Case 10-2006 — A 66-Year-Old Woman with Barrett's Esophagus with High-Grade Dysplasia
http://www.100md.com
《新英格兰医药杂志》
Presentation of Case
A 66-year-old woman was referred to the gastroenterology clinic for evaluation and management of Barrett's esophagus with high-grade dysplasia.
Seven months earlier, she had been seen at another hospital because of rectal bleeding. She had occasional heartburn but no dysphagia, anorexia, abdominal pain, or weight loss. Colonoscopy revealed a cecal polyp, which was resected. A histopathological examination revealed a tubulovillous adenoma. Esophagogastroduodenoscopy with biopsy of the distal esophagus showed metaplastic glandular mucosa with goblet cells consistent with a diagnosis of Barrett's esophagus, with high-grade dysplasia. Treatment with lansoprazole (60 mg daily) was started.
A follow-up endoscopic examination and esophageal biopsy performed four months later showed persistent signs of Barrett's esophagus with high-grade dysplasia. Five weeks later, endoscopic esophageal ultrasonography revealed a 5-cm-long segment with signs consistent with Barrett's esophagus and a polypoid lesion, 1 cm in diameter, within the distal esophagus. The lesion did not penetrate the muscularis propria, and there was no lymphadenopathy.
The patient had a lifelong history of morbid obesity. There was a 15-year history of inflammatory polyarthritis treated with prednisone and, for the past year, additional treatment with methotrexate. She was confined to a wheelchair because of her arthritis and obesity. She had had hypertension for many years. Four years before her current evaluation, she had had an episode of chest pain; a coronary angiogram did not show clinically important coronary artery disease. Two years later, a diagnosis of type 2 diabetes was made.
The patient was referred to a thoracic surgeon for consideration of esophagectomy. Because of her obesity and other medical problems, she was thought to be at high risk for operative complications and death. She was referred to the gastroenterology clinic of this hospital.
The patient resided with her husband and had four children. She had a 20-pack-year history of cigarette smoking but had stopped smoking and consuming alcohol six years earlier. Her medications included quinapril, glyburide, hydrochlorothiazide–triamterene, atenolol, lansoprazole, methotrexate, prednisone, and folate.
The pulse was 65 beats per minute, the respiratory rate 18 breaths per minute, blood pressure 124/69 mm Hg, weight 140 kg, and height 166 cm. On physical examination, the patient was markedly obese, but the examination was otherwise normal.
A chest radiograph revealed multiple calcified nodular opacities that were less than 5 mm in diameter scattered throughout the lungs. Computed tomography (CT) of the chest after the intravenous administration of contrast material confirmed the presence of nodular opacities consistent with granulomas; the lungs, heart, and mediastinum were otherwise normal. There was mild thickening of the distal esophagus.
A repeated esophagogastroduodenoscopy was performed with biopsy of the distal esophagus that showed gastric mucosal erythema, a hiatal hernia, and Barrett's esophagus with a single esophageal nodule located 35 cm from the incisors (Figure 1); biopsy samples were obtained 33, 35, and 37 cm from the incisors and from the nodule.
Figure 1. Image from Screening Endoscopy.
Salmon-colored esophageal mucosa characteristic of Barrett's esophagus is present, with islands of pearly white squamous mucosa within the Barrett's segment, as well as a small nodule (arrow).
Pathological Discussion
Dr. Gregory Y. Lauwers: The esophageal-biopsy specimens obtained 33, 35, and 37 cm from the incisors showed a metaplastic columnar epithelium with numerous goblet cells, consistent with a diagnosis of Barrett's esophagus (Figure 2A). Atypical columnar epithelium was also seen, indicating the presence of dysplasia. The biopsy specimen of a mucosal nodule identified at the 35-cm location showed an atypical columnar epithelium composed of irregular glandular elements lined by pleomorphic cells with hyperchromatic nuclei, as well as focal back-to-back crowding of small atypical glands consistent with a diagnosis of intramucosal carcinoma arising in a background of dysplasia (Figure 2B).
Figure 2. Biopsy Specimens of the Esophagus (Hematoxylin and Eosin).
There is low-grade dysplasia (Panel A, right) arising in the specialized columnar epithelium, which is characterized by the presence of goblet cells (Panel A, left). The dysplastic epithelium shows architectural abnormalities, nuclear stratification, and hyperchromasia. An endoscopically resected nodule (Panel B) shows complex glandular proliferation with striking cytologic atypia, areas of back-to-back glands with no intervening lamina propria, and small abortive glands, consistent with a diagnosis of intramucosal adenocarcinoma.
