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Management of High-Grade Dysplasia in Patients With Barrett’s Esophagus
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:1434 –1439
CLINICAL PATHOLOGY Management of High-Grade Dysplasia in Patients With Barrett’s Esophagus ELIZABETH MONTGOMERY* and MARCIA IRENE CANTO‡ *Department of Pathology and ‡Division of Gastroenterology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
In the past, the standard management for patients with high-grade dysplasia in Barrett’s esophagus was esophagectomy, in part on the basis of the assumption that the patient was likely to harbor an undetected carcinoma. With better awareness of the safety of surveillance protocols, improved prospective surveillance, and experience with cohorts of patients in whom incident early lesions unassociated with invasive carcinomas are detected, endoscopic techniques for treatment of Barrett-associated neoplasia have become excellent alternatives to esophagectomy for appropriately selected patients. Emerging endoscopic techniques offer an opportunity for better evaluation of patients with Barrett’s-associated neoplasia.
Case Report
A
62-year-old man with a 40-year history of gastroesophageal reflux presented to his community gastroenterologist in 2000 complaining of dysphagia. Endoscopy with biopsies was performed, and the patient was told he had a 3-cm segment of Barrett’s esophagus (BE) extending from 33–35 cm from his incisors. At the time of surveillance endoscopy in September 2002, a diagnosis of high-grade dysplasia (HGD) was made on biopsies from 34 cm after consultation with a second pathologist. The patient was referred to a surgeon at our hospital for operative management, but he was reluctant to undergo esophagectomy and consulted the gastroenterology service for the possibility of endoscopic therapy. Repeat endoscopic biopsy confirmed the impression of HGD, again detected at 35 cm (Figure 1). The patient was treated with endoscopic mucosal resection in March 2003 (Figure 2), which showed a focus of intramucosal adenocarcinoma (invasion into the lamina propria) (Figures 3–5) in a background of HGD (Figures 6 and 7). To eliminate the remaining Barrett’s mucosa, photodynamic therapy was performed 6 weeks later (Figure 8). At his most recent follow-up of May 2006 (32 months from initial HGD diagnosis), he had no endoscopic evidence of BE (Figure 9A), and biopsies from the distal esophagus showed neosquamous epithelium, whereas those obtained distal to the normal-appearing neosquamocolumnar junction showed columnar epithelium lacking goblet cells (Figure 9B).
for esophageal adenocarcinoma on epidemiologic grounds.1 Guidelines proposed by the American College of Gastroenterology for the diagnosis and management of BE appeared in 1998.2 At this time, it was believed that a biopsy diagnosis of HGD in BE should be confirmed by review by an expert gastrointestinal pathologist and should then prompt esophagectomy. When these guidelines were revisited in 2002, expert pathologic confirmation was still advocated, but a host of management strategies were offered as alternatives to esophagectomy.3 Indeed, esophagectomy was removed from the proposed options for management and intervention suggested for multifocal HGD, and endoscopic mucosal resection was specifically proposed for mucosal irregularity (Figure 10).3 Whereas it was assumed in the past that there was at least a 40% chance of detecting occult carcinoma in a resection specimen from esophagectomy for HGD,4 the prevalence of a missed cancer in endoscopic biopsies in patients with HGD is probably considerably lower in patients followed on aggressive surveillance protocols in whom incident (rather than prevalent) cancers might be detected.5 Among patients with baseline histology showing HGD (this assumes that a systematic biopsy protocol has been used to obtain multiple biopsies to exclude prevalent adenocarcinoma5), 20%6– 60%7 progress to invasive carcinoma in 5 years. Some observers suggest far lower cancer incidence rates,8 although some divergences between institutions might reflect interobserver variation between pathologists interpreting the biopsies.9 In general, however, pathologists are fairly proficient at agreement on diagnoses of HGD.9,10
Endoscopic Evaluation of Patients Our patient had no dysplasia in his BE at baseline, but HGD was noted 2 years later during routine endoscopic surveillance. Endoscopic surveillance is usually recommended to detect early adenocarcinoma and dysplasia.3,11 Although the optimal technique and surveillance interval remain controversial, surveillance has been associated with improved survival.12 However, the diagnosis of BE and associated neoplasia with standard videoendoscopy remains challenging. The endoscopic appearance of BE with dysplasia and early cancer can be indistinguishable from non-dysplastic BE. Standard biopsy protocols consist of 4 quadrant biopsies every 1–2 cm and work well,5 but dysplasia and adenocarcinoma can sometimes go undetected on the basis of sampling error.13
Discussion Our understanding of reflux esophagitis as a preneoplastic condition is, in some respects, still in its infancy, despite a massive literature devoted to this topic. It had been long assumed that reflux disease promoted carcinogenesis, but it was not until 1999 that reflux was demonstrated as a risk factor
Abbreviations used in this paper: BE, Barrett’s esophagus; HGD, high-grade dysplasia; LGD, low-grade dysplasia. © 2006 by the AGA Institute 1542-3565/06/$32.00 doi:10.1016/j.cgh.2006.09.037
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Figure 1.
Endoscopic image of BE with subtle mucosal irregularity at the site of HGD.
