were used for the lesion versus the surroundings. Mean number of specimen per patient was 4 (range 1–6). All patients underwent meticulous staging including EUS, CT and PET scan. Results: Complete endoscopic excision was achieved in fifty patients. Cancer extending to the lateral margin of the specimen was seen in (n = 8). HGD extending to the margin of the surrounding tissue was seen in (n = 14). Tumor was upgraded from T1 to T2 was seen in 2 patients, while it was downgraded from T1 to HGD in 5, and to LGD in one patient. Photodynamic therapy was used in 21 patients to ablate residual HGD/T1 cancer. Follow up for up to 3 years revealed HGD± T1 cancer-free in all but three patients. Two patients died from progressive disease and one from unrelated cancer. Conclusions: EMR with or without other modality should be considered as a treatment option in all esophageal HGD or superficial adenocarcinoma

EUS followed by EMR for staging of high-grade dysplasia and early cancer in Barrett's esophagus

Accurate staging of high-grade dysplasia and of early cancer in Barrett's esophagus is important in the selection of patients for endoscopic therapy. Patients with Barrett's esophagus and biopsy specimen proven high-grade dysplasia and adenocarcinoma in focal nodular lesions or in endoscopically unapparent flat lesions in short-segment Barrett's esophagus were initially staged with EUS. In patients with disease limited to the mucosa on EUS, cap-assisted EMR was performed. The depth of tumor invasion on EMR specimens was classified in a similar manner to squamous-cell cancer of the esophagus: m1 (epithelial layer, dysplasia), m2 (lamina propria invasion), m3 (muscularis mucosae invasion), sm (submucosal invasion). EUS was performed in 48 consecutive patients (27 with focal nodular lesions and 21 with microscopic lesions), and submucosal invasion was diagnosed in 8 (confirmed in 7/8 at surgery). EMR was carried out in the remaining 40 patients without significant complications. In the 25 patients with high-grade dysplasia on prior biopsy specimens, EMR confirmed m1 disease in 19; whereas in 6 (24%), invasive adenocarcinoma was detected (to m2 in 4; to m3 in 2). In the 15 patients with invasive cancer on prior biopsy specimens and staged as intramucosal cancer on EUS, intramucosal carcinoma was confirmed in 9 (m2 in 3; m3 in 6); whereas, in 6 patients (40%), submucosal invasion was found. Overall, EUS provided accurate staging in 41/48 patients (85%) with one patient overstaged and 6 patients understaged compared with pathologic staging obtained by surgery or EMR. Of the 34 patients with m1 to m3 staging after EMR, 29 were treated endoscopically and had no evidence of cancer after a mean follow-up of 22.9 months(standard deviation 9.2 months). EMR provides pathologic staging information that, in addition, may be helpful after EUS if a stage-determined approach is used in the management of high-grade dysplasia and of early cancer in Barrett's esophagus. EMR may be particularly useful for staging of focal nodules or in short-segment Barrett's esophagus with microscopic lesions when endoscopic therapy is an option.

High‐grade dysplasia in Barrett's oesophagus: natural history and review of clinical practice

Management of high-grade dysplasia in Barrett's oesophagus is controversial: surgery carries an appreciable morbidity/mortality, high-grade dysplasia may not progress to cancer and endoscopic ablation is an emerging option. To review Barrett's oesophagus-related high-grade dysplasia management and outcome over a 10-year period. This was a retrospective case note review of 36 patients identified from a pathology database. There were 31 men of mean age 67 years. Endoscopic surveillance identified nine. Median follow-up was 21 months. Seven patients had no further intervention because of age/comorbidity. The other 29 had repeat endoscopic biopsies, nine showing cancer (six oesophagectomized). Of the 20 remaining patients with persisting high-grade dysplasia, eight had surgery (histology showed cancer in six), seven continued endoscopic surveillance (high-grade dysplasia regressed in four) and five had 'curative' argon ablation. An intensive biopsy protocol was not followed in 55% of endoscopies. Prevalent cancers occurred in 44% with an annual incidence of 5% over 5 years. All cause mortality was 39% (14 of 36, eight of 14 from cancer). Management of high-grade dysplasia was not uniform. Unsuspected cancer was common in high-grade dysplasia patients undergoing surgery but 13% regressed under surveillance. High-grade dysplasia patients have a high mortality but 43% did not die from cancer.