Barrett's esophagus is an acquired condition resulting from injury of the esophageal mucosa due to chronic gastroesophageal reflux disease. It is defined as "a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy."1 The estimated annual risk of cancer in patients with Barrett's esophagus ranges from 0.4 to 2.0 percent, a risk that is 10 to 125 times that in an age-matched population.2,3 Adenocarcinomas appear to develop in a stepwise progression, from low-grade to high-grade dysplasia,4 and to intramucosal and then invasive carcinoma. In addition, an unsuspected carcinoma is found in approximately 45 percent of patients in whom the esophagus is resected because of high-grade dysplasia.5
Dysplasia in Barrett's Esophagus
Two grades of dysplasia are recognized. In low-grade dysplasia, the epithelial architecture tends to be normal or to display only minimal distortion and the cells are closely packed with basal nuclei, variable hyperchromasia, and irregular nuclear contours. High-grade dysplasia shows more severe architectural distortion and more marked nuclear pleomorphism, nuclear stratification, and increased mitotic figures.4
In several series, between 6 and 28 percent of patients with low-grade dysplasia had progression to high-grade dysplasia or carcinoma.6,7
Discussion of Management
Dr. Norman S. Nishioka: This 66-year-old woman was found on endoscopy to have Barrett's esophagus with high-grade dysplasia and intramucosal adenocarcinoma. The management of high-grade dysplasia that arises in a segment affected by Barrett's esophagus poses a challenge because the optimal treatment strategy has not been established and controversy surrounds the various management options.8 Because patients such as the woman in this case with high-grade dysplasia are at risk for esophageal adenocarcinoma,9 and because esophageal adenocarcinoma carries a poor long-term prognosis, therapeutic intervention as soon as high-grade dysplasia is identified might prevent esophageal cancer and avoid the high mortality associated with it. However, although the paradigm of early intervention is compelling, the precise risk that the disease will evolve from high-grade dysplasia to esophageal cancer is not known, and the estimated rates of progression range from 16 percent over a seven-year period10 to 59 percent over a five-year observation period.11
Prophylactic Esophagectomy
Prophylactic resection of the affected esophagus has become the standard of care for patients with Barrett's esophagus with high-grade dysplasia. However, partial esophagectomy is associated with substantial rates of complications and death, even when performed by experienced surgeons, and its long-term effectiveness for preventing cancer in the remaining segment of the esophagus has not been established. Gastroesophageal reflux is usually worse after esophagectomy, and the remaining esophageal segment may be at continued risk for Barrett's esophagus and dysplasia or cancer.
This patient's age, morbid obesity, and other medical problems placed her at high risk for a complication or death from surgery. The patient was evaluated by an experienced thoracic surgeon, and both the patient and the surgeon thought that nonsurgical options should be pursued.
Observation
Patients with Barrett's esophagus can be treated with medications to control reflux, such as omeprazole, and observation that includes endoscopy and biopsies at regular intervals, with the frequency depending on the grade of dysplasia.1 In this patient with high-grade dysplasia, surveillance at three-month intervals might have been a reasonable strategy. However, she had intramucosal cancer, in addition to high-grade dysplasia, so that surveillance was not a realistic option for her.
Mucosal Ablation
Areas affected by Barrett's esophagus can be replaced by normal squamous epithelium if the intestinal metaplasia is ablated and permitted to heal with medical control of reflux.12 Numerous methods for mucosal ablation have been described, including electrocautery, mucosal stripping, argon-plasma-beam fulguration, laser photothermal coagulation, heater-probe ablation, and cryotherapy. All these procedures have enjoyed some degree of success.13,14 Although no direct comparative studies have been performed, the method used to ablate the mucosa does not appear to affect the outcome.
Photodynamic Therapy
For this patient, photodynamic therapy was suggested as a method of mucosal ablation, an alternative to surgical resection. The photodynamic process requires two steps. In the first step, a photosensitizing agent is administered. Photosensitizing agents are biologically inert in their native state but have physical properties that cause them to be taken up and retained by the target tissues. In the second step, light of the appropriate wavelength is administered to the target tissues. The light energy is absorbed by the photosensitizing agent and activates the drug. The electronically excited photosensitizing agent interacts with an oxygen molecule, resulting in the formation of a reactive oxygen species, typically singlet oxygen. The singlet oxygen then damages tissue by oxidizing tissue components, usually cellular membranes.
Photodynamic therapy has some advantages over other endoscopic means of tissue ablation. First, because the drug is inert until activated and because light delivery can easily be controlled during upper gastrointestinal endoscopy, photodynamic therapy provides a means of providing localized tissue destruction. In addition, the muscular layers of the esophagus are relatively resistant to photodynamic therapy, which provides another level of safety. Esophageal perforation resulting from this therapy has been extremely rare.15 Patients continue long-term medical therapy for control of reflux after this treatment.
Photodynamic therapy as currently implemented has several disadvantages, which were discussed with this patient. A recent randomized study found that 94 percent of patients had treatment-related adverse events; the most common were photosensitivity, occurring in 68 percent of the patients, and esophageal stricture, occurring in 32 percent.16 The main disadvantage is prolonged photosensitivity of the skin. One approved photosensitizing agent in the United States is porfimer sodium, which remains in the skin at low levels for up to 90 days, leaving patients with photosensitive skin for this period. Thus, the patient was advised to protect herself from exposure to sunlight for several months after the procedure. In almost all patients, esophageal strictures readily respond to dilatation, although multiple dilatations are typically required to achieve complete relief. Other disadvantages of photodynamic therapy include the high cost and the need for the patient to return to the hospital three times within five days. The drug, the light-delivery fibers, and laser light sources are expensive.