Emerging endoscopic techniques offer an opportunity for better evaluation of patients with Barrett’s-associated neoplasia. These have included methylene blue chromoendoscopy14,15 and a new generation of endoscopes linked to modern imaging devices. Some examples of these emerging endoscopic techniques are confocal laser endomicroscopy,16 optical coherence tomography,17 autofluorescence endoscopy,18 high-resolution and high-magnification endoscopy, and narrow band imaging.19 All of these novel techniques offer the potential to enhance real-time diagnosis of esophageal lesions. They might allow reduction in the number of biopsies required to manage such patients and eliminate the need for biopsies in others. The need
Figure 2. Figure 3. Low-magnification image of the endoscopic mucosal resection performed in 2003. In this specimen, there is lesional tissue (intramucosal adenocarcinoma) at the lower right. Normal squamous mucosa is seen at the left portion of the field.
Endoscopic images of endoscopic mucosal resection (EMR). (A) Injection of saline into the submucosa to raise the mucosa, (B) suction of the target lesion into the cap attached to the tip of the endoscope, followed by closure of snare, and (C) after resection of the lesion with electrocautery, the EMR site shows submucosa with no bleeding or free perforation.
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Figure 4. Focus of intramucosal carcinoma. There is effacement of the lamina propria by atypical glands, many with intraluminal necrosis, although desmoplasia (stromal scarring pattern) is not present.
Figure 6. Zone of HGD adjoining the area of intramucosal carcinoma. The lamina propria, the zone containing lymphoplasmacytic cells, is readily identified, in contrast to that in Figure 4.
for conventional histology might ultimately be subsumed by these techniques, but until they are validated and endoscopists are trained in interpreting images, conventional histologic evaluation, while imperfect, remains the foundation of assessment of surveillance biopsies. Furthermore, advances in endoscopic therapy, particularly techniques for endoscopic mucosal resection, might also eliminate the need for multiple surveillance biopsies in the future, because complete resection of the Barrett’s mucosa might become a more cost-effective approach to managing intraepithelial neoplasia.
rithm consists of (1) surface maturation compared with the underlying glands, (2) architecture of the glands, (3) cytologic features, and (4) inflammation and erosions/ulcers. Each feature might vary, and they are combined to arrive at a diagnosis.
Conventional Histopathologic Evaluation of Biopsies With histopathologic criteria published in 1988,10,20 we suggested an algorithm for assessment of biopsies in BE.9 The algorithm was based on 4 mucosal features in BE and presupposes that the biopsy is from the esophagus, has compatible endoscopic features of BE, and that intestinal metaplasia is found. The algo-
Figure 7. Figure 5.
Higher magnification of the intramucosal carcinoma; note the nucleoli in the proliferating cells. Nucleoli are not usually a feature of HGD.
High magnification of the image in Figure 6. There is loss of nuclear polarity (the cells have no orderly relationship to the basement membrane), but nucleoli are inconspicuous compared with those in Figure 5.
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Figure 8.
Endoscopic image of distal esophagus 2 days after laser photoirradiation, showing the necrotic mucosa characteristic of photodynamic therapy effect.
Surface maturation is assessed at low magnification and confirmed at high magnification. In non-dysplastic BE, the proliferating nuclei in the most basal layers of the glands are larger, more hyperchromatic, and more stratified than those at the surface, which are generally arranged in a monolayer with polarized basal nuclei. The glands in BE are characteristically mildly atypical when viewed in comparison to adjacent nonmetaplastic gastric fundic or cardiac-type glands. Thus, an eye-catching feature when scanning a biopsy at low magnification is the tinctorial comparison between the deep portions of the biopsy specimen and the surface. This feature is quite helpful, but there is a small subset of patients who display dysplasia confined to the deep glands.21 Architecture is also best assessed at low magnification. The glandular architecture of a biopsy specimen is the relation between the glands and the lamina propria and also encompasses the outline of the glands. Architectural abnormalities encompass both increased numbers of glands and changes in their shape.
Figure 9.
Endoscopic image of the patient’s distal esophagus almost 3 years later, showing no endoscopic evidence of columnar mucosa (A). Biopies taken just distal to the neosquamocolumnar junction show no goblet cells but rather gastric cardiac-type columnar epithelium and squamous epithelium (B).
Figure 10. A recent endoscopic mucosal resection specimen from our institution. There is squamous mucosa at both margins, and the lesion is in the center, consisting of hyperchromatic glands. The glands seen in the submucosal fat are benign esophageal submucosal glands.