Photodynamic Therapy in High Grade Dysplasia in Barrett's Oesophagus Using 5 Amino-Laevulinic Acid Sensitization

Barrett's oesophagus may progress to high grade dysplasia and cancer. Management of high grade dysplasia is a problematic due to the high risks of surgery in this often elderly population with co-morbidities. Ablative therapeutic options include photodynamic therapy (PDT). Aim: The aim of this project is an audit of photodynamic therapy in patients with high grade dysplasia using 5 amino-laevulinic as the photosensitizing agent. Methods: PDT was used after sensitizing with 5-amino-laevulinic acid at 60 mg/kg in three divided doses over the previous 18 hours in 8 patients. A dye module attached to a KTP laser (Laserscope) was used to deliver laser light at 628 nm at 0.5 to 2.6 watts power, aiming to deliver 150 j/cm2 to the Barrett's mucosa. Results: Over 85% of our group of patients had a successful response to PDT, of which nearly 43% (three of eight) had no evidence of dysplasia ie complete eradication of Barrett's at follow up over 5 to 98 months. One had persistent high grade dysplasia, and only one developed adenocarcinoma. Residual islands of Barrett's after PDT could be managed relatively easily with argon plasma coagulation. There was no treatment related mortality or extended length of stay; one patient with a post PDT stricture was easily dilated. Sunburn occurred in the first three days after treatment, but skin photosensitivity was not persistent. Conclusion: This experience indicates PDT is a safe procedure which successfully ablates either all or a substantial surface area involved with Barretts including with high grade dysplasia. The possibility of buried Barrett's remains, but has not emerged as a clinical problem including in our patients with extended follow up over 8 years.

Barrett’s esophagus: management of high-grade dysplasia and cancer

Esophagectomy remains the treatment of choice for the appropriate patient with Barrett’s adenocarcinoma invading beyond the mucosa, without evidence of distant metastasis or invasion of adjacent organs. On the other hand, therapeutic management of patients with Barrett’s high-grade dysplasia (HGD) or mucosal adenocarcinoma should be individualized, taking into account the patient’s preferences, willingness to return for frequent endoscopic biopsies, and medical fitness to undergo esophagectomy. Surgery has to be considered the best treatment for HGD or superficial carcinoma, unless contraindicated by severe comorbidities, because it has proven to be the only treatment that is successful in curing the condition and preventing recurrent HGD or the development of invasive cancer. Nonsurgical treatment by photodynamic therapy or endoscopic mucosal resection may be a less invasive and organ-sparing option for elderly, poor-risk patients but it is still to be considered an investigational therapy that should only be conducted under a clinical trial protocol. Finally, intensive endoscopic biopsy surveillance of patients with HGD is another investigational option that may allow prompt treatment of cancer if it develops. However, few data document the safety of this observational approach.

High Grade Dysplasia: Surveillance, Mucosal Ablation, or Resection?

Barrett's esophagus is a common premalignant condition that results from chronic gastroesophageal reflux. High grade dysplasia in the metaplastic esophagus is thought to be the last step in the metaplasia-to-carcinoma sequence that characterizes this disease. The management of high grade dysplasia in Barrett's esophagus is controversial. Some investigators advocate a rigorous endoscopic surveillance program with biopsies, but this approach has been questioned because of its clinical impracticality, high cost, possibility of sampling errors, and difficulty demonstrating effectiveness on a reproducible basis. Others advocate mucosal ablative therapy to eradicate the dysplastic and metaplastic epithelium. This approach, still in its infancy, cannot be accepted as standard therapy at the present time because of limited follow-up, its questionable ability to completely eradicate the abnormal mucosa, the phenomenon of pseudoregression, and the patients require continued rigorous endoscopic surveillance. Esophagectomy, on the other hand, can be accomplished with a low mortality rate in these patients. We advocate this approach because a large number of them have invasive cancer in the esophagus despite a preoperative diagnosis of only high grade dysplasia. In addition, the 5-year survival is excellent even if invasive cancer is present, and these patients are liberated from rigorous endoscopic surveillance for the rest of their lives. For patients with high grade dysplasia in Barrett's esophagus who are poor operative risks, less invasive approaches such as mucosal ablation may play a role, but longer follow-up information is needed before this technique can be accepted even in this setting.

Outcomes of minimally invasive esophagectomy (MIE) for high-grade dysplasia of the esophagus.