In initial results, successful ablation has been reported in 77 percent of cancers and 90 percent of dysplasias,17,18 with approximately 75 percent of the treated patients remaining free of dysplasia for up to 18 months, although Barrett's epithelium may persist in 10 to 50 percent of the cases. A recently completed randomized clinical trial16 found that patients receiving photodynamic therapy plus omeprazole had ablation of the high-grade dysplasia significantly more often than patients treated with omeprazole alone (77 percent vs. 39 percent) and a lower rate of development of adenocarcinoma (13 percent vs. 28 percent). Complete ablation of Barrett's metaplasia and dysplasia was seen in 52 percent of patients treated with photodynamic therapy and ablation of all grades of dysplasia in 59 percent, as compared with 5 and 10 percent, respectively, in the control group. However, the long-term efficacy of the treatment is unknown, and controlled data are lacking to prove that endoscopic intervention at this point would increase this patient's overall life expectancy. After lengthy discussions with the patient, we elected to proceed with endoscopic ablation of the epithelium affected by Barrett's esophagus with the use of photodynamic therapy.
Endoscopic Submucosal Resection
One confounding issue in this case was the presence of an esophageal mucosal nodule. Although the nodule might have been removed by mucosal ablation with the use of photodynamic therapy, many investigators treating similar cases have resected the nodule before proceeding with mucosal ablation.19 In this strategy, endoscopic mucosal resection of the nodule can be viewed as a "debulking" procedure. In the case of this patient, the nodule was resected with use of a straightforward saline lift-and-snare technique, in which the mucosal nodule is elevated by the submucosal injection of saline, followed by snare resection. This procedure was completed without incident (Figure 3).
Figure 3. Endoscopic Mucosal Resection of the Small Nodule.
This endoscopic image shows the resection site after the removal of the lesion (arrow).
Dr. Lauwers: One month after the biopsy, an endoscopic mucosal resection of the nodule at 35 cm was performed. The diagnosis of intramucosal carcinoma arising in high-grade dysplasia was confirmed; high-grade dysplasia extended to the lateral margin (Figure 2B). Although endoscopic mucosal resection often does not completely remove the tumor, as in this case, the status of the deep margin is more important than that of the lateral margins in predicting recurrence. In our experience, 86 percent of tumors with positive deep margins recurred, as compared with 56 percent of those with positive lateral margins. Repeated endoscopic mucosal resections are feasible and may be necessary to remove the tumor completely. Endoscopic mucosal resection is also important in staging cancers; in our experience, it corrected overestimation and underestimation of staging by ultrasonographic examination in 18 percent and 12 percent of cases, respectively.20
Dr. Nishioka: One month after resection of the esophageal nodule, the patient received porfimer sodium (2 mg per kilogram of body weight) by intravenous injection, and two days later she underwent upper gastrointestinal endoscopy with laser illumination of the involved segment. A 5-cm cylindrical diffuser was used to deliver a total light dose of 150 J per centimeter at a wavelength of 630 nm. Two days later, the patient underwent a second endoscopic examination. The examination revealed moderately severe esophagitis within the treated segment, although the changes were not uniform. Because of the relatively long half-life of porfimer sodium, it is possible to deliver additional light to the segment for as long as 96 hours after the administration of the drug. Thus, the segment was again illuminated with use of a 5-cm cylindrical diffuser in an attempt to make the mucosal ablation more uniform (Figure 4).
Figure 4. Endoscopic Image Obtained 48 Hours after Initial Laser Illumination.
Moderately severe esophagitis is present, induced by the photodynamic therapy, but the ablation is not completely uniform; therefore, additional light was administered. The laser fiber used is evident.
During the first week after photodynamic therapy, the patient had nausea, odynophagia, and chest discomfort, each of which occurred in 10 to 20 percent of the cases in a recent trial,16 but her symptoms were controlled with narcotic analgesic drugs and antiemetic medications. Erythema of the face and neck developed, consistent with the occurrence of a mild photosensitivity reaction of the skin. A skin reaction such as this is the most common side effect of photodynamic therapy with porfimer sodium,16 seen in 30 to 70 percent of patients.16,21
Four weeks later, dysphagia and hiccups developed. An upper endoscopy revealed a short, benign-appearing stenosis in the distal esophagus. This was dilated with a balloon dilator, and the patient's symptoms improved. Stricture formation severe enough to produce dysphagia has been seen in approximately one third of patients who have undergone photodynamic therapy with porfimer sodium.16
During follow-up endoscopies, several small patches of Barrett's epithelium appeared to be present. Rather than administering a second course of photodynamic therapy, I elected simply to fulgurate the areas with a multipolar electrocautery probe. Subsequent endoscopies have revealed an esophagus lined by squamous mucosa. It has been nearly three years since the photodynamic therapy, and the patient is doing well. Her reflux symptoms are well controlled by high-dose proton-pump inhibitors, which she will continue to take indefinitely. We plan to continue endoscopic surveillance at six-month intervals for one more year and then perform annual surveillance thereafter.