Cytologic features are assessed at high magnification in zones selected as abnormal during the assessment of surface maturation and architecture. Also included in the assessment of cytologic features is the assessment of the relationship of the nuclei to one another, referred to as nuclear polarity. In normal polarity, the long axis of the nucleus remains perpendicular to the basement membrane, and the nuclei are aligned parallel one to another,
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Table 1. Summary of Pathologic Characteristics for Diagnosis of Intraepithelial Neoplasia Grade of intraepithelial neoplasia No dysplasia Indefinite Low grade High grade
Intramucosal carcinoma
Surface maturation
Glandular architecture
Present Present Altered nuclei extend to surface Absent
Normal Mildly altered Mildly altered
Absent
Effacement of lamina propria by proliferated glands; intraluminal necrosis in glands; desmoplasia not well-developed
Crowded glands with intervening lamina propria
whereas loss of nuclear polarity refers to loss of this perpendicular orientation and a random “jumbled” appearance of the nuclei in relation to the basement membrane and one another. The presence of inflammation and erosions/ulcers adds difficulty to pathologic interpretation and is assessed at both scanning and high magnification. It can obscure a truly malignant lesion or impart cytologic alterations that are attributable to a reparative process. Applying the algorithm, the classification of dysplasia follows and appears in Table 1. Barrett’s esophagus, negative for dysplasia. In BE without dysplasia, the surface appears more mature than the underlying glands, in that the nuclear-to-cytoplasmic ratio of surface cells is lower than that of the deeper glands. The architecture is normal, with abundant lamina propria between glands. The cytologic features are normal, noting that mitoses might be present in deeper glands as well as nuclear stratification. The individual nuclei should have smooth nuclear membranes, and nucleoli, if present, should be small with smooth outlines. Nuclear polarity should be maintained in deep and superficial aspects of the biopsy specimen. If inflammation is a component, reparative features might be present. In this setting, nuclear membranes should remain smooth, although the cells might display nuclear-to-cytoplasmic enlargement, and nucleoli might become more prominent but retain smooth contours. The surface should show maturation compared with the deeper glands. Barrett’s esophagus, indefinite for dysplasia. With the algorithm, we included cases that had deeper cytologic changes suggestive of dysplasia but that showed surface maturation in the indefinite category, whereas other observers have used the indefinite category as a “waste can.” Cases in the indefinite category could have normal architecture or some degree of glandular crowding. On cytologic evaluation, lesions could have hyperchromasia, nuclear membrane irregularities, and increased mitoses in the deeper aspects and these matured to the surface. Loss of nuclear polarity was not a feature. In the presence of inflammation, more striking architectural abnormalities were to be included in the indefinite category. This category encompasses cases with peculiar morphology, such that it is unclear whether they are neoplastic or reparative.
Cytologic (nuclear) features Normal Mildly altered Nuclear hyperchromasia; nucleoli inconspicuous Nuclear hyperchromasia and irregular nuclear membranes; nucleoli inconspicuous; loss of nuclear polarity Nuclear hyperchromasia and irregular nuclear membranes; nucleoli
Inflammation Present or absent Often a feature Usually minimal Usually minimal
Erosions might appear
Barrett’s esophagus, low-grade dysplasia. In BE with low-grade dysplasia (LGD), the surface appears similar to the underlying glands at low magnification or displays only slight maturation. The architecture might be mildly to markedly distorted with glandular crowding, although lamina propria should be identifiable between glands. The cytologic features are important, and the changes should extend at least focally to the surface. These include nuclear hyperchromasia with some chromatin clumping. The nuclei show nuclear membrane irregularities but not pronounced nuclear enlargement, although there might be focal marked enlargement if the other features support an interpretation of LGD. Nucleoli are not typically prominent in LGD. Loss of nuclear polarity is not a feature of LGD, although nuclear stratification similar to that seen in colonic adenomas is within the spectrum of LGD and might be present at the surface. Inflammation is typically minimal; cases with abundant inflammation and the other features of LG are usually best classified in the indefinite category. If tangential embedding precludes evaluation of the surface, LGD can be diagnosed if there are dysplastic features in the deep aspects in the absence of inflammation, provided that the features of HGD are lacking. Barrett’s esophagus, high-grade dysplasia. As in LGD, in HGD, surface maturation is lacking. The architecture might show crowding of cytologically abnormal glands or be markedly distorted with prominent glandular crowding and little intervening lamina propria. If the cytologic features are sufficiently dysplastic, lesser architectural distortion is acceptable. Nuclei are hyperchromatic, and nuclear membranes are irregular. Most examples are similar to dysplasia in the uterine cervix in not displaying prominent nucleoli, which, like in the cervix, tend to be present either in marked repair or when invasion has begun; both are situations that are associated with ulcers. Cells might have delicately clumped dark heterochromatin and inconspicuous nucleoli or prominent irregular nuclei with irregularly clumped chromatin and irregular nucleoli. Markedly enlarged hyperchromatic cells are a feature of HGD, and these might extend to the surface. Loss of nuclear polarity is seen in HGD. Mitoses are readily identifiable. Inflammation is typically minimal. There is some evidence to suggest that HGD accompanied by an ulcer is a worrisome feature for an associated unsampled invasive carcinoma, and we suggest
December 2006