The management of high-grade dysplasia (HGD) of the esophagus is controversial with some clinicians advocating non-operative ablation or surveillance. Minimally invasive esophagectomy (MIE) allows re-section of the esophagus and may minimize morbidity. This report summarizes our experience with MIE for HGD. A retrospective review of 28 patients who underwent MIE for a pre-operative diagnosis of HGD. MIE initially involved a laparoscopic transhiatal approach (n=1), but subsequently evolved to laparoscopy with VATS mobilization (n=27) of the esophagus. From August 1996 to March 2001, 28 patients underwent MIE. There were 23 males and five females; median age was 61 (40-78) years. Median hospital stay was 5 (3-20) days and ICU stay was 1 (1-20) day. One patient required conversion to laparotomy because of dense adhesions. There were ten other patients who had successful MIE despite prior laparotomy. Median operating time was 8 (5.8-13) h. One death occurred from sepsis, pneumonia and multi-system organ failure. Complications occurred in 15 patients. In addition to the patient who died, five re-operations were required for: small bowel perforation (n=1), jejunostomy leak (n=1), pyloric dilation for gastric outlet obstruction (n=1), cholecystectomy (n=1), incision and drainage of an abdominal abscess (n=1). Final pathologies were HGD (n=17), in situ cancer (n=6) and invasive cancer (n=5). At a median follow-up of 13 (2-41) months all hospital survivors are alive and free of disease. This report confirms the risk of occult cancer in patients with HGD (39% in this series) supporting the recommendation for esophagectomy. MIE can be performed with acceptable results and may minimize morbidity compared to previous reports of open esophagectomy for HGD.

Argon plasma coagulation in the treatment of Barrett's high-grade dysplasia and in situ adenocarcinoma.

Endoscopic therapy of high-grade dysplasia (HGD) and superficial adenocarcinoma associated with Barrett's esophagus (BE), using Nd:YAG laser, KTP laser, or photodynamic therapy (PDT), has been reported to be effective in a curative role. Argon plasma coagulation (APC) appears to be effective in the eradication of nondysplastic Barrett's mucosa, but no results are available in the management of early neoplasms complicating BE. We report our initial experience in the application of APC in this indication. Ten patients (mean age 74.2) with histologically proven HGD (n = 7) or in situ adenocarcinoma (n = 3) associated with BE (mean length 6 cm) and unfit for surgery were treated using APC and high-dose omeprazole (40 mg daily) until squamous re-epithelialization or complete eradication of the initially apparent lesions. Endoscopic follow-up was maintained at every 3 months. Complete eradication of HGD and in situ adenocarcinoma was achieved after a mean number of 3.3+/-1.5 APC sessions in 8/10 patients (80%). The eight patients with complete clearance of the neoplastic areas did not show any evidence of local recurrence during a median follow-up of 24 months (range 12-36 months). One patient with initial HGD had persistence of HGD 30 months after initial diagnosis, and one patient progressed to invasive adenocarcinoma after failure of APC and PDT. APC is safe and effective in the management of HGD and in situ adenocarcinoma associated with BE, and might represent an interesting alternative in selected patients who are not candidates for surgery.

Optimizing endoscopic biopsy detection of early cancers in Barrett’s high-grade dysplasia

OBJECTIVE: The management of high-grade dysplasia (HGD) in Barrett’s esophagus remains controversial, in part, because of uncertainty about the ability of endoscopic biopsies to consistently detect early, curable cancers. METHODS: Here we report cancers we have diagnosed in 45 patients with Barrett’s HGD using a protocol involving serial endoscopies with four-quadrant biopsies taken at 1-cm intervals. We compare these results to a modeled endoscopic biopsy protocol in which four-quadrant biopsies are taken every 2 cm in the Barrett’s segment. RESULTS: Thirteen cancers were detected at the baseline endoscopy and 32 in surveillance. In 82% of patients, cancer was detected at a single 1-cm level of the esophagus, and in 69% the cancer was detected in a single endoscopic biopsy specimen. A 2-cm protocol missed 50% of cancers that were detected by a 1-cm protocol in Barrett’s segments 2 cm or more without visible lesions. The maximum depth of cancer invasion was intramucosal in 96% of patients. Only 39% of patients who had endoscopic biopsy cancer diagnoses had cancer detected in the esophagectomy specimen. Adverse outcomes included the development of regional metastatic disease during surveillance (1 of 32), operative mortality (3 of 36), including two patients who had their primary surgeries at other institutions, and death from metastatic disease after endoscopic ablation performed at another institution (1 of 3). CONCLUSIONS: A four-quadrant, 1-cm endoscopic biopsy protocol performed at closely timed intervals consistently detects early cancers arising in HGD in Barrett’s esophagus and should be used in patients with HGD who do not undergo surgical resection.

Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets.