Dr. Lauwers: After the patient received the photodynamic therapy, the next set of biopsy specimens and all the specimens obtained from subsequent biopsies showed specialized columnar epithelium without dysplasia. The absence of neoplastic epithelium and the presence of squamous reepithelialization were confirmed on the review of three sets of biopsy specimens obtained during the subsequent year.
Dr. Nishioka: At the time of the most recent follow-up visit 46 months after the procedure, the patient was asymptomatic and biopsies showed no recurrence of either Barrett's esophagus or dysplasia.
Dr. Lauwers: This patient has had a good outcome. We recently reviewed pretreatment and post-treatment biopsies in 33 patients treated with photodynamic therapy at our hospital in order to evaluate the effectiveness of treatment and identify pretreatment features that might predict response.22 Ablation of dysplasia or intramucosal carcinoma occurred in 52 percent of the cases. However, one problem with the follow-up of these patients is the presence of foci of Barrett's epithelium underlying areas of squamous epithelium — so-called buried Barrett's — that may contain dysplasia or intramucosal carcinoma. Buried Barrett's was found in 51 percent of the patients we evaluated after photodynamic therapy, and buried dysplasia or carcinoma or both were seen in 27 percent. The presence of buried dysplasia, carcinoma, or a papillary architecture in pretreatment-biopsy specimens was associated with a failure to eradicate the disease. Continued endoscopic surveillance with biopsies will be an important part of the care of these patients.
Anatomical Diagnosis
Barrett's esophagus with high-grade dysplasia and intramucosal carcinoma with regression of dysplasia and regression of Barrett's esophagus after endoscopic mucosal resection and photodynamic therapy.
Dr. Nishioka reports having received lecture fees and grant support from Axcan Pharma.
Source Information
From the Gastrointestinal Unit (N.S.N.) and the Department of Pathology (G.Y.L.), Massachusetts General Hospital; and the Departments of Medicine (N.S.N.) and Pathology (G.Y.L.), Harvard Medical School.
References
Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett's esophagus. Am J Gastroenterol 2002;97:1888-1895.
Provenzale D, Schmitt C, Wong JB. Barrett's esophagus: a new look at surveillance based on emerging estimates of cancer risk. Am J Gastroenterol 1999;94:2043-2053.
Hameeteman W, Tytgat GN, Houthoff HJ, van den Tweel JG. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249-1256.
Goldblum JR, Lauwers GY. Dysplasia arising in Barrett's esophagus: diagnostic pitfalls and natural history. Semin Diagn Pathol 2002;19:12-19.
Wright TA. High-grade dysplasia in Barrett's oesophagus. Br J Surg 1997;84:760-766.
Skacel M, Petras RE, Gramlich TL, Sigel JE, Richter JE, Goldblum JR. The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression. Am J Gastroenterol 2000;95:3383-3387.
Weston AP, Sharma P, Topalovski M, Richards R, Cherian R, Dixon A. Long-term follow-up of Barrett's high-grade dysplasia. Am J Gastroenterol 2000;95:1888-1893.
Spechler SJ. Barrett's esophagus. N Engl J Med 2002;346:836-842.
Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003;349:2241-2252.
Schnell TG, Sontag SJ, Chejfec G, et al. Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia. Gastroenterology 2001;120:1607-1619.
Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroenterol 2000;95:1669-1676.
Sampliner RE, Faigel D, Fennerty MB, et al. Effective and safe endoscopic reversal of nondysplastic Barrett's esophagus with thermal electrocoagulation combined with high-dose acid inhibition: a multicenter study. Gastrointest Endosc 2001;53:554-558.
Schulz H, Miehlke S, Antos D, et al. Ablation of Barrett's epithelium by endoscopic argon plasma coagulation in combination with high-dose omeprazole. Gastrointest Endosc 2000;51:659-663.
Ell C, May A, Gossner L, et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett's esophagus. Gastroenterology 2000;118:670-677.
Lightdale C, Heier SK, Marcon NE, et al. Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: a multicenter randomized trial. Gastrointest Endosc 1995;42:507-512.
Overholt BF, Lightdale CJ, Wank KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488-498.
Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett's esophagus: follow-up in 100 patients. Gastrointest Endosc 1999;49:1-7.
Wolfsen HC, Woodward TA, Raimondo M. Photodynamic therapy for dysplastic Barrett esophagus and early esophageal cancer. Mayo Clin Proc 2002;77:1176-1181.
Buttar NS, Wang KK, Lutzke LS, Krishnadath KK, Anderson MA. Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett's esophagus. Gastrointest Endosc 2001;54:682-688.
Mino-Kenudson M, Brugge WR, Puricelli WP, et al. Management of superficial Barrett's epithelium-related neoplasms by endoscopic mucosal resection: clinicopathological analysis of 27 cases. Am J Surg Pathol 2005;29:680-686.
Lightdale CJ. Role of photodynamic therapy in the management of advanced esophageal cancer. Gastrointest Endosc Clin N Am 2000;10:397-408.