additional biopsies and/or endoscopic ultrasound when we see this pattern.22 Intramucosal carcinoma. The distinction between HGD and the earliest intramucosal carcinoma (defined as invasion through the basement membrane into the lamina propria or muscularis mucosae but not beyond) remains difficult, and observer variation between HGD and intramucosal carcinoma is not good.23 In general, these cases begin to demonstrate an effacement of lamina propria architecture and a syncytial growth pattern, extensive back-to-back microglands, and an intermingling of single cells and small clusters within the lamina propria. Desmoplasia is absent to incompletely developed at this stage; hence its recognition is difficult and subjective. In carcinoma that has invaded more deeply (into the submucosa), desmoplasia and a clearly infiltrative growth pattern become readily apparent, although tangentially embedded and scarred tissue can pose diagnostic problems. In the upper gastrointestinal tract, invasion into the lamina propria is more significant than in the colon because the colon lamina propria lacks significant lymphatic access. In the colon, invasion into the lamina propria is biologically equivalent to HGD, whereas in the esophagus, invasion into the lamina propria can lead to metastatic disease. Pathologists tend to agree on the diagnosis of HGD and carcinoma. In our multicenter study,9 we found that when kappa scores were calculated by diagnostic category, our score for HGD/carcinoma was 0.65 (substantial), and for BE without dysplasia it was 0.58 (moderate to substantial), but the scores for LGD and indefinite for dysplasia were 0.32 (fair) and 0.15 (slight), respectively. Given the imperfect nature of routine histologic evaluation and our inability to predict which patients are likely to progress, other adjunct techniques have been tested and have resulted in a large body of literature. Discussion of these markers is beyond the scope of this review, but, essentially, for practical purposes, there is presently no better “cancer marker” than HGD. In summary, endoscopic evaluation, pathologic diagnosis, and endoscopic treatment of Barrett-associated neoplasia remain imperfect, but the accumulated evidence shows that endoscopic therapy in a subgroup of patients with HGD is appropriate.11 A team approach between endoscopists and pathologists offers a chance to replace esophagectomy as treatment for BE with HGD and early carcinomas in appropriately selected patients.
HIGH-GRADE DYSPLASIA AND BARRETT’S ESOPHAGUS
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References 1. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma . N Engl J Med 1999;340:825– 831. 2. Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus: the Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1998;93:1028 –1032. 3. Sampliner RE. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 2002; 97:1888 –1895. 4. Heitmiller RF, Redmond M, Hamilton SR. Barrett’s esophagus with high-grade dysplasia: an indication for prophylactic esophagectomy. Ann Surg 1996;224:66 –71. 5. Levine DS, Haggitt RC, Blount PL, et al. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993;105: 40 –50. 6. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Bar-
21.
22.
23.
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rett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488 – 498. Montgomery E, Goldblum JR, Greenson JK, et al. Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study. Hum Pathol 2001;32:379 –388. 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. Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol 2001;32:368 –378. Reid BJ, Haggitt RC, Rubin CE, et al. Observer variation in the diagnosis of dysplasia in Barrett’s esophagus. Hum Pathol 1988; 19:166 –178. Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett’s esophagus: the AGA Chicago Workshop. Gastroenterology 2004;127:310 –330. van Sandick JW, van Lanschot JJ, Kuiken BW, et al. Impact of endoscopic biopsy surveillance of Barrett’s oesophagus on pathological stage and clinical outcome of Barrett’s carcinoma. Gut 1998;43:216 –222. Levine DS, Haggitt RC, Blount PL, et al. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993;105: 40 –50. Canto MI, Setrakian S, Willis J, et al. Methylene blue-directed biopsies improve detection of intestinal metaplasia and dysplasia in Barrett’s esophagus. Gastrointest Endosc 2000;51:560 –568. Canto MI. Methylene blue chromoendoscopy for Barrett’s esophagus: coming soon to your GI unit? Gastrointest Endosc 2001; 54:403– 409. Kiesslich R, Gossner L, Goetz M, et al. In vivo histology of Barrett’s esophagus and associated neoplasia by confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006;4:979 –987. Evans JA, Poneros JM, Bouma BE, et al. Optical coherence tomography to identify intramucosal carcinoma and high-grade dysplasia in Barrett’s esophagus. Clin Gastroenterol Hepatol 2006;4:38 – 43. Kara MA, Peters FP, Ten Kate FJ, et al. Endoscopic video autofluorescence imaging may improve the detection of early neoplasia in patients with Barrett’s esophagus. Gastrointest Endosc 2005;61: 679 – 685. Kara MA, Peters FP, Rosmolen WD, et al. High-resolution endoscopy plus chromoendoscopy or narrow-band imaging in Barrett’s esophagus: a prospective randomized crossover study. Endoscopy 2005;37:929 –936. Reid BJ, Weinstein WM, Lewin KJ, et al. Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett’s esophagus without grossly recognizable neoplastic lesions. Gastroenterology 1988;94:81–90. Lomo LC, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation: a clinical, pathologic, and molecular study of a Barrett’s esophagus cohort. Am J Surg Pathol 2006;30:423– 435. Montgomery E, Bronner MP, Greenson JK, et al. Are ulcers a marker for invasive carcinoma in Barrett’s esophagus? data from a diagnostic variability study with clinical follow-up. Am J Gastroenterol 2002;97:27–31. Ormsby AH, Petras RE, Henricks WH, et al. Observer variation in the diagnosis of superficial oesophageal adenocarcinoma. Gut 2002;51:671– 676.
Address correspondence to: Elizabeth Montgomery, MD, Department of Pathology, Johns Hopkins Hospital, Weinberg 2242, 401 N Broadway, Baltimore, Maryland 21231. e-mail: [email protected]; fax: (443) 287-3818.