Barrett's esophagus develops in 5-20% of patients with gastroesophageal reflux disease and predisposes to esophageal adenocarcinoma. The value of endoscopic biopsy surveillance is questioned because most patients do not develop cancer. Furthermore, observer variation in histological diagnosis makes validation of surveillance guidelines difficult because varying histological interpretations may lead to different estimated rates of progression. Thus, objective biomarkers need to be validated for use with histology to stratify patients according to their risk for progression to cancer. We prospectively evaluated patients using a systematic endoscopic biopsy protocol with baseline histological and flow cytometric abnormalities as predictors and cancer as the outcome. Among patients with negative, indefinite, or low-grade dysplasia, those with neither aneuploidy nor increased 4N fractions had a 0% 5-yr cumulative cancer incidence compared with 28% for those with either aneuploidy or increased 4N. Patients with baseline increased 4N, aneuploidy, and high-grade dysplasia had 5-yr cancer incidences of 56%, 43%, and 59%, respectively. Aneuploidy, increased 4N, or HGD were detected at baseline in all 35 patients who developed cancer within 5 yr. A systematic baseline endoscopic biopsy protocol using histology and flow cytometry identifies subsets of patients with Barrett's esophagus at low and high risk for progression to cancer. Patients whose baseline biopsies are negative, indefinite, or low-grade displasia without increased 4N or aneuploidy may have surveillance deferred for up to 5 yr. Patients with cytometric abnormalities merit more frequent surveillance, and management of high-grade dysplasia can be individualized.

Management of Barrett's esophagus.

There have been major recent advances in the understanding of the pathogenesis and epidemiology of Barrett's esophagus and adenocarcinoma of the esophagus. The advent of potent acid suppression with proton pump inhibitors and safe, minimally invasive antireflux procedures has made alleviating symptoms and eliminating peptic complications achievable goals for the vast majority of patients. Endoscopic surveillance of Barrett's esophagus is considered the standard of care and is widely used in clinical practice. Neither medical nor surgical antireflux procedures, however, result in the regression of Barrett's esophagus in any consistent manner. Thermal and chemical endoscopic ablation techniques show promise in both the management of high grade dysplasia and the reversal of Barrett's esophagus, but these techniques are still of unproven benefit, and can be costly and risky. Therefore, prospective and controlled studies with long term follow-up are needed before incorporating ablative techniques into routine clinical practice. Management of high grade dysplasia remains controversial. Alternative management strategies include surveillance, resection or ablation, tailored to the individual patient and the available expertise. Targets for future research include defining appropriate surveillance intervals; finding biological markers that identify patients at higher risk of progressing to cancer; defining the cancer risk and the appropriate management of patients with short segment Barrett's esophagus; understanding the natural history of dysplasia and comparing alternatives for the management of high grade dysplasia; and studying whether surgical management can delay or prevent the progression to dysplasia and adenocarcinoma.

Management of high grade dysplasia in Barrett’s esophagus – Results of a panel discussion at the IGSC Congress 1994

Management of high grade dysplasia in Barrett’s esophagus – Results of a panel discussion at the IGSC Congress 1994

The management of high grade dysplasia and early cancer in Barrett's esophagus

The incidence of Barrett's-associated esophageal adenocarcinoma is rising, but experience in the treatment of high-grade dysplasia (HGD) or early cancer is limited. Based on an endoscopic surveillance program, the authors developed a systematic multidisciplinary approach to this problem. Surgical resection was considered if biopsies of the Barrett's segment, performed according to a published protocol, showed invasive cancer, intramucosal carcinoma, or repeated evidence of HGD. The type of resection was based on the length of the Barrett's segment and included an en bloc lymph node dissection for staging purposes. Careful intraoperative pathologic evaluation ensured that all of the Barrett's mucosa was resected. From 1984 to 1993, 27 consecutive patients (23 men, 4 women), with median age of 61 years (range, 45-75 years) underwent surgical exploration. Indications for operation were invasive cancer in 17 patients, intramucosal carcinoma in 5 patients, and HGD in 5 patients. Median length of the Barrett's segment was 9 cm (range, 1-17 cm). Only 15 patients (55%) had abnormalities visible with endoscopic examination that were potentially suspicious for malignancy. Twenty-six patients underwent resection with complete removal of the Barrett's mucosa, 20 by Ivor Lewis esophagogastrectomy, and 6 by transhiatal esophagectomy. Pathologic tumor stages were: TisN0M0 in 10 patients; T1N0M0 in 11 patients; T2N0M0 in 2 patients; T3N0M0 in 3 patients; and T1NXM1 in 1 patient. There were no postoperative deaths or anastomotic leaks. Major complications occurred in 4 patients. With a median follow-up of 3.7 years, 22 patients were alive, and only 2 patients had recurrences. This increasingly important group of patients with HGD or early carcinoma in the Barrett's esophagus has a high chance of cure but requires careful multidisciplinary treatment by the surgeon, gastroenterologist, and pathologist.