Ban S, Mino M, Nishioka NS, et al. Histopathologic aspects of photodynamic therapy for dysplasia and early adenocarcinoma arising in Barrett's esophagus. Am J Surg Pathol 2004;28:1466-1473.(Norman S. Nishioka, M.D.,)
A 66-year-old woman was referred to the gastroenterology clinic for evaluation and management of Barrett's esophagus with high-grade dysplasia.
Seven months earlier, she had been seen at another hospital because of rectal bleeding. She had occasional heartburn but no dysphagia, anorexia, abdominal pain, or weight loss. Colonoscopy revealed a cecal polyp, which was resected. A histopathological examination revealed a tubulovillous adenoma. Esophagogastroduodenoscopy with biopsy of the distal esophagus showed metaplastic glandular mucosa with goblet cells consistent with a diagnosis of Barrett's esophagus, with high-grade dysplasia. Treatment with lansoprazole (60 mg daily) was started.
A follow-up endoscopic examination and esophageal biopsy performed four months later showed persistent signs of Barrett's esophagus with high-grade dysplasia. Five weeks later, endoscopic esophageal ultrasonography revealed a 5-cm-long segment with signs consistent with Barrett's esophagus and a polypoid lesion, 1 cm in diameter, within the distal esophagus. The lesion did not penetrate the muscularis propria, and there was no lymphadenopathy.
The patient had a lifelong history of morbid obesity. There was a 15-year history of inflammatory polyarthritis treated with prednisone and, for the past year, additional treatment with methotrexate. She was confined to a wheelchair because of her arthritis and obesity. She had had hypertension for many years. Four years before her current evaluation, she had had an episode of chest pain; a coronary angiogram did not show clinically important coronary artery disease. Two years later, a diagnosis of type 2 diabetes was made.
The patient was referred to a thoracic surgeon for consideration of esophagectomy. Because of her obesity and other medical problems, she was thought to be at high risk for operative complications and death. She was referred to the gastroenterology clinic of this hospital.
The patient resided with her husband and had four children. She had a 20-pack-year history of cigarette smoking but had stopped smoking and consuming alcohol six years earlier. Her medications included quinapril, glyburide, hydrochlorothiazide–triamterene, atenolol, lansoprazole, methotrexate, prednisone, and folate.
The pulse was 65 beats per minute, the respiratory rate 18 breaths per minute, blood pressure 124/69 mm Hg, weight 140 kg, and height 166 cm. On physical examination, the patient was markedly obese, but the examination was otherwise normal.
A chest radiograph revealed multiple calcified nodular opacities that were less than 5 mm in diameter scattered throughout the lungs. Computed tomography (CT) of the chest after the intravenous administration of contrast material confirmed the presence of nodular opacities consistent with granulomas; the lungs, heart, and mediastinum were otherwise normal. There was mild thickening of the distal esophagus.
A repeated esophagogastroduodenoscopy was performed with biopsy of the distal esophagus that showed gastric mucosal erythema, a hiatal hernia, and Barrett's esophagus with a single esophageal nodule located 35 cm from the incisors (Figure 1); biopsy samples were obtained 33, 35, and 37 cm from the incisors and from the nodule.
Figure 1. Image from Screening Endoscopy.
Salmon-colored esophageal mucosa characteristic of Barrett's esophagus is present, with islands of pearly white squamous mucosa within the Barrett's segment, as well as a small nodule (arrow).
Pathological Discussion
Dr. Gregory Y. Lauwers: The esophageal-biopsy specimens obtained 33, 35, and 37 cm from the incisors showed a metaplastic columnar epithelium with numerous goblet cells, consistent with a diagnosis of Barrett's esophagus (Figure 2A). Atypical columnar epithelium was also seen, indicating the presence of dysplasia. The biopsy specimen of a mucosal nodule identified at the 35-cm location showed an atypical columnar epithelium composed of irregular glandular elements lined by pleomorphic cells with hyperchromatic nuclei, as well as focal back-to-back crowding of small atypical glands consistent with a diagnosis of intramucosal carcinoma arising in a background of dysplasia (Figure 2B).
Figure 2. Biopsy Specimens of the Esophagus (Hematoxylin and Eosin).
There is low-grade dysplasia (Panel A, right) arising in the specialized columnar epithelium, which is characterized by the presence of goblet cells (Panel A, left). The dysplastic epithelium shows architectural abnormalities, nuclear stratification, and hyperchromasia. An endoscopically resected nodule (Panel B) shows complex glandular proliferation with striking cytologic atypia, areas of back-to-back glands with no intervening lamina propria, and small abortive glands, consistent with a diagnosis of intramucosal adenocarcinoma.