CLINICAL PATHOLOGY Management of High-Grade Dysplasia in Patients With Barrett’s Esophagus ELIZABETH MONTGOMERY* and MARCIA IRENE CANTO‡ *Department of Pathology and ‡Division of Gastroenterology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
In the past, the standard management for patients with high-grade dysplasia in Barrett’s esophagus was esophagectomy, in part on the basis of the assumption that the patient was likely to harbor an undetected carcinoma. With better awareness of the safety of surveillance protocols, improved prospective surveillance, and experience with cohorts of patients in whom incident early lesions unassociated with invasive carcinomas are detected, endoscopic techniques for treatment of Barrett-associated neoplasia have become excellent alternatives to esophagectomy for appropriately selected patients. Emerging endoscopic techniques offer an opportunity for better evaluation of patients with Barrett’s-associated neoplasia.
Case Report
A
62-year-old man with a 40-year history of gastroesophageal reflux presented to his community gastroenterologist in 2000 complaining of dysphagia. Endoscopy with biopsies was performed, and the patient was told he had a 3-cm segment of Barrett’s esophagus (BE) extending from 33–35 cm from his incisors. At the time of surveillance endoscopy in September 2002, a diagnosis of high-grade dysplasia (HGD) was made on biopsies from 34 cm after consultation with a second pathologist. The patient was referred to a surgeon at our hospital for operative management, but he was reluctant to undergo esophagectomy and consulted the gastroenterology service for the possibility of endoscopic therapy. Repeat endoscopic biopsy confirmed the impression of HGD, again detected at 35 cm (Figure 1). The patient was treated with endoscopic mucosal resection in March 2003 (Figure 2), which showed a focus of intramucosal adenocarcinoma (invasion into the lamina propria) (Figures 3–5) in a background of HGD (Figures 6 and 7). To eliminate the remaining Barrett’s mucosa, photodynamic therapy was performed 6 weeks later (Figure 8). At his most recent follow-up of May 2006 (32 months from initial HGD diagnosis), he had no endoscopic evidence of BE (Figure 9A), and biopsies from the distal esophagus showed neosquamous epithelium, whereas those obtained distal to the normal-appearing neosquamocolumnar junction showed columnar epithelium lacking goblet cells (Figure 9B).
for esophageal adenocarcinoma on epidemiologic grounds.1 Guidelines proposed by the American College of Gastroenterology for the diagnosis and management of BE appeared in 1998.2 At this time, it was believed that a biopsy diagnosis of HGD in BE should be confirmed by review by an expert gastrointestinal pathologist and should then prompt esophagectomy. When these guidelines were revisited in 2002, expert pathologic confirmation was still advocated, but a host of management strategies were offered as alternatives to esophagectomy.3 Indeed, esophagectomy was removed from the proposed options for management and intervention suggested for multifocal HGD, and endoscopic mucosal resection was specifically proposed for mucosal irregularity (Figure 10).3 Whereas it was assumed in the past that there was at least a 40% chance of detecting occult carcinoma in a resection specimen from esophagectomy for HGD,4 the prevalence of a missed cancer in endoscopic biopsies in patients with HGD is probably considerably lower in patients followed on aggressive surveillance protocols in whom incident (rather than prevalent) cancers might be detected.5 Among patients with baseline histology showing HGD (this assumes that a systematic biopsy protocol has been used to obtain multiple biopsies to exclude prevalent adenocarcinoma5), 20%6– 60%7 progress to invasive carcinoma in 5 years. Some observers suggest far lower cancer incidence rates,8 although some divergences between institutions might reflect interobserver variation between pathologists interpreting the biopsies.9 In general, however, pathologists are fairly proficient at agreement on diagnoses of HGD.9,10
Endoscopic Evaluation of Patients Our patient had no dysplasia in his BE at baseline, but HGD was noted 2 years later during routine endoscopic surveillance. Endoscopic surveillance is usually recommended to detect early adenocarcinoma and dysplasia.3,11 Although the optimal technique and surveillance interval remain controversial, surveillance has been associated with improved survival.12 However, the diagnosis of BE and associated neoplasia with standard videoendoscopy remains challenging. The endoscopic appearance of BE with dysplasia and early cancer can be indistinguishable from non-dysplastic BE. Standard biopsy protocols consist of 4 quadrant biopsies every 1–2 cm and work well,5 but dysplasia and adenocarcinoma can sometimes go undetected on the basis of sampling error.13
Discussion Our understanding of reflux esophagitis as a preneoplastic condition is, in some respects, still in its infancy, despite a massive literature devoted to this topic. It had been long assumed that reflux disease promoted carcinogenesis, but it was not until 1999 that reflux was demonstrated as a risk factor
Abbreviations used in this paper: BE, Barrett’s esophagus; HGD, high-grade dysplasia; LGD, low-grade dysplasia. © 2006 by the AGA Institute 1542-3565/06/$32.00 doi:10.1016/j.cgh.2006.09.037
December 2006
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Figure 1.
Endoscopic image of BE with subtle mucosal irregularity at the site of HGD.