Barrett's esophagus is an acquired condition resulting from injury of the esophageal mucosa due to chronic gastroesophageal reflux disease. It is defined as "a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy."1 The estimated annual risk of cancer in patients with Barrett's esophagus ranges from 0.4 to 2.0 percent, a risk that is 10 to 125 times that in an age-matched population.2,3 Adenocarcinomas appear to develop in a stepwise progression, from low-grade to high-grade dysplasia,4 and to intramucosal and then invasive carcinoma. In addition, an unsuspected carcinoma is found in approximately 45 percent of patients in whom the esophagus is resected because of high-grade dysplasia.5
Dysplasia in Barrett's Esophagus
Two grades of dysplasia are recognized. In low-grade dysplasia, the epithelial architecture tends to be normal or to display only minimal distortion and the cells are closely packed with basal nuclei, variable hyperchromasia, and irregular nuclear contours. High-grade dysplasia shows more severe architectural distortion and more marked nuclear pleomorphism, nuclear stratification, and increased mitotic figures.4
In several series, between 6 and 28 percent of patients with low-grade dysplasia had progression to high-grade dysplasia or carcinoma.6,7
Discussion of Management
Dr. Norman S. Nishioka: This 66-year-old woman was found on endoscopy to have Barrett's esophagus with high-grade dysplasia and intramucosal adenocarcinoma. The management of high-grade dysplasia that arises in a segment affected by Barrett's esophagus poses a challenge because the optimal treatment strategy has not been established and controversy surrounds the various management options.8 Because patients such as the woman in this case with high-grade dysplasia are at risk for esophageal adenocarcinoma,9 and because esophageal adenocarcinoma carries a poor long-term prognosis, therapeutic intervention as soon as high-grade dysplasia is identified might prevent esophageal cancer and avoid the high mortality associated with it. However, although the paradigm of early intervention is compelling, the precise risk that the disease will evolve from high-grade dysplasia to esophageal cancer is not known, and the estimated rates of progression range from 16 percent over a seven-year period10 to 59 percent over a five-year observation period.11
Prophylactic Esophagectomy
Prophylactic resection of the affected esophagus has become the standard of care for patients with Barrett's esophagus with high-grade dysplasia. However, partial esophagectomy is associated with substantial rates of complications and death, even when performed by experienced surgeons, and its long-term effectiveness for preventing cancer in the remaining segment of the esophagus has not been established. Gastroesophageal reflux is usually worse after esophagectomy, and the remaining esophageal segment may be at continued risk for Barrett's esophagus and dysplasia or cancer.
This patient's age, morbid obesity, and other medical problems placed her at high risk for a complication or death from surgery. The patient was evaluated by an experienced thoracic surgeon, and both the patient and the surgeon thought that nonsurgical options should be pursued.
Observation
Patients with Barrett's esophagus can be treated with medications to control reflux, such as omeprazole, and observation that includes endoscopy and biopsies at regular intervals, with the frequency depending on the grade of dysplasia.1 In this patient with high-grade dysplasia, surveillance at three-month intervals might have been a reasonable strategy. However, she had intramucosal cancer, in addition to high-grade dysplasia, so that surveillance was not a realistic option for her.
Mucosal Ablation
Areas affected by Barrett's esophagus can be replaced by normal squamous epithelium if the intestinal metaplasia is ablated and permitted to heal with medical control of reflux.12 Numerous methods for mucosal ablation have been described, including electrocautery, mucosal stripping, argon-plasma-beam fulguration, laser photothermal coagulation, heater-probe ablation, and cryotherapy. All these procedures have enjoyed some degree of success.13,14 Although no direct comparative studies have been performed, the method used to ablate the mucosa does not appear to affect the outcome.
Photodynamic Therapy
For this patient, photodynamic therapy was suggested as a method of mucosal ablation, an alternative to surgical resection. The photodynamic process requires two steps. In the first step, a photosensitizing agent is administered. Photosensitizing agents are biologically inert in their native state but have physical properties that cause them to be taken up and retained by the target tissues. In the second step, light of the appropriate wavelength is administered to the target tissues. The light energy is absorbed by the photosensitizing agent and activates the drug. The electronically excited photosensitizing agent interacts with an oxygen molecule, resulting in the formation of a reactive oxygen species, typically singlet oxygen. The singlet oxygen then damages tissue by oxidizing tissue components, usually cellular membranes.
Photodynamic therapy has some advantages over other endoscopic means of tissue ablation. First, because the drug is inert until activated and because light delivery can easily be controlled during upper gastrointestinal endoscopy, photodynamic therapy provides a means of providing localized tissue destruction. In addition, the muscular layers of the esophagus are relatively resistant to photodynamic therapy, which provides another level of safety. Esophageal perforation resulting from this therapy has been extremely rare.15 Patients continue long-term medical therapy for control of reflux after this treatment.
Photodynamic therapy as currently implemented has several disadvantages, which were discussed with this patient. A recent randomized study found that 94 percent of patients had treatment-related adverse events; the most common were photosensitivity, occurring in 68 percent of the patients, and esophageal stricture, occurring in 32 percent.16 The main disadvantage is prolonged photosensitivity of the skin. One approved photosensitizing agent in the United States is porfimer sodium, which remains in the skin at low levels for up to 90 days, leaving patients with photosensitive skin for this period. Thus, the patient was advised to protect herself from exposure to sunlight for several months after the procedure. In almost all patients, esophageal strictures readily respond to dilatation, although multiple dilatations are typically required to achieve complete relief. Other disadvantages of photodynamic therapy include the high cost and the need for the patient to return to the hospital three times within five days. The drug, the light-delivery fibers, and laser light sources are expensive.