Emerging endoscopic techniques offer an opportunity for better evaluation of patients with Barrett’s-associated neoplasia. These have included methylene blue chromoendoscopy14,15 and a new generation of endoscopes linked to modern imaging devices. Some examples of these emerging endoscopic techniques are confocal laser endomicroscopy,16 optical coherence tomography,17 autofluorescence endoscopy,18 high-resolution and high-magnification endoscopy, and narrow band imaging.19 All of these novel techniques offer the potential to enhance real-time diagnosis of esophageal lesions. They might allow reduction in the number of biopsies required to manage such patients and eliminate the need for biopsies in others. The need
Figure 2. Figure 3. Low-magnification image of the endoscopic mucosal resection performed in 2003. In this specimen, there is lesional tissue (intramucosal adenocarcinoma) at the lower right. Normal squamous mucosa is seen at the left portion of the field.
Endoscopic images of endoscopic mucosal resection (EMR). (A) Injection of saline into the submucosa to raise the mucosa, (B) suction of the target lesion into the cap attached to the tip of the endoscope, followed by closure of snare, and (C) after resection of the lesion with electrocautery, the EMR site shows submucosa with no bleeding or free perforation.
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Figure 4. Focus of intramucosal carcinoma. There is effacement of the lamina propria by atypical glands, many with intraluminal necrosis, although desmoplasia (stromal scarring pattern) is not present.
Figure 6. Zone of HGD adjoining the area of intramucosal carcinoma. The lamina propria, the zone containing lymphoplasmacytic cells, is readily identified, in contrast to that in Figure 4.
for conventional histology might ultimately be subsumed by these techniques, but until they are validated and endoscopists are trained in interpreting images, conventional histologic evaluation, while imperfect, remains the foundation of assessment of surveillance biopsies. Furthermore, advances in endoscopic therapy, particularly techniques for endoscopic mucosal resection, might also eliminate the need for multiple surveillance biopsies in the future, because complete resection of the Barrett’s mucosa might become a more cost-effective approach to managing intraepithelial neoplasia.
rithm consists of (1) surface maturation compared with the underlying glands, (2) architecture of the glands, (3) cytologic features, and (4) inflammation and erosions/ulcers. Each feature might vary, and they are combined to arrive at a diagnosis.
Conventional Histopathologic Evaluation of Biopsies With histopathologic criteria published in 1988,10,20 we suggested an algorithm for assessment of biopsies in BE.9 The algorithm was based on 4 mucosal features in BE and presupposes that the biopsy is from the esophagus, has compatible endoscopic features of BE, and that intestinal metaplasia is found. The algo-
Figure 7. Figure 5.
Higher magnification of the intramucosal carcinoma; note the nucleoli in the proliferating cells. Nucleoli are not usually a feature of HGD.
High magnification of the image in Figure 6. There is loss of nuclear polarity (the cells have no orderly relationship to the basement membrane), but nucleoli are inconspicuous compared with those in Figure 5.
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Figure 8.
Endoscopic image of distal esophagus 2 days after laser photoirradiation, showing the necrotic mucosa characteristic of photodynamic therapy effect.
Surface maturation is assessed at low magnification and confirmed at high magnification. In non-dysplastic BE, the proliferating nuclei in the most basal layers of the glands are larger, more hyperchromatic, and more stratified than those at the surface, which are generally arranged in a monolayer with polarized basal nuclei. The glands in BE are characteristically mildly atypical when viewed in comparison to adjacent nonmetaplastic gastric fundic or cardiac-type glands. Thus, an eye-catching feature when scanning a biopsy at low magnification is the tinctorial comparison between the deep portions of the biopsy specimen and the surface. This feature is quite helpful, but there is a small subset of patients who display dysplasia confined to the deep glands.21 Architecture is also best assessed at low magnification. The glandular architecture of a biopsy specimen is the relation between the glands and the lamina propria and also encompasses the outline of the glands. Architectural abnormalities encompass both increased numbers of glands and changes in their shape.
Figure 9.
Endoscopic image of the patient’s distal esophagus almost 3 years later, showing no endoscopic evidence of columnar mucosa (A). Biopies taken just distal to the neosquamocolumnar junction show no goblet cells but rather gastric cardiac-type columnar epithelium and squamous epithelium (B).
Figure 10. A recent endoscopic mucosal resection specimen from our institution. There is squamous mucosa at both margins, and the lesion is in the center, consisting of hyperchromatic glands. The glands seen in the submucosal fat are benign esophageal submucosal glands.
Cytologic features are assessed at high magnification in zones selected as abnormal during the assessment of surface maturation and architecture. Also included in the assessment of cytologic features is the assessment of the relationship of the nuclei to one another, referred to as nuclear polarity. In normal polarity, the long axis of the nucleus remains perpendicular to the basement membrane, and the nuclei are aligned parallel one to another,
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Table 1. Summary of Pathologic Characteristics for Diagnosis of Intraepithelial Neoplasia Grade of intraepithelial neoplasia No dysplasia Indefinite Low grade High grade
Intramucosal carcinoma
Surface maturation
Glandular architecture
Present Present Altered nuclei extend to surface Absent
Normal Mildly altered Mildly altered
Absent
Effacement of lamina propria by proliferated glands; intraluminal necrosis in glands; desmoplasia not well-developed
Crowded glands with intervening lamina propria
whereas loss of nuclear polarity refers to loss of this perpendicular orientation and a random “jumbled” appearance of the nuclei in relation to the basement membrane and one another. The presence of inflammation and erosions/ulcers adds difficulty to pathologic interpretation and is assessed at both scanning and high magnification. It can obscure a truly malignant lesion or impart cytologic alterations that are attributable to a reparative process. Applying the algorithm, the classification of dysplasia follows and appears in Table 1. Barrett’s esophagus, negative for dysplasia. In BE without dysplasia, the surface appears more mature than the underlying glands, in that the nuclear-to-cytoplasmic ratio of surface cells is lower than that of the deeper glands. The architecture is normal, with abundant lamina propria between glands. The cytologic features are normal, noting that mitoses might be present in deeper glands as well as nuclear stratification. The individual nuclei should have smooth nuclear membranes, and nucleoli, if present, should be small with smooth outlines. Nuclear polarity should be maintained in deep and superficial aspects of the biopsy specimen. If inflammation is a component, reparative features might be present. In this setting, nuclear membranes should remain smooth, although the cells might display nuclear-to-cytoplasmic enlargement, and nucleoli might become more prominent but retain smooth contours. The surface should show maturation compared with the deeper glands. Barrett’s esophagus, indefinite for dysplasia. With the algorithm, we included cases that had deeper cytologic changes suggestive of dysplasia but that showed surface maturation in the indefinite category, whereas other observers have used the indefinite category as a “waste can.” Cases in the indefinite category could have normal architecture or some degree of glandular crowding. On cytologic evaluation, lesions could have hyperchromasia, nuclear membrane irregularities, and increased mitoses in the deeper aspects and these matured to the surface. Loss of nuclear polarity was not a feature. In the presence of inflammation, more striking architectural abnormalities were to be included in the indefinite category. This category encompasses cases with peculiar morphology, such that it is unclear whether they are neoplastic or reparative.
Cytologic (nuclear) features Normal Mildly altered Nuclear hyperchromasia; nucleoli inconspicuous Nuclear hyperchromasia and irregular nuclear membranes; nucleoli inconspicuous; loss of nuclear polarity Nuclear hyperchromasia and irregular nuclear membranes; nucleoli
Inflammation Present or absent Often a feature Usually minimal Usually minimal
Erosions might appear
Barrett’s esophagus, low-grade dysplasia. In BE with low-grade dysplasia (LGD), the surface appears similar to the underlying glands at low magnification or displays only slight maturation. The architecture might be mildly to markedly distorted with glandular crowding, although lamina propria should be identifiable between glands. The cytologic features are important, and the changes should extend at least focally to the surface. These include nuclear hyperchromasia with some chromatin clumping. The nuclei show nuclear membrane irregularities but not pronounced nuclear enlargement, although there might be focal marked enlargement if the other features support an interpretation of LGD. Nucleoli are not typically prominent in LGD. Loss of nuclear polarity is not a feature of LGD, although nuclear stratification similar to that seen in colonic adenomas is within the spectrum of LGD and might be present at the surface. Inflammation is typically minimal; cases with abundant inflammation and the other features of LG are usually best classified in the indefinite category. If tangential embedding precludes evaluation of the surface, LGD can be diagnosed if there are dysplastic features in the deep aspects in the absence of inflammation, provided that the features of HGD are lacking. Barrett’s esophagus, high-grade dysplasia. As in LGD, in HGD, surface maturation is lacking. The architecture might show crowding of cytologically abnormal glands or be markedly distorted with prominent glandular crowding and little intervening lamina propria. If the cytologic features are sufficiently dysplastic, lesser architectural distortion is acceptable. Nuclei are hyperchromatic, and nuclear membranes are irregular. Most examples are similar to dysplasia in the uterine cervix in not displaying prominent nucleoli, which, like in the cervix, tend to be present either in marked repair or when invasion has begun; both are situations that are associated with ulcers. Cells might have delicately clumped dark heterochromatin and inconspicuous nucleoli or prominent irregular nuclei with irregularly clumped chromatin and irregular nucleoli. Markedly enlarged hyperchromatic cells are a feature of HGD, and these might extend to the surface. Loss of nuclear polarity is seen in HGD. Mitoses are readily identifiable. Inflammation is typically minimal. There is some evidence to suggest that HGD accompanied by an ulcer is a worrisome feature for an associated unsampled invasive carcinoma, and we suggest
December 2006
additional biopsies and/or endoscopic ultrasound when we see this pattern.22 Intramucosal carcinoma. The distinction between HGD and the earliest intramucosal carcinoma (defined as invasion through the basement membrane into the lamina propria or muscularis mucosae but not beyond) remains difficult, and observer variation between HGD and intramucosal carcinoma is not good.23 In general, these cases begin to demonstrate an effacement of lamina propria architecture and a syncytial growth pattern, extensive back-to-back microglands, and an intermingling of single cells and small clusters within the lamina propria. Desmoplasia is absent to incompletely developed at this stage; hence its recognition is difficult and subjective. In carcinoma that has invaded more deeply (into the submucosa), desmoplasia and a clearly infiltrative growth pattern become readily apparent, although tangentially embedded and scarred tissue can pose diagnostic problems. In the upper gastrointestinal tract, invasion into the lamina propria is more significant than in the colon because the colon lamina propria lacks significant lymphatic access. In the colon, invasion into the lamina propria is biologically equivalent to HGD, whereas in the esophagus, invasion into the lamina propria can lead to metastatic disease. Pathologists tend to agree on the diagnosis of HGD and carcinoma. In our multicenter study,9 we found that when kappa scores were calculated by diagnostic category, our score for HGD/carcinoma was 0.65 (substantial), and for BE without dysplasia it was 0.58 (moderate to substantial), but the scores for LGD and indefinite for dysplasia were 0.32 (fair) and 0.15 (slight), respectively. Given the imperfect nature of routine histologic evaluation and our inability to predict which patients are likely to progress, other adjunct techniques have been tested and have resulted in a large body of literature. Discussion of these markers is beyond the scope of this review, but, essentially, for practical purposes, there is presently no better “cancer marker” than HGD. In summary, endoscopic evaluation, pathologic diagnosis, and endoscopic treatment of Barrett-associated neoplasia remain imperfect, but the accumulated evidence shows that endoscopic therapy in a subgroup of patients with HGD is appropriate.11 A team approach between endoscopists and pathologists offers a chance to replace esophagectomy as treatment for BE with HGD and early carcinomas in appropriately selected patients.