In initial results, successful ablation has been reported in 77 percent of cancers and 90 percent of dysplasias,17,18 with approximately 75 percent of the treated patients remaining free of dysplasia for up to 18 months, although Barrett's epithelium may persist in 10 to 50 percent of the cases. A recently completed randomized clinical trial16 found that patients receiving photodynamic therapy plus omeprazole had ablation of the high-grade dysplasia significantly more often than patients treated with omeprazole alone (77 percent vs. 39 percent) and a lower rate of development of adenocarcinoma (13 percent vs. 28 percent). Complete ablation of Barrett's metaplasia and dysplasia was seen in 52 percent of patients treated with photodynamic therapy and ablation of all grades of dysplasia in 59 percent, as compared with 5 and 10 percent, respectively, in the control group. However, the long-term efficacy of the treatment is unknown, and controlled data are lacking to prove that endoscopic intervention at this point would increase this patient's overall life expectancy. After lengthy discussions with the patient, we elected to proceed with endoscopic ablation of the epithelium affected by Barrett's esophagus with the use of photodynamic therapy.
Endoscopic Submucosal Resection
One confounding issue in this case was the presence of an esophageal mucosal nodule. Although the nodule might have been removed by mucosal ablation with the use of photodynamic therapy, many investigators treating similar cases have resected the nodule before proceeding with mucosal ablation.19 In this strategy, endoscopic mucosal resection of the nodule can be viewed as a "debulking" procedure. In the case of this patient, the nodule was resected with use of a straightforward saline lift-and-snare technique, in which the mucosal nodule is elevated by the submucosal injection of saline, followed by snare resection. This procedure was completed without incident (Figure 3).
Figure 3. Endoscopic Mucosal Resection of the Small Nodule.
This endoscopic image shows the resection site after the removal of the lesion (arrow).
Dr. Lauwers: One month after the biopsy, an endoscopic mucosal resection of the nodule at 35 cm was performed. The diagnosis of intramucosal carcinoma arising in high-grade dysplasia was confirmed; high-grade dysplasia extended to the lateral margin (Figure 2B). Although endoscopic mucosal resection often does not completely remove the tumor, as in this case, the status of the deep margin is more important than that of the lateral margins in predicting recurrence. In our experience, 86 percent of tumors with positive deep margins recurred, as compared with 56 percent of those with positive lateral margins. Repeated endoscopic mucosal resections are feasible and may be necessary to remove the tumor completely. Endoscopic mucosal resection is also important in staging cancers; in our experience, it corrected overestimation and underestimation of staging by ultrasonographic examination in 18 percent and 12 percent of cases, respectively.20
Dr. Nishioka: One month after resection of the esophageal nodule, the patient received porfimer sodium (2 mg per kilogram of body weight) by intravenous injection, and two days later she underwent upper gastrointestinal endoscopy with laser illumination of the involved segment. A 5-cm cylindrical diffuser was used to deliver a total light dose of 150 J per centimeter at a wavelength of 630 nm. Two days later, the patient underwent a second endoscopic examination. The examination revealed moderately severe esophagitis within the treated segment, although the changes were not uniform. Because of the relatively long half-life of porfimer sodium, it is possible to deliver additional light to the segment for as long as 96 hours after the administration of the drug. Thus, the segment was again illuminated with use of a 5-cm cylindrical diffuser in an attempt to make the mucosal ablation more uniform (Figure 4).
Figure 4. Endoscopic Image Obtained 48 Hours after Initial Laser Illumination.
Moderately severe esophagitis is present, induced by the photodynamic therapy, but the ablation is not completely uniform; therefore, additional light was administered. The laser fiber used is evident.
During the first week after photodynamic therapy, the patient had nausea, odynophagia, and chest discomfort, each of which occurred in 10 to 20 percent of the cases in a recent trial,16 but her symptoms were controlled with narcotic analgesic drugs and antiemetic medications. Erythema of the face and neck developed, consistent with the occurrence of a mild photosensitivity reaction of the skin. A skin reaction such as this is the most common side effect of photodynamic therapy with porfimer sodium,16 seen in 30 to 70 percent of patients.16,21
Four weeks later, dysphagia and hiccups developed. An upper endoscopy revealed a short, benign-appearing stenosis in the distal esophagus. This was dilated with a balloon dilator, and the patient's symptoms improved. Stricture formation severe enough to produce dysphagia has been seen in approximately one third of patients who have undergone photodynamic therapy with porfimer sodium.16
During follow-up endoscopies, several small patches of Barrett's epithelium appeared to be present. Rather than administering a second course of photodynamic therapy, I elected simply to fulgurate the areas with a multipolar electrocautery probe. Subsequent endoscopies have revealed an esophagus lined by squamous mucosa. It has been nearly three years since the photodynamic therapy, and the patient is doing well. Her reflux symptoms are well controlled by high-dose proton-pump inhibitors, which she will continue to take indefinitely. We plan to continue endoscopic surveillance at six-month intervals for one more year and then perform annual surveillance thereafter.