HIGH-GRADE DYSPLASIA AND BARRETT’S ESOPHAGUS
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References 1. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma . N Engl J Med 1999;340:825– 831. 2. Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus: the Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1998;93:1028 –1032. 3. Sampliner RE. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 2002; 97:1888 –1895. 4. Heitmiller RF, Redmond M, Hamilton SR. Barrett’s esophagus with high-grade dysplasia: an indication for prophylactic esophagectomy. Ann Surg 1996;224:66 –71. 5. Levine DS, Haggitt RC, Blount PL, et al. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993;105: 40 –50. 6. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Bar-
21.
22.
23.
1439
rett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488 – 498. Montgomery E, Goldblum JR, Greenson JK, et al. Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study. Hum Pathol 2001;32:379 –388. 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. Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol 2001;32:368 –378. Reid BJ, Haggitt RC, Rubin CE, et al. Observer variation in the diagnosis of dysplasia in Barrett’s esophagus. Hum Pathol 1988; 19:166 –178. Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett’s esophagus: the AGA Chicago Workshop. Gastroenterology 2004;127:310 –330. van Sandick JW, van Lanschot JJ, Kuiken BW, et al. Impact of endoscopic biopsy surveillance of Barrett’s oesophagus on pathological stage and clinical outcome of Barrett’s carcinoma. Gut 1998;43:216 –222. Levine DS, Haggitt RC, Blount PL, et al. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993;105: 40 –50. Canto MI, Setrakian S, Willis J, et al. Methylene blue-directed biopsies improve detection of intestinal metaplasia and dysplasia in Barrett’s esophagus. Gastrointest Endosc 2000;51:560 –568. Canto MI. Methylene blue chromoendoscopy for Barrett’s esophagus: coming soon to your GI unit? Gastrointest Endosc 2001; 54:403– 409. Kiesslich R, Gossner L, Goetz M, et al. In vivo histology of Barrett’s esophagus and associated neoplasia by confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006;4:979 –987. Evans JA, Poneros JM, Bouma BE, et al. Optical coherence tomography to identify intramucosal carcinoma and high-grade dysplasia in Barrett’s esophagus. Clin Gastroenterol Hepatol 2006;4:38 – 43. Kara MA, Peters FP, Ten Kate FJ, et al. Endoscopic video autofluorescence imaging may improve the detection of early neoplasia in patients with Barrett’s esophagus. Gastrointest Endosc 2005;61: 679 – 685. Kara MA, Peters FP, Rosmolen WD, et al. High-resolution endoscopy plus chromoendoscopy or narrow-band imaging in Barrett’s esophagus: a prospective randomized crossover study. Endoscopy 2005;37:929 –936. Reid BJ, Weinstein WM, Lewin KJ, et al. Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett’s esophagus without grossly recognizable neoplastic lesions. Gastroenterology 1988;94:81–90. Lomo LC, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation: a clinical, pathologic, and molecular study of a Barrett’s esophagus cohort. Am J Surg Pathol 2006;30:423– 435. Montgomery E, Bronner MP, Greenson JK, et al. Are ulcers a marker for invasive carcinoma in Barrett’s esophagus? data from a diagnostic variability study with clinical follow-up. Am J Gastroenterol 2002;97:27–31. Ormsby AH, Petras RE, Henricks WH, et al. Observer variation in the diagnosis of superficial oesophageal adenocarcinoma. Gut 2002;51:671– 676.
Address correspondence to: Elizabeth Montgomery, MD, Department of Pathology, Johns Hopkins Hospital, Weinberg 2242, 401 N Broadway, Baltimore, Maryland 21231. e-mail: [email protected]; fax: (443) 287-3818.