Dr. Lauwers: After the patient received the photodynamic therapy, the next set of biopsy specimens and all the specimens obtained from subsequent biopsies showed specialized columnar epithelium without dysplasia. The absence of neoplastic epithelium and the presence of squamous reepithelialization were confirmed on the review of three sets of biopsy specimens obtained during the subsequent year.
Dr. Nishioka: At the time of the most recent follow-up visit 46 months after the procedure, the patient was asymptomatic and biopsies showed no recurrence of either Barrett's esophagus or dysplasia.
Dr. Lauwers: This patient has had a good outcome. We recently reviewed pretreatment and post-treatment biopsies in 33 patients treated with photodynamic therapy at our hospital in order to evaluate the effectiveness of treatment and identify pretreatment features that might predict response.22 Ablation of dysplasia or intramucosal carcinoma occurred in 52 percent of the cases. However, one problem with the follow-up of these patients is the presence of foci of Barrett's epithelium underlying areas of squamous epithelium — so-called buried Barrett's — that may contain dysplasia or intramucosal carcinoma. Buried Barrett's was found in 51 percent of the patients we evaluated after photodynamic therapy, and buried dysplasia or carcinoma or both were seen in 27 percent. The presence of buried dysplasia, carcinoma, or a papillary architecture in pretreatment-biopsy specimens was associated with a failure to eradicate the disease. Continued endoscopic surveillance with biopsies will be an important part of the care of these patients.
Anatomical Diagnosis
Barrett's esophagus with high-grade dysplasia and intramucosal carcinoma with regression of dysplasia and regression of Barrett's esophagus after endoscopic mucosal resection and photodynamic therapy.
Dr. Nishioka reports having received lecture fees and grant support from Axcan Pharma.
Source Information
From the Gastrointestinal Unit (N.S.N.) and the Department of Pathology (G.Y.L.), Massachusetts General Hospital; and the Departments of Medicine (N.S.N.) and Pathology (G.Y.L.), Harvard Medical School.
References
Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett's esophagus. Am J Gastroenterol 2002;97:1888-1895.
Provenzale D, Schmitt C, Wong JB. Barrett's esophagus: a new look at surveillance based on emerging estimates of cancer risk. Am J Gastroenterol 1999;94:2043-2053.
Hameeteman W, Tytgat GN, Houthoff HJ, van den Tweel JG. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249-1256.
Goldblum JR, Lauwers GY. Dysplasia arising in Barrett's esophagus: diagnostic pitfalls and natural history. Semin Diagn Pathol 2002;19:12-19.
Wright TA. High-grade dysplasia in Barrett's oesophagus. Br J Surg 1997;84:760-766.
Skacel M, Petras RE, Gramlich TL, Sigel JE, Richter JE, Goldblum JR. The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression. Am J Gastroenterol 2000;95:3383-3387.
Weston AP, Sharma P, Topalovski M, Richards R, Cherian R, Dixon A. Long-term follow-up of Barrett's high-grade dysplasia. Am J Gastroenterol 2000;95:1888-1893.
Spechler SJ. Barrett's esophagus. N Engl J Med 2002;346:836-842.
Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003;349:2241-2252.
Schnell TG, Sontag SJ, Chejfec G, et al. Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia. Gastroenterology 2001;120:1607-1619.
Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroenterol 2000;95:1669-1676.
Sampliner RE, Faigel D, Fennerty MB, et al. Effective and safe endoscopic reversal of nondysplastic Barrett's esophagus with thermal electrocoagulation combined with high-dose acid inhibition: a multicenter study. Gastrointest Endosc 2001;53:554-558.
Schulz H, Miehlke S, Antos D, et al. Ablation of Barrett's epithelium by endoscopic argon plasma coagulation in combination with high-dose omeprazole. Gastrointest Endosc 2000;51:659-663.
Ell C, May A, Gossner L, et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett's esophagus. Gastroenterology 2000;118:670-677.
Lightdale C, Heier SK, Marcon NE, et al. Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: a multicenter randomized trial. Gastrointest Endosc 1995;42:507-512.
Overholt BF, Lightdale CJ, Wank KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488-498.
Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett's esophagus: follow-up in 100 patients. Gastrointest Endosc 1999;49:1-7.
Wolfsen HC, Woodward TA, Raimondo M. Photodynamic therapy for dysplastic Barrett esophagus and early esophageal cancer. Mayo Clin Proc 2002;77:1176-1181.
Buttar NS, Wang KK, Lutzke LS, Krishnadath KK, Anderson MA. Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett's esophagus. Gastrointest Endosc 2001;54:682-688.
Mino-Kenudson M, Brugge WR, Puricelli WP, et al. Management of superficial Barrett's epithelium-related neoplasms by endoscopic mucosal resection: clinicopathological analysis of 27 cases. Am J Surg Pathol 2005;29:680-686.
Lightdale CJ. Role of photodynamic therapy in the management of advanced esophageal cancer. Gastrointest Endosc Clin N Am 2000;10:397-408.
Ban S, Mino M, Nishioka NS, et al. Histopathologic aspects of photodynamic therapy for dysplasia and early adenocarcinoma arising in Barrett's esophagus. Am J Surg Pathol 2004;28:1466-1473.(Norman S. Nishioka, M.D.